Dithiol sugar mucilage agents and uses thereof

Abstract

To provide methods for decreasing mucus elasticity or mucus viscosity in patients with lower and upper airway diseases such as asthma, cystic fibrosis (CF), acute and chronic bronchitis, and acute and chronic sinusitis, or in patients on mechanical ventilators, and compounds and pharmaceutical compositions useful for the methods.SOLUTION: The present invention provides compounds represented by following formulae, having at least two thiol moieties, or pharmaceutically acceptable salts thereof. Methods according to the present invention include administering effective amounts of dithiolsaccharide mucolytic agents including the compounds to subjects.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 729,327, filed September 10, 2018, and U.S. Provisional Application No. 62 / 755,073, filed November 2, 2018, which are incorporated herein by reference in their entireties for all purposes.

[0002] STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant Nos. P01 HL128191 and R01 HL080414 awarded by the National Institutes of Health. The government has certain rights in this invention. [Background technology]

[0003] Increased mucoelasticity is a major cause of morbidity in patients with upper and lower respiratory tract diseases, such as asthma, cystic fibrosis (CF), acute and chronic bronchitis, and acute and chronic sinusitis, and also causes clinical problems such as pneumonia and respiratory failure in patients on mechanical ventilation. There is a need for novel mucolytic therapies for a wide range of acute and chronic airway diseases. Specifically, solutions to these and other problems in the art are disclosed herein. Summary of the Invention

[0004] Provided herein, inter alia, are methods for reducing mucus elasticity or reducing mucus viscosity in a subject in need thereof, methods comprising administering to the subject an effective amount of a dithiol sugar mucolytic agent, and compounds and pharmaceutical compositions useful therein.

[0005] In one aspect, compounds are provided having the formula: [ka] R 1 -SR 1A , -OR 1A , -NR 1B R 1C , -NR 1B C(O)R 1C , -NR 1B C(O)OR 1C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 2 -SR 2A , -OR 2A , -NR 2B R 2C , -NR 2B C(O)R 2C , -NR 2B C(O)OR 2C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 3 -SR 3A , -OR 3A , -NR 3B R 3C , -NR 3B C(O)R 3C , -NR 3B C(O)OR 3C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 4 -SR 4A , -SC(O)R 4A , -OR 4A , -NR 4B R 4C , -NR 4B C(O)R 4C , -NR 4B C(O)OR 4C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 5 is hydrogen, -SR 5A , -OR 5A , -NR 5B R 5C , -NR 5B C(O)R 5C , -NR5B C(O)OR 5C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 6 -SR 6A , -OR 6A , -NR 6B R 6C , -NR 6B C(O)R 6C , -NR 6B C(O)OR 6C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 1B , R 2B , R 3B , R 4B , R 5B , R 6B , R 1C , R 2C , R 3C , R 4C , R 5C , and R 6C are each independently hydrogen, substituted or unsubstituted C-C 10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, and the compound contains at least two thiol moieties, or a pharmaceutically acceptable salt thereof.

[0006] In one aspect, compounds are provided having the formula: [ka] R 2 -SR 2A , -OR 2A , -NR 2B R 2C , -NR 2B C(O)R 2C , -NR 2B C(O)OR 2C , substituted or unsubstituted C1-C 10alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 3 -SR 3A , -OR 3A , -NR 3B R 3C , -NR 3B C(O)R 3C , -NR 3B C(O)OR 3C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 4 -SR 4A , -SC(O)R 4A , -OR 4A , -NR 4B R 4C , -NR 4B C(O)R 4C , -NR 4B C(O)OR 4C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 5 is hydrogen, -SR 5A , -OR 5A , -NR 5B R 5C , -NR 5B C(O)R 5C , -NR 5B C(O)OR 5C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 6 -SR 6A , -OR 6A , -NR 6B R 6C , -NR 6B C(O)R 6C , -NR 6B C(O)OR 6C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 7 -SR 7A , -OR 7A , -NR 7B R 7C , -NR 7BC(O)R 7C , -NR 7B C(O)OR 7C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 8 -SR 8A , -OR 8A , -NR 8B R 8C , -NR 8B C(O)R 8C , -NR 8B C(O)OR 8C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 9 -SR 9A , -SC(O)R 9A , -OR 9A , -NR 9B R 9C , -NR 9B C(O)R 9C , -NR 9B C(O)OR 9C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 10 is hydrogen, -SR 10A , -OR 10A , -NR 10B R 10C , -NR 10B C(O)R 10C , -NR 10B C(O)OR 10C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 11 -SR 11A , -OR 11A , -NR 11B R 11C , -NR 11B C(O)R 11C , -NR 11B C(O)OR 11C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 12 -SR12A , -OR 12A , -NR 12B R 12C , -NR 12B C(O)R 12C , -NR 12B C(O)OR 12C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 11A , R 12A , R 2B , R 3B , R 4B , R 5B , R 6B , R 7B , R 8B , R 9B , R 10B , R 11B , R 12B , R 2C , R 3C , R 4C , R 5C , R 6C , R 7C , R 8C , R 9C , R 10C , R 11C , and R 12C are each independently hydrogen, substituted or unsubstituted C-C 10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, and the compound contains at least two thiol moieties, or a pharmaceutically acceptable salt thereof.

[0007] In one aspect, compounds are provided having the formula: [ka] R 13 is hydrogen, -SR 13A , -OR 13A , -NR 13B R13C , -NR 13B C(O)R 13C , -NR 13B C(O)OR 13C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 14 -SR 14A , -OR 14A , -NR 14B R 14C , -NR 14B C(O)R 14C , -NR 14B C(O)OR 14C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 15 -SR 15A , -OR 15A , -NR 15B R 15C , -NR 15B C(O)R 15C , -NR 15B C(O)OR 15C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 16 is hydrogen, -SR 16A , -OR 16A , -NR 16B R 16C , -NR 16B C(O)R 16C , -NR 16B C(O)OR 16C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 17 is hydrogen, -SR 17A , -OR 17A , -NR 17B R 17C , -NR 17B C(O)R 17C , -NR 17B C(O)OR 17C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl.18 -SR 18A , -OR 18A , -NR 18B R 18C , -NR 18B C(O)R 18C , -NR 18B C(O)OR 18C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 19 is hydrogen, -SR 19A , -OR 19A , -NR 19B R 19C , -NR 19B C(O)R 19C , -NR 19B C(O)OR 19C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 20 -SR 20A , -OR 20A , -NR 20B R 20C , -NR 20B C(O)R 20C , -NR 20B C(O)OR 20C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 13A , R 14A , R 15A , R 16A , R 17A , R 18A , R 19A , R 20A , R 13B , R 14B , R 15B , R 16B , R 17B , R 18B , R 19B , R 20B , R 13C , R 14C , R 15C , R 16C , R 17C , R 18C , R 19C , and R 20Care each independently hydrogen, substituted or unsubstituted C-C 10 Compounds are provided which are alkyl, substituted or unsubstituted 2-10 membered heteroalkyl and contain at least two thiol moieties, or a pharmaceutically acceptable salt thereof.

[0008] In one aspect, compounds are provided having the formula: [ka] R 2 -SR 2A , -OR 2A , -NR 2B R 2C , -NR 2B C(O)R 2C , -NR 2B C(O)OR 2C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 3 -SR 3A , -OR 3A , -NR 3B R 3C , -NR 3B C(O)R 3C , -NR 3B C(O)OR 3C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 4 -SR 4A , -SC(O)R 4A , -OR 4A , -NR 4B R 4C , -NR 4B C(O)R 4C , -NR 4B C(O)OR 4C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 5 is hydrogen, -SR 5A , -OR 5A , -NR 5B R 5C , -NR 5BC(O)R 5C , -NR 5B C(O)OR 5C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 6 -SR 6A , -OR 6A , -NR 6B R 6C , -NR 6B C(O)R 6C , -NR 6B C(O)OR 6C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 13 is hydrogen, -SR 13A , -OR 13A , -NR 13B R 13C , -NR 13B C(O)R 13C , -NR 13B C(O)OR 13C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 14 -SR 14A , -OR 14A , -NR 14B R 14C , -NR 14B C(O)R 14C , -NR 14B C(O)OR 14C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 15 -SR 15A , -OR 15A , -NR 15B R 15C , -NR 15B C(O)R 15C , -NR 15B C(O)OR 15C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 17 is hydrogen, -SR 17A , -OR17A , -NR 17B R 17C , -NR 17B C(O)R 17C , -NR 17B C(O)OR 17C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 18 -SR 18A , -OR 18A , -NR 18B R 18C , -NR 18B C(O)R 18C , -NR 18B C(O)OR 18C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 19 is hydrogen, -SR 19A , -OR 19A , -NR 19B R 19C , -NR 19B C(O)R 19C , -NR 19B C(O)OR 19C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 20 -SR 20A , -OR 20A , -NR 20B R 20C , -NR 20B C(O)R 20C , -NR 20B C(O)OR 20C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl, and R 2A , R 3A , R 4A , R 5A , R 6A , R 2B , R 3B , R 4B , R 5B , R 6B , R 2C , R 3C , R 4C, R 5C , R 6C , R 13A , R 14A , R 15A , R 17A , R 18A , R 19A , R 20A , R 13B , R 14B , R 15B , R 17B , R 18B , R 19B , R 20B , R 13C , R 14C , R 15C , R 17C , R 18C , R 19C , and R 20C are each independently hydrogen, substituted or unsubstituted C-C 10 Compounds are provided which are alkyl, substituted or unsubstituted 2-10 membered heteroalkyl and contain at least two thiol moieties, or a pharmaceutically acceptable salt thereof.

[0009] In one aspect, a pulmonary pharmaceutical composition is provided that includes a pulmonary pharmaceutical carrier and a dithiol glycomucolytic agent (eg, a compound described herein).

[0010] In one aspect, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to the present invention, or an embodiment thereof, or a pharmaceutically acceptable salt thereof.

[0011] In one aspect, a method of decreasing mucus elasticity or decreasing mucus viscosity in a subject in need thereof is provided.

[0012] In one aspect, a method for treatment in a subject in need thereof is provided. The method includes administering an effective amount of a compound disclosed herein in combination with another therapeutic agent, wherein the therapeutic effect of the therapeutic agent is enhanced by reducing mucoelasticity or reducing mucus viscosity. In embodiments, administration of a compound disclosed herein in combination with another therapeutic agent provides additive or synergistic treatment to the subject. In embodiments, the other therapeutic agent is a mucoactive agent (e.g., recombinant human DNAse, or hypertonic saline), a steroid (e.g., fluticasone, budesonide, beclomethasone, mometasone), or an antibiotic. In embodiments, the reduction in mucoelasticity or mucus viscosity in a subject in need thereof by administration of a compound disclosed herein results in a reduced dosage requirement for the other therapeutic agent or improved efficacy of the other therapeutic agent.

[0013] In one aspect, a method for treating a subject in need thereof is provided, the method comprising administering an effective amount of a compound disclosed herein in combination with another therapeutic agent. In embodiments, the "another therapeutic agent" is a beta-agonist, an anticholinergic, a corticosteroid, an antibiotic, recombinant human DNAse (rhDNAse), or a treatment designed to regulate the genome of airway or alveolar epithelial cells using siRNA, cDNA overexpression, zinc finger nuclease, transcription activator-like effector nuclease, or RNA interference with clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9)-mediated system. [Brief explanation of the drawings]

[0014] [Figure 1A]1 is a graph showing the effect of 6,6'-dithio-6,6'-dideoxy-α,α-trehalose (Compound 5, squares) versus N-acetylcysteine ​​(NAC, circles) on the elastic modulus (G') of spontaneously expectorated sputum collected from patients with cystic fibrosis (CF). Sputum G' is measured using a cone and plate rheometer. The Y-axis is the % of baseline G' of the sputum samples as a function of time after addition of Compound 5 or NAC to a final concentration of 5 mM in the sputum. [Figure 1B] 1 is a graph showing the performance of methyl-6,6'-dithio-6,6'-dideoxy-β-lactoside (Compound 6, squares) versus N-acetylcysteine ​​(NAC, circles) on the elastic modulus (G') of spontaneously expectorated sputum collected from patients with cystic fibrosis (CF). The G' of the sputum is measured using a cone and plate rheometer. The Y-axis is the % of baseline G' of the sputum sample as a function of time after addition of Compound 6 or NAC to a final concentration of 5 mM in the sputum. [Figure 1C] 1 is a graph showing the performance of 3-thiopropyl-6-thio-6-deoxy-β-D-galactopyranoside (Compound 3, squares) versus N-acetylcysteine ​​(NAC, circles) on the elastic modulus (G') of spontaneously expectorated sputum collected from patients with cystic fibrosis (CF). The G' of sputum is measured using a cone and plate rheometer. The Y-axis is the % of baseline G' of the sputum sample as a function of time after addition of Compound 3 or NAC to a final concentration of 5 mM in the sputum. [Figure 2]This graph shows the relative effects of several dithiol sugars and N-acetylcysteine ​​(NAC) on the elastic modulus (G') of spontaneously expectorated sputum collected from patients with cystic fibrosis (CF). The G' of sputum samples is measured using a cone and plate rheometer. The Y-axis is the change in G' (ΔG') that occurs after incubating sputum samples with mucolytic compounds at a final concentration of 5 mM in sputum for 30 minutes. The histogram bars show the mean and standard deviation of the mucolytic efficacy of each compound tested on sputum samples from multiple subjects. The graph shows that the mucolytic efficacy of dithiol sugars is significantly greater than that of NAC. *Indicates significantly different from NAC, p<0.05. [Figure 3] This graph shows the mucolytic dose-response effect of three dithiols and N-acetylcysteine ​​(NAC) in a thiolated hydrogel matrix. Compound 1 is 1,6-dithio-6-deoxy-β-D-galactopyranoside, compound 5 is 6,6'-dithio-6,6'-dideoxy-α,α-trehalose, and compound 9 is methyl-1,6-dithio-1,6-dideoxy-β-D-fructofuranoside. The hydrogel is a thiolated hyaluronic acid hydrogel (Glycosil®) that is hardened by chemical oxidation to a modulus (G') that reflects the G' of sputum from patients with cystic fibrosis. The Y-axis is the change in G' (ΔG') that occurs after incubating the hydrogel sample with the mucolytic compounds at a final concentration of 5 mM in the sputum sample for 30 minutes. The G' of the hydrogel is measured using a cone and plate rheometer. The graph shows that the concentration of test agent required to reduce the G' of the hydrogel by 40% (ΔG' = -40%) varies significantly. For example, ΔG' = -40% is achieved by 0.7 mM of Compound 1 and Compound 9, and by 1.0 mM of Compound 5. In contrast, ΔG' = -40% is achieved by 8 mM of NAC. [Figure 4]This graph shows the relative effects of several dithiol sugars and N-acetylcysteine ​​(NAC) on the elastic modulus (G') of a thiolated hydrogel. The hydrogel is a thiolated hyaluronic acid hydrogel (Glycosil®) that is cured by chemical oxidation to a modulus (G') that reflects the G' of sputum from patients with cystic fibrosis. The Y-axis is the change in G' (ΔG') that occurs after incubating the hydrogel sample with a mucolytic compound at a final concentration of 5 mM in the sputum sample for 30 minutes. The G' of the hydrogel is measured using a cone and plate rheometer. The histogram bars show the mean and standard deviation of the mucolytic efficacy of each compound tested on multiple hydrogel samples. The graph shows that the mucolytic efficacy of the dithiol sugars is significantly greater than that of NAC. *Indicates significantly different from NAC, p<0.05. [Figure 5] This graph shows the effect of compound 1 (1,6-dithio-6-deoxy-β-D-galactopyranoside, disodium salt) and NAC on the measurement of cytotoxicity of primary human airway epithelial cells (AECs) cultured at the air-liquid interface. The measure of cytotoxicity was glucose 6-phosphate dehydrogenase (G6PD) release. The Y-axis shows the release of G6PD from AECs into the basolateral medium as a percentage of total G6PD measured in AEC lysates. Cells were exposed to compound 1 on the apical surface at concentrations of 5, 25, and 50 mM for 1 hour at 37°C. After an additional 6 hours, cells and basolateral medium were collected so that the % G6PD release could be calculated. The graph shows that the % G6PD release with compound 1 was minimal and similar to that of the phosphate-buffered saline (PBS) control. [Figure 6] The synthesis of compound 3 (3-thiopropyl-6-thio-6-deoxy-β-D galactopyranoside) is shown below. [Figure 7] The synthesis of compound 5 (6,6'-dithio-6,6'-dideoxy-α,α-trehalose) is shown. [Figure 8] The synthesis of compound 6 (methyl-6,6'-dithio-6,6'-dideoxy-β-lactoside) is shown below. [Figure 9]The synthesis of compound 7 (methyl-6,6'-dithio-6,6'-dideoxy-β-cellobioside) is shown. [Figure 10] The synthesis of compound 8 (3-thiopropyl-6'-thio-6'-deoxy-β-D-lactoside) is shown below. [Figure 11] The synthesis of compound 9 (methyl-1,6-dithio-1,6-dideoxy-β-D-fructofuranoside) is shown. DETAILED DESCRIPTION OF THE INVENTION

[0015] Provided herein are a set of compounds (sugar scaffolds modified with two thiol groups) that liquefy elastic mucus gels and have potential utility as mucolytic agents for the treatment of patients with mucus-related diseases of the lower airway (e.g., asthma, cystic fibrosis, chronic bronchitis, etc.), upper airway (e.g., chronic sinusitis, etc.), and eye. In embodiments, these compounds significantly reduce mucus elasticity and viscosity when applied ex vivo to sputum from patients with cystic fibrosis, and have similar biophysical effects in a synthetic thiolated hydrogel model of pathological airway mucus. In embodiments, the compounds are safe when administered in vitro to airway epithelial cells in air-liquid interface culture and in vivo to the airways of mice. In embodiments, the compounds are readily formulated in solution for inhalation delivery via a nebulizer. In embodiments, the compounds provided herein are formulated in a dry powder composition. The dithiol sugar mucolytic agents included herein provide a safe and effective treatment for patients with diseases associated with highly elastic obstructive mucus, for example, in the lungs, sinuses, or eyes.

[0016] I. Definition The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0017] As used herein, the term "about" in the context of a numerical value or range means ±10% of the recited or claimed numerical value or range, unless the context requires a more restrictive range.

[0018] In the description and claims herein, phrases such as "at least one" or "one or more" may appear followed by a combined list of elements or features. The term "and / or" may also appear with a list of two or more elements or features. Unless implicitly or explicitly contradicted by the context in which it is used, such a phrase is intended to mean any of the listed elements or features individually, or any of the cited elements or features in combination with any of the other cited elements or features. For example, the phrases "at least one of A and B," "one or more of A and B," and "A and / or B" are intended to mean "A only, B only, or A and B together," respectively. A similar interpretation applies to lists containing more than two items. For example, the phrases "at least one of A, B, and C," "one or more of A, B, and C," and "A, B and / or C" are intended to mean "A only, B only, C only, A and B together, A and C together, B and C together, or A, B, and C together," respectively. Additionally, use of the term "based on" above and in the claims is intended to mean "based at least in part on," such that unrecited features or elements are also allowed for.

[0019] When a parameter range is provided, it is understood that all integers and tenths thereof within that range are also provided by the present invention. For example, "0.2 to 5 mg" is a disclosure of 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, etc., up to 5.0 mg.

[0020] As used throughout this description and the claims that follow, the meanings of "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0021] The transitional term "comprising," which is synonymous with "comprising," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements, method steps, or ingredients (as appropriate for the context). In contrast, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the claim to specific materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. When methods and compositions are disclosed using the transitional term "comprising," it will be understood that corresponding methods and compositions with the transitional terms "consisting of" and "essentially consisting of" are also disclosed.

[0022] Where substituents are specified by their conventional chemical formula written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0023] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, linear (i.e., unbranched) or branched carbon chains (or carbons), or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and which may include monovalent, divalent, and polyvalent radicals. An alkyl can contain the specified number of carbons (e.g., C-C 10("means 1 to 10 carbons"). Alkyl is a non-cyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl groups are those with one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. The alkenyl may contain, in addition to one or more double bonds, two or more double bonds and / or one or more triple bonds. The alkynyl may contain, in addition to one or more triple bonds, two or more triple bonds and / or one or more double bonds.

[0024] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, exemplified by, but not limited to, -CHCHCHCH-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0025] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise specified, a stable linear or branched chain containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), or a combination thereof, wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) (e.g., O, N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is a non-cyclized chain. Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-S-CH2, -S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH=CH-O-CH 3、Examples include, but are not limited to, -Si(CH), -CH-CH=N-OCH, -CH=CH-N(CH)-CH, -O-CH, -O-CH-CH, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH-NH-OCH and -CH-O-Si(CH). A heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety can contain up to eight optionally different heteroatoms (e.g., O, N, S, Si, or P). The term "heteroalkenyl," alone or in combination with another term, means, unless otherwise specified, a heteroalkyl containing at least one double bond. A heteroalkenyl can optionally contain, in addition to one or more double bonds, two or more double bonds and / or one or more triple bonds. The term "heteroalkynyl," alone or in combination with another term, means, unless otherwise specified, a heteroalkyl containing at least one triple bond. A heteroalkynyl can optionally contain, in addition to one or more triple bonds, two or more triple bonds and / or one or more double bonds.

[0026] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, heteroalkyl groups as used herein include groups attached to the remainder of the molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SOR'. When "heteroalkyl" is recited followed by a specific heteroalkyl group, e.g., -NR'R'', it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited for clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups, e.g., -NR'R'', etc.

[0027] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0028] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl.

[0029] The term "acyl," unless otherwise specified, means -C(O)R, in which R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0030] The term "aryl," unless otherwise specified, refers to a polyunsaturated, aromatic, hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1 to 3 rings) fused together (i.e., fused-ring aryl) or covalently linked together. Fused-ring aryl refers to multiple rings fused together, at least one of which is an aryl ring. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, at least one of which is an aromatic heterocycle). 5,6-fused-ring heteroarylene refers to two rings fused together, one ring having five members and the other having six members, and at least one ring being a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, one having 6 members and the other having 6 members, and at least one ring being a heteroaryl ring. A 6,5-fused ring heteroarylene refers to two rings fused together, one having 6 members and the other having 5 members, and at least one ring being a heteroaryl ring. The heteroaryl group can be attached to the remainder of the molecule through a carbon atom or a heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, and the like. aryl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms "arylene" and "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. The heteroaryl group substituent may be -O-bonded to a ring heteroatom nitrogen.

[0031] For brevity, the term "aryl," when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl), includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" includes radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.) in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc.).

[0032] symbol [ka] indicates the point of attachment of the chemical moiety to the rest of the molecule or chemical formula.

[0033] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0034] As used herein, the term "alkylsulfonyl" refers to a moiety having the formula -S(O2)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' can have a specified number of carbon atoms (e.g., "C1-C4 alkylsulfonyl").

[0035] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0036] Substituents for alkyl and heteroalkyl radicals (including groups also referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) range in number from 0 to (2m'+1), where m' is the total number of carbon atoms in such radical, and include -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', R′, R″, R′″, and R′″ can each preferably independently represent hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes two or more R groups, e.g., when two or more of these groups are present, each of the R groups is independently selected as each R′, R″, R′″, and R′″ group. When R′ and R″ are attached to the same nitrogen atom, they may be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is intended to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF and -CHCF) and acyl (e.g., -C(O)CH, -C(O)CF, -C(O)CHOCH, etc.).

[0037] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and range in number from 0 to the total number of open valences on the aromatic ring system, e.g., -OR', -NR'R'', -SR', Halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -CN, -NO2, -R', -N3, and R', R", R'", and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, e.g., when more than one of these groups is present, each of the R groups is independently selected as an R', R", R'", and R"" group, respectively.

[0038] Two or more substituents may optionally combine to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically, but not necessarily, found attached to a cyclic base structure. In an embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure form a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0039] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring are of the formula -TC(O)-(CRR') q The aryl or heteroaryl ring may optionally form a ring of the formula -U-, where T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be a group of the formula -A-(CH2) rwherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4. One of the single bonds in the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be replaced with a group of the formula -(CRR') s -X'-(C''R'') d -, where s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0040] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0041] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be shown as substituents on the ring (commonly referred to as floating substituents) rather than on a specific atom of the ring. In such cases, the substituent may be attached to any of the ring atoms (according to the rules of chemical valence), and in the case of a fused or spirocyclic ring, a substituent shown as attached to one member of the fused or spirocyclic ring (a floating substituent on a single ring) may be a substituent on either the fused or spirocyclic ring (a floating substituent on a polycyclic ring). When a substituent is attached to a ring rather than to a specific atom (a floating substituent), and the substituent subscript is an integer greater than 1, multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent may optionally be different. When the point of attachment of a ring to the rest of the molecule is not limited to a single atom (a floating substituent), the point of attachment may be any atom of the ring, or, in the case of a fused or spirocyclic ring, any atom of the fused or spirocyclic ring, according to the rules of chemical valence. When a ring, fused ring, or spirocyclic ring contains one or more ring heteroatoms and the ring, fused ring, or spirocyclic ring is shown with another floating substituent (including, but not limited to, the point of attachment to the rest of the molecule), the floating substituent may be bonded to the heteroatom. When a ring heteroatom is shown bonded to one or more hydrogens in a structure or formula with a floating substituent (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen), it will be understood that when the heteroatom is bonded to the floating substituent, the substituent replaces the hydrogen, according to the rules of chemical valence.

[0042] Two or more substituents may optionally combine to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically, but not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure form a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0043] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -TC(O)-(CRR') q Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -A-(CH2) r A and B may be substituted with a substituent of the formula -B- (wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4). One of the single bonds in the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be substituted with a substituent of the formula -(CRR') s -X'-(C''R''R'') d- (wherein s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-). The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0044] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0045] As used herein, a "substituent" means a group selected from the following moieties: (A) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the following: (i) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO 2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2 Cl, -OCH2Br, -OCHI, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the following: (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (b) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0046] As used herein, a "size-limited substituent" or "size-limited substituent group" means a group selected from all of the substituents described above for "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C-C 20 each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0047] As used herein, a "lower substituent" or "lower substituent group" means a group selected from all of the substituents described above for "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0048] In embodiments, each substituent described in the compounds herein is substituted with at least one substituent.More specifically, in embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent.In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent.In other embodiments, at least one or all of these groups are substituted with at least one lower-rank substituent.

[0049] In embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C-C 20each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and / or each substituted or unsubstituted heteroaryl may be a substituted or unsubstituted 5-10 membered heteroaryl. In embodiments of the compounds herein, each substituted or unsubstituted alkylene may be a substituted or unsubstituted C-C 20 each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene; each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene; each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene; and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0050] In embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-7 membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C 10In embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2-8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3-7 membered heterocycloalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is a species described in the Examples section, Figures, or Tables below.

[0051] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively).

[0052] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, and when a substituted moiety is substituted with multiple substituents, each substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple substituents, each substituent is different.

[0053] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-limiting substituent, and when a substituted moiety is substituted with multiple substituents, each size-limiting substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent is different.

[0054] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent, and when a substituted moiety is substituted with multiple lower substituents, each lower substituent may optionally be different. In embodiments, when a substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0055] In embodiments, a substituted moiety (e.g., a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limiting substituent, or lower substituent; when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be different.

[0056] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein.When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are amino acid salts such as arginate salts, and organic acid salts such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0057] Therefore, the compounds of the present invention can exist as salts with pharmaceutically acceptable acids, etc. The present invention includes such salts. Examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof, including a racemic mixture), succinate, benzoate, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

[0058] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0059] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to yield compounds of the present invention. Furthermore, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0060] Certain compounds of the present invention can exist in non-solvated form and solvated form, including hydrated form.In general, solvated form is equivalent to non-solvated form and is included in the scope of the present invention.Certain compounds of the present invention can exist in multiple crystalline forms or amorphous forms.In general, all physical forms are equivalent for the use contemplated by the present invention and are intended to be within the scope of the present invention.

[0061] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, tautomers, geometric isomers, and individual isomers are encompassed within the scope of the present invention. Compounds of the present invention do not include those known in the art to be too unstable to synthesize and / or isolate.

[0062] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ with regard to the structural arrangement or configuration of the atoms.

[0063] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0064] It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.

[0065] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

[0066] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0067] The term "treating" or "treatment" refers to any indication of success in treating or ameliorating an injury, disease, pathology, or condition, including any objective or subjective parameter, such as remission, remission; reducing symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; or improving the patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. The term "treating" and its conjugations can include prevention of an injury, disease, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing.

[0068] As used herein (and as is well understood in the art), "treating" or "treatment" broadly encompasses any approach to achieving beneficial or desired results in a subject's condition, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether partial or total, detectable or undetectable, reduction in the extent of disease, stabilization of disease conditions (i.e., not worsening), prevention of disease infection or spread, delay or slowing of disease progression, improvement or relief of disease conditions, reduction in disease recurrence, and remission. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of disease. Treatment may prevent disease from developing, inhibit the spread of disease, relieve symptoms of disease (e.g., eye pain, seeing halos around lights, eye redness, elevated intraocular pressure), completely or partially eliminate the underlying cause of disease, shorten the duration of disease, or a combination thereof. In embodiments, treatment includes prophylactic treatment. The treatment method includes administering a therapeutically effective amount of an active agent to a subject. In embodiments, the administering step can consist of a single administration or can include a series of administrations. The length of the treatment period depends on various factors, such as the severity of the condition, the age of the patient, the concentration of the active agent, the activity of the composition used for treatment, or a combination thereof. It will also be understood that the effective dosage of an agent used for treatment or prevention may increase or decrease during a particular treatment or prevention regimen. Dosage changes can be effected or determined by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the composition is administered to the subject in an amount and for a duration sufficient to treat the patient. In embodiments, the treatment or treatment is not a prophylactic treatment.

[0069] An "effective amount" is an amount sufficient to achieve the stated purpose (e.g., achieve the effect for which it is administered, treat a disease, reduce mucus in a target organ, reduce one or more symptoms of a disease or condition, etc.). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or alleviation of a symptom or symptoms of a disease, which may also be referred to as a "therapeutically effective amount." "Alleviation" of a symptom(s) (and grammatical equivalents of this phrase) means a decrease in the severity or frequency of the symptom(s), or the elimination of the symptom(s). A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, will produce the intended prophylactic effect, for example, an amount of drug that prevents or delays the onset (or recurrence) of an injury, disease, lesion, or condition, or reduces the likelihood of the onset (or recurrence) of an injury, disease, lesion, or condition, or its symptoms. A complete prophylactic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. As used herein, " activity-reducing amount " refers to the amount of compound disclosed herein that is required to reduce mucus elasticity or reduce mucus viscosity in the subject in need thereof.The exact amount depends on the purpose of treatment and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols.1-3,1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999) and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0070] "Subject," "patient," or "subject in need thereof" refers to a living member of the animal kingdom that is suffering from or may suffer from the indicated disease or disorder. In embodiments, the subject is a member of a species that includes individuals that naturally suffer from the disease or disorder. In embodiments, the subject is a mammal. Non-limiting examples of mammals include rodents (e.g., mice and rats), primates (e.g., lemurs, bushbabies, monkeys, apes, and humans), rabbits, dogs (e.g., companion dogs, service dogs, or working dogs such as police dogs, military dogs, racing dogs, and show dogs), horses (such as race horses and working horses), cats (e.g., domestic cats), livestock (such as pigs, cows, donkeys, mules, bison, goats, camels, and sheep), and deer. In embodiments, the subject is a human. In embodiments, the subject is a non-mammal, such as a turkey, duck, or chicken. In embodiments, a subject refers to an organism suffering from or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition as provided herein. Terms such as "subject," "patient," and "individual" are not intended to be limiting and are generally interchangeable. In embodiments, an individual described as a "patient" does not necessarily have a given disease, but may, for example, simply be seeking medical advice.

[0071] In embodiments, the disease or disorder is or involves an abnormal (e.g., increased) amount of mucus (e.g., in the mucous membranes, eyes, or respiratory tract), or mucus with an abnormal (e.g., increased) viscosity or elasticity compared to the mucus of a typical healthy subject. In embodiments, the abnormal increase is at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% increase. In embodiments, the abnormal increase is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% to about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% increase.

[0072] As used herein, a "symptom" of a disease includes any clinical or laboratory symptom associated with the disease, including but not limited to those perceptible or observable by a subject.

[0073] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration and absorption of an active agent by a subject and can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Unless otherwise indicated, terms such as "active agent," "active ingredient," "therapeutically active agent," and "therapeutic agent" are used interchangeably. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, saline (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, polyethylene glycol, and coloring agents. Such preparations may be sterilized and, if desired, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances which do not deleteriously react with the compounds of the invention. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0074] As used herein, the term "administering" refers to oral administration, administration as an aerosol or dry powder inhalation, suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or implantation of a sustained-release device, such as a mini-osmotic pump, to a subject. Administration can be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery modes include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Co-administration" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies, such as cancer therapies, such as bronchodilators (beta-agonists, anticholinergics), corticosteroids, antibiotics, chemotherapy, hormone therapy, radiation therapy, or immunotherapy. The compounds of the present invention can be administered alone or simultaneously to a patient. Co-administration is intended to include simultaneous or sequential administration of compounds, individually or in combination (two or more compounds or agents). Thus, the preparations can also be combined with other active substances, as needed (e.g., to reduce metabolic degradation or promote penetration of tissues, mucus, or pathological biofilms by the active substance). The preparations may also be combined with other mucolytic drug classes (e.g., rhDNase, as known in the art) or with inhaled bronchodilators (short- or long-acting beta-agonists, short- or long-acting anticholinergics), inhaled corticosteroids, or inhaled antibiotics to provide additive or synergistic effects, thereby improving the efficacy of these drugs. The compositions of the present invention can be delivered transdermally by topical routes or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, nanoparticles, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like suitable for ingestion by the patient.Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid preparations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. The compositions of the present invention may further contain ingredients for sustained release and / or comfort. Such ingredients include high molecular weight anionic mucosomimetic polymers, gelling polysaccharides, and finely divided drug carrier substrates. These ingredients are described in further detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760, the entire contents of which are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for sustained release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres that are slowly released subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995), as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995), or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, formulations of the compositions of the invention can be delivered by the use of liposomes that fuse with or are endocytosed by cell membranes, i.e., by using receptor ligands attached to the liposomes that bind to surface membrane protein receptors of the cell, causing endocytosis. In particular, liposomes that fuse with or are endocytosed by ... bind to surface membrane protein receptors of the cell, causing endocytosis. Liposomes can be used to target delivery of the compositions of the invention to target cells in vivo if the liposome surface carries target cell-specific receptor ligands or is otherwise preferentially directed to a particular organ (see, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

[0075] The pharmaceutical compositions provided herein include compositions containing an active ingredient (e.g., a compound described herein, including an embodiment or example) in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. Determination of a therapeutically effective amount of a compound of the present invention is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.

[0076] The dosage and frequency (single or multiple administrations) administered to a mammal can vary depending on various factors, such as whether the mammal is suffering from another disease and the route of administration, the recipient's size, age, sex, health, weight, body mass index, and diet, the nature and extent of symptoms of the disease being treated, the type of concurrent treatment, coexisting conditions with the disease being treated, or other health-related issues. Other therapeutic regimens or agents may be used in conjunction with the methods and compounds of Applicant's invention. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the capabilities of one of ordinary skill in the art.

[0077] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively).

[0078] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, and when a substituted moiety is substituted with multiple substituents, each substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple substituents, each substituent is different.

[0079] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-limiting substituent, and when a substituted moiety is substituted with multiple substituents, each size-limiting substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent is different.

[0080] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent, and when a substituted moiety is substituted with multiple lower substituents, each lower substituent may optionally be different. In embodiments, when a substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0081] In embodiments, a substituted moiety (e.g., a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limiting substituent, or lower substituent; when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be different.

[0082] When a moiety is substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene), the moiety is substituted with at least one substituent (e.g., a substituent, a size-limited substituent, or a lower substituent), and each substituent is optionally different. Furthermore, when multiple substituents are present on a moiety, each substituent may optionally be different.

[0083] The term "thiol" is used according to its ordinary meaning in the art to refer to a moiety. [ka]

[0084] The terms "dithiol sugar mucolytic agent" and "mucolytic dithiol sugar agent" refer to a compound that includes at least one sugar moiety covalently bonded to at least two thiol moieties.

[0085] I. Compound In one aspect, compounds are provided having the formula: [ka] R 1 -SR 1A , -OR 1A , -NR 1B R 1C , -NR 1B C(O)R 1C , -NR 1B C(O)OR 1C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 2 -SR 2A , -OR 2A , -NR 2B R 2C , -NR 2B C(O)R 2C , -NR 2B C(O)OR 2C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 3 -SR 3A , -OR 3A , -NR 3B R 3C , -NR 3B C(O)R 3C , -NR 3B C(O)OR 3C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 4 -SR 4A , -SC(O)R 4A , -OR 4A , -NR 4B R 4C , -NR 4B C(O)R 4C , -NR 4B C(O)OR 4C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 5 is hydrogen, -SR 5A , -OR 5A , -NR 5B R5C , -NR 5B C(O)R 5C , -NR 5B C(O)OR 5C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 6 -SR 6A , -OR 6A , -NR 6B R 6C , -NR 6B C(O)R 6C , -NR 6B C(O)OR 6C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 1B , R 2B , R 3B , R 4B , R 5B , R 6B , R 1C , R 2C , R 3C , R 4C , R 5C , and R 6C are each independently hydrogen, substituted or unsubstituted C-C 10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, or a pharmaceutically acceptable salt thereof.

[0086] In embodiments, the compound comprises at least two thiol moieties. In embodiments, the compound comprises: [ka] In embodiments, the compound comprises at most two thiol moieties.

[0087] In one aspect, compounds are provided having the formula: [ka] R 2 -SR 2A , -OR 2A , -NR 2B R 2C , -NR 2B C(O)R 2C , -NR 2B C(O)OR 2C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 3 -SR 3A , -OR 3A , -NR 3B R 3C , -NR 3B C(O)R 3C , -NR 3B C(O)OR 3C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 4 -SR 4A , -SC(O)R 4A , -OR 4A , -NR 4B R 4C , -NR 4B C(O)R 4C , -NR 4B C(O)OR 4C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 5 is hydrogen, -SR 5A , -OR 5A , -NR 5B R 5C , -NR 5B C(O)R 5C , -NR 5B C(O)OR 5C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 6 -SR 6A , -OR 6A , -NR 6B R 6C , -NR 6B C(O)R6C , -NR 6B C(O)OR 6C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 7 -SR 7A , -OR 7A , -NR 7B R 7C , -NR 7B C(O)R 7C , -NR 7B C(O)OR 7C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 8 -SR 8A , -OR 8A , -NR 8B R 8C , -NR 8B C(O)R 8C , -NR 8B C(O)OR 8C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 9 But, -SR 9A , -SC(O)R 9A , -OR 9A , -NR 9B R 9C , -NR 9B C(O)R 9C , -NR 9B C(O)OR 9C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 10 is hydrogen, -SR 10A , -OR 10A , -NR 10B R 10C , -NR 10B C(O)R 10C , -NR 10B C(O)OR 10C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 11 -SR11A , -OR 11A , -NR 11B R 11C , -NR 11B C(O)R 11C , -NR 11B C(O)OR 11C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 12 -SR 12A , -OR 12A , -NR 12B R 12C , -NR 12B C(O)R 12C , -NR 12B C(O)OR 12C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 11A , R 12A , R 2B , R 3B , R 4B , R 5B , R 6B , R 7B , R 8B , R 9B , R 10B , R 11B , R 12B , R 2C , R 3C , R 4C , R 5C , R 6C , R 7C , R 8C , R 9C , R 10C , R 11C , and R 12C are each independently hydrogen, substituted or unsubstituted C-C 10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, or a pharmaceutically acceptable salt thereof.

[0088] In embodiments, the compound comprises at least two thiol moieties. In embodiments, the compound comprises: [ka] In an embodiment, the compound is not 6,6'-dithiol-6,6'-dideoxy-α,α-trehalose. In an embodiment, the compound is not methyl-6,6'-dithio-6,6'-dideoxy-β-lactoside. In an embodiment, the compound is [ka] isn't it.

[0089] In embodiments, the compound has the formula: [ka] and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is as described herein.

[0090] In embodiments, the compound has the formula: [ka] and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , and R 12 is as described herein.

[0091] In embodiments, the compound has the formula: [ka]

[0092] In embodiments, the compound has the formula: [ka]

[0093] In embodiments, the compound has the formula: [ka]

[0094] In embodiments, R 1 -SR 1A , -OR 1A , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl. 1 -SR 1A , -OR 1A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl. 1 -SR 1A -OR 1A In an embodiment, R 1 -SR 1A In an embodiment, R 1 -OR 1A In an embodiment, R 1 is -SH. In embodiments, R 1 is -OH.

[0095] In embodiments, R 1 is -SH, -OH, -OCH3, -NH2, -NHC(O)H, -NHC(O)OH, substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl. 1 is -OCH3.

[0096] In embodiments, R 1 is substituted or unsubstituted methyl. In embodiments, R 1 is a substituted or unsubstituted C alkyl. In embodiments, R 1 is a substituted or unsubstituted C alkyl. In embodiments, R 1 is a substituted or unsubstituted C4 alkyl. In embodiments, R 1 is a substituted or unsubstituted C alkyl. In embodiments, R 1 is a substituted or unsubstituted C alkyl. In embodiments, R 1 is a substituted or unsubstituted C alkyl. In embodiments, R 1 is a substituted or unsubstituted C alkyl. In embodiments, R 1 is a substituted methyl. In embodiments, R 1 is a substituted C alkyl. In embodiments, R 1 is a substituted C alkyl. In embodiments, R 1 is a substituted C4 alkyl. In embodiments, R 1 is a substituted C alkyl. In embodiments, R 1 is a substituted C alkyl. In embodiments, R 1 is a substituted C7 alkyl. In embodiments, R 1 is a substituted C alkyl. In embodiments, R 1 is unsubstituted methyl. In embodiments, R 1 is an unsubstituted C alkyl. In embodiments, R 1 is an unsubstituted C alkyl. In embodiments, R 1 is an unsubstituted C4 alkyl. In embodiments, R 1 is an unsubstituted C alkyl. In embodiments, R 1 is an unsubstituted C alkyl. In embodiments, R 1 is an unsubstituted C7 alkyl. In embodiments, R 1 is an unsubstituted C8 alkyl.

[0097] In embodiments, R 1 is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R1 is a substituted 2-10 membered heteroalkyl. In embodiments, R 1 is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 1 is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 1 is a substituted 2-6 membered heteroalkyl. In embodiments, R 1 is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 1 is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 1 is a substituted 2-membered heteroalkyl. In embodiments, R 1 is an unsubstituted 2-membered heteroalkyl. In embodiments, R 1 is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 1 is a substituted 3-membered heteroalkyl. In embodiments, R 1 is an unsubstituted 3-membered heteroalkyl. In embodiments, R 1 is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 1 is a substituted 4-membered heteroalkyl. In embodiments, R 1 is an unsubstituted 4-membered heteroalkyl. In embodiments, R 1 is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 1 is a substituted 5-membered heteroalkyl. In embodiments, R 1 is an unsubstituted 5-membered heteroalkyl. In embodiments, R 1 is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 1 is a substituted 6-membered heteroalkyl. In embodiments, R 1 is an unsubstituted 6-membered heteroalkyl.

[0098] In embodiments, R 1 is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 1is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 1 is unsubstituted alkyl or unsubstituted heteroalkyl.

[0099] In embodiments, the substitution R 1 (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 1 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 1 If is substituted, R 1 is substituted with at least one substituent. In embodiments, R 1 If is substituted, R 1 is substituted with at least one size-limited substituent. In embodiments, R 1 If is substituted, R 1 is substituted with at least one lower substituent.

[0100] In embodiments, R 2 -SR 2A , -OR 2A , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl. 2 -SR 2A , -OR 2A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl. 2 -SR 2A -OR 2A In an embodiment, R 2 -SR 2A -OR 2A In an embodiment, R 2-SR 2A In an embodiment, R 2 -OR 2A In an embodiment, R 2 is -SH. In embodiments, R 2 is -OH.

[0101] In embodiments, R 2 is -SH, -OH, -OCH3, -NH2, -NHC(O)H, -NHC(O)OH, substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl. 2 is -OCH3.

[0102] In embodiments, R 2 is substituted or unsubstituted methyl. In embodiments, R 2 is a substituted or unsubstituted C alkyl. In embodiments, R 2 is a substituted or unsubstituted C alkyl. In embodiments, R 2 is a substituted or unsubstituted C4 alkyl. In embodiments, R 2 is a substituted or unsubstituted C alkyl. In embodiments, R 2 is a substituted or unsubstituted C alkyl. In embodiments, R 2 is a substituted or unsubstituted C alkyl. In embodiments, R 2 is a substituted or unsubstituted C alkyl. In embodiments, R 2 is a substituted methyl. In embodiments, R 2 is a substituted C alkyl. In embodiments, R 2 is a substituted C alkyl. In embodiments, R 2 is a substituted C4 alkyl. In embodiments, R 2 is a substituted C alkyl. In embodiments, R 2 is a substituted C alkyl. In embodiments, R 2 is a substituted C7 alkyl. In embodiments, R 2 is a substituted C alkyl. In embodiments, R 2 is unsubstituted methyl. In embodiments, R2 is an unsubstituted C alkyl. In embodiments, R 2 is an unsubstituted C alkyl. In embodiments, R 2 is an unsubstituted C4 alkyl. In embodiments, R 2 is an unsubstituted C alkyl. In embodiments, R 2 is an unsubstituted C alkyl. In embodiments, R 2 is an unsubstituted C7 alkyl. In embodiments, R 2 is an unsubstituted C8 alkyl.

[0103] In embodiments, R 2 is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 2 is a substituted 2-10 membered heteroalkyl. In embodiments, R 2 is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 2 is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 2 is a substituted 2-6 membered heteroalkyl. In embodiments, R 2 is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 2 is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 2 is a substituted 2-membered heteroalkyl. In embodiments, R 2 is an unsubstituted 2-membered heteroalkyl. In embodiments, R 2 is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 2 is a substituted 3-membered heteroalkyl. In embodiments, R 2 is an unsubstituted 3-membered heteroalkyl. In embodiments, R 2 is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 2 is a substituted 4-membered heteroalkyl. In embodiments, R 2 is an unsubstituted 4-membered heteroalkyl. In embodiments, R 2 is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 2 is a substituted 5-membered heteroalkyl. In embodiments, R2 is an unsubstituted 5-membered heteroalkyl. In embodiments, R 2 is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 2 is a substituted 6-membered heteroalkyl. In embodiments, R 2 is an unsubstituted 6-membered heteroalkyl.

[0104] In embodiments, R 2 is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 2 is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 2 is unsubstituted alkyl or unsubstituted heteroalkyl.

[0105] In embodiments, the substitution R 2 (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 2 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 2 If is substituted, R 2 is substituted with at least one substituent. In embodiments, R 2 If is substituted, R 2 is substituted with at least one size-limited substituent. In embodiments, R 2 If is substituted, R 2 is substituted with at least one lower substituent.

[0106] In embodiments, R 3 -SR 3A , -OR3A , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl. 3 -SR 3A , -OR 3A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl. 3 -SR 3A -OR 3A In an embodiment, R 3 -SR 3A -OR 3A In an embodiment, R 3 -SR 3A In an embodiment, R 3 -OR 3A In an embodiment, R 3 is -SH. In embodiments, R 3 is -OH.

[0107] In embodiments, R 3 is -SH, -OH, -OCH3, -NH2, -NHC(O)H, -NHC(O)OH, substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl. 3 is -OCH3.

[0108] In embodiments, R 3 is substituted or unsubstituted methyl. In embodiments, R 3 is a substituted or unsubstituted C alkyl. In embodiments, R 3 is a substituted or unsubstituted C alkyl. In embodiments, R 3 is a substituted or unsubstituted C4 alkyl. In embodiments, R 3 is a substituted or unsubstituted C alkyl. In embodiments, R 3 is a substituted or unsubstituted C alkyl. In embodiments, R 3 is a substituted or unsubstituted C alkyl. In embodiments, R 3is a substituted or unsubstituted C alkyl. In embodiments, R 3 is a substituted methyl. In embodiments, R 3 is a substituted C alkyl. In embodiments, R 3 is a substituted C alkyl. In embodiments, R 3 is a substituted C4 alkyl. In embodiments, R 3 is a substituted C alkyl. In embodiments, R 3 is a substituted C alkyl. In embodiments, R 3 is a substituted C7 alkyl. In embodiments, R 3 is a substituted C alkyl. In embodiments, R 3 is unsubstituted methyl. In embodiments, R 3 is an unsubstituted C alkyl. In embodiments, R 3 is an unsubstituted C alkyl. In embodiments, R 3 is an unsubstituted C4 alkyl. In embodiments, R 3 is an unsubstituted C alkyl. In embodiments, R 3 is an unsubstituted C alkyl. In embodiments, R 3 is an unsubstituted C7 alkyl. In embodiments, R 3 is an unsubstituted C8 alkyl.

[0109] In embodiments, R 3 is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 3 is a substituted 2-10 membered heteroalkyl. In embodiments, R 3 is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 3 is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 3 is a substituted 2-6 membered heteroalkyl. In embodiments, R 3 is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 3 is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 3 is a substituted 2-membered heteroalkyl. In embodiments, R 3is an unsubstituted 2-membered heteroalkyl. In embodiments, R 3 is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 3 is a substituted 3-membered heteroalkyl. In embodiments, R 3 is an unsubstituted 3-membered heteroalkyl. In embodiments, R 3 is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 3 is a substituted 4-membered heteroalkyl. In embodiments, R 3 is an unsubstituted 4-membered heteroalkyl. In embodiments, R 3 is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 3 is a substituted 5-membered heteroalkyl. In embodiments, R 3 is an unsubstituted 5-membered heteroalkyl. In embodiments, R 3 is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 3 is a substituted 6-membered heteroalkyl. In embodiments, R 3 is an unsubstituted 6-membered heteroalkyl.

[0110] In embodiments, R 3 is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 3 is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 3 is unsubstituted alkyl or unsubstituted heteroalkyl.

[0111] In embodiments, the substitution R 3 (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 3When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 3 If is substituted, R 3 is substituted with at least one substituent. In embodiments, R 3 If is substituted, R 3 is substituted with at least one size-limited substituent. In embodiments, R 3 If is substituted, R 3 is substituted with at least one lower substituent.

[0112] In embodiments, R 4 -SR 4A , -OR 4A , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl. 4 -SR 4A , -OR 4A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl. 4 -SR 4A -OR 4A In an embodiment, R 4 -SR 4A -OR 4A In an embodiment, R 4 -SR 4A In an embodiment, R 4 -OR 4A In an embodiment, R 4 is -SH. In embodiments, R 4 is -OH.

[0113] In embodiments, R 4 is -SH, -OH, -OCH3, -NH2, -NHC(O)H, -NHC(O)OH, substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl.4 is -OCH3.

[0114] In embodiments, R 4 is substituted or unsubstituted methyl. In embodiments, R 4 is a substituted or unsubstituted C alkyl. In embodiments, R 4 is a substituted or unsubstituted C alkyl. In embodiments, R 4 is a substituted or unsubstituted C4 alkyl. In embodiments, R 4 is a substituted or unsubstituted C alkyl. In embodiments, R 4 is a substituted or unsubstituted C alkyl. In embodiments, R 4 is a substituted or unsubstituted C alkyl. In embodiments, R 4 is a substituted or unsubstituted C alkyl. In embodiments, R 4 is a substituted methyl. In embodiments, R 4 is a substituted C alkyl. In embodiments, R 4 is a substituted C alkyl. In embodiments, R 4 is a substituted C4 alkyl. In embodiments, R 4 is a substituted C alkyl. In embodiments, R 4 is a substituted C alkyl. In embodiments, R 4 is a substituted C7 alkyl. In embodiments, R 4 is a substituted C alkyl. In embodiments, R 4 is unsubstituted methyl. In embodiments, R 4 is an unsubstituted C alkyl. In embodiments, R 4 is an unsubstituted C alkyl. In embodiments, R 4 is an unsubstituted C4 alkyl. In embodiments, R 4 is an unsubstituted C alkyl. In embodiments, R 4 is an unsubstituted C alkyl. In embodiments, R 4 is an unsubstituted C7 alkyl. In embodiments, R 4 is an unsubstituted C8 alkyl.

[0115] In embodiments, R4 is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 4 is a substituted 2-10 membered heteroalkyl. In embodiments, R 4 is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 4 is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 4 is a substituted 2-6 membered heteroalkyl. In embodiments, R 4 is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 4 is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 4 is a substituted 2-membered heteroalkyl. In embodiments, R 4 is an unsubstituted 2-membered heteroalkyl. In embodiments, R 4 is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 4 is a substituted 3-membered heteroalkyl. In embodiments, R 4 is an unsubstituted 3-membered heteroalkyl. In embodiments, R 4 is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 4 is a substituted 4-membered heteroalkyl. In embodiments, R 4 is an unsubstituted 4-membered heteroalkyl. In embodiments, R 4 is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 4 is a substituted 5-membered heteroalkyl. In embodiments, R 4 is an unsubstituted 5-membered heteroalkyl. In embodiments, R 4 is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 4 is a substituted 6-membered heteroalkyl. In embodiments, R 4 is an unsubstituted 6-membered heteroalkyl.

[0116] In embodiments, R 4is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 4 is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 4 is unsubstituted alkyl or unsubstituted heteroalkyl.

[0117] In embodiments, the substitution R 4 (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 4 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 4 If is substituted, R 4 is substituted with at least one substituent. In embodiments, R 4 If is substituted, R 4 is substituted with at least one size-limited substituent. In embodiments, R 4 If is substituted, R 4 is substituted with at least one lower substituent.

[0118] In embodiments, R 5 is hydrogen, -SR 5A , -OR 5A , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl. 5 is hydrogen, -SR 5A , -OR 5A or thiol-substituted or unsubstituted C1-C 10 alkyl, thiol, or substituted or unsubstituted 2-10 membered heteroalkyl.5 -SR 5A -OR 5A In an embodiment, R 5 -SR 5A In an embodiment, R 5 -OR 5A In an embodiment, R 5 is -SH. In embodiments, R 5 is —OH. In embodiments, R 5 is hydrogen.

[0119] In embodiments, R 5 is -SH, -OH, -OCH3, -NH2, -NHC(O)H, -NHC(O)OH, substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl. 5 is -OCH3.

[0120] In embodiments, R 5 is substituted or unsubstituted methyl. In embodiments, R 5 is a substituted or unsubstituted C alkyl. In embodiments, R 5 is a substituted or unsubstituted C alkyl. In embodiments, R 5 is a substituted or unsubstituted C4 alkyl. In embodiments, R 5 is a substituted or unsubstituted C alkyl. In embodiments, R 5 is a substituted or unsubstituted C alkyl. In embodiments, R 5 is a substituted or unsubstituted C alkyl. In embodiments, R 5 is a substituted or unsubstituted C alkyl. In embodiments, R 5 is a substituted methyl. In embodiments, R 5 is a substituted C alkyl. In embodiments, R 5 is a substituted C alkyl. In embodiments, R 5 is a substituted C4 alkyl. In embodiments, R 5 is a substituted C alkyl. In embodiments, R 5 is a substituted C alkyl. In embodiments, R5 is a substituted C7 alkyl. In embodiments, R 5 is a substituted C alkyl. In embodiments, R 5 is unsubstituted methyl. In embodiments, R 5 is an unsubstituted C alkyl. In embodiments, R 5 is an unsubstituted C alkyl. In embodiments, R 5 is an unsubstituted C4 alkyl. In embodiments, R 5 is an unsubstituted C alkyl. In embodiments, R 5 is an unsubstituted C alkyl. In embodiments, R 5 is an unsubstituted C7 alkyl. In embodiments, R 5 is an unsubstituted C8 alkyl.

[0121] In embodiments, R 5 is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 5 is a substituted 2-10 membered heteroalkyl. In embodiments, R 5 is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 5 is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 5 is a substituted 2-6 membered heteroalkyl. In embodiments, R 5 is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 5 is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 5 is a substituted 2-membered heteroalkyl. In embodiments, R 5 is an unsubstituted 2-membered heteroalkyl. In embodiments, R 5 is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 5 is a substituted 3-membered heteroalkyl. In embodiments, R 5 is an unsubstituted 3-membered heteroalkyl. In embodiments, R 5 is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 5 is a substituted 4-membered heteroalkyl. In embodiments, R 5is an unsubstituted 4-membered heteroalkyl. In embodiments, R 5 is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 5 is a substituted 5-membered heteroalkyl. In embodiments, R 5 is an unsubstituted 5-membered heteroalkyl. In embodiments, R 5 is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 5 is a substituted 6-membered heteroalkyl. In embodiments, R 5 is an unsubstituted 6-membered heteroalkyl.

[0122] In embodiments, R 5 is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 5 is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 5 is unsubstituted alkyl or unsubstituted heteroalkyl.

[0123] In embodiments, the substitution R 5 (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 5 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 5 If is substituted, R 5 is substituted with at least one substituent. In embodiments, R 5 If is substituted, R 5 is substituted with at least one size-limited substituent. In embodiments, R 5 If is substituted, R 5is substituted with at least one lower substituent.

[0124] In embodiments, R 6 -SR 6A , -OR 6A , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl. 6 -SR 6A , -OR 6A or thiol-substituted or unsubstituted C1-C 10 alkyl, thiol, or substituted or unsubstituted 2-10 membered heteroalkyl. 6 -SR 6A -OR 6A In an embodiment, R 6 -SR 6A -OR 6A In an embodiment, R 6 -SR 6A In an embodiment, R 6 -OR 6A In an embodiment, R 6 is -SH. In embodiments, R 6 is -OH.

[0125] In embodiments, R 6 is -SH, -OH, -OCH3, -NH2, -NHC(O)H, -NHC(O)OH, substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl. 6 is -OCH3.

[0126] In embodiments, R 6 is substituted or unsubstituted methyl. In embodiments, R 6 is a substituted or unsubstituted C alkyl. In embodiments, R 6 is a substituted or unsubstituted C alkyl. In embodiments, R 6 is a substituted or unsubstituted C4 alkyl. In embodiments, R 6is a substituted or unsubstituted C alkyl. In embodiments, R 6 is a substituted or unsubstituted C alkyl. In embodiments, R 6 is a substituted or unsubstituted C alkyl. In embodiments, R 6 is a substituted or unsubstituted C alkyl. In embodiments, R 6 is a substituted methyl. In embodiments, R 6 is a substituted C alkyl. In embodiments, R 6 is a substituted C alkyl. In embodiments, R 6 is a substituted C4 alkyl. In embodiments, R 6 is a substituted C alkyl. In embodiments, R 6 is a substituted C alkyl. In embodiments, R 6 is a substituted C7 alkyl. In embodiments, R 6 is a substituted C alkyl. In embodiments, R 6 is unsubstituted methyl. In embodiments, R 6 is an unsubstituted C alkyl. In embodiments, R 6 is an unsubstituted C alkyl. In embodiments, R 6 is an unsubstituted C4 alkyl. In embodiments, R 6 is an unsubstituted C alkyl. In embodiments, R 6 is an unsubstituted C alkyl. In embodiments, R 6 is an unsubstituted C7 alkyl. In embodiments, R 6 is an unsubstituted C8 alkyl.

[0127] In embodiments, R 6 is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 6 is a substituted 2-10 membered heteroalkyl. In embodiments, R 6 is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 6 is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 6 is a substituted 2-6 membered heteroalkyl. In embodiments, R 6is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 6 is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 6 is a substituted 2-membered heteroalkyl. In embodiments, R 6 is an unsubstituted 2-membered heteroalkyl. In embodiments, R 6 is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 6 is a substituted 3-membered heteroalkyl. In embodiments, R 6 is an unsubstituted 3-membered heteroalkyl. In embodiments, R 6 is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 6 is a substituted 4-membered heteroalkyl. In embodiments, R 6 is an unsubstituted 4-membered heteroalkyl. In embodiments, R 6 is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 6 is a substituted 5-membered heteroalkyl. In embodiments, R 6 is an unsubstituted 5-membered heteroalkyl. In embodiments, R 6 is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 6 is a substituted 6-membered heteroalkyl. In embodiments, R 6 is an unsubstituted 6-membered heteroalkyl.

[0128] In embodiments, R 6 is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 6 is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 6 is unsubstituted alkyl or unsubstituted heteroalkyl.

[0129] In embodiments, the substitution R 6 (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 6 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 6 If is substituted, R 6 is substituted with at least one substituent. In embodiments, R 6 If is substituted, R 6 is substituted with at least one size-limited substituent. In embodiments, R 6 If is substituted, R 6 is substituted with at least one lower substituent.

[0130] In embodiments, R 7 -SR 7A , -OR 7A , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl. 7 -SR 7A , -OR 7A or thiol-substituted or unsubstituted C1-C 10 alkyl, thiol, or substituted or unsubstituted 2-10 membered heteroalkyl. 7 -SR 7A -OR 7A In an embodiment, R 7 -SR 7A -OR 7A In an embodiment, R 7 -SR 7A In an embodiment, R 7 -OR 7A In an embodiment, R 7 is -SH. In embodiments, R 7 is -OH.

[0131] In embodiments, R 7is -SH, -OH, -OCH3, -NH2, -NHC(O)H, -NHC(O)OH, substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl. 7 is -OCH3.

[0132] In embodiments, R 7 is substituted or unsubstituted methyl. In embodiments, R 7 is a substituted or unsubstituted C alkyl. In embodiments, R 7 is a substituted or unsubstituted C alkyl. In embodiments, R 7 is a substituted or unsubstituted C4 alkyl. In embodiments, R 7 is a substituted or unsubstituted C alkyl. In embodiments, R 7 is a substituted or unsubstituted C alkyl. In embodiments, R 7 is a substituted or unsubstituted C alkyl. In embodiments, R 7 is a substituted or unsubstituted C alkyl. In embodiments, R 7 is a substituted methyl. In embodiments, R 7 is a substituted C alkyl. In embodiments, R 7 is a substituted C alkyl. In embodiments, R 7 is a substituted C4 alkyl. In embodiments, R 7 is a substituted C alkyl. In embodiments, R 7 is a substituted C alkyl. In embodiments, R 7 is a substituted C7 alkyl. In embodiments, R 7 is a substituted C alkyl. In embodiments, R 7 is unsubstituted methyl. In embodiments, R 7 is an unsubstituted C alkyl. In embodiments, R 7 is an unsubstituted C alkyl. In embodiments, R 7 is an unsubstituted C4 alkyl. In embodiments, R 7 is an unsubstituted C alkyl. In embodiments, R 7 is an unsubstituted C alkyl. In embodiments, R7 is an unsubstituted C7 alkyl. In embodiments, R 7 is an unsubstituted C8 alkyl.

[0133] In embodiments, R 7 is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 7 is a substituted 2-10 membered heteroalkyl. In embodiments, R 7 is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 7 is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 7 is a substituted 2-6 membered heteroalkyl. In embodiments, R 7 is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 7 is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 7 is a substituted 2-membered heteroalkyl. In embodiments, R 7 is an unsubstituted 2-membered heteroalkyl. In embodiments, R 7 is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 7 is a substituted 3-membered heteroalkyl. In embodiments, R 7 is an unsubstituted 3-membered heteroalkyl. In embodiments, R 7 is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 7 is a substituted 4-membered heteroalkyl. In embodiments, R 7 is an unsubstituted 4-membered heteroalkyl. In embodiments, R 7 is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 7 is a substituted 5-membered heteroalkyl. In embodiments, R 7 is an unsubstituted 5-membered heteroalkyl. In embodiments, R 7 is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 7 is a substituted 6-membered heteroalkyl. In embodiments, R 7 is an unsubstituted 6-membered heteroalkyl.

[0134] In embodiments, R 7 is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 7 is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 7 is unsubstituted alkyl or unsubstituted heteroalkyl.

[0135] In embodiments, the substitution R 7 (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 7 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 7 If is substituted, R 7 is substituted with at least one substituent. In embodiments, R 7 If is substituted, R 7 is substituted with at least one size-limited substituent. In embodiments, R 7 If is substituted, R 7 is substituted with at least one lower substituent.

[0136] In embodiments, R 8 -SR 8A , -OR 8A , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl. 8 -SR 8A , -OR 8A or thiol-substituted or unsubstituted C1-C 10alkyl, thiol, or substituted or unsubstituted 2-10 membered heteroalkyl. 8 -SR 8A -OR 8A In an embodiment, R 8 -SR 8A -OR 8A In an embodiment, R 8 -SR 8A In an embodiment, R 8 -OR 8A In an embodiment, R 8 is -SH. In embodiments, R 8 is -OH.

[0137] In embodiments, R 8 is -SH, -OH, -OCH3, -NH2, -NHC(O)H, -NHC(O)OH, substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl. 8 is -OCH3.

[0138] In embodiments, R 8 is substituted or unsubstituted methyl. In embodiments, R 8 is a substituted or unsubstituted C alkyl. In embodiments, R 8 is a substituted or unsubstituted C alkyl. In embodiments, R 8 is a substituted or unsubstituted C4 alkyl. In embodiments, R 8 is a substituted or unsubstituted C alkyl. In embodiments, R 8 is a substituted or unsubstituted C alkyl. In embodiments, R 8 is a substituted or unsubstituted C alkyl. In embodiments, R 8 is a substituted or unsubstituted C alkyl. In embodiments, R 8 is a substituted methyl. In embodiments, R 8 is a substituted C alkyl. In embodiments, R 8 is a substituted C alkyl. In embodiments, R 8is a substituted C4 alkyl. In embodiments, R 8 is a substituted C alkyl. In embodiments, R 8 is a substituted C alkyl. In embodiments, R 8 is a substituted C7 alkyl. In embodiments, R 8 is a substituted C alkyl. In embodiments, R 8 is unsubstituted methyl. In embodiments, R 8 is an unsubstituted C alkyl. In embodiments, R 8 is an unsubstituted C alkyl. In embodiments, R 8 is an unsubstituted C4 alkyl. In embodiments, R 8 is an unsubstituted C alkyl. In embodiments, R 8 is an unsubstituted C alkyl. In embodiments, R 8 is an unsubstituted C7 alkyl. In embodiments, R 8 is an unsubstituted C8 alkyl.

[0139] In embodiments, R 8 is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 8 is a substituted 2-10 membered heteroalkyl. In embodiments, R 8 is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 8 is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 8 is a substituted 2-6 membered heteroalkyl. In embodiments, R 8 is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 8 is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 8 is a substituted 2-membered heteroalkyl. In embodiments, R 8 is an unsubstituted 2-membered heteroalkyl. In embodiments, R 8 is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 8 is a substituted 3-membered heteroalkyl. In embodiments, R 8 is an unsubstituted 3-membered heteroalkyl. In embodiments, R 8is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 8 is a substituted 4-membered heteroalkyl. In embodiments, R 8 is an unsubstituted 4-membered heteroalkyl. In embodiments, R 8 is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 8 is a substituted 5-membered heteroalkyl. In embodiments, R 8 is an unsubstituted 5-membered heteroalkyl. In embodiments, R 8 is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 8 is a substituted 6-membered heteroalkyl. In embodiments, R 8 is an unsubstituted 6-membered heteroalkyl.

[0140] In embodiments, R 8 is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 8 is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 8 is unsubstituted alkyl or unsubstituted heteroalkyl.

[0141] In embodiments, the substitution R 8 (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 8 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 8 If is substituted, R 8 is substituted with at least one substituent. In embodiments, R 8 If is substituted, R8 is substituted with at least one size-limited substituent. In embodiments, R 8 If is substituted, R 8 is substituted with at least one lower substituent.

[0142] In embodiments, R 9 -SR 9A , -OR 9A , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl. 9 -SR 9A , -OR 9A or thiol-substituted or unsubstituted C1-C 10 alkyl, thiol, or substituted or unsubstituted 2-10 membered heteroalkyl. 9 -SR 9A -OR 9A In an embodiment, R 9 -SR 9A -OR 9A In an embodiment, R 9 -SR 9A In an embodiment, R 9 -OR 9A In an embodiment, R 9 is -SH. In embodiments, R 9 is -OH.

[0143] In embodiments, R 9 is -SH, -OH, -OCH3, -NH2, -NHC(O)H, -NHC(O)OH, substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl. 9 is -OCH3.

[0144] In embodiments, R 9 is substituted or unsubstituted methyl. In embodiments, R 9 is a substituted or unsubstituted C alkyl. In embodiments, R 9is a substituted or unsubstituted C alkyl. In embodiments, R 9 is a substituted or unsubstituted C4 alkyl. In embodiments, R 9 is a substituted or unsubstituted C alkyl. In embodiments, R 9 is a substituted or unsubstituted C alkyl. In embodiments, R 9 is a substituted or unsubstituted C alkyl. In embodiments, R 9 is a substituted or unsubstituted C alkyl. In embodiments, R 9 is a substituted methyl. In embodiments, R 9 is a substituted C alkyl. In embodiments, R 9 is a substituted C alkyl. In embodiments, R 9 is a substituted C4 alkyl. In embodiments, R 9 is a substituted C alkyl. In embodiments, R 9 is a substituted C alkyl. In embodiments, R 9 is a substituted C7 alkyl. In embodiments, R 9 is a substituted C alkyl. In embodiments, R 9 is unsubstituted methyl. In embodiments, R 9 is an unsubstituted C alkyl. In embodiments, R 9 is an unsubstituted C alkyl. In embodiments, R 9 is an unsubstituted C4 alkyl. In embodiments, R 9 is an unsubstituted C alkyl. In embodiments, R 9 is an unsubstituted C alkyl. In embodiments, R 9 is an unsubstituted C7 alkyl. In embodiments, R 9 is an unsubstituted C8 alkyl.

[0145] In embodiments, R 9 is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 9 is a substituted 2-10 membered heteroalkyl. In embodiments, R 9 is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 9is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 9 is a substituted 2-6 membered heteroalkyl. In embodiments, R 9 is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 9 is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 9 is a substituted 2-membered heteroalkyl. In embodiments, R 9 is an unsubstituted 2-membered heteroalkyl. In embodiments, R 9 is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 9 is a substituted 3-membered heteroalkyl. In embodiments, R 9 is an unsubstituted 3-membered heteroalkyl. In embodiments, R 9 is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 9 is a substituted 4-membered heteroalkyl. In embodiments, R 9 is an unsubstituted 4-membered heteroalkyl. In embodiments, R 9 is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 9 is a substituted 5-membered heteroalkyl. In embodiments, R 9 is an unsubstituted 5-membered heteroalkyl. In embodiments, R 9 is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 9 is a substituted 6-membered heteroalkyl. In embodiments, R 9 is an unsubstituted 6-membered heteroalkyl.

[0146] In embodiments, R 9 is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 9is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 9 is unsubstituted alkyl or unsubstituted heteroalkyl.

[0147] In embodiments, the substitution R 9 (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 9 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 9 If is substituted, R 9 is substituted with at least one substituent. In embodiments, R 9 If is substituted, R 9 is substituted with at least one size-limited substituent. In embodiments, R 9 If is substituted, R 9 is substituted with at least one lower substituent.

[0148] In embodiments, R 10 is hydrogen, -SR 10A , -OR 10A , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl. 10 is hydrogen, -SR 10A , -OR 10A or thiol-substituted or unsubstituted C1-C 10 alkyl, thiol, or substituted or unsubstituted 2-10 membered heteroalkyl. 10 -SR 10A -OR 10A In an embodiment, R 10 -SR 10A In an embodiment, R 10 -OR 10AIn an embodiment, R 10 is -SH. In embodiments, R 10 is —OH. In embodiments, R 10 is hydrogen.

[0149] In embodiments, R 10 is -SH, -OH, -OCH3, -NH2, -NHC(O)H, -NHC(O)OH, substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl. 10 is -OCH3.

[0150] In embodiments, R 10 is substituted or unsubstituted methyl. In embodiments, R 10 is a substituted or unsubstituted C alkyl. In embodiments, R 10 is a substituted or unsubstituted C alkyl. In embodiments, R 10 is a substituted or unsubstituted C4 alkyl. In embodiments, R 10 is a substituted or unsubstituted C alkyl. In embodiments, R 10 is a substituted or unsubstituted C alkyl. In embodiments, R 10 is a substituted or unsubstituted C alkyl. In embodiments, R 10 is a substituted or unsubstituted C alkyl. In embodiments, R 10 is a substituted methyl. In embodiments, R 10 is a substituted C alkyl. In embodiments, R 10 is a substituted C alkyl. In embodiments, R 10 is a substituted C4 alkyl. In embodiments, R 10 is a substituted C alkyl. In embodiments, R 10 is a substituted C alkyl. In embodiments, R 10 is a substituted C7 alkyl. In embodiments, R 10 is a substituted C alkyl. In embodiments, R 10 is unsubstituted methyl. In embodiments, R 10is an unsubstituted C alkyl. In embodiments, R 10 is an unsubstituted C alkyl. In embodiments, R 10 is an unsubstituted C4 alkyl. In embodiments, R 10 is an unsubstituted C alkyl. In embodiments, R 10 is an unsubstituted C alkyl. In embodiments, R 10 is an unsubstituted C7 alkyl. In embodiments, R 10 is an unsubstituted C8 alkyl.

[0151] In embodiments, R 10 is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 10 is a substituted 2-10 membered heteroalkyl. In embodiments, R 10 is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 10 is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 10 is a substituted 2-6 membered heteroalkyl. In embodiments, R 10 is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 10 is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 10 is a substituted 2-membered heteroalkyl. In embodiments, R 10 is an unsubstituted 2-membered heteroalkyl. In embodiments, R 10 is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 10 is a substituted 3-membered heteroalkyl. In embodiments, R 10 is an unsubstituted 3-membered heteroalkyl. In embodiments, R 10 is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 10 is a substituted 4-membered heteroalkyl. In embodiments, R 10 is an unsubstituted 4-membered heteroalkyl. In embodiments, R 10 is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 10 is a substituted 5-membered heteroalkyl. In embodiments, R 10is an unsubstituted 5-membered heteroalkyl. In embodiments, R 10 is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 10 is a substituted 6-membered heteroalkyl. In embodiments, R 10 is an unsubstituted 6-membered heteroalkyl.

[0152] In embodiments, R 10 is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 10 is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 10 is unsubstituted alkyl or unsubstituted heteroalkyl.

[0153] In embodiments, the substitution R 10 (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 10 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 10 If is substituted, R 10 is substituted with at least one substituent. In embodiments, R 10 If is substituted, R 10 is substituted with at least one size-limited substituent. In embodiments, R 10 If is substituted, R 10 is substituted with at least one lower substituent.

[0154] In embodiments, R 11 -SR 11A , -OR 11A, or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl. 11 -SR 11A , -OR 11A or thiol-substituted or unsubstituted C1-C 10 alkyl, thiol, or substituted or unsubstituted 2-10 membered heteroalkyl. 11 -SR 11A -OR 11A In an embodiment, R 11 -SR 11A -OR 11A In an embodiment, R 11 -SR 11A In an embodiment, R 11 -OR 11A In an embodiment, R 11 is -SH. In embodiments, R 11 is -OH.

[0155] In embodiments, R 11 is -SH, -OH, -OCH3, -NH2, -NHC(O)H, -NHC(O)OH, substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl. 11 is -OCH3.

[0156] In embodiments, R 11 is substituted or unsubstituted methyl. In embodiments, R 11 is a substituted or unsubstituted C alkyl. In embodiments, R 11 is a substituted or unsubstituted C alkyl. In embodiments, R 11 is a substituted or unsubstituted C4 alkyl. In embodiments, R 11 is a substituted or unsubstituted C alkyl. In embodiments, R 11 is a substituted or unsubstituted C alkyl. In embodiments, R 11 is a substituted or unsubstituted C alkyl. In embodiments, R 11is a substituted or unsubstituted C alkyl. In embodiments, R 11 is a substituted methyl. In embodiments, R 11 is a substituted C alkyl. In embodiments, R 11 is a substituted C alkyl. In embodiments, R 11 is a substituted C4 alkyl. In embodiments, R 11 is a substituted C alkyl. In embodiments, R 11 is a substituted C alkyl. In embodiments, R 11 is a substituted C7 alkyl. In embodiments, R 11 is a substituted C alkyl. In embodiments, R 11 is unsubstituted methyl. In embodiments, R 11 is an unsubstituted C alkyl. In embodiments, R 11 is an unsubstituted C alkyl. In embodiments, R 11 is an unsubstituted C4 alkyl. In embodiments, R 11 is an unsubstituted C alkyl. In embodiments, R 11 is an unsubstituted C alkyl. In embodiments, R 11 is an unsubstituted C7 alkyl. In embodiments, R 11 is an unsubstituted C8 alkyl.

[0157] In embodiments, R 11 is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 11 is a substituted 2-10 membered heteroalkyl. In embodiments, R 11 is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 11 is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 11 is a substituted 2-6 membered heteroalkyl. In embodiments, R 11 is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 11 is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 11 is a substituted 2-membered heteroalkyl. In embodiments, R 11is an unsubstituted 2-membered heteroalkyl. In embodiments, R 11 is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 11 is a substituted 3-membered heteroalkyl. In embodiments, R 11 is an unsubstituted 3-membered heteroalkyl. In embodiments, R 11 is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 11 is a substituted 4-membered heteroalkyl. In embodiments, R 11 is an unsubstituted 4-membered heteroalkyl. In embodiments, R 11 is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 11 is a substituted 5-membered heteroalkyl. In embodiments, R 11 is an unsubstituted 5-membered heteroalkyl. In embodiments, R 11 is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 11 is a substituted 6-membered heteroalkyl. In embodiments, R 11 is an unsubstituted 6-membered heteroalkyl.

[0158] In embodiments, R 11 is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 11 is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 11 is unsubstituted alkyl or unsubstituted heteroalkyl.

[0159] In embodiments, the substitution R 11 (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 11When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 11 If is substituted, R 11 is substituted with at least one substituent. In embodiments, R 11 If is substituted, R 11 is substituted with at least one size-limited substituent. In embodiments, R 11 If is substituted, R 11 is substituted with at least one lower substituent.

[0160] In embodiments, R 12 -SR 12A , -OR 12A , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl. 12 -SR 12A , -OR 12A or thiol-substituted or unsubstituted C1-C 10 alkyl, thiol, or substituted or unsubstituted 2-10 membered heteroalkyl. 12 -SR 12A -OR 12A In an embodiment, R 12 -SR 12A -OR 12A In an embodiment, R 12 -SR 12A In an embodiment, R 12 -OR 12A In an embodiment, R 12 is -SH. In embodiments, R 12 is -OH.

[0161] In embodiments, R 12 is -SH, -OH, -OCH3, -NH2, -NHC(O)H, -NHC(O)OH, substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2-10 membered heteroalkyl.12 is —OCH. In embodiments, R 12 is not -OCH3.

[0162] In embodiments, R 12 is substituted or unsubstituted methyl. In embodiments, R 12 is a substituted or unsubstituted C alkyl. In embodiments, R 12 is a substituted or unsubstituted C alkyl. In embodiments, R 12 is a substituted or unsubstituted C4 alkyl. In embodiments, R 12 is a substituted or unsubstituted C alkyl. In embodiments, R 12 is a substituted or unsubstituted C alkyl. In embodiments, R 12 is a substituted or unsubstituted C alkyl. In embodiments, R 12 is a substituted or unsubstituted C alkyl. In embodiments, R 12 is a substituted methyl. In embodiments, R 12 is a substituted C alkyl. In embodiments, R 12 is a substituted C alkyl. In embodiments, R 12 is a substituted C4 alkyl. In embodiments, R 12 is a substituted C alkyl. In embodiments, R 12 is a substituted C alkyl. In embodiments, R 12 is a substituted C7 alkyl. In embodiments, R 12 is a substituted C alkyl. In embodiments, R 12 is unsubstituted methyl. In embodiments, R 12 is an unsubstituted C alkyl. In embodiments, R 12 is an unsubstituted C alkyl. In embodiments, R 12 is an unsubstituted C4 alkyl. In embodiments, R 12 is an unsubstituted C alkyl. In embodiments, R 12 is an unsubstituted C alkyl. In embodiments, R 12 is an unsubstituted C7 alkyl. In embodiments, R 12 is an unsubstituted C8 alkyl.

[0163] In embodiments, R 12 is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 12 is a substituted 2-10 membered heteroalkyl. In embodiments, R 12 is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 12 is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 12 is a substituted 2-6 membered heteroalkyl. In embodiments, R 12 is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 12 is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 12 is a substituted 2-membered heteroalkyl. In embodiments, R 12 is an unsubstituted 2-membered heteroalkyl. In embodiments, R 12 is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 12 is a substituted 3-membered heteroalkyl. In embodiments, R 12 is an unsubstituted 3-membered heteroalkyl. In embodiments, R 12 is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 12 is a substituted 4-membered heteroalkyl. In embodiments, R 12 is an unsubstituted 4-membered heteroalkyl. In embodiments, R 12 is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 12 is a substituted 5-membered heteroalkyl. In embodiments, R 12 is an unsubstituted 5-membered heteroalkyl. In embodiments, R 12 is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 12 is a substituted 6-membered heteroalkyl. In embodiments, R 12 is an unsubstituted 6-membered heteroalkyl.

[0164] In embodiments, R 12is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 12 is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 12 is unsubstituted alkyl or unsubstituted heteroalkyl.

[0165] In embodiments, the substitution R 12 (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 12 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 12 If is substituted, R 12 is substituted with at least one substituent. In embodiments, R 12 If is substituted, R 12 is substituted with at least one size-limited substituent. In embodiments, R 12 If is substituted, R 12 is substituted with at least one lower substituent.

[0166] In embodiments, R 1A is hydrogen. In embodiments, R 2A is hydrogen. In embodiments, R 3A is hydrogen. In embodiments, R 4A is hydrogen. In embodiments, R 5A is hydrogen. In embodiments, R 6A is hydrogen. In embodiments, R 1B is hydrogen. In embodiments, R 2B is hydrogen. In embodiments, R 3Bis hydrogen. In embodiments, R 4B is hydrogen. In embodiments, R 5B is hydrogen. In embodiments, R 6B is hydrogen. In embodiments, R 1C is hydrogen. In embodiments, R 2C is hydrogen. In embodiments, R 3C is hydrogen. In embodiments, R 4C is hydrogen. In embodiments, R 5C is hydrogen. In embodiments, R 6C is hydrogen.

[0167] In embodiments, R 7A is hydrogen. In embodiments, R 8A is hydrogen. In embodiments, R 9A is hydrogen. In embodiments, R 10A is hydrogen. In embodiments, R 11A is hydrogen. In embodiments, R 12A is hydrogen. In embodiments, R 7B is hydrogen. In embodiments, R 8B is hydrogen. In embodiments, R 9B is hydrogen. In embodiments, R 10B is hydrogen. In embodiments, R 11B is hydrogen. In embodiments, R 12B is hydrogen. In embodiments, R 7C is hydrogen. In embodiments, R 8C is hydrogen. In embodiments, R 9C is hydrogen. In embodiments, R 10C is hydrogen. In embodiments, R 11C is hydrogen. In embodiments, R 12C is hydrogen.

[0168] In embodiments, R 1A is a substituted or unsubstituted C1-C 10 In embodiments, R 2A is a substituted or unsubstituted C1-C 10 In embodiments, R 3Ais a substituted or unsubstituted C1-C 10 In embodiments, R 4A is a substituted or unsubstituted C1-C 10 In embodiments, R 5A is a substituted or unsubstituted C1-C 10 In embodiments, R 6A is a substituted or unsubstituted C1-C 10 In embodiments, R 1B is a substituted or unsubstituted C1-C 10 In embodiments, R 2B is a substituted or unsubstituted C1-C 10 In embodiments, R 3B is a substituted or unsubstituted C1-C 10 In embodiments, R 4B is a substituted or unsubstituted C1-C 10 In embodiments, R 5B is a substituted or unsubstituted C1-C 10 In embodiments, R 6B is a substituted or unsubstituted C1-C 10 In embodiments, R 1C is a substituted or unsubstituted C1-C 10 In embodiments, R 2C is a substituted or unsubstituted C1-C 10 In embodiments, R 3C is a substituted or unsubstituted C1-C 10 In embodiments, R 4C is a substituted or unsubstituted C1-C 10 In embodiments, R 5C is a substituted or unsubstituted C1-C 10 In embodiments, R 6C is a substituted or unsubstituted C1-C 10 In embodiments, R 1A is the substitution C1-C 10 In embodiments, R 2A is the substitution C1-C 10 In embodiments, R 3Ais the substitution C1-C 10 In embodiments, R 4A is the substitution C1-C 10 In embodiments, R 5A is the substitution C1-C 10 In embodiments, R 6A is the substitution C1-C 10 In embodiments, R 1B is the substitution C1-C 10 In embodiments, R 2B is the substitution C1-C 10 In embodiments, R 3B is the substitution C1-C 10 In embodiments, R 4B is the substitution C1-C 10 In embodiments, R 5B is the substitution C1-C 10 In embodiments, R 6B is the substitution C1-C 10 In embodiments, R 1C is the substitution C1-C 10 In embodiments, R 2C is the substitution C1-C 10 In embodiments, R 3C is the substitution C1-C 10 In embodiments, R 4C is the substitution C1-C 10 In embodiments, R 5C is the substitution C1-C 10 In embodiments, R 6C is the substitution C1-C 10 In embodiments, R 1A is unsubstituted C1-C 10 In embodiments, R 2A is unsubstituted C1-C 10 In embodiments, R 3A is unsubstituted C1-C 10 In embodiments, R 4A is unsubstituted C1-C 10 In embodiments, R5A is unsubstituted C1-C 10 In embodiments, R 6A is unsubstituted C1-C 10 In embodiments, R 1B is unsubstituted C1-C 10 In embodiments, R 2B is unsubstituted C1-C 10 In embodiments, R 3B is unsubstituted C1-C 10 In embodiments, R 4B is unsubstituted C1-C 10 In embodiments, R 5B is unsubstituted C1-C 10 In embodiments, R 6B is unsubstituted C1-C 10 In embodiments, R 1C is unsubstituted C1-C 10 In embodiments, R 2C is unsubstituted C1-C 10 In embodiments, R 3C is unsubstituted C1-C 10 In embodiments, R 4C is unsubstituted C1-C 10 In embodiments, R 5C is unsubstituted C1-C 10 In embodiments, R 6C is unsubstituted C1-C 10 It is alkyl.

[0169] In embodiments, R 1A is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 2A is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 3A is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 4A is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 5A is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 6Ais a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 1B is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 2B is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 3B is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 4B is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 5B is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 6B is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 1C is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 2C is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 3C is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 4C is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 5C is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 6C is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 1A is a substituted 2-10 membered heteroalkyl. In embodiments, R 2A is a substituted 2-10 membered heteroalkyl. In embodiments, R 3A is a substituted 2-10 membered heteroalkyl. In embodiments, R 4A is a substituted 2-10 membered heteroalkyl. In embodiments, R 5A is a substituted 2-10 membered heteroalkyl. In embodiments, R 6A is a substituted 2-10 membered heteroalkyl. In embodiments, R 1B is a substituted 2-10 membered heteroalkyl. In embodiments, R 2B is a substituted 2-10 membered heteroalkyl. In embodiments, R 3B is a substituted 2-10 membered heteroalkyl. In embodiments, R 4Bis a substituted 2-10 membered heteroalkyl. In embodiments, R 5B is a substituted 2-10 membered heteroalkyl. In embodiments, R 6B is a substituted 2-10 membered heteroalkyl. In embodiments, R 1C is a substituted 2-10 membered heteroalkyl. In embodiments, R 2C is a substituted 2-10 membered heteroalkyl. In embodiments, R 3C is a substituted 2-10 membered heteroalkyl. In embodiments, R 4C is a substituted 2-10 membered heteroalkyl. In embodiments, R 5C is a substituted 2-10 membered heteroalkyl. In embodiments, R 6C is a substituted 2-10 membered heteroalkyl. In embodiments, R 1A is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 2A is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 3A is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 4A is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 5A is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 6A is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 1B is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 2B is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 3B is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 4B is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 5B is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 6B is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 1C is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 2C is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 3C is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 4Cis an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 5C is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 6C is an unsubstituted 2-10 membered heteroalkyl.

[0170] In embodiments, R 1A is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 2A is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 3A is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 4A is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 5A is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 6A is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 1B is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 2B is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 3B is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 4B is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 5B is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 6B is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 1C is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 2C is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 3C is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 4C is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 5C is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 6C is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 1Ais a substituted 2-6 membered heteroalkyl. In embodiments, R 2A is a substituted 2-6 membered heteroalkyl. In embodiments, R 3A is a substituted 2-6 membered heteroalkyl. In embodiments, R 4A is a substituted 2-6 membered heteroalkyl. In embodiments, R 5A is a substituted 2-6 membered heteroalkyl. In embodiments, R 6A is a substituted 2-6 membered heteroalkyl. In embodiments, R 1B is a substituted 2-6 membered heteroalkyl. In embodiments, R 2B is a substituted 2-6 membered heteroalkyl. In embodiments, R 3B is a substituted 2-6 membered heteroalkyl. In embodiments, R 4B is a substituted 2-6 membered heteroalkyl. In embodiments, R 5B is a substituted 2-6 membered heteroalkyl. In embodiments, R 6B is a substituted 2-6 membered heteroalkyl. In embodiments, R 1C is a substituted 2-6 membered heteroalkyl. In embodiments, R 2C is a substituted 2-6 membered heteroalkyl. In embodiments, R 3C is a substituted 2-6 membered heteroalkyl. In embodiments, R 4C is a substituted 2-6 membered heteroalkyl. In embodiments, R 5C is a substituted 2-6 membered heteroalkyl. In embodiments, R 6C is a substituted 2-6 membered heteroalkyl. In embodiments, R 1A is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 2A is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 3A is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 4A is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 5A is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 6A is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 1B is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R2B is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 3B is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 4B is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 5B is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 6B is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 1C is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 2C is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 3C is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 4C is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 5C is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 6C is an unsubstituted 2-6 membered heteroalkyl.

[0171] In embodiments, R 1A is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 2A is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 3A is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 4A is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 5A is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 6A is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 1B is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 2B is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 3B is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 4B is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 5B is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 6Bis a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 1C is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 2C is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 3C is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 4C is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 5C is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 6C is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 1A is a substituted 2-membered heteroalkyl. In embodiments, R 2A is a substituted 2-membered heteroalkyl. In embodiments, R 3A is a substituted 2-membered heteroalkyl. In embodiments, R 4A is a substituted 2-membered heteroalkyl. In embodiments, R 5A is a substituted 2-membered heteroalkyl. In embodiments, R 6A is a substituted 2-membered heteroalkyl. In embodiments, R 1B is a substituted 2-membered heteroalkyl. In embodiments, R 2B is a substituted 2-membered heteroalkyl. In embodiments, R 3B is a substituted 2-membered heteroalkyl. In embodiments, R 4B is a substituted 2-membered heteroalkyl. In embodiments, R 5B is a substituted 2-membered heteroalkyl. In embodiments, R 6B is a substituted 2-membered heteroalkyl. In embodiments, R 1C is a substituted 2-membered heteroalkyl. In embodiments, R 2C is a substituted 2-membered heteroalkyl. In embodiments, R 3C is a substituted 2-membered heteroalkyl. In embodiments, R 4C is a substituted 2-membered heteroalkyl. In embodiments, R 5C is a substituted 2-membered heteroalkyl. In embodiments, R 6C is a substituted 2-membered heteroalkyl. In embodiments, R 1Ais an unsubstituted 2-membered heteroalkyl. In embodiments, R 2A is an unsubstituted 2-membered heteroalkyl. In embodiments, R 3A is an unsubstituted 2-membered heteroalkyl. In embodiments, R 4A is an unsubstituted 2-membered heteroalkyl. In embodiments, R 5A is an unsubstituted 2-membered heteroalkyl. In embodiments, R 6A is an unsubstituted 2-membered heteroalkyl. In embodiments, R 1B is an unsubstituted 2-membered heteroalkyl. In embodiments, R 2B is an unsubstituted 2-membered heteroalkyl. In embodiments, R 3B is an unsubstituted 2-membered heteroalkyl. In embodiments, R 4B is an unsubstituted 2-membered heteroalkyl. In embodiments, R 5B is an unsubstituted 2-membered heteroalkyl. In embodiments, R 6B is an unsubstituted 2-membered heteroalkyl. In embodiments, R 1C is an unsubstituted 2-membered heteroalkyl. In embodiments, R 2C is an unsubstituted 2-membered heteroalkyl. In embodiments, R 3C is an unsubstituted 2-membered heteroalkyl. In embodiments, R 4C is an unsubstituted 2-membered heteroalkyl. In embodiments, R 5C is an unsubstituted 2-membered heteroalkyl. In embodiments, R 6C is an unsubstituted 2-membered heteroalkyl.

[0172] In embodiments, R 1A is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 2A is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 3A is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 4A is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 5A is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 6A is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R1B is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 2B is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 3B is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 4B is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 5B is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 6B is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 1C is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 2C is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 3C is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 4C is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 5C is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 6C is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 1A is a substituted 3-membered heteroalkyl. In embodiments, R 2A is a substituted 3-membered heteroalkyl. In embodiments, R 3A is a substituted 3-membered heteroalkyl. In embodiments, R 4A is a substituted 3-membered heteroalkyl. In embodiments, R 5A is a substituted 3-membered heteroalkyl. In embodiments, R 6A is a substituted 3-membered heteroalkyl. In embodiments, R 1B is a substituted 3-membered heteroalkyl. In embodiments, R 2B is a substituted 3-membered heteroalkyl. In embodiments, R 3B is a substituted 3-membered heteroalkyl. In embodiments, R 4B is a substituted 3-membered heteroalkyl. In embodiments, R 5B is a substituted 3-membered heteroalkyl. In embodiments, R 6B is a substituted 3-membered heteroalkyl. In embodiments, R 1Cis a substituted 3-membered heteroalkyl. In embodiments, R 2C is a substituted 3-membered heteroalkyl. In embodiments, R 3C is a substituted 3-membered heteroalkyl. In embodiments, R 4C is a substituted 3-membered heteroalkyl. In embodiments, R 5C is a substituted 3-membered heteroalkyl. In embodiments, R 6C is a substituted 3-membered heteroalkyl. In embodiments, R 1A is an unsubstituted 3-membered heteroalkyl. In embodiments, R 2A is an unsubstituted 3-membered heteroalkyl. In embodiments, R 3A is an unsubstituted 3-membered heteroalkyl. In embodiments, R 4A is an unsubstituted 3-membered heteroalkyl. In embodiments, R 5A is an unsubstituted 3-membered heteroalkyl. In embodiments, R 6A is an unsubstituted 3-membered heteroalkyl. In embodiments, R 1B is an unsubstituted 3-membered heteroalkyl. In embodiments, R 2B is an unsubstituted 3-membered heteroalkyl. In embodiments, R 3B is an unsubstituted 3-membered heteroalkyl. In embodiments, R 4B is an unsubstituted 3-membered heteroalkyl. In embodiments, R 5B is an unsubstituted 3-membered heteroalkyl. In embodiments, R 6B is an unsubstituted 3-membered heteroalkyl. In embodiments, R 1C is an unsubstituted 3-membered heteroalkyl. In embodiments, R 2C is an unsubstituted 3-membered heteroalkyl. In embodiments, R 3C is an unsubstituted 3-membered heteroalkyl. In embodiments, R 4C is an unsubstituted 3-membered heteroalkyl. In embodiments, R 5C is an unsubstituted 3-membered heteroalkyl. In embodiments, R 6C is an unsubstituted 3-membered heteroalkyl.

[0173] In embodiments, R 1A is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R2A is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 3A is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 4A is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 5A is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 6A is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 1B is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 2B is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 3B is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 4B is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 5B is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 6B is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 1C is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 2C is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 3C is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 4C is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 5C is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 6C is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 1A is a substituted 4-membered heteroalkyl. In embodiments, R 2A is a substituted 4-membered heteroalkyl. In embodiments, R 3A is a substituted 4-membered heteroalkyl. In embodiments, R 4A is a substituted 4-membered heteroalkyl. In embodiments, R 5A is a substituted 4-membered heteroalkyl. In embodiments, R 6A is a substituted 4-membered heteroalkyl. In embodiments, R 1Bis a substituted 4-membered heteroalkyl. In embodiments, R 2B is a substituted 4-membered heteroalkyl. In embodiments, R 3B is a substituted 4-membered heteroalkyl. In embodiments, R 4B is a substituted 4-membered heteroalkyl. In embodiments, R 5B is a substituted 4-membered heteroalkyl. In embodiments, R 6B is a substituted 4-membered heteroalkyl. In embodiments, R 1C is a substituted 4-membered heteroalkyl. In embodiments, R 2C is a substituted 4-membered heteroalkyl. In embodiments, R 3C is a substituted 4-membered heteroalkyl. In embodiments, R 4C is a substituted 4-membered heteroalkyl. In embodiments, R 5C is a substituted 4-membered heteroalkyl. In embodiments, R 6C is a substituted 4-membered heteroalkyl. In embodiments, R 1A is an unsubstituted 4-membered heteroalkyl. In embodiments, R 2A is an unsubstituted 4-membered heteroalkyl. In embodiments, R 3A is an unsubstituted 4-membered heteroalkyl. In embodiments, R 4A is an unsubstituted 4-membered heteroalkyl. In embodiments, R 5A is an unsubstituted 4-membered heteroalkyl. In embodiments, R 6A is an unsubstituted 4-membered heteroalkyl. In embodiments, R 1B is an unsubstituted 4-membered heteroalkyl. In embodiments, R 2B is an unsubstituted 4-membered heteroalkyl. In embodiments, R 3B is an unsubstituted 4-membered heteroalkyl. In embodiments, R 4B is an unsubstituted 4-membered heteroalkyl. In embodiments, R 5B is an unsubstituted 4-membered heteroalkyl. In embodiments, R 6B is an unsubstituted 4-membered heteroalkyl. In embodiments, R 1C is an unsubstituted 4-membered heteroalkyl. In embodiments, R 2C is an unsubstituted 4-membered heteroalkyl. In embodiments, R 3Cis an unsubstituted 4-membered heteroalkyl. In embodiments, R 4C is an unsubstituted 4-membered heteroalkyl. In embodiments, R 5C is an unsubstituted 4-membered heteroalkyl. In embodiments, R 6C is an unsubstituted 4-membered heteroalkyl.

[0174] In embodiments, R 1A is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 2A is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 3A is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 4A is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 5A is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 6A is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 1B is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 2B is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 3B is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 4B is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 5B is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 6B is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 1C is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 2C is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 3C is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 4C is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 5C is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 6C is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 1Ais a substituted 5-membered heteroalkyl. In embodiments, R 2A is a substituted 5-membered heteroalkyl. In embodiments, R 3A is a substituted 5-membered heteroalkyl. In embodiments, R 4A is a substituted 5-membered heteroalkyl. In embodiments, R 5A is a substituted 5-membered heteroalkyl. In embodiments, R 6A is a substituted 5-membered heteroalkyl. In embodiments, R 1B is a substituted 5-membered heteroalkyl. In embodiments, R 2B is a substituted 5-membered heteroalkyl. In embodiments, R 3B is a substituted 5-membered heteroalkyl. In embodiments, R 4B is a substituted 5-membered heteroalkyl. In embodiments, R 5B is a substituted 5-membered heteroalkyl. In embodiments, R 6B is a substituted 5-membered heteroalkyl. In embodiments, R 1C is a substituted 5-membered heteroalkyl. In embodiments, R 2C is a substituted 5-membered heteroalkyl. In embodiments, R 3C is a substituted 5-membered heteroalkyl. In embodiments, R 4C is a substituted 5-membered heteroalkyl. In embodiments, R 5C is a substituted 5-membered heteroalkyl. In embodiments, R 6C is a substituted 5-membered heteroalkyl. In embodiments, R 1A is an unsubstituted 5-membered heteroalkyl. In embodiments, R 2A is an unsubstituted 5-membered heteroalkyl. In embodiments, R 3A is an unsubstituted 5-membered heteroalkyl. In embodiments, R 4A is an unsubstituted 5-membered heteroalkyl. In embodiments, R 5A is an unsubstituted 5-membered heteroalkyl. In embodiments, R 6A is an unsubstituted 5-membered heteroalkyl. In embodiments, R 1B is an unsubstituted 5-membered heteroalkyl. In embodiments, R 2B is an unsubstituted 5-membered heteroalkyl. In embodiments, R 3Bis an unsubstituted 5-membered heteroalkyl. In embodiments, R 4B is an unsubstituted 5-membered heteroalkyl. In embodiments, R 5B is an unsubstituted 5-membered heteroalkyl. In embodiments, R 6B is an unsubstituted 5-membered heteroalkyl. In embodiments, R 1C is an unsubstituted 5-membered heteroalkyl. In embodiments, R 2C is an unsubstituted 5-membered heteroalkyl. In embodiments, R 3C is an unsubstituted 5-membered heteroalkyl. In embodiments, R 4C is an unsubstituted 5-membered heteroalkyl. In embodiments, R 5C is an unsubstituted 5-membered heteroalkyl. In embodiments, R 6C is an unsubstituted 5-membered heteroalkyl.

[0175] In embodiments, R 1A is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 2A is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 3A is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 4A is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 5A is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 6A is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 1B is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 2B is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 3B is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 4B is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 5B is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 6B is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 1C is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 2Cis a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 3C is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 4C is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 5C is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 6C is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 1A is a substituted 6-membered heteroalkyl. In embodiments, R 2A is a substituted 6-membered heteroalkyl. In embodiments, R 3A is a substituted 6-membered heteroalkyl. In embodiments, R 4A is a substituted 6-membered heteroalkyl. In embodiments, R 5A is a substituted 6-membered heteroalkyl. In embodiments, R 6A is a substituted 6-membered heteroalkyl. In embodiments, R 1B is a substituted 6-membered heteroalkyl. In embodiments, R 2B is a substituted 6-membered heteroalkyl. In embodiments, R 3B is a substituted 6-membered heteroalkyl. In embodiments, R 4B is a substituted 6-membered heteroalkyl. In embodiments, R 5B is a substituted 6-membered heteroalkyl. In embodiments, R 6B is a substituted 6-membered heteroalkyl. In embodiments, R 1C is a substituted 6-membered heteroalkyl. In embodiments, R 2C is a substituted 6-membered heteroalkyl. In embodiments, R 3C is a substituted 6-membered heteroalkyl. In embodiments, R 4C is a substituted 6-membered heteroalkyl. In embodiments, R 5C is a substituted 6-membered heteroalkyl. In embodiments, R 6C is a substituted 6-membered heteroalkyl. In embodiments, R 1A is an unsubstituted 6-membered heteroalkyl. In embodiments, R 2A is an unsubstituted 6-membered heteroalkyl. In embodiments, R 3Ais an unsubstituted 6-membered heteroalkyl. In embodiments, R 4A is an unsubstituted 6-membered heteroalkyl. In embodiments, R 5A is an unsubstituted 6-membered heteroalkyl. In embodiments, R 6A is an unsubstituted 6-membered heteroalkyl. In embodiments, R 1B is an unsubstituted 6-membered heteroalkyl. In embodiments, R 2B is an unsubstituted 6-membered heteroalkyl. In embodiments, R 3B is an unsubstituted 6-membered heteroalkyl. In embodiments, R 4B is an unsubstituted 6-membered heteroalkyl. In embodiments, R 5B is an unsubstituted 6-membered heteroalkyl. In embodiments, R 6B is an unsubstituted 6-membered heteroalkyl. In embodiments, R 1C is an unsubstituted 6-membered heteroalkyl. In embodiments, R 2C is an unsubstituted 6-membered heteroalkyl. In embodiments, R 3C is an unsubstituted 6-membered heteroalkyl. In embodiments, R 4C is an unsubstituted 6-membered heteroalkyl. In embodiments, R 5C is an unsubstituted 6-membered heteroalkyl. In embodiments, R 6C is an unsubstituted 6-membered heteroalkyl.

[0176] In embodiments, R 1A teeth, [ka] In an embodiment, R 2A teeth, [ka] In an embodiment, R 3A teeth, [ka] In an embodiment, R 4A teeth, [ka] In an embodiment, R 5A teeth, [ka] In an embodiment, R 6A teeth, [ka] is.

[0177] In embodiments, R 1A teeth, [ka] [ka] In an embodiment, R 3A teeth, [ka] In an embodiment, R 4A teeth, [ka] In an embodiment, R 5A teeth, [ka] In an embodiment, R 6A teeth, [ka] is.

[0178] In embodiments, R 1A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 1Ais a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 1A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0179] In embodiments, the substitution R 1A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 1A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 1A If is substituted, R 1A is substituted with at least one substituent. In embodiments, R 1A If is substituted, R 1A is substituted with at least one size-limited substituent. In embodiments, R 1A If is substituted, R 1A is substituted with at least one lower substituent.

[0180] In embodiments, R 1B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 1B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 1B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0181] In embodiments, the substitution R 1B(e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 1B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 1B If is substituted, R 1B is substituted with at least one substituent. In embodiments, R 1B If is substituted, R 1B is substituted with at least one size-limited substituent. In embodiments, R 1B If is substituted, R 1B is substituted with at least one lower substituent.

[0182] In embodiments, R 1C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 1C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 1C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0183] In embodiments, the substitution R 1C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 1C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 1C If is substituted, R 1C is substituted with at least one substituent. In embodiments, R1C If is substituted, R 1C is substituted with at least one size-limited substituent. In embodiments, R 1C If is substituted, R 1C is substituted with at least one lower substituent.

[0184] In embodiments, R 2A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 2A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 2A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0185] In embodiments, the substitution R 2A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 2A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 2A If is substituted, R 2A is substituted with at least one substituent. In embodiments, R 2A If is substituted, R 2A is substituted with at least one size-limited substituent. In embodiments, R 2A If is substituted, R 2A is substituted with at least one lower substituent.

[0186] In embodiments, R 2Bis substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 2B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 2B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0187] In embodiments, the substitution R 2B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 2B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 2B If is substituted, R 2B is substituted with at least one substituent. In embodiments, R 2B If is substituted, R 2B is substituted with at least one size-limited substituent. In embodiments, R 2B If is substituted, R 2B is substituted with at least one lower substituent.

[0188] In embodiments, R 2C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 2C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl.2C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0189] In embodiments, the substitution R 2C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 2C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 2C If is substituted, R 2C is substituted with at least one substituent. In embodiments, R 2C If is substituted, R 2C is substituted with at least one size-limited substituent. In embodiments, R 2C If is substituted, R 2C is substituted with at least one lower substituent.

[0190] In embodiments, R 3A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 3A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 3A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0191] In embodiments, the substitution R 3A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 3AWhen R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 3A If is substituted, R 3A is substituted with at least one substituent. In embodiments, R 3A If is substituted, R 3A is substituted with at least one size-limited substituent. In embodiments, R 3A If is substituted, R 3A is substituted with at least one lower substituent.

[0192] In embodiments, R 3B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 3B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 3B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0193] In embodiments, the substitution R 3B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 3B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 3B If is substituted, R 3B is substituted with at least one substituent. In embodiments, R 3B If is substituted, R 3B is substituted with at least one size-limited substituent. In embodiments, R 3BIf is substituted, R 3B is substituted with at least one lower substituent.

[0194] In embodiments, R 3C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 3C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 3C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0195] In embodiments, the substitution R 3C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 3C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 3C If is substituted, R 3C is substituted with at least one substituent. In embodiments, R 3C If is substituted, R 3C is substituted with at least one size-limited substituent. In embodiments, R 3C If is substituted, R 3C is substituted with at least one lower substituent.

[0196] In embodiments, R 4A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 4Ais a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 4A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0197] In embodiments, the substitution R 4A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 4A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 4A If is substituted, R 4A is substituted with at least one substituent. In embodiments, R 4A If is substituted, R 4A is substituted with at least one size-limited substituent. In embodiments, R 4A If is substituted, R 4A is substituted with at least one lower substituent.

[0198] In embodiments, R 4B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 4B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 4B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0199] In embodiments, the substitution R 4B(e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 4B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 4B If is substituted, R 4B is substituted with at least one substituent. In embodiments, R 4B If is substituted, R 4B is substituted with at least one size-limited substituent. In embodiments, R 4B If is substituted, R 4B is substituted with at least one lower substituent.

[0200] In embodiments, R 4C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 4C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 4C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0201] In embodiments, the substitution R 4C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 4C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 4C If is substituted, R 4C is substituted with at least one substituent. In embodiments, R4C If is substituted, R 4C is substituted with at least one size-limited substituent. In embodiments, R 4C If is substituted, R 4C is substituted with at least one lower substituent.

[0202] In embodiments, R 5A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 5A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 5A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0203] In embodiments, the substitution R 5A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 5A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 5A If is substituted, R 5A is substituted with at least one substituent. In embodiments, R 5A If is substituted, R 5A is substituted with at least one size-limited substituent. In embodiments, R 5A If is substituted, R 5A is substituted with at least one lower substituent.

[0204] In embodiments, R 5Bis substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 5B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 5B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0205] In embodiments, the substitution R 5B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 5B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 5B If is substituted, R 5B is substituted with at least one substituent. In embodiments, R 5B If is substituted, R 5B is substituted with at least one size-limited substituent. In embodiments, R 5B If is substituted, R 5B is substituted with at least one lower substituent.

[0206] In embodiments, R 5C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 5C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl.5C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0207] In embodiments, the substitution R 5C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 5C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 5C If is substituted, R 5C is substituted with at least one substituent. In embodiments, R 5C If is substituted, R 5C is substituted with at least one size-limited substituent. In embodiments, R 5C If is substituted, R 5C is substituted with at least one lower substituent.

[0208] In embodiments, R 6A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 6A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 6A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0209] In embodiments, the substitution R 6A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 6AWhen R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 6A If is substituted, R 6A is substituted with at least one substituent. In embodiments, R 6A If is substituted, R 6A is substituted with at least one size-limited substituent. In embodiments, R 6A If is substituted, R 6A is substituted with at least one lower substituent.

[0210] In embodiments, R 6B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 6B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 6B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0211] In embodiments, the substitution R 6B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 6B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 6B If is substituted, R 6B is substituted with at least one substituent. In embodiments, R 6B If is substituted, R 6B is substituted with at least one size-limited substituent. In embodiments, R 6BIf is substituted, R 6B is substituted with at least one lower substituent.

[0212] In embodiments, R 6C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 6C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 6C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0213] In embodiments, the substitution R 6C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 6C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 6C If is substituted, R 6C is substituted with at least one substituent. In embodiments, R 6C If is substituted, R 6C is substituted with at least one size-limited substituent. In embodiments, R 6C If is substituted, R 6C is substituted with at least one lower substituent.

[0214] In embodiments, R 7A is a substituted or unsubstituted C1-C 10 In embodiments, R 8A is a substituted or unsubstituted C1-C 10 In embodiments, R 9A is a substituted or unsubstituted C1-C 10In embodiments, R 10A is a substituted or unsubstituted C1-C 10 In embodiments, R 11A is a substituted or unsubstituted C1-C 10 In embodiments, R 12A is a substituted or unsubstituted C1-C 10 In embodiments, R 7B is a substituted or unsubstituted C1-C 10 In embodiments, R 8B is a substituted or unsubstituted C1-C 10 In embodiments, R 9B is a substituted or unsubstituted C1-C 10 In embodiments, R 10B is a substituted or unsubstituted C1-C 10 In embodiments, R 7B is a substituted or unsubstituted C1-C 10 In embodiments, R 8B is a substituted or unsubstituted C1-C 10 In embodiments, R 7C is a substituted or unsubstituted C1-C 10 In embodiments, R 8C is a substituted or unsubstituted C1-C 10 In embodiments, R 9C is a substituted or unsubstituted C1-C 10 In embodiments, R 10C is a substituted or unsubstituted C1-C 10 In embodiments, R 11C is a substituted or unsubstituted C1-C 10 In embodiments, R 12C is a substituted or unsubstituted C1-C 10 In embodiments, R 7A is the substitution C1-C 10 In embodiments, R 8A is the substitution C1-C 10 In embodiments, R 9A is the substitution C1-C 10In embodiments, R 10A is the substitution C1-C 10 In embodiments, R 11A is the substitution C1-C 10 In embodiments, R 12A is the substitution C1-C 10 In embodiments, R 7B is the substitution C1-C 10 In embodiments, R 8B is the substitution C1-C 10 In embodiments, R 9B is the substitution C1-C 10 In embodiments, R 10B is the substitution C1-C 10 In embodiments, R 7B is the substitution C1-C 10 In embodiments, R 8B is the substitution C1-C 10 In embodiments, R 7C is the substitution C1-C 10 In embodiments, R 8C is the substitution C1-C 10 In embodiments, R 9C is the substitution C1-C 10 In embodiments, R 10C is the substitution C1-C 10 In embodiments, R 11C is the substitution C1-C 10 In embodiments, R 12C is the substitution C1-C 10 In embodiments, R 7A is unsubstituted C1-C 10 In embodiments, R 8A is unsubstituted C1-C 10 In embodiments, R 9A is unsubstituted C1-C 10 In embodiments, R 10A is unsubstituted C1-C 10 In embodiments, R 11A is unsubstituted C1-C10 In embodiments, R 12A is unsubstituted C1-C 10 In embodiments, R 7B is unsubstituted C1-C 10 In embodiments, R 8B is unsubstituted C1-C 10 In embodiments, R 9B is unsubstituted C1-C 10 In embodiments, R 10B is unsubstituted C1-C 10 In embodiments, R 7B is unsubstituted C1-C 10 In embodiments, R 8B is unsubstituted C1-C 10 In embodiments, R 7C is unsubstituted C1-C 10 In embodiments, R 8C is unsubstituted C1-C 10 In embodiments, R 9C is unsubstituted C1-C 10 In embodiments, R 10C is unsubstituted C1-C 10 In embodiments, R 11C is unsubstituted C1-C 10 In embodiments, R 12C is unsubstituted C1-C 10 It is alkyl.

[0215] In embodiments, R 7A is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 8A is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 9A is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 10A is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 11A is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 12Ais a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 7B is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 8B is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 9B is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 10B is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 7B is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 8B is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 7C is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 8C is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 9C is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 10C is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 11C is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 12C is a substituted or unsubstituted 2-10 membered heteroalkyl. In embodiments, R 7A is a substituted 2-10 membered heteroalkyl. In embodiments, R 8A is a substituted 2-10 membered heteroalkyl. In embodiments, R 9A is a substituted 2-10 membered heteroalkyl. In embodiments, R 10A is a substituted 2-10 membered heteroalkyl. In embodiments, R 11A is a substituted 2-10 membered heteroalkyl. In embodiments, R 12A is a substituted 2-10 membered heteroalkyl. In embodiments, R 7B is a substituted 2-10 membered heteroalkyl. In embodiments, R 8B is a substituted 2-10 membered heteroalkyl. In embodiments, R 9B is a substituted 2-10 membered heteroalkyl. In embodiments, R 10Bis a substituted 2-10 membered heteroalkyl. In embodiments, R 7B is a substituted 2-10 membered heteroalkyl. In embodiments, R 8B is a substituted 2-10 membered heteroalkyl. In embodiments, R 7C is a substituted 2-10 membered heteroalkyl. In embodiments, R 8C is a substituted 2-10 membered heteroalkyl. In embodiments, R 9C is a substituted 2-10 membered heteroalkyl. In embodiments, R 10C is a substituted 2-10 membered heteroalkyl. In embodiments, R 11C is a substituted 2-10 membered heteroalkyl. In embodiments, R 12C is a substituted 2-10 membered heteroalkyl. In embodiments, R 7A is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 8A is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 9A is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 10A is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 11A is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 12A is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 7B is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 8B is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 9B is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 10B is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 7B is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 8B is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 7C is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 8C is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 9C is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 10Cis an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 11C is an unsubstituted 2-10 membered heteroalkyl. In embodiments, R 12C is an unsubstituted 2-10 membered heteroalkyl.

[0216] In embodiments, R 7A is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 8A is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 9A is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 10A is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 11A is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 12A is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 7B is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 8B is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 9B is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 10B is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 7B is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 8B is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 7C is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 8C is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 9C is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 10C is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 11C is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 12C is a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 7Ais a substituted 2-6 membered heteroalkyl. In embodiments, R 8A is a substituted 2-6 membered heteroalkyl. In embodiments, R 9A is a substituted 2-6 membered heteroalkyl. In embodiments, R 10A is a substituted 2-6 membered heteroalkyl. In embodiments, R 11A is a substituted 2-6 membered heteroalkyl. In embodiments, R 12A is a substituted 2-6 membered heteroalkyl. In embodiments, R 7B is a substituted 2-6 membered heteroalkyl. In embodiments, R 8B is a substituted 2-6 membered heteroalkyl. In embodiments, R 9B is a substituted 2-6 membered heteroalkyl. In embodiments, R 10B is a substituted 2-6 membered heteroalkyl. In embodiments, R 7B is a substituted 2-6 membered heteroalkyl. In embodiments, R 8B is a substituted 2-6 membered heteroalkyl. In embodiments, R 7C is a substituted 2-6 membered heteroalkyl. In embodiments, R 8C is a substituted 2-6 membered heteroalkyl. In embodiments, R 9C is a substituted 2-6 membered heteroalkyl. In embodiments, R 10C is a substituted 2-6 membered heteroalkyl. In embodiments, R 11C is a substituted 2-6 membered heteroalkyl. In embodiments, R 12C is a substituted 2-6 membered heteroalkyl. In embodiments, R 7A is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 8A is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 9A is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 10A is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 11A is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 12A is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 7B is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R8B is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 9B is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 10B is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 7B is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 8B is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 7C is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 8C is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 9C is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 10C is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 11C is an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 12C is an unsubstituted 2-6 membered heteroalkyl.

[0217] In embodiments, R 7A is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 8A is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 9A is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 10A is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 11A is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 12A is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 7B is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 8B is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 9B is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 10B is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 7B is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 8Bis a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 7C is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 8C is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 9C is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 10C is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 11C is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 12C is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 7A is a substituted 2-membered heteroalkyl. In embodiments, R 8A is a substituted 2-membered heteroalkyl. In embodiments, R 9A is a substituted 2-membered heteroalkyl. In embodiments, R 10A is a substituted 2-membered heteroalkyl. In embodiments, R 11A is a substituted 2-membered heteroalkyl. In embodiments, R 12A is a substituted 2-membered heteroalkyl. In embodiments, R 7B is a substituted 2-membered heteroalkyl. In embodiments, R 8B is a substituted 2-membered heteroalkyl. In embodiments, R 9B is a substituted 2-membered heteroalkyl. In embodiments, R 10B is a substituted 2-membered heteroalkyl. In embodiments, R 7B is a substituted 2-membered heteroalkyl. In embodiments, R 8B is a substituted 2-membered heteroalkyl. In embodiments, R 7C is a substituted 2-membered heteroalkyl. In embodiments, R 8C is a substituted 2-membered heteroalkyl. In embodiments, R 9C is a substituted 2-membered heteroalkyl. In embodiments, R 10C is a substituted 2-membered heteroalkyl. In embodiments, R 11C is a substituted 2-membered heteroalkyl. In embodiments, R 12C is a substituted 2-membered heteroalkyl. In embodiments, R 7Ais an unsubstituted 2-membered heteroalkyl. In embodiments, R 8A is an unsubstituted 2-membered heteroalkyl. In embodiments, R 9A is an unsubstituted 2-membered heteroalkyl. In embodiments, R 10A is an unsubstituted 2-membered heteroalkyl. In embodiments, R 11A is an unsubstituted 2-membered heteroalkyl. In embodiments, R 12A is an unsubstituted 2-membered heteroalkyl. In embodiments, R 7B is an unsubstituted 2-membered heteroalkyl. In embodiments, R 8B is an unsubstituted 2-membered heteroalkyl. In embodiments, R 9B is an unsubstituted 2-membered heteroalkyl. In embodiments, R 10B is an unsubstituted 2-membered heteroalkyl. In embodiments, R 7B is an unsubstituted 2-membered heteroalkyl. In embodiments, R 8B is an unsubstituted 2-membered heteroalkyl. In embodiments, R 7C is an unsubstituted 2-membered heteroalkyl. In embodiments, R 8C is an unsubstituted 2-membered heteroalkyl. In embodiments, R 9C is an unsubstituted 2-membered heteroalkyl. In embodiments, R 10C is an unsubstituted 2-membered heteroalkyl. In embodiments, R 11C is an unsubstituted 2-membered heteroalkyl. In embodiments, R 12C is an unsubstituted 2-membered heteroalkyl.

[0218] In embodiments, R 7A is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 8A is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 9A is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 10A is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 11A is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 12A is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R7B is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 8B is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 9B is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 10B is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 7B is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 8B is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 7C is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 8C is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 9C is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 10C is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 11C is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 12C is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 7A is a substituted 3-membered heteroalkyl. In embodiments, R 8A is a substituted 3-membered heteroalkyl. In embodiments, R 9A is a substituted 3-membered heteroalkyl. In embodiments, R 10A is a substituted 3-membered heteroalkyl. In embodiments, R 11A is a substituted 3-membered heteroalkyl. In embodiments, R 12A is a substituted 3-membered heteroalkyl. In embodiments, R 7B is a substituted 3-membered heteroalkyl. In embodiments, R 8B is a substituted 3-membered heteroalkyl. In embodiments, R 9B is a substituted 3-membered heteroalkyl. In embodiments, R 10B is a substituted 3-membered heteroalkyl. In embodiments, R 7B is a substituted 3-membered heteroalkyl. In embodiments, R 8B is a substituted 3-membered heteroalkyl. In embodiments, R 7Cis a substituted 3-membered heteroalkyl. In embodiments, R 8C is a substituted 3-membered heteroalkyl. In embodiments, R 9C is a substituted 3-membered heteroalkyl. In embodiments, R 10C is a substituted 3-membered heteroalkyl. In embodiments, R 11C is a substituted 3-membered heteroalkyl. In embodiments, R 12C is a substituted 3-membered heteroalkyl. In embodiments, R 7A is an unsubstituted 3-membered heteroalkyl. In embodiments, R 8A is an unsubstituted 3-membered heteroalkyl. In embodiments, R 9A is an unsubstituted 3-membered heteroalkyl. In embodiments, R 10A is an unsubstituted 3-membered heteroalkyl. In embodiments, R 11A is an unsubstituted 3-membered heteroalkyl. In embodiments, R 12A is an unsubstituted 3-membered heteroalkyl. In embodiments, R 7B is an unsubstituted 3-membered heteroalkyl. In embodiments, R 8B is an unsubstituted 3-membered heteroalkyl. In embodiments, R 9B is an unsubstituted 3-membered heteroalkyl. In embodiments, R 10B is an unsubstituted 3-membered heteroalkyl. In embodiments, R 7B is an unsubstituted 3-membered heteroalkyl. In embodiments, R 8B is an unsubstituted 3-membered heteroalkyl. In embodiments, R 7C is an unsubstituted 3-membered heteroalkyl. In embodiments, R 8C is an unsubstituted 3-membered heteroalkyl. In embodiments, R 9C is an unsubstituted 3-membered heteroalkyl. In embodiments, R 10C is an unsubstituted 3-membered heteroalkyl. In embodiments, R 11C is an unsubstituted 3-membered heteroalkyl. In embodiments, R 12C is an unsubstituted 3-membered heteroalkyl.

[0219] In embodiments, R 7A is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R8A is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 9A is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 10A is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 11A is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 12A is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 7B is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 8B is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 9B is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 10B is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 7B is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 8B is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 7C is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 8C is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 9C is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 10C is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 11C is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 12C is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 7A is a substituted 4-membered heteroalkyl. In embodiments, R 8A is a substituted 4-membered heteroalkyl. In embodiments, R 9A is a substituted 4-membered heteroalkyl. In embodiments, R 10A is a substituted 4-membered heteroalkyl. In embodiments, R 11A is a substituted 4-membered heteroalkyl. In embodiments, R 12A is a substituted 4-membered heteroalkyl. In embodiments, R 7Bis a substituted 4-membered heteroalkyl. In embodiments, R 8B is a substituted 4-membered heteroalkyl. In embodiments, R 9B is a substituted 4-membered heteroalkyl. In embodiments, R 10B is a substituted 4-membered heteroalkyl. In embodiments, R 7B is a substituted 4-membered heteroalkyl. In embodiments, R 8B is a substituted 4-membered heteroalkyl. In embodiments, R 7C is a substituted 4-membered heteroalkyl. In embodiments, R 8C is a substituted 4-membered heteroalkyl. In embodiments, R 9C is a substituted 4-membered heteroalkyl. In embodiments, R 10C is a substituted 4-membered heteroalkyl. In embodiments, R 11C is a substituted 4-membered heteroalkyl. In embodiments, R 12C is a substituted 4-membered heteroalkyl. In embodiments, R 7A is an unsubstituted 4-membered heteroalkyl. In embodiments, R 8A is an unsubstituted 4-membered heteroalkyl. In embodiments, R 9A is an unsubstituted 4-membered heteroalkyl. In embodiments, R 10A is an unsubstituted 4-membered heteroalkyl. In embodiments, R 11A is an unsubstituted 4-membered heteroalkyl. In embodiments, R 12A is an unsubstituted 4-membered heteroalkyl. In embodiments, R 7B is an unsubstituted 4-membered heteroalkyl. In embodiments, R 8B is an unsubstituted 4-membered heteroalkyl. In embodiments, R 9B is an unsubstituted 4-membered heteroalkyl. In embodiments, R 10B is an unsubstituted 4-membered heteroalkyl. In embodiments, R 7B is an unsubstituted 4-membered heteroalkyl. In embodiments, R 8B is an unsubstituted 4-membered heteroalkyl. In embodiments, R 7C is an unsubstituted 4-membered heteroalkyl. In embodiments, R 8C is an unsubstituted 4-membered heteroalkyl. In embodiments, R 9Cis an unsubstituted 4-membered heteroalkyl. In embodiments, R 10C is an unsubstituted 4-membered heteroalkyl. In embodiments, R 11C is an unsubstituted 4-membered heteroalkyl. In embodiments, R 12C is an unsubstituted 4-membered heteroalkyl.

[0220] In embodiments, R 7A is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 8A is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 9A is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 10A is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 11A is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 12A is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 7B is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 8B is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 9B is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 10B is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 7B is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 8B is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 7C is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 8C is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 9C is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 10C is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 11C is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 12C is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 7Ais a substituted 5-membered heteroalkyl. In embodiments, R 8A is a substituted 5-membered heteroalkyl. In embodiments, R 9A is a substituted 5-membered heteroalkyl. In embodiments, R 10A is a substituted 5-membered heteroalkyl. In embodiments, R 11A is a substituted 5-membered heteroalkyl. In embodiments, R 12A is a substituted 5-membered heteroalkyl. In embodiments, R 7B is a substituted 5-membered heteroalkyl. In embodiments, R 8B is a substituted 5-membered heteroalkyl. In embodiments, R 9B is a substituted 5-membered heteroalkyl. In embodiments, R 10B is a substituted 5-membered heteroalkyl. In embodiments, R 7B is a substituted 5-membered heteroalkyl. In embodiments, R 8B is a substituted 5-membered heteroalkyl. In embodiments, R 7C is a substituted 5-membered heteroalkyl. In embodiments, R 8C is a substituted 5-membered heteroalkyl. In embodiments, R 9C is a substituted 5-membered heteroalkyl. In embodiments, R 10C is a substituted 5-membered heteroalkyl. In embodiments, R 11C is a substituted 5-membered heteroalkyl. In embodiments, R 12C is a substituted 5-membered heteroalkyl. In embodiments, R 7A is an unsubstituted 5-membered heteroalkyl. In embodiments, R 8A is an unsubstituted 5-membered heteroalkyl. In embodiments, R 9A is an unsubstituted 5-membered heteroalkyl. In embodiments, R 10A is an unsubstituted 5-membered heteroalkyl. In embodiments, R 11A is an unsubstituted 5-membered heteroalkyl. In embodiments, R 12A is an unsubstituted 5-membered heteroalkyl. In embodiments, R 7B is an unsubstituted 5-membered heteroalkyl. In embodiments, R 8B is an unsubstituted 5-membered heteroalkyl. In embodiments, R 9Bis an unsubstituted 5-membered heteroalkyl. In embodiments, R 10B is an unsubstituted 5-membered heteroalkyl. In embodiments, R 7B is an unsubstituted 5-membered heteroalkyl. In embodiments, R 8B is an unsubstituted 5-membered heteroalkyl. In embodiments, R 7C is an unsubstituted 5-membered heteroalkyl. In embodiments, R 8C is an unsubstituted 5-membered heteroalkyl. In embodiments, R 9C is an unsubstituted 5-membered heteroalkyl. In embodiments, R 10C is an unsubstituted 5-membered heteroalkyl. In embodiments, R 11C is an unsubstituted 5-membered heteroalkyl. In embodiments, R 12C is an unsubstituted 5-membered heteroalkyl.

[0221] In embodiments, R 7A is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 8A is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 9A is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 10A is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 11A is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 12A is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 7B is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 8B is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 9B is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 10B is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 7B is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 8B is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 7C is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 8Cis a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 9C is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 10C is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 11C is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 12C is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 7A is a substituted 6-membered heteroalkyl. In embodiments, R 8A is a substituted 6-membered heteroalkyl. In embodiments, R 9A is a substituted 6-membered heteroalkyl. In embodiments, R 10A is a substituted 6-membered heteroalkyl. In embodiments, R 11A is a substituted 6-membered heteroalkyl. In embodiments, R 12A is a substituted 6-membered heteroalkyl. In embodiments, R 7B is a substituted 6-membered heteroalkyl. In embodiments, R 8B is a substituted 6-membered heteroalkyl. In embodiments, R 9B is a substituted 6-membered heteroalkyl. In embodiments, R 10B is a substituted 6-membered heteroalkyl. In embodiments, R 7B is a substituted 6-membered heteroalkyl. In embodiments, R 8B is a substituted 6-membered heteroalkyl. In embodiments, R 7C is a substituted 6-membered heteroalkyl. In embodiments, R 8C is a substituted 6-membered heteroalkyl. In embodiments, R 9C is a substituted 6-membered heteroalkyl. In embodiments, R 10C is a substituted 6-membered heteroalkyl. In embodiments, R 11C is a substituted 6-membered heteroalkyl. In embodiments, R 12C is a substituted 6-membered heteroalkyl. In embodiments, R 7A is an unsubstituted 6-membered heteroalkyl. In embodiments, R 8A is an unsubstituted 6-membered heteroalkyl. In embodiments, R 9Ais an unsubstituted 6-membered heteroalkyl. In embodiments, R 10A is an unsubstituted 6-membered heteroalkyl. In embodiments, R 11A is an unsubstituted 6-membered heteroalkyl. In embodiments, R 12A is an unsubstituted 6-membered heteroalkyl. In embodiments, R 7B is an unsubstituted 6-membered heteroalkyl. In embodiments, R 8B is an unsubstituted 6-membered heteroalkyl. In embodiments, R 9B is an unsubstituted 6-membered heteroalkyl. In embodiments, R 10B is an unsubstituted 6-membered heteroalkyl. In embodiments, R 7B is an unsubstituted 6-membered heteroalkyl. In embodiments, R 8B is an unsubstituted 6-membered heteroalkyl. In embodiments, R 7C is an unsubstituted 6-membered heteroalkyl. In embodiments, R 8C is an unsubstituted 6-membered heteroalkyl. In embodiments, R 9C is an unsubstituted 6-membered heteroalkyl. In embodiments, R 10C is an unsubstituted 6-membered heteroalkyl. In embodiments, R 11C is an unsubstituted 6-membered heteroalkyl. In embodiments, R 12C is an unsubstituted 6-membered heteroalkyl.

[0222] In embodiments, R 7A teeth, [ka] In an embodiment, R 8A teeth, [ka] In an embodiment, R 9A teeth, [ka] In an embodiment, R 10A teeth, [ka] In an embodiment, R 11A teeth, [ka] In an embodiment, R 12A teeth, [ka] is.

[0223] In embodiments, R 7A teeth, [ka] In an embodiment, R 8A teeth, [ka] In an embodiment, R 9A teeth, [ka] In an embodiment, R 10A teeth, [ka] In an embodiment, R 11A teeth, [ka] In an embodiment, R 12A teeth, [ka] is.

[0224] In embodiments, R 7A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered).7A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 7A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0225] In embodiments, the substitution R 7A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 7A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 7A If is substituted, R 7A is substituted with at least one substituent. In embodiments, R 7A If is substituted, R 7A is substituted with at least one size-limited substituent. In embodiments, R 7A If is substituted, R 7A is substituted with at least one lower substituent.

[0226] In embodiments, R 7B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 7B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 7B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0227] In embodiments, the substitution R 7B(e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 7B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 7B If is substituted, R 7B is substituted with at least one substituent. In embodiments, R 7B If is substituted, R 7B is substituted with at least one size-limited substituent. In embodiments, R 7B If is substituted, R 7B is substituted with at least one lower substituent.

[0228] In embodiments, R 7C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 7C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 7C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0229] In embodiments, the substitution R 7C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 7C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 7C If is substituted, R 7C is substituted with at least one substituent. In embodiments, R7C If is substituted, R 7C is substituted with at least one size-limited substituent. In embodiments, R 7C If is substituted, R 7C is substituted with at least one lower substituent.

[0230] In embodiments, R 8A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 8A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 8A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0231] In embodiments, the substitution R 8A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 8A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 8A If is substituted, R 8A is substituted with at least one substituent. In embodiments, R 8A If is substituted, R 8A is substituted with at least one size-limited substituent. In embodiments, R 8A If is substituted, R 8A is substituted with at least one lower substituent.

[0232] In embodiments, R 8Bis substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 8B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 8B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0233] In embodiments, the substitution R 8B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 8B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 8B If is substituted, R 8B is substituted with at least one substituent. In embodiments, R 8B If is substituted, R 8B is substituted with at least one size-limited substituent. In embodiments, R 8B If is substituted, R 8B is substituted with at least one lower substituent.

[0234] In embodiments, R 8C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 8C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl.8C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0235] In embodiments, the substitution R 8C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 8C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 8C If is substituted, R 8C is substituted with at least one substituent. In embodiments, R 8C If is substituted, R 8C is substituted with at least one size-limited substituent. In embodiments, R 8C If is substituted, R 8C is substituted with at least one lower substituent.

[0236] In embodiments, R 9A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 9A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 9A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0237] In embodiments, the substitution R 9A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 9AWhen R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 9A If is substituted, R 9A is substituted with at least one substituent. In embodiments, R 9A If is substituted, R 9A is substituted with at least one size-limited substituent. In embodiments, R 9A If is substituted, R 9A is substituted with at least one lower substituent.

[0238] In embodiments, R 9B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 9B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 9B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0239] In embodiments, the substitution R 9B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 9B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 9B If is substituted, R 9B is substituted with at least one substituent. In embodiments, R 9B If is substituted, R 9B is substituted with at least one size-limited substituent. In embodiments, R 9BIf is substituted, R 9B is substituted with at least one lower substituent.

[0240] In embodiments, R 9C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 9C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 9C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0241] In embodiments, the substitution R 9C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 9C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 9C If is substituted, R 9C is substituted with at least one substituent. In embodiments, R 9C If is substituted, R 9C is substituted with at least one size-limited substituent. In embodiments, R 9C If is substituted, R 9C is substituted with at least one lower substituent.

[0242] In embodiments, R 10A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 10Ais a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 10A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0243] In embodiments, the substitution R 10A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 10A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 10A If is substituted, R 10A is substituted with at least one substituent. In embodiments, R 10A If is substituted, R 10A is substituted with at least one size-limited substituent. In embodiments, R 10A If is substituted, R 10A is substituted with at least one lower substituent.

[0244] In embodiments, R 10B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 10B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 10B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0245] In embodiments, the substitution R 10B(e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 10B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 10B If is substituted, R 10B is substituted with at least one substituent. In embodiments, R 10B If is substituted, R 10B is substituted with at least one size-limited substituent. In embodiments, R 10B If is substituted, R 10B is substituted with at least one lower substituent.

[0246] In embodiments, R 10C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 10C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 10C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0247] In embodiments, the substitution R 10C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 10C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 10C If is substituted, R 10C is substituted with at least one substituent. In embodiments, R10C If is substituted, R 10C is substituted with at least one size-limited substituent. In embodiments, R 10C If is substituted, R 10C is substituted with at least one lower substituent.

[0248] In embodiments, R 11A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 11A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 11A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0249] In embodiments, the substitution R 11A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 11A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 11A If is substituted, R 11A is substituted with at least one substituent. In embodiments, R 11A If is substituted, R 11A is substituted with at least one size-limited substituent. In embodiments, R 11A If is substituted, R 11A is substituted with at least one lower substituent.

[0250] In embodiments, R 11Bis substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 11B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 11B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0251] In embodiments, the substitution R 11B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 11B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 11B If is substituted, R 11B is substituted with at least one substituent. In embodiments, R 11B If is substituted, R 11B is substituted with at least one size-limited substituent. In embodiments, R 11B If is substituted, R 11B is substituted with at least one lower substituent.

[0252] In embodiments, R 11C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 11C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl.11C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0253] In embodiments, the substitution R 11C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 11C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 11C If is substituted, R 11C is substituted with at least one substituent. In embodiments, R 11C If is substituted, R 11C is substituted with at least one size-limited substituent. In embodiments, R 11C If is substituted, R 11C is substituted with at least one lower substituent.

[0254] In embodiments, R 12A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 12A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 12A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0255] In embodiments, the substitution R 12A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 12AWhen R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 12A If is substituted, R 12A is substituted with at least one substituent. In embodiments, R 12A If is substituted, R 12A is substituted with at least one size-limited substituent. In embodiments, R 12A If is substituted, R 12A is substituted with at least one lower substituent.

[0256] In embodiments, R 12B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 12B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 12B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0257] In embodiments, the substitution R 12B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 12B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 12B If is substituted, R 12A is substituted with at least one substituent. In embodiments, R 12B If is substituted, R 12A is substituted with at least one size-limited substituent. In embodiments, R 12BIf is substituted, R 12B is substituted with at least one lower substituent.

[0258] In embodiments, R 12C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 12C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 12C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0259] In embodiments, the substitution R 12C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 12C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 12C If is substituted, R 12C is substituted with at least one substituent. In embodiments, R 12C If is substituted, R 12C is substituted with at least one size-limited substituent. In embodiments, R 12C If is substituted, R 12C is substituted with at least one lower substituent.

[0260] In embodiments, R 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R11A , R 12A , R 2B , R 3B , R 4B , R 5B , R 6B , R 7B , R 8B , R 9B , R 10B , R 11B , R 12B , R 2C , R 3C , R 4C , R 5C , R 6C , R 7C , R 8C , R 9C , R 10C , R 11C , and R 12C are each independently substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 11A , R 12A , R 2B , R 3B , R 4B , R 5B , R 6B , R 7B , R 8B , R 9B , R 10B , R 11B , R 12B , R 2C , R 3C , R 4C , R 5C , R 6C , R 7C , R 8C , R 9C , R 10C , R 11C , and R 12Care each independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 11A , R 12A , R 2B , R 3B , R 4B , R 5B , R 6B , R 7B , R 8B , R 9B , R 10B , R 11B , R 12B , R 2C , R 3C , R 4C , R 5C , R 6C , R 7C , R 8C , R 9C , R 10C , R 11C , and R 12C are each independently unsubstituted alkyl or unsubstituted heteroalkyl.

[0261] In embodiments, R 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 11A , R 12A , R 1B , R 2B , R 3B , R 4B , R 5B , R 6B , R 7B , R8B , R 9B , R 10B , R 11B , R 12B , R 1C , R 2C , R 3C , R 4C , R 5C , R 6C , R 7C , R 8C , R 9C , R 10C , R 11C , and R 12C are each independently substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 11A , R 12A , R 1B , R 2B , R 3B , R 4B , R 5B , R 6B , R 7B , R 8B , R 9B , R 10B , R 11B , R 12B , R 1C , R 2C , R 3C , R 4C , R 5C , R 6C , R 7C , R 8C , R 9C , R 10C , R 11C , and R 12Care each independently substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 11A , R 12A , R 1B , R 2B , R 3B , R 4B , R 5B , R 6B , R 7B , R 8B , R 9B , R 10B , R 11B , R 12B , R 1C , R 2C , R 3C , R 4C , R 5C , R 6C , R 7C , R 8C , R 9C , R 10C , R 11C , and R 12C are each independently unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered).

[0262] In embodiments, the substitution R 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R9A , R 10A , R 11A , R 12A , R 1B , R 2B , R 3B , R 4B , R 5B , R 6B , R 7B , R 8B , R 9B , R 10B , R 11B , R 12B , R 1C , R 2C , R 3C , R 4C , R 5C , R 6C , R 7C , R 8C , R 9C , R 10C , R 11C , or R 12C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 11A , R 12A , R 1B , R 2B , R 3B , R 4B , R 5B , R 6B , R 7B , R 8B , R 9B , R 10B , R 11B , R 12B , R 1C , R 2C , R 3C , R 4C , R 5C , R 6C , R 7C , R 8C , R 9C , R 10C , R11C , or R 12C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 11A , R 12A , R 1B , R 2B , R 3B , R 4B , R 5B , R 6B , R 7B , R 8B , R 9B , R 10B , R 11B , R 12B , R 1C , R 2C , R 3C , R 4C , R 5C , R 6C , R 7C , R 8C , R 9C , R 10C , R 11C , or R 12C When R is substituted, it is substituted with at least one substituent. 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 11A , R 12A , R 1B , R 2B , R 3B , R 4B , R 5B , R 6B , R 7B , R 8B, R 9B , R 10B , R 11B , R 12B , R 1C , R 2C , R 3C , R 4C , R 5C , R 6C , R 7C , R 8C , R 9C , R 10C , R 11C , or R 12C When R is substituted, it is substituted with at least one size-limited substituent. 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 11A , R 12A , R 1B , R 2B , R 3B , R 4B , R 5B , R 6B , R 7B , R 8B , R 9B , R 10B , R 11B , R 12B , R 1C , R 2C , R 3C , R 4C , R 5C , R 6C , R 7C , R 8C , R 9C , R 10C , R 11C , or R 12C When is substituted, it is substituted with at least one lower substituent.

[0263] In embodiments, the compound has the formula: [ka]

[0264] In embodiments, the compound has the formula: [ka] In embodiments, the compound has the formula [ka] In embodiments, the compound has the formula: [ka] One of ordinary skill in the art will recognize that this salt form is within the scope of Formula I and its embodiments.

[0265] In embodiments, the compound has the formula: [ka] It has.

[0266] In embodiments, the compound has the following structure: [ka] In the formula, n is 1 to 5. In an embodiment, n is 1 to 3. In an embodiment, n is 1.

[0267] In embodiments, the compound has the formula: [ka] It has.

[0268] In embodiments, the compound has the formula: [ka]

[0269] In embodiments, the compound has the following structure: [ka] In the formula, n is 1 to 5. In an embodiment, n is 1 to 3. In an embodiment, n is 1.

[0270] In embodiments, the compound has the formula: [ka]

[0271] In one aspect, compounds are provided having the formula: [ka] R 13 is hydrogen, -SR 13A , -OR 13A , -NR 13B R 13C , -NR 13B C(O)R 13C , -NR 13B C(O)OR 13C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 14 -SR 14A , -OR 14A , -NR 14B R 14C , -NR 14B C(O)R 14C , -NR 14B C(O)OR 14C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 15 -SR 15A , -OR 15A , -NR 15B R 15C , -NR 15B C(O)R 15C , -NR 15B C(O)OR 15C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 16 is hydrogen, -SR 16A , -OR16A , -NR 16B R 16C , -NR 16B C(O)R 16C , -NR 16B C(O)OR 16C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 17 is hydrogen, -SR 17A , -OR 17A , -NR 17B R 17C , -NR 17B C(O)R 17C , -NR 17B C(O)OR 17C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 18 -SR 18A , -OR 18A , -NR 18B R 18C , -NR 18B C(O)R 18C , -NR 18B C(O)OR 18C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 19 is hydrogen, -SR 19A , -OR 19A , -NR 19B R 19C , -NR 19B C(O)R 19C , -NR 19B C(O)OR 19C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 20 -SR 20A , -OR 20A , -NR 20B R 20C , -NR 20B C(O)R 20C , -NR 20B C(O)OR 20C , or substituted or unsubstituted C1-C 10alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 13A , R 14A , R 15A , R 16A , R 17A , R 18A , R 19A , R 20A , R 13B , R 14B , R 15B , R 16B , R 17B , R 18B , R 19B , R 20B , R 13C , R 14C , R 15C , R 16C , R 17C , R 18C , R 19C , and R 20C are each independently hydrogen, substituted or unsubstituted C-C 10 Compounds are provided which are alkyl, substituted or unsubstituted 2-10 membered heteroalkyl and contain at least two thiol moieties, or a pharmaceutically acceptable salt thereof.

[0272] In embodiments, the compound has the formula: [ka]

[0273] In embodiments, R 13 is hydrogen, -SR 13A , -OR 13A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl. 14 -SR 14A , -OR 14A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl. 15 -SR 15A , -OR 15A , thiol-substituted or unsubstituted C1-C10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl. 16 is hydrogen, -SR 16A , -OR 16A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl. 17 is hydrogen, -SR 17A , -OR 17A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl. 18 -SR 18A , -OR 18A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl. 19 is hydrogen, -SR 19A , -OR 19A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl. 20 -SR 20A , -OR 20A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl.

[0274] In embodiments, R 13 is hydrogen, -SR 13A , -OR 13A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl; R 14 -SR 14A , -OR 14A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl; R 15 -SR 15A , -OR15A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl; R 16 is hydrogen, -SR 16A , -OR 16A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl; R 17 is hydrogen, -SR 17A , -OR 17A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl; R 18 -SR 18A , -OR 18A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl; R 19 is hydrogen, -SR 19A , -OR 19A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl; R 20 -SR 20A , -OR 20A , thiol-substituted or unsubstituted C1-C 10 alkyl, or thiol substituted or unsubstituted 2-10 membered heteroalkyl.

[0275] In embodiments, R 13 is hydrogen, -SR 13A , or -OR 13A and R 14 -SR 14A -OR 14A and R 15 teeth, -SR 15A -OR 15A and R 16 is hydrogen, -SR 16A -OR 16A and R 18 -SR 18A-OR 18Aで Yes, R 20 teeth, -SR 20A -OR 20A is.

[0276] In embodiments, the compound has the following structure: [ka] where R 13A is as described herein.

[0277] In embodiments, the compound has the following structure: [ka] It has.

[0278] In one aspect, compounds are provided having the formula: [ka] R 2 -SR 2A , -OR 2A , -NR 2B R 2C , -NR 2B C(O)R 2C , -NR 2B C(O)OR 2C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 3 -SR 3A , -OR 3A , -NR 3B R 3C , -NR 3B C(O)R 3C , -NR 3B C(O)OR 3C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 4 -SR 4A , -SC(O)R 4A , -OR4A , -NR 4B R 4C , -NR 4B C(O)R 4C , -NR 4B C(O)OR 4C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 5 is hydrogen, -SR 5A , -OR 5A , -NR 5B R 5C , -NR 5B C(O)R 5C , -NR 5B C(O)OR 5C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 6 -SR 6A , -OR 6A , -NR 6B R 6C , -NR 6B C(O)R 6C , -NR 6B C(O)OR 6C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 13 is hydrogen, -SR 13A , -OR 13A , -NR 13B R 13C , -NR 13B C(O)R 13C , -NR 13B C(O)OR 13C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 14 -SR 14A , -OR 14A , -NR 14B R 14C , -NR 14B C(O)R 14C , -NR 14B C(O)OR 14C , substituted or unsubstituted C1-C 10alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 15 -SR 15A , -OR 15A , -NR 15B R 15C , -NR 15B C(O)R 15C , -NR 15B C(O)OR 15C , substituted or unsubstituted C1-C 10 alkyl, or substituted or unsubstituted 2- to 10-membered heteroalkyl. 17 is hydrogen, -SR 17A , -OR 17A , -NR 17B R 17C , -NR 17B C(O)R 17C , -NR 17B C(O)OR 17C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 18 -SR 18A , -OR 18A , -NR 18B R 18C , -NR 18B C(O)R 18C , -NR 18B C(O)OR 18C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 19 is hydrogen, -SR 19A , -OR 19A , -NR 19B R 19C , -NR 19B C(O)R 19C , -NR 19B C(O)OR 19C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl. 20 -SR 20A , -OR 20A , -NR 20B R 20C , -NR 20B C(O)R 20C, -NR 20B C(O)OR 20C , or substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl, and R 2A , R 3A , R 4A , R 5A , R 6A , R 2B , R 3B , R 4B , R 5B , R 6B , R 2C , R 3C , R 4C , R 5C , R 6C , R 13A , R 14A , R 15A , R 17A , R 18A , R 19A , R 20A , R 13B , R 14B , R 15B , R 17B , R 18B , R 19B , R 20B , R 13C , R 14C , R 15C , R 17C , R 18C , R 19C , and R 20C are each independently hydrogen, substituted or unsubstituted C-C 10

[0013] Compounds are provided which are alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, and contain at least two thiol moieties, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is [ka] isn't it.

[0279] In embodiments, the compound comprises up to two thiol moieties.

[0280] In embodiments, R 13Ais substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 13A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 13A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0281] In embodiments, the substitution R 13A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 13A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 13A If is substituted, R 13A is substituted with at least one substituent. In embodiments, R 13A If is substituted, R 13A is substituted with at least one size-limited substituent. In embodiments, R 13A If is substituted, R 13A is substituted with at least one lower substituent.

[0282] In embodiments, R 13B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 13B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl.13B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0283] In embodiments, the substitution R 13B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 13B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 13B If is substituted, R 13B is substituted with at least one substituent. In embodiments, R 13B If is substituted, R 13B is substituted with at least one size-limited substituent. In embodiments, R 13B If is substituted, R 13B is substituted with at least one lower substituent.

[0284] In embodiments, R 13C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 13C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 13C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0285] In embodiments, the substitution R 13C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 13CWhen R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 13C If is substituted, R 13C is substituted with at least one substituent. In embodiments, R 13C If is substituted, R 13C is substituted with at least one size-limited substituent. In embodiments, R 13C If is substituted, R 13C is substituted with at least one lower substituent.

[0286] In embodiments, R 14A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 14A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 14A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0287] In embodiments, the substitution R 14A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 14A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 14A If is substituted, R 14A is substituted with at least one substituent. In embodiments, R 14A If is substituted, R 14A is substituted with at least one size-limited substituent. In embodiments, R 14AIf is substituted, R 14A is substituted with at least one lower substituent.

[0288] In embodiments, R 14B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 14B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 14B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0289] In embodiments, the substitution R 14B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 14B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 14B If is substituted, R 14B is substituted with at least one substituent. In embodiments, R 14B If is substituted, R 14B is substituted with at least one size-limited substituent. In embodiments, R 14B If is substituted, R 14B is substituted with at least one lower substituent.

[0290] In embodiments, R 14C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 14Cis a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 14C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0291] In embodiments, the substitution R 14C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 14C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 14C If is substituted, R 14C is substituted with at least one substituent. In embodiments, R 14C If is substituted, R 14C is substituted with at least one size-limited substituent. In embodiments, R 14C If is substituted, R 14C is substituted with at least one lower substituent.

[0292] In embodiments, R 15A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 15A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 15A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0293] In embodiments, the substitution R 15A(e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 15A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 15A If is substituted, R 15A is substituted with at least one substituent. In embodiments, R 15A If is substituted, R 15A is substituted with at least one size-limited substituent. In embodiments, R 15A If is substituted, R 15A is substituted with at least one lower substituent.

[0294] In embodiments, R 15B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 15B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 15B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0295] In embodiments, the substitution R 15B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 15B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 15B If is substituted, R 15B is substituted with at least one substituent. In embodiments, R15B If is substituted, R 15B is substituted with at least one size-limited substituent. In embodiments, R 15B If is substituted, R 15B is substituted with at least one lower substituent.

[0296] In embodiments, R 15C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 15C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 15C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0297] In embodiments, the substitution R 15C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 15C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 15C If is substituted, R 15C is substituted with at least one substituent. In embodiments, R 15C If is substituted, R 15C is substituted with at least one size-limited substituent. In embodiments, R 15C If is substituted, R 15C is substituted with at least one lower substituent.

[0298] In embodiments, R 16Ais substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 16A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 16A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0299] In embodiments, the substitution R 16A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 16A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 16A If is substituted, R 16A is substituted with at least one substituent. In embodiments, R 16A If is substituted, R 16A is substituted with at least one size-limited substituent. In embodiments, R 16A If is substituted, R 16A is substituted with at least one lower substituent.

[0300] In embodiments, R 16B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 16B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl.16B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0301] In embodiments, the substitution R 16B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 16B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 16B If is substituted, R 16B is substituted with at least one substituent. In embodiments, R 16B If is substituted, R 16B is substituted with at least one size-limited substituent. In embodiments, R 16B If is substituted, R 16B is substituted with at least one lower substituent.

[0302] In embodiments, R 16C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 16C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 16C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0303] In embodiments, the substitution R 16C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 16CWhen R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 16C If is substituted, R 16C is substituted with at least one substituent. In embodiments, R 16C If is substituted, R 16C is substituted with at least one size-limited substituent. In embodiments, R 16C If is substituted, R 16C is substituted with at least one lower substituent.

[0304] In embodiments, R 17A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 17A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 17A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0305] In embodiments, the substitution R 17A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 17A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 17A If is substituted, R 17A is substituted with at least one substituent. In embodiments, R 17A If is substituted, R 17A is substituted with at least one size-limited substituent. In embodiments, R 17AIf is substituted, R 17A is substituted with at least one lower substituent.

[0306] In embodiments, R 17B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 17B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 17B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0307] In embodiments, the substitution R 17B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 17B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 17B If is substituted, R 17B is substituted with at least one substituent. In embodiments, R 17B If is substituted, R 17B is substituted with at least one size-limited substituent. In embodiments, R 17B If is substituted, R 17B is substituted with at least one lower substituent.

[0308] In embodiments, R 17C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 17Cis a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 17C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0309] In embodiments, the substitution R 17C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 17C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 17C If is substituted, R 17C is substituted with at least one substituent. In embodiments, R 17C If is substituted, R 17C is substituted with at least one size-limited substituent. In embodiments, R 17C If is substituted, R 17C is substituted with at least one lower substituent.

[0310] In embodiments, R 18A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 18A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 18A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0311] In embodiments, the substitution R 18A(e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 18A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 18A If is substituted, R 18A is substituted with at least one substituent. In embodiments, R 18A If is substituted, R 18A is substituted with at least one size-limited substituent. In embodiments, R 18A If is substituted, R 18A is substituted with at least one lower substituent.

[0312] In embodiments, R 18B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 18B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 18B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0313] In embodiments, the substitution R 18B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 18B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 18B If is substituted, R 18B is substituted with at least one substituent. In embodiments, R18B If is substituted, R 18B is substituted with at least one size-limited substituent. In embodiments, R 18B If is substituted, R 18B is substituted with at least one lower substituent.

[0314] In embodiments, R 18C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 18C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 18C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0315] In embodiments, the substitution R 18C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 18C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 18C If is substituted, R 18C is substituted with at least one substituent. In embodiments, R 18C If is substituted, R 18C is substituted with at least one size-limited substituent. In embodiments, R 18C If is substituted, R 18C is substituted with at least one lower substituent.

[0316] In embodiments, R 19Ais substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 19A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 19A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0317] In embodiments, the substitution R 19A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 19A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 19A If is substituted, R 19A is substituted with at least one substituent. In embodiments, R 19A If is substituted, R 19A is substituted with at least one size-limited substituent. In embodiments, R 19A If is substituted, R 19A is substituted with at least one lower substituent.

[0318] In embodiments, R 19B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 19B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl.19B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0319] In embodiments, the substitution R 19B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 19B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 19B If is substituted, R 19B is substituted with at least one substituent. In embodiments, R 19B If is substituted, R 19B is substituted with at least one size-limited substituent. In embodiments, R 19B If is substituted, R 19B is substituted with at least one lower substituent.

[0320] In embodiments, R 19C is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 19C is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 19C is unsubstituted alkyl or unsubstituted heteroalkyl.

[0321] In embodiments, the substitution R 19C (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 19CWhen R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 19C If is substituted, R 19C is substituted with at least one substituent. In embodiments, R 19C If is substituted, R 19C is substituted with at least one size-limited substituent. In embodiments, R 19C If is substituted, R 19C is substituted with at least one lower substituent.

[0322] In embodiments, R 20A is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 20A is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 20A is unsubstituted alkyl or unsubstituted heteroalkyl.

[0323] In embodiments, the substitution R 20A (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 20A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 20A If is substituted, R 20A is substituted with at least one substituent. In embodiments, R 20A If is substituted, R 20A is substituted with at least one size-limited substituent. In embodiments, R 20AIf is substituted, R 20A is substituted with at least one lower substituent.

[0324] In embodiments, R 20B is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), or substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 20B is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl, or a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl. 20B is unsubstituted alkyl or unsubstituted heteroalkyl.

[0325] In embodiments, the substitution R 20B (e.g., substituted alkyl and / or substituted cycloalkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 20B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 20B If is substituted, R 20B is substituted with at least one substituent. In embodiments, R 20B If is substituted, R 20B is substituted with at least one size-limited substituent. In embodiments, R 20B If is substituted, R 20B is substituted with at least one lower substituent. 【03...

Claims

1. Formula II: 【Chemistry 1】 (In the formula, R ２ is -OR ２Ａ and R ３ is -OR ３Ａ and R ４ is -OR ４Ａ and R ５ is hydrogen, R ６ is -SH, R ７ is -OR ７Ａ and R ８ is -OR ８Ａ and R ９ is -OR ９Ａ and R １０ is hydrogen, R １１ is -SH, and R ２Ａ , R ３Ａ , R ４Ａ , R ７Ａ , R ８Ａ , and R ９Ａ are each independently hydrogen or unsubstituted C １ -C １０ is alkyl) or a pharmaceutical acceptable salt thereof for treating a condition selected from chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), asthma, chronic asthma, acute asthma, bronchitis, chronic bronchitis, acute bronchitis, bronchiectasis, traction bronchiectasis, primary ciliary dyskinesia, bronchiolitis, allergic bronchopulmonary aspergillosis, pneumonia, ventilator associated lung injury, sinusitis, chronic rhinitis, acute sinusitis, chronic sinusitis, chronic rhinosinusitis with nasal polyps, chronic rhinosinusitis without nasal polyps, rhinorrhea, or post nasal drip, wherein the compound of formula II or a pharmaceutical acceptable salt thereof is used in combination with another therapeutic agent, and the therapeutic effect of the other therapeutic agent is enhanced by decreasing mucus elasticity or decreasing mucus viscosity.

2. 2. The pharmaceutical composition of claim 1, wherein the condition is characterized by the rapid onset of chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), asthma, bronchiectasis, traction bronchiectasis, primary ciliary dyskinesia, bronchiolitis, or allergic bronchopulmonary aspergillosis.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the condition is chronic obstructive pulmonary disease (COPD).

4. 3. The pharmaceutical composition of claim 1 or 2, wherein the condition is cystic fibrosis (CF).

5. 3. The pharmaceutical composition of claim 1 or 2, wherein the condition is asthma.

6. The compound has the formula IIa: 【Chemistry 2】 The pharmaceutical composition according to any one of claims 1 to 5, wherein the compound is represented by the formula:

7. R ２Ａ and R ３Ａ The pharmaceutical composition of any one of claims 1 to 6, wherein is hydrogen.

8. R ４Ａ and R ７Ａ The pharmaceutical composition of any one of claims 1 to 7, wherein is hydrogen.

9. R ８Ａ and R ９Ａ The pharmaceutical composition of any one of claims 1 to 8, wherein is hydrogen.

10. The compound is 【Chemistry 3】 The pharmaceutical composition according to any one of claims 1 to 5,

11. The compound is 【Chemistry 4】 The pharmaceutical composition according to any one of claims 1 to 5,

12. Pulmonary Pharmaceutical Carriers and Formula II: 【Chemistry 5】 (In the formula, R ２ is -OR ２Ａ and R ３ is -OR ３Ａ and R ４ is -OR ４Ａ and R ５ is hydrogen, R ６ is -SH, R ７ is -OR ７Ａ and R ８ is -OR ８Ａ and R ９ is -OR ９Ａ and R １０ is hydrogen, R １１ is -SH, and R ２Ａ , R ３Ａ , R ４Ａ , R ７Ａ , R ８Ａ , and R ９Ａ are each independently hydrogen or unsubstituted C １ -C １０ is alkyl) or a pharma- ceutically acceptable salt thereof.

13. 13. The pharmaceutical composition of claim 12, wherein the pulmonary pharmaceutical carrier is a pulmonary pharmaceutical liquid or a pulmonary pharmaceutical powder.

14. 14. The pharmaceutical composition of claim 13, wherein the pulmonary pharmaceutical carrier is a pulmonary pharmaceutical liquid, the pulmonary pharmaceutical liquid comprising a polar liquid, and the compound is dissolved or suspended in the polar liquid.

15. 15. The pharmaceutical composition of claim 14, wherein the polar liquid is water.

16. 14. The pharmaceutical composition of claim 12 or 13, wherein the pulmonary pharmaceutical carrier is lactose, trehalose, mannitol, a phospholipid, or cholesterol.

17. 14. The pharmaceutical composition of claim 12 or 13, wherein the pulmonary pharmaceutical carrier is a parent glycoside of the compound that lacks a thiol moiety.

18. The pharmaceutical composition of any one of claims 1 to 17, in a pulmonary pharmaceutical delivery device.

19. 20. The pharmaceutical composition of claim 18, wherein the pulmonary pharmaceutical delivery device is a pulmonary pharmaceutical nebulizer, a pulmonary pharmaceutical dry powder inhaler, or a pulmonary pharmaceutical pressurized metered dose inhaler.

20. The compound is 【Chemistry 6】 The pharmaceutical composition according to any one of claims 12 to 19, wherein

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