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CYCLIC SULFONAMIDE DERIVATIVES AS TRAP1 MODULATORS AND USES THEREOF

20230218632 · 2023-07-13

Assignee

Inventors

Cpc classification

International classification

Abstract

The present disclosure provides compounds of Formula (I): and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof. The provided compounds may be tumor necrosis factor (“TNF”) receptor associated protein 1 (“TRAP1”) modulators (e.g., TRAP1 activators). The provided compounds may also rescue the activity in PTEN-induced kinase 1 (“PINK1”) loss of function contexts. The provided compounds may also improve mitochondrial health, function, quality, quantity, and/or activity, and/or reduce the production of reactive oxygen species. The provided compounds may also refold or solubilize aggregated or misfolded proteins such as α-synuclein. The present disclosure also provides pharmaceutical compositions comprising the provided compounds; kits comprising the provided compounds or pharmaceutical compositions; and methods of using the provided compounds and pharmaceutical compositions (e.g., for treating a disease in a subject in need thereof).

Claims

1. A compound of Formula (I): ##STR00659## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: ##STR00660## is carbocyclyl, heterocyclyl, aryl, or heteroaryl; each ##STR00661## is independently a single or double bond, as valency permits; when attached to a carbon atom, each R.sup.1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.a).sub.2, —SR.sup.a, —CN, —SCN, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.a).sub.2, —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, —C(═NR.sup.a)N(R.sup.a).sub.2, —NO.sub.2, —N.sub.3, —NR.sup.aC(═O)R.sup.a, —NR.sup.aC(═O)OR.sup.a, —NR.sup.aC(═O)N(R.sup.a).sub.2, —NR.sup.aC(═NR.sup.a)R.sup.a, —NR.sup.aC(═NR.sup.a)OR.sup.a, —NR.sup.aC(═NR.sup.a)N(R.sup.a).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, —OC(═O)N(R.sup.a).sub.2, —OC(═NR.sup.a)R.sup.a, —OC(═NR.sup.a)OR.sup.a, —OC(═NR.sup.a)N(R.sup.a).sub.2, —NR.sup.aS(═O).sub.2R.sup.a, —NR.sup.aS(═O).sub.2OR.sup.a, —NR.sup.aS(═O).sub.2N(R.sup.a).sub.2, —OS(═O).sub.2R.sup.a, —OS(═O).sub.2OR.sup.a, —OS(═O).sub.2N(R.sup.a).sub.2, —S(═O).sub.2R.sup.a, —S(═O).sub.2OR.sup.a, —S(═O).sub.2N(R.sup.a).sub.2, —P(═O)(R.sup.a).sub.2, or ═O, as valency permits; when attached to a nitrogen atom, each R.sup.1 is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.a).sub.2, —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, —C(═NR.sup.a)N(R.sup.a).sub.2, —S(═O).sub.2R.sup.a, —S(═O).sub.2OR.sup.a, —S(═O).sub.2N(R.sup.a).sub.2, —P(═O)(R.sup.a).sub.2, a nitrogen protecting group, or ═O, as valency permits; or one R.sup.1 and R.sup.3 are joined with their intervening atoms to form substituted or unsubstituted heterocyclyl; each R.sup.a is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.a on a nitrogen atom are joined with the nitrogen atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; k is 0 or an integer between 1 and 13, inclusive, as valency permits; each R.sup.2 is independently hydrogen, halogen, or substituted or unsubstituted alkyl; q is 0 or 1; R.sup.3 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; one of X.sup.1, X.sup.2, and X.sup.3 is CR.sup.4, N, or N(O); each of the other two of X.sup.1, X.sup.2, and X.sup.3 is CR.sup.4; each R.sup.4 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.a).sub.2, —SR.sup.a, —CN, —SCN, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.a).sub.2, —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, —C(═NR.sup.a)N(R.sup.a).sub.2, —NO.sub.2, —N.sub.3, —NR.sup.aC(═O)R.sup.a, —NR.sup.aC(═O)OR.sup.a, —NR.sup.aC(═O)N(R.sup.a).sub.2, —NR.sup.aC(═NR.sup.a)R.sup.a, —NR.sup.aC(═NR.sup.a)OR.sup.a, —NR.sup.aC(═NR.sup.a)N(R.sup.a).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, —OC(═O)N(R.sup.a).sub.2, —OC(═NR.sup.a)R.sup.a, —OC(═NR.sup.a)OR.sup.a, —OC(═NR.sup.a)N(R.sup.a).sub.2, —NR.sup.aS(═O).sub.2R.sup.a, —NR.sup.aS(═O).sub.2OR.sup.a, —NR.sup.aS(═O).sub.2N(R.sup.a).sub.2, —OS(═O).sub.2R.sup.a, —OS(═O).sub.2OR.sup.a, —OS(═O).sub.2N(R.sup.a).sub.2, —S(═O).sub.2R.sup.a, —S(═O).sub.2OR.sup.a, or —S(═O).sub.2N(R.sup.a).sub.2; Y is O, C(R.sup.8).sub.2, or NR.sup.9; each instance of R.sup.8 is independently hydrogen, halogen, or substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.a).sub.2, —SR.sup.a, —CN, —SCN, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.a).sub.2, —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, —C(═NR.sup.a)N(R.sup.a).sub.2, —NO.sub.2, —N.sub.3, —NR.sup.aC(═O)R.sup.a, —NR.sup.aC(═O)OR.sup.a, —NR.sup.aC(═O)N(R.sup.a).sub.2, —NR.sup.aC(═NR.sup.a)R.sup.a, —NR.sup.aC(═NR.sup.a)OR.sup.a, —NR.sup.aC(═NR.sup.a)N(R.sup.a).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, —OC(═O)N(R.sup.a).sub.2, —OC(═NR.sup.a)R.sup.a, —OC(═NR.sup.a)OR.sup.a, —OC(═NR.sup.a)N(R.sup.a).sub.2, —NR.sup.aS(═O).sub.2R.sup.a, —NR.sup.aS(═O).sub.2OR.sup.a, —NR.sup.aS(═O).sub.2N(R.sup.a).sub.2, —OS(═O).sub.2R.sup.a, —OS(═O).sub.2OR.sup.a, —OS(═O).sub.2N(R.sup.a).sub.2, —S(═O).sub.2R.sup.a, —S(═O).sub.2OR.sup.a, or —S(═O).sub.2N(R.sup.a).sub.2, or two R.sup.8 on the same carbon atom are joined with the intervening carbon atom to form C═O; R.sup.9 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; m is 2 or 3; ##STR00662## is carbocyclyl, heterocyclyl, aryl, or heteroaryl; when attached to a carbon atom, each R.sup.7 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.a).sub.2, —SR.sup.a, —CN, —SCN, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.a).sub.2, —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, —C(═NR.sup.a)N(R.sup.a).sub.2, —NO.sub.2, —N.sub.3, —NR.sup.aC(═O)R.sup.a, —NR.sup.aC(═O)OR.sup.a, —NR.sup.aC(═O)N(R.sup.a).sub.2, —NR.sup.aC(═NR.sup.a)R.sup.a, —NR.sup.aC(═NR.sup.a)OR.sup.a, —NR.sup.aC(═NR.sup.a)N(R.sup.a).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, —OC(═O)N(R.sup.a).sub.2, —OC(═NR.sup.a)R.sup.a, —OC(═NR.sup.a)OR.sup.a, —OC(═NR.sup.a)N(R.sup.a).sub.2, —NR.sup.aS(═O).sub.2R.sup.a, —NR.sup.aS(═O).sub.2OR.sup.a, —NR.sup.aS(═O).sub.2N(R.sup.a).sub.2, —OS(═O).sub.2R.sup.a, —OS(═O).sub.2OR.sup.a, —OS(═O).sub.2N(R.sup.a).sub.2, —S(═O).sub.2R.sup.a, —S(═O).sub.2OR.sup.a, —S(═O).sub.2N(R.sup.a).sub.2, —P(═O)(R.sup.a).sub.2, or ═O, as valency permits; when attached to a nitrogen atom, each R.sup.7 is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.a).sub.2, —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, —C(═NR.sup.a)N(R.sup.a).sub.2, —S(═O).sub.2R.sup.a, —S(═O).sub.2OR.sup.a, —S(═O).sub.2N(R.sup.a).sub.2, —P(═O)(R.sup.a).sub.2, a nitrogen protecting group, or ═O, as valency permits; and n is 0 or an integer between 1 and 13, inclusive, as valency permits.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00663## .

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00664## .

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00665## .

5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00666## .

6. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00667## .

7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00668## .

8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00669## .

9. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00670## .

10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00671## .

11. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00672## .

12. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00673## .

13. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00674## .

14. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00675## .

15. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00676## .

16. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00677## .

17. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00678## .

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00679## is heteroaryl.

19. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00680## is 5- or 6-membered monocyclic heteroaryl.

20. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00681## ##STR00682## ##STR00683## ##STR00684## .

21. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00685## ##STR00686## ##STR00687## ##STR00688## .

22. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00689## ##STR00690## ##STR00691## ##STR00692## ##STR00693## ##STR00694## ##STR00695## .

23. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00696## ##STR00697## ##STR00698## ##STR00699## ##STR00700## ##STR00701## ##STR00702## ##STR00703## ##STR00704## ##STR00705## ##STR00706## ##STR00707## ##STR00708## ##STR00709## ##STR00710## ##STR00711## ##STR00712## ##STR00713## .

24. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00714## ##STR00715## .

25. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00716## ##STR00717## .

26. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00718## ##STR00719## .

27. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00720## ##STR00721## .

28. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00722## ##STR00723## ##STR00724## ##STR00725## .

29. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00726## ##STR00727## .

30. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00728## ##STR00729## .

31. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00730## ##STR00731## ##STR00732## ##STR00733## ##STR00734## ##STR00735## ##STR00736## .

32. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00737## is 5- or 6-membered monocyclic heteroaryl fused with monocyclic or bicyclic, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein bond a is attached to the 5- or 6-membered monocyclic heteroaryl.

33. The compound of claim 32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00738## ##STR00739## .

34. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00740## is 3- to 7-membered monocyclic heterocyclyl.

35. The compound of claim 34, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00741## ##STR00742## ##STR00743## ##STR00744## ##STR00745## .

36. The compound of claim 34, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00746## ##STR00747## ##STR00748## ##STR00749## ##STR00750## ##STR00751## ##STR00752## ##STR00753## ##STR00754## ##STR00755## ##STR00756## ##STR00757## .

37. The compound of claim 34, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00758## ##STR00759## ##STR00760## .

38. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00761## is phenyl.

39. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00762## .

40. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00763## .

41. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00764## .

42. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00765## .

43. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00766## .

44. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00767## .

45. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00768## .

46. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00769## .

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the molecular weight of each R.sup.1 is less than 150 g/mol.

48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R.sup.1 attached to a carbon atom is halogen, substituted or unsubstituted alkyl, —OR.sup.a, or substituted or unsubstituted phenyl.

49. The compound of claim 48, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R.sup.1 attached to a carbon atom is halogen or unsubstituted C.sub.1-6 alkyl.

50. The compound of claim 48, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R.sup.1 attached to a carbon atom is —O(substituted or unsubstituted alkyl).

51. The compound of claim 48, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R.sup.1 attached to a carbon atom is —OCH.sub.2CH(OH)CH.sub.2OH.

52. The compound of any one of claims 1-24, 26, 28, 29, and 31-51, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein k is 0, 1, or 2.

53. The compound of any one of claims 1-3, 6-7, 10-11, 14-15, 18-38, and 47-52, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein q is 0.

54. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, provided that R.sup.1 and R.sup.3 are not joined with their intervening atoms to form substituted or unsubstituted heterocyclyl.

55. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R.sup.3 is hydrogen.

56. The compound of any one of claims 1-2, 4, 6, 8, 10, 12, 14, 16, 18-39, 41, 43, 45, and 47-55, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of X.sup.1, X.sup.2, and X.sup.3 is CR.sup.4.

57. The compound of any one of claims 1-2, 4, 6, 8, 10, 12, 14, 16, 18-39, 41, 43, 45, and 47-55, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein X.sup.1 is N, and each of X.sup.2 and X.sup.3 is CR.sup.4.

58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each instance of R.sup.4 is hydrogen.

59. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R.sup.4 is —O(substituted or unsubstituted alkyl).

60. The compound of claim 59, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R.sup.4 is —OCH.sub.2CH(OH)CH.sub.2OH.

61. The compound of any one of claims 1, 18-40, 43-44, and 47-60, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein Y is O.

62. The compound of any one of claims 1, 18-40, 43-44, and 47-60, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein Y is C(R.sup.8).sub.2.

63. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each R.sup.8 is hydrogen.

64. The compound of any one of claims 1, 18-40, 43-44, and 47-63, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein m is 2.

65. The compound of any one of claims 1, 18-40, 43-44, and 47-63, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein m is 3.

66. The compound of any one of claims 1-9, 18-42, and 47-65, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00770## is phenyl.

67. The compound of claim 66, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00771## .

68. The compound of claim 66, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00772## ##STR00773## ##STR00774## .

69. The compound of any one of claims 1-9, 18-42, and 47-65, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00775## is 5- or 6-membered monocyclic heteroaryl.

70. The compound of claim 69, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein ##STR00776## ##STR00777## ##STR00778## ##STR00779## .

71. The compound of any one of claims 1-70, a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the molecular weight of each R.sup.7 is less than 150 g/mol.

72. The compound of any one of claims 1-71, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one R.sup.7 attached to a carbon atom is halogen, substituted or unsubstituted alkyl, —OR.sup.a, or —CN.

73. The compound of claim 72, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one R.sup.7 attached to a carbon atom is —CF.sub.3.

74. The compound of claim 72, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one R.sup.7 attached to a carbon atom is halogen, unsubstituted C.sub.1-6 alkyl, C.sub.1-.sub.6 alkyl substituted with one or more halogen, —O(unsubstituted C.sub.1-6 alkyl), or —CN.

75. The compound of claim 72, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R.sup.7 attached to a carbon atom is —O(substituted or unsubstituted alkyl), e.g., —OCH.sub.2CH(OH)CH.sub.2OH.

76. The compound of any one of claims 1-66 and 69-75, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein n is 0, 1, or 2.

77. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: TABLE-US-00006 No. Formula 1190 embedded image 1209 embedded image 1210 embedded image 1212 embedded image 1331 embedded image 1974 embedded image 1975 embedded image 1976 embedded image 1989 embedded image 1992 embedded image 1994 embedded image 2058 embedded image 2075 embedded image 2080 embedded image 2085 embedded image 2090 embedded image 2096 embedded image 2135 embedded image 2167 embedded image 2172 embedded image 2173 embedded image 2174 embedded image 2175 embedded image 2179 embedded image 2180 embedded image 2181 embedded image 2184 embedded image 2187 embedded image 2190 embedded image 2191 embedded image 2192 embedded image 2194 embedded image 2197 embedded image 2198 embedded image 2199 embedded image 2200 embedded image 2202 embedded image 2206 embedded image 2209 embedded image 2210 embedded image 2213 embedded image 2215 embedded image 2219 embedded image 2221 embedded image 2222 embedded image 2224 embedded image 2226 embedded image 2227 embedded image 2228 embedded image 2230 embedded image 2234 embedded image 2236 embedded image 2240 embedded image 2241 embedded image 2242 embedded image 2245 embedded image 2248 embedded image 2249 embedded image 2254 embedded image 2257 embedded image 2258 embedded image 2261 embedded image 2264 embedded image 2265 embedded image 2268 embedded image 2275 embedded image 2280 embedded image 2286 embedded image 2288 embedded image 2290 embedded image 2291 embedded image 2294 embedded image 2295 embedded image 2296 embedded image 2299 embedded image 2305 embedded image 2317 embedded image 2323 embedded image 2334 embedded image 2337 embedded image 2339 embedded image 2343 embedded image 2344 embedded image 2345 embedded image 2351 embedded image 2375 embedded image 2377 embedded image .

78. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00867## ##STR00868## .

79. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00869## .

80. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: ##STR00870## .

81. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: TABLE-US-00007 No. Formula 2355 embedded image 2362 embedded image 2388 embedded image 2398 embedded image 2402 embedded image 2410 embedded image 2417 embedded image 2423 embedded image 2433 embedded image 2439 embedded image 2443 embedded image 2449 embedded image 2451 embedded image 2458 embedded image 2462 embedded image 2472 embedded image 2473 embedded image 2494 embedded image 2495 embedded image 2503 embedded image 2510 embedded image 2513 embedded image 2514 embedded image 2515 embedded image 2516 embedded image .

82. The compound of any one of claims 1-81, or a pharmaceutically acceptable salt thereof.

83. A pharmaceutical composition comprising: a compound of any one of claims 1-81, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and optionally a pharmaceutically acceptable excipient.

84. The pharmaceutical composition of claim 83 further comprising an additional pharmaceutical agent.

85. The pharmaceutical composition of claim 84, wherein the additional pharmaceutical agent is metformin.

86. A kit comprising: a compound of any one of claims 1-81, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 83-85; and instructions for using the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition.

87. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1-81, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 83-85.

88. A method of preventing a disease in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1-81, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 83-85.

89. The method of any one of claims 87-88, wherein the disease is associated with decreased expression and/or activity of tumor necrosis factor (TNF) receptor associated protein 1 (TRAP1).

90. The method of claim 89, wherein the disease is associated with decreased activity of TRAP1.

91. The method of any one of claims 87-90, wherein the disease is associated with a mutation in the gene encoding tumor necrosis factor (TNF) receptor associated protein 1 (TRAP1).

92. The method of any one of claims 87-91, wherein the effective amount is effective in increasing the expression and/or activity of tumor necrosis factor (TNF) receptor associated protein 1 (TRAP1).

93. The method of claim 92, wherein the effective amount is effective in increasing the activity of TRAP1.

94. The method of any one of claims 87-93, wherein the disease is associated with decreased expression and/or activity of PTEN induced putative kinase 1 (PINK1).

95. The method of any one of claims 87-94, wherein the disease is associated with a mutation in the gene encoding PTEN induced putative kinase 1 (PINK1).

96. The method of any one of claims 87-95, wherein the disease is associated with increased protein misfolding and/or protein aggregation.

97. The method of any one of claims 87-96, wherein the disease is a proteopathy.

98. The method of claim 97, wherein the disease is a synucleinopathy.

99. The method of claim 96, wherein the protein is α-synuclein.

100. The method of claim 98, wherein the disease is Lewy body dementia or multiple system atrophy.

101. The method of any one of claims 87-100, wherein the disease is associated with decreased health, quality, function, quantity, and/or activity of mitochondria.

102. The method of any one of claims 87-101, wherein the disease is a mitochondrial disease.

103. The method of any one of claims 87-102, wherein the disease is associated with increased production of reactive oxygen species.

104. The method of any one of claims 87-103, wherein the disease is a neurodegenerative disease.

105. The method of claim 104, wherein the disease is Parkinson’s disease.

106. The method of claim 104, wherein the disease is Parkinson’s disease associated with a mutation in the gene encoding PINK1.

107. The method of claim 104, wherein the disease is Huntington’s disease, Alzheimer’s disease, dementia, amyotrophic lateral sclerosis, or Friedreich’s ataxia.

108. The method of claim 104, wherein the disease is frontotemporal dementia.

109. The method of any one of claims 87-99 and 101-103, wherein the disease is a kidney disease.

110. The method of claim 109, wherein the disease is polycystic kidney disease.

111. The method of claim 109, wherein the disease is autosomal dominant polycystic kidney disease.

112. The method of any one of claims 87-99 and 101-103, wherein the disease is a lysosomal storage disease.

113. The method of claim 112, wherein the disease is Tay-Sachs disease, Sandhoff disease, Niemann-Pick disease, Fabry disease, or Gaucher’s disease.

114. The method of any one of claims 87-99 and 101-103, wherein the disease is chronic pain, fatigue, gastrointestinal dysmotility, congenital abnormality of the kidney and urinary tract, VACTERL association, or cardiac hypertrophy.

115. A method of increasing the expression and/or activity of tumor necrosis factor (TNF) receptor associated protein 1 (TRAP1) in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1-81, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 83-85.

116. A method of increasing the health, quality, function, quantity, and/or activity of mitochondria in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1-81, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 83-85.

117. The method of any one of claims 87-116, wherein the subject is a human.

118. A method of increasing the expression and/or activity of tumor necrosis factor (TNF) receptor associated protein 1 (TRAP1) in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound of any one of claims 1-81, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 83-85.

119. A method of increasing the health, quality, function, quantity, and/or activity of mitochondria in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound of any one of claims 1-81, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 83-85.

120. The method of any one of claims 118-119, wherein the cell, tissue, or biological sample is in vitro.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0096] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention. Unless otherwise provided, “uM” refers to “.Math.M”.

[0097] FIG. 1 shows ROS production in primary rat dopaminergic neurons after an injury with 6-OHDA (20 .Math.M, 4 h), and reduction in ROS in presence of compound 1331.

[0098] FIG. 2 shows a dose response curve of compound 1331 displacing the nanoBRET tracer molecule (probe-385, 1 .Math.M) from nanoLuc TRAP1 in live SHSY5Y cells.

[0099] FIG. 3 shows the activation of TRAP1 (E.sub.max and EC.sub.50) in the ADP-Glo biochemical assay by compound 1331.

[0100] FIG. 4 shows the effect of compound 1331 in Hsp90-β ADP-Glo biochemical assay.

[0101] FIG. 5 shows the effect of compound 1331 in Grp94 ADP-Glo biochemical assay.

[0102] FIG. 6 shows effect of compound 1331 in preventing cyst formation in a Pkd 1 KO mouse cell derived cyst forming assay.

[0103] FIG. 7 shows brain and plasma concentration time curves following a 30 mg/kg IP dose of compound 2058 in mice.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE DISCLOSURE

[0104] In one aspect, the present disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof.

[0105] In other aspects, the present disclosure provides pharmaceutical compositions comprising a provided compound; kits comprising a provided pharmaceutical composition or compound; and methods of using the provided compounds, pharmaceutical compositions, and kits.

Compounds

[0106] In one aspect, the present disclosure provides a compound of Formula (I):

##STR00006##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: is carbocyclyl, heterocyclyl, aryl, or heteroaryl; [0108] each is independently a single or double bond, as valency permits; [0109] when attached to a carbon atom, each R.sup.1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.a).sub.2, —SR.sup.a, —CN, —SCN, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.a).sub.2, —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, —C(═NR.sup.a)N(R.sup.a).sub.2, —NO.sub.2, —N.sub.3, —NR.sup.aC(═O)R.sup.a, —NR.sup.aC(═O)OR.sup.a, —NR.sup.aC(═O)N(R.sup.a).sub.2, —NR.sup.aC(═NR.sup.a)R.sup.a, —NR.sup.aC(═NR.sup.a)OR.sup.a, —NR.sup.aC(═NR.sup.a)N(R.sup.a).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, —OC(═O)N(R.sup.a).sub.2, —OC(═NR.sup.a)R.sup.a, —OC(═NR.sup.a)OR.sup.a, —OC(═NR.sup.a)N(R.sup.a).sub.2, —NR.sup.aS(═O).sub.2R.sup.a, —NR.sup.aS(═O).sub.2OR.sup.a, —NR.sup.aS(═O).sub.2N(R.sup.a).sub.2, —OS(═O).sub.2R.sup.a, —OS(═O).sub.2OR.sup.a, —OS(═O).sub.2N(R.sup.a).sub.2, —S(═O).sub.2R.sup.a, —S(═O).sub.2OR.sup.a, —S(═O).sub.2N(R.sup.a).sub.2, —P(═O)(R.sup.a).sub.2, or =O, as valency permits; [0110] when attached to a nitrogen atom, each R.sup.1 is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.a).sub.2, —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, —C(═NR.sup.a)N(R.sup.a).sub.2, —S(═O).sub.2R.sup.a, —S(═O).sub.2OR.sup.a, —S(═O).sub.2N(R.sup.a).sub.2, —P(═O)(R.sup.a).sub.2, a nitrogen protecting group, or ═O, as valency permits; [0111] or one R.sup.1 and R.sup.3 are joined with their intervening atoms to form substituted or unsubstituted heterocyclyl; [0112] each R.sup.a is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.a on a nitrogen atom are joined with the nitrogen atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; [0113] k is 0 or an integer between 1 and 13, inclusive, as valency permits; [0114] each R.sup.2 is independently hydrogen, halogen, or substituted or unsubstituted alkyl; [0115] q is 0 or 1; [0116] R.sup.3 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; [0117] one of X.sup.1, X.sup.2, and X.sup.3 is CR.sup.4, N, or N(O); [0118] each of the other two of X.sup.1, X.sup.2, and X.sup.3 is CR.sup.4; [0119] each R.sup.4 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.a).sub.2, —SR.sup.a, —CN, —SCN, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.a).sub.2, —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, —C(═NR.sup.a)N(R.sup.a).sub.2, —NO.sub.2, —N.sub.3, —NR.sup.aC(═O)R.sup.a, —NR.sup.aC(═O)OR.sup.a, —NR.sup.aC(═O)N(R.sup.a).sub.2, —NR.sup.aC(═NR.sup.a)R.sup.a, —NR.sup.aC(═NR.sup.a)OR.sup.a, —NR.sup.aC(═NR.sup.a)N(R.sup.a).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, —OC(═O)N(R.sup.a).sub.2, —OC(═NR.sup.a)R.sup.a, — OC(═NR.sup.a)OR.sup.a, —OC(═NR.sup.a)N(R.sup.a).sub.2, —NR.sup.aS(═O).sub.2R.sup.a, —NR.sup.aS(═O).sub.2OR.sup.a, —NR.sup.aS(═O).sub.2N(R.sup.a).sub.2, —OS(═O).sub.2R.sup.a, —OS(═O).sub.2OR.sup.a, —OS(═O).sub.2N(R.sup.a).sub.2, —S(═O).sub.2R.sup.a, —S(═O).sub.2OR.sup.a, or —S(═O).sub.2N(R.sup.a).sub.2; [0120] Y is O, C(R.sup.8).sub.2, or NR.sup.9.sub.; [0121] each instance of R.sup.8 is independently hydrogen, halogen, or substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.a).sub.2, —SR.sup.a, —CN, —SCN, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.a).sub.2, —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, —C(═NR.sup.a)N(R.sup.a).sub.2, —NO.sub.2, —N.sub.3, —NR.sup.aC(═O)R.sup.a, —NR.sup.aC(═O)OR.sup.a, —NR.sup.aC(═O)N(R.sup.a).sub.2, —NR.sup.aC(═NR.sup.a)R.sup.a, —NR.sup.aC(═NR.sup.a)OR.sup.a, —NR.sup.aC(═NR.sup.a)N(R.sup.a).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, —OC(═O)N(R.sup.a).sub.2, —OC(═NR.sup.a)R.sup.a, —OC(═NR.sup.a)OR.sup.a, —OC(═NR.sup.a)N(R.sup.a).sub.2, —NR.sup.aS(═O).sub.2R.sup.a, —NR.sup.aS(═O).sub.2OR.sup.a, —NR.sup.aS(═O).sub.2N(R.sup.a).sub.2, —OS(═O).sub.2R.sup.a, —OS(═O).sub.2OR.sup.a, —OS(═O).sub.2N(R.sup.a).sub.2, —S(═O).sub.2R.sup.a, —S(═O).sub.2OR.sup.a, or —S(═O).sub.2N(R.sup.a).sub.2, or two R.sup.8 on the same carbon atom are joined with the intervening carbon atom to form C═O; [0122] R.sup.9 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; [0123] m is 2 or 3; is carbocyclyl, heterocyclyl, aryl, or heteroaryl; [0124] when attached to a carbon atom, each R.sup.7 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.a).sub.2, —SR.sup.a, —CN, —SCN, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.a).sub.2, —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, —C(═NR.sup.a)N(R.sup.a).sub.2, —NO.sub.2, —N.sub.3, —NR.sup.aC(═O)R.sup.a, —NR.sup.aC(═O)OR.sup.a, —NR.sup.aC(═O)N(R.sup.a).sub.2, —NR.sup.aC(═NR.sup.a)R.sup.a, —NR.sup.aC(═NR.sup.a)OR.sup.a, —NR.sup.aC(═NR.sup.a)N(R.sup.a).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, —OC(═O)N(R.sup.a).sub.2, —OC(═NR.sup.a)R.sup.a, —OC(═NR.sup.a)OR.sup.a, —OC(═NR.sup.a)N(R.sup.a).sub.2, —NR.sup.aS(═O).sub.2R.sup.a, —NR.sup.aS(═O).sub.2OR.sup.a, —NR.sup.aS(═O).sub.2N(R.sup.a).sub.2, —OS(═O).sub.2R.sup.a, —OS(═O).sub.2OR.sup.a, —OS(═O).sub.2N(R.sup.a).sub.2, —S(═O).sub.2R.sup.a, —S(═O).sub.2OR.sup.a, —S(═O).sub.2N(R.sup.a).sub.2, —P(═O)(R.sup.a).sub.2, or ═O, as valency permits; [0125] when attached to a nitrogen atom, each R.sup.7 is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.a).sub.2, —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, —C(═NR.sup.a)N(R.sup.a).sub.2, —S(═O).sub.2R.sup.a, —S(═O).sub.2OR.sup.a, —S(═O).sub.2N(R.sup.a).sub.2, —P(═O)(R.sup.a).sub.2, a nitrogen protecting group, or ═O, as valency permits; and [0126] n is 0 or an integer between 1 and 13, inclusive, as valency permits.

[0127] When Formula (I) includes two or more instances of a moiety, unless otherwise provided, any two instances of the moiety may be the same or different from each other.

[0128] In certain embodiments,

##STR00010##

(“Ring A”) is aryl. In certain embodiments, Ring A is phenyl. In certain embodiments,

##STR00011##

is unsubstituted phenyl. In certain embodiments,

##STR00012##

##STR00013##

##STR00014##

##STR00015##

In certain embodiments,

##STR00016##

##STR00017##

##STR00018##

##STR00019##

##STR00020##

##STR00021##

##STR00022##

[0129] In certain embodiments, Ring A is heteroaryl. In certain embodiments, Ring A is 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring A is furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or

##STR00023##

[0130] In certain embodiments,

##STR00024##

##STR00025##

##STR00026##

##STR00027##

In certain embodiments,

##STR00028##

##STR00029##

In certain embodiments,

##STR00030##

##STR00031##

certain embodiments,

##STR00032##

##STR00033##

In certain embodiments,

##STR00034##

##STR00035##

In certain embodiments,

##STR00036##

##STR00037##

In certain embodiments,

##STR00038##

##STR00039##

In certain embodiments,

##STR00040##

##STR00041##

In certain embodiments,

##STR00042##

##STR00043##

In certain embodiments,

##STR00044##

##STR00045##

In certain embodiments,

##STR00046##

##STR00047##

In certain embodiments,

##STR00048##

##STR00049##

[0131] In certain embodiments,

##STR00050##

##STR00051##

##STR00052##

##STR00053##

[0132] In certain embodiments,

##STR00054##

##STR00055##

##STR00056##

##STR00057##

In certain embodiments,

##STR00058##

##STR00059##

In certain embodiments,

##STR00060##

##STR00061##

certain embodiments,

##STR00062##

##STR00063##

In certain embodiments,

##STR00064##

##STR00065##

In certain embodiments,

##STR00066##

##STR00067##

In certain embodiments,

##STR00068##

##STR00069##

In certain embodiments,

##STR00070##

##STR00071##

In certain embodiments,

##STR00072##

##STR00073##

In certain embodiments,

##STR00074##

##STR00075##

In certain embodiments,

##STR00076##

##STR00077##

certain embodiments,

##STR00078##

##STR00079##

[0133] In certain embodiments,

##STR00080##

##STR00081##

##STR00082##

##STR00083##

[0134] In certain embodiments,

##STR00084##

##STR00085##

##STR00086##

##STR00087##

##STR00088##

In certain embodiments,

##STR00089##

##STR00090##

##STR00091##

##STR00092##

##STR00093##

In certain embodiments,

##STR00094##

##STR00095##

In certain embodiments,

##STR00096##

##STR00097##

[0135] In certain embodiments,

##STR00098##

##STR00099##

In certain embodiments,

##STR00100##

##STR00101##

##STR00102##

##STR00103##

##STR00104##

In certain embodiments,

##STR00105##

##STR00106##

In certain embodiments,

##STR00107##

##STR00108##

##STR00109##

##STR00110##

##STR00111##

##STR00112##

##STR00113##

In certain embodiments,

##STR00114##

##STR00115##

In certain embodiments,

##STR00116##

##STR00117##

certain embodiments,

##STR00118##

##STR00119##

In certain embodiments,

##STR00120##

##STR00121##

##STR00122##

##STR00123##

##STR00124##

In certain embodiments,

##STR00125##

##STR00126##

( certain embodiments,

##STR00127##

##STR00128##

##STR00129##

##STR00130##

##STR00131##

In certain embodiments,

##STR00132##

##STR00133##

##STR00134##

##STR00135##

##STR00136##

##STR00137##

##STR00138##

In certain embodiments,

##STR00139##

##STR00140##

In certain embodiments,

##STR00141##

##STR00142##

##STR00143##

In certain embodiments,

##STR00144##

##STR00145##

##STR00146##

##STR00147##

##STR00148##

##STR00149##

##STR00150##

##STR00151##

##STR00152##

##STR00153##

##STR00154##

[0136] In certain embodiments,

##STR00155##

##STR00156##

In certain embodiments,

##STR00157##

##STR00158##

In certain embodiments,

##STR00159##

##STR00160##

##STR00161##

In certain embodiments,

##STR00162##

##STR00163##

In certain embodiments,

##STR00164##

##STR00165##

In certain embodiments,

##STR00166##

##STR00167##

[0137] In certain embodiments,

##STR00168##

##STR00169##

##STR00170##

In certain embodiments,

##STR00171##

##STR00172##

##STR00173##

In certain embodiments,

##STR00174##

##STR00175##

##STR00176##

##STR00177##

[0138] In certain embodiments,

##STR00178##

##STR00179##

##STR00180##

##STR00181##

certain embodiments,

##STR00182##

##STR00183##

##STR00184##

##STR00185##

In certain embodiments,

##STR00186##

##STR00187##

##STR00188##

##STR00189##

##STR00190##

##STR00191##

[0139] In certain embodiments,

##STR00192##

is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In certain embodiments,

##STR00193##

##STR00194##

##STR00195##

##STR00196##

In certain embodiments,

##STR00197##

##STR00198##

In certain embodiments,

##STR00199##

##STR00200##

##STR00201##

##STR00202##

In certain embodiments,

##STR00203##

##STR00204##

##STR00205##

##STR00206##

In certain embodiments,

##STR00207##

##STR00208##

##STR00209##

In certain embodiments,

##STR00210##

##STR00211##

In certain embodiments,

##STR00212##

##STR00213##

In certain embodiments,

##STR00214##

##STR00215##

##STR00216##

In certain embodiments,

##STR00217##

##STR00218##

##STR00219##

##STR00220##

##STR00221##

##STR00222##

##STR00223##

[0140] In certain embodiments, Ring A is phenyl fused with monocyclic or bicyclic, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein bond a is attached to the phenyl. In certain embodiments, Ring A is naphthyl. In certain embodiments, Ring A is phenyl fused with naphthyl, wherein bond a is attached to the phenyl. In certain embodiments, Ring A is phenyl fused with 5- to 6-membered, monocyclic heteroaryl, wherein bond a is attached to the phenyl. In certain embodiments, Ring A is phenyl fused with 8-14 membered, bicyclic heteroaryl, wherein bond a is attached to the phenyl. In certain embodiments, Ring A is phenyl fused with 4-to 7-membered, monocyclic carbocyclyl, wherein bond a is attached to the phenyl. In certain embodiments, Ring A is phenyl fused with 6- to 13-membered, bicyclic carbocyclyl, wherein bond a is attached to the phenyl. In certain embodiments, Ring A is phenyl fused with 4- to 7-membered, monocyclic heterocyclyl, wherein bond a is attached to the phenyl. In certain embodiments, Ring A is phenyl fused with 6- to 13-membered, bicyclic heterocyclyl, wherein bond a is attached to the phenyl.

[0141] In certain embodiments, Ring A is 5- or 6-membered monocyclic heteroaryl fused with monocyclic or bicyclic, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein bond a is attached to the 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring A is 5- or 6-membered monocyclic heteroaryl fused with phenyl, wherein bond a is attached to the 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring A is 5- or 6-membered monocyclic heteroaryl fused with naphthyl, wherein bond a is attached to the 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring A is 5- or 6-membered monocyclic heteroaryl fused with another 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, Ring A is 5- or 6-membered monocyclic heteroaryl fused with 8-14 membered, bicyclic heteroaryl, wherein bond a is attached to the 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring A is 5- or 6-membered monocyclic heteroaryl fused with 4- to 7-membered, monocyclic carbocyclyl, wherein bond a is attached to the 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring A is 5- or 6-membered monocyclic heteroaryl fused with 6- to 13-membered, bicyclic carbocyclyl, wherein bond a is attached to the 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring A is 5- or 6-membered monocyclic heteroaryl fused with 4- to 7-membered, monocyclic heterocyclyl, wherein bond a is attached to the 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring A is 5- or 6-membered monocyclic heteroaryl fused with 6- to 13-membered, bicyclic heterocyclyl, wherein bond a is attached to the 5- or 6-membered monocyclic heteroaryl.

[0142] In certain embodiments,

##STR00224##

##STR00225##

In certain embodiments,

##STR00226##

##STR00227##

##STR00228##

##STR00229##

##STR00230##

In certain embodiments,

##STR00231##

##STR00232##

In certain embodiments,

##STR00233##

##STR00234##

##STR00235##

In certain embodiments,

##STR00236##

##STR00237##

certain embodiments,

##STR00238##

##STR00239##

##STR00240##

##STR00241##

##STR00242##

##STR00243##

##STR00244##

##STR00245##

In certain embodiments,

##STR00246##

##STR00247##

##STR00248##

##STR00249##

##STR00250##

##STR00251##

##STR00252##

##STR00253##

##STR00254##

##STR00255##

##STR00256##

##STR00257##

##STR00258##

##STR00259##

##STR00260##

In certain embodiments,

##STR00261##

##STR00262##

[0143] In certain embodiments, Ring A is heterocyclyl. In certain embodiments, Ring A is 3- to 7-membered monocyclic heterocyclyl. In certain embodiments,

##STR00263##

##STR00264##

##STR00265##

##STR00266##

##STR00267##

In certain embodiments,

##STR00268##

##STR00269##

##STR00270##

##STR00271##

##STR00272##

In certain embodiments,

##STR00273##

##STR00274##

##STR00275##

##STR00276##

##STR00277##

certain embodiments,

##STR00278##

##STR00279##

##STR00280##

##STR00281##

##STR00282##

##STR00283##

##STR00284##

##STR00285##

##STR00286##

##STR00287##

##STR00288##

##STR00289##

In certain embodiments,

##STR00290##

##STR00291##

##STR00292##

##STR00293##

##STR00294##

##STR00295##

##STR00296##

##STR00297##

##STR00298##

##STR00299##

##STR00300##

##STR00301##

In certain embodiments,

##STR00302##

##STR00303##

##STR00304##

##STR00305##

##STR00306##

##STR00307##

##STR00308##

##STR00309##

##STR00310##

##STR00311##

##STR00312##

##STR00313##

In certain embodiments,

##STR00314##

##STR00315##

##STR00316##

In certain embodiments,

##STR00317##

##STR00318##

##STR00319##

##STR00320##

In certain embodiments,

##STR00321##

##STR00322##

##STR00323##

##STR00324##

In certain embodiments,

##STR00325##

##STR00326##

##STR00327##

##STR00328##

In certain embodiments,

##STR00329##

##STR00330##

##STR00331##

##STR00332##

In certain embodiments,

##STR00333##

##STR00334##

##STR00335##

In certain embodiments,

##STR00336##

##STR00337##

##STR00338##

[0144] In certain embodiments, the molecular weight of each R.sup.1 is less than 200 g/mol. In certain embodiments, the molecular weight of each R.sup.1 is less than 150 g/mol. In certain embodiments, the molecular weight of each R.sup.1 is less than 100 g/mol.

[0145] This paragraph applies when R.sup.1 is attached to a carbon atom. In certain embodiments, at least one instance of R.sup.1 is halogen (e.g., F, Cl, or Br). In certain embodiments, at least one instance of R.sup.1 is unsubstituted alkyl (e.g., unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.1 is Me. In certain embodiments, at least one instance of R.sup.1 is Et, Pr, or Bu. In certain embodiments, at least one instance of R.sup.1 is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, at least one instance of R.sup.1 is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.1 is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of R.sup.1 is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted, C.sub.2-6 alkynyl (e.g., substituted or unsubstituted ethynyl). In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.1 is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.1 is —OR.sup.a (e.g., —OH, —O(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —OMe, —OCF.sub.3, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstituted phenyl) (e.g., -OPh)). In certain embodiments, at least one instance of R.sup.1 is —O(substituted or unsubstituted alkyl). In certain embodiments, at least one instance of R.sup.1 is —O(alkyl substituted with at least one -OH). In certain embodiments, at least one instance of R.sup.1 is —OCH.sub.2CH(OH)CH.sub.2OH. In certain embodiments, at least one instance of R.sup.1 is —O(unsubstituted alkyl). In certain embodiments, at least one instance of R.sup.1 is —OMe. In certain embodiments, at least one instance of R.sup.1 is —SR.sup.a (e.g., —SH, -S(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —SMe, —SCF.sub.3, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g., —SPh)). In certain embodiments, at least one instance of R.sup.1 is —N(R.sup.a).sub.2 (e.g., —NH.sub.2, —NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHMe), or —N(substituted or unsubstituted, C.sub.1-6 alkyl)-(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NMe.sub.2)). In certain embodiments, at least one instance of R.sup.1 is —CN or —SCN. In certain embodiments, at least one instance of R.sup.1 is —NO.sub.2. In certain embodiments, at least one instance of R.sup.1 is —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, or —C(═NR.sup.a)N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.1 is —C(═O)R.sup.a (e.g., —C(═O)(substituted or unsubstituted alkyl) (e.g., —C(═O)Me) or —C(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —C(═O)OR.sup.a (e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), or —C(═O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —C(═O)N(R.sup.a).sub.2 (e.g., —C(═O)NH.sub.2, —C(═O)NH(substituted or unsubstituted alkyl) (e.g., —C(═O)NHMe), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R.sup.1 is —NR.sup.aC(═O)R.sup.a (e.g., —NHC(═O)(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)Me) or —NHC(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —NR.sup.aC(═O)OR.sup.a. In certain embodiments, at least one instance of R.sup.1 is —NR.sup.aC(═O)N(R.sup.a).sub.2 (e.g., —NHC(═O)NH.sub.2, —NHC(═O)NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)NHMe)). In certain embodiments, at least one instance of R.sup.1 is —OC(═O)R.sup.a (e.g., —OC(═O)(substituted or unsubstituted alkyl) or —OC(═O)(substituted or unsubstituted phenyl)), —OC(═O)OR.sup.a (e.g., —OC(═O)O(substituted or unsubstituted alkyl) or —OC(═O)O(substituted or unsubstituted phenyl)), or —OC(═O)N(R.sup.a).sub.2 (e.g., —OC(═O)NH.sub.2, —OC(═O)NH(substituted or unsubstituted alkyl), —OC(═O)NH(substituted or unsubstituted phenyl), —OC(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or —OC(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R.sup.1 is —NR.sup.aS(═O).sub.2R.sup.a (e.g., —NHS(═O).sub.2R.sup.a, —NHS(═O).sub.2(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —NR.sup.aS(═O).sub.2OR.sup.a (e.g., —NHS(═O).sub.2OR.sup.a, —NHS(═O).sub.2OH, —NHS(═O).sub.2O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —NR.sup.aS(═O).sub.2N(R.sup.a).sub.2 (e.g., —NHS(═O).sub.2N(R.sup.a).sub.2, —NHS(═O).sub.2NH.sub.2, —NHS(═O).sub.2NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), —NHS(═O).sub.2N(substituted or unsubstituted alkyl).sub.2, —NHS(═O).sub.2N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —OS(═O).sub.2R.sup.a (e.g., —OS(═O).sub.2(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —OS(═O).sub.2OR.sup.a (e.g., —OS(═O).sub.2OH, —OS(═O).sub.2O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —OS(═O).sub.2N(R.sup.a).sub.2 (e.g., —OS(═O).sub.2NH.sub.2, —OS(═O).sub.2NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), —OS(═O).sub.2N(substituted or unsubstituted alkyl).sub.2, —OS(═O).sub.2N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —S(═O).sub.2R.sup.a (e.g., —S(═O).sub.2(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —S(═O).sub.2OR.sup.a (e.g., —S(═O).sub.2OH, —S(═O).sub.2O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). or In certain embodiments, at least one instance of R.sup.1 is —S(═O).sub.2N(R.sup.a).sub.2 (e.g., —S(═O).sub.2NH.sub.2, —S(═O).sub.2NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), —S(═O).sub.2N(substituted or unsubstituted alkyl).sub.2, —S(═O).sub.2N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —P(═O)(R.sup.a).sub.2 (e.g., —P(═O)(substituted or unsubstituted phenyl).sub.2). In certain embodiments, at least one instance of R.sup.1 is ═O. In certain embodiments, at least one instance of R.sup.1 is halogen, substituted or unsubstituted alkyl, —OR.sup.a, —C(═O)R.sup.a, —C(═O)OR.sup.a, substituted or unsubstituted, 3-to 7-membered, monocyclic heterocyclyl, substituted or unsubstituted phenyl, or substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, each R.sup.1 is independently halogen, substituted or unsubstituted alkyl, —OR.sup.a, —C(═O)R.sup.a, —C(═O)OR.sup.a, substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, substituted or unsubstituted phenyl, or substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one R.sup.1 is halogen, substituted or unsubstituted alkyl (e.g., unsubstituted C.sub.1-6 alkyl), or substituted or unsubstituted phenyl. In certain embodiments, each R.sup.1 is independently halogen, substituted or unsubstituted alkyl (e.g., unsubstituted C.sub.1-6 alkyl), or substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.1 is halogen, substituted or unsubstituted alkyl, —OR.sup.a, or substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.1 is halogen or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.1 is halogen, unsubstituted C.sub.1-6 alkyl, C.sub.1-6 alkyl independently substituted with one or more halogen and/or one or more —OR.sup.a. In certain embodiments, each instance of R.sup.1 is independently halogen, unsubstituted C.sub.1-6 alkyl, C.sub.1-6 alkyl independently substituted with one or more halogen and/or one or more —OR.sup.a.

[0146] This paragraph applies when R.sup.1 is attached to a nitrogen atom. In certain embodiments, at least one instance of R.sup.1 is unsubstituted alkyl (e.g., unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.1 is Me. In certain embodiments, at least one instance of R.sup.1 is Et, Pr, or Bu. In certain embodiments, at least one instance of R.sup.1 is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, at least one instance of R.sup.1 is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.1 is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of R.sup.1 is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted, C.sub.2-6 alkynyl (e.g., substituted or unsubstituted ethynyl). In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.1 is —C(═O)R.sup.a (e.g., —C(═O)(substituted or unsubstituted alkyl) (e.g., —C(═O)Me) or —C(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —C(═O)OR.sup.a(e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), or —C(═O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —C(═O)N(R.sup.a).sub.2 (e.g., —C(═O)NH.sub.2, —C(═O)NH(substituted or unsubstituted alkyl) (e.g., —C(═O)NHMe), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R.sup.1 is —S(═O).sub.2R.sup.a (e.g., —S(═O).sub.2(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —S(═O).sub.2OR.sup.a (e.g., —S(═O).sub.2OH, —S(═O).sub.2O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). or In certain embodiments, at least one instance of R.sup.1 is —S(═O).sub.2N(R.sup.a).sub.2 (e.g., —S(═O).sub.2NH.sub.2, —S(═O).sub.2NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), —S(═O).sub.2N(substituted or unsubstituted alkyl).sub.2, —S(═O).sub.2N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.1 is —P(═O)(R.sup.a).sub.2 (e.g., —P(═O)(substituted or unsubstituted phenyl).sub.2). In certain embodiments, at least one instance of R.sup.1 is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, at least one instance of R.sup.1 is =O.

[0147] In certain embodiments, one R.sup.1 and R.sup.3 are joined with their intervening atoms to form substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R.sup.1 and R.sup.3 are not joined with their intervening atoms to form substituted or unsubstituted heterocyclyl.

[0148] In certain embodiments, when R.sup.1 of

##STR00339##

is a monovalent substituent,

##STR00340##

is a single bond. In certain embodiments, when R.sup.1 of

##STR00341##

is a divalent substituent (e.g., =O),

##STR00342##

is a double bond. In certain embodiments, when R.sup.7 of

##STR00343##

is a monovalent substituent,

##STR00344##

is a single bond. In certain embodiments, when R.sup.7 of

##STR00345##

is a divalent substituent (e.g., =O),

##STR00346##

is a double bond.

[0149] In certain embodiments, at least one instance of R.sup.a is hydrogen. In certain embodiments, each instance of R.sup.a is hydrogen. In certain embodiments, at least one instance of R.sup.a is not hydrogen. In certain embodiments, no instance of R.sup.a is hydrogen. In certain embodiments, at least one instance of R.sup.a is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, at least one instance of R.sup.a is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.a is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.a is Me. In certain embodiments, at least one instance of R.sup.a is Et, Pr, or Bu. In certain embodiments, at least one instance of R.sup.a is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.a is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of R.sup.a is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted, C.sub.2-6 alkynyl (e.g., substituted or unsubstituted ethynyl). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, as valency permits). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.a is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom. In certain embodiments, at least one instance of R.sup.a is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom. In certain embodiments, two instances of R.sup.a are joined to form substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, two instances of R.sup.a are joined to form substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl).

[0150] In certain embodiments, k is 0. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4. In certain embodiments, k is 5. In certain embodiments, k is 0, 1, or 2. In certain embodiments, k is such an integer between 1 and 13, inclusive, that Ring A is fully substituted.

[0151] In certain embodiments, at least one instance of R.sup.2 is hydrogen. In certain embodiments, each instance of R.sup.2 is hydrogen. In certain embodiments, at least one instance of R.sup.2 is halogen. In certain embodiments, at least one instance of R.sup.2 is F. In certain embodiments, each R.sup.2 is F. In certain embodiments, at least one instance of R.sup.2 is Cl. In certain embodiments, at least one instance of R.sup.2 is Br. In certain embodiments, at least one instance of R.sup.2 is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, at least one instance of R.sup.2 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.2 is Me. In certain embodiments, each R.sup.2 is Me. In certain embodiments, at least one instance of R.sup.2 is Et, Pr, or Bu. In certain embodiments, at least one instance of R.sup.2 is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.2 is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of R.sup.2 is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, one R.sup.2 is hydrogen, and the other R.sup.2 is unsubstituted C.sub.1-6 alkyl (e.g., Me). In certain embodiments, one R.sup.2 is hydrogen, and the other R.sup.2 is halogen (e.g., F).

[0152] In certain embodiments, q is 0. In certain embodiments, q is 1.

[0153] In certain embodiments, R.sup.3 is hydrogen. In certain embodiments, R.sup.3 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted, C.sub.1-6 alkyl). In certain embodiments, R.sup.3 is Me. In certain embodiments, R.sup.3 is Et, Pr, Bu, substituted methyl (e.g., fluorinated methyl or Bn), substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R.sup.3 is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0154] In certain embodiments, X.sup.1 is N. In certain embodiments, X.sup.2 is N. In certain embodiments, X.sup.3 is N. In certain embodiments, X.sup.1 is N(O). In certain embodiments, X.sup.2 is N(O). In certain embodiments, X.sup.3 is N(O). In certain embodiments, each of X.sup.1, X.sup.2, and X.sup.3 is CR.sup.4. In certain embodiments, each of X.sup.1, X.sup.2, and X.sup.3 is CH. In certain embodiments, X.sup.1 is N, and each of X.sup.2 and X.sup.3 is CR.sup.4. In certain embodiments, X.sup.1 is N, and each of X.sup.2 and X.sup.3 is CH.

[0155] In certain embodiments, at least one instance of R.sup.4 is hydrogen. In certain embodiments, each instance of R.sup.4 is hydrogen. In certain embodiments, at least one instance of R.sup.4 is not hydrogen. In certain embodiments, no instance of R.sup.4 is hydrogen. In certain embodiments, at least one instance of R.sup.4 is halogen. In certain embodiments, at least one instance of R.sup.4 is F. In certain embodiments, at least one instance of R.sup.4 is Cl. In certain embodiments, at least one instance of R.sup.4 is Br. In certain embodiments, at least one instance of R.sup.4 is unsubstituted alkyl (e.g., unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.4 is Me. In certain embodiments, at least one instance of R.sup.4 is Et, Pr, or Bu. In certain embodiments, at least one instance of R.sup.4 is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, at least one instance of R.sup.4 is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.4 is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of R.sup.4 is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted, C.sub.2-6 alkynyl (e.g., substituted or unsubstituted ethynyl). In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.4 is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.4 is —OR.sup.a (e.g., —OH, —O(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —OMe, —OCF.sub.3, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, at least one instance of R.sup.4 is —O(substituted or unsubstituted alkyl). In certain embodiments, at least one instance of R.sup.4 is —O(alkyl substituted with at least one —OH). In certain embodiments, at least one instance of R.sup.4 is —OCH.sub.2CH(OH)CH.sub.2OH. In certain embodiments, at least one instance of R.sup.4 is —O(unsubstituted alkyl). In certain embodiments, at least one instance of R.sup.4 is —OMe. In certain embodiments, at least one instance of R.sup.4 is —SR.sup.a (e.g., —SH, —S(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —SMe, —SCF.sub.3, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g., —SPh)). In certain embodiments, at least one instance of R.sup.4 is —N(R.sup.a).sub.2 (e.g., —NH.sub.2, —NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHMe), or —N(substituted or unsubstituted, C.sub.1-6 alkyl)-(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NMe.sub.2)). In certain embodiments, at least one instance of R.sup.4 is —CN or —SCN. In certain embodiments, at least one instance of R.sup.4 is —NO.sub.2. In certain embodiments, at least one instance of R.sup.4 is —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, or —C(═NR.sup.a)N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.4 is —C(═O)R.sup.a (e.g., —C(═O)(substituted or unsubstituted alkyl) (e.g., —C(═O)Me) or —C(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.4 is —C(═O)OR.sup.a (e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), or —C(═O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.4 is —C(═O)N(R.sup.a).sub.2 (e.g., —C(═O)NH.sub.2, —C(═O)NH(substituted or unsubstituted alkyl) (e.g., —C(═O)NHMe), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R.sup.4 is —NR.sup.aC(═O)R.sup.a (e.g., —NHC(═O)(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)Me) or —NHC(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.4 is —NR.sup.aC(═O)OR.sup.a. In certain embodiments, at least one instance of R.sup.4 is —NR.sup.aC(═O)N(R.sup.a).sub.2 (e.g., —NHC(═O)NH.sub.2, —NHC(═O)NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)NHMe)). In certain embodiments, at least one instance of R.sup.4 is —OC(═O)R.sup.a (e.g., —OC(═O)(substituted or unsubstituted alkyl) or —OC(═O)(substituted or unsubstituted phenyl)), —OC(═O)OR.sup.a (e.g., —OC(═O)O(substituted or unsubstituted alkyl) or —OC(═O)O(substituted or unsubstituted phenyl)), or —OC(═O)N(R.sup.a).sub.2 (e.g., —OC(═O)NH.sub.2, —OC(═O)NH(substituted or unsubstituted alkyl), —OC(═O)NH(substituted or unsubstituted phenyl), —OC(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or —OC(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R.sup.4 is —NR.sup.aS(═O).sub.2R.sup.a (e.g., —NHS(═O).sub.2R.sup.a, —NHS(═O).sub.2(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.4 is —NR.sup.aS(═O).sub.2OR.sup.a (e.g., —NHS(═O).sub.2OR.sup.a, —NHS(═O).sub.2OH, —NHS(═O).sub.2O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.4 is —NR.sup.aS(═O).sub.2N(R.sup.a).sub.2 (e.g., —NHS(═O).sub.2N(R.sup.a).sub.2, —NHS(═O).sub.2NH.sub.2, —NHS(═O).sub.2NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), —NHS(═O).sub.2N(substituted or unsubstituted alkyl).sub.2, —NHS(═O).sub.2N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.4 is —OS(═O).sub.2R.sup.a (e.g., —OS(═O).sub.2(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.4 is —OS(═O).sub.2OR.sup.a (e.g., —OS(═O).sub.2OH, —OS(═O).sub.2O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.4 is —OS(═O).sub.2N(R.sup.a).sub.2 (e.g., —OS(═O).sub.2NH.sub.2, —OS(═O).sub.2NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), —OS(═O).sub.2N(substituted or unsubstituted alkyl).sub.2, —OS(═O).sub.2N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.4 is —S(═O).sub.2R.sup.a (e.g., —S(═O).sub.2(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.4 is —S(═O).sub.2OR.sup.a (e.g., —S(═O).sub.2OH, —S(═O).sub.2O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). or In certain embodiments, at least one instance of R.sup.4 is —S(═O).sub.2N(R.sup.a).sub.2 (e.g., —S(═O).sub.2NH.sub.2, —S(═O).sub.2NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), —S(═O).sub.2N(substituted or unsubstituted alkyl).sub.2, —S(═O).sub.2N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)).

[0156] In certain embodiments, Y is O. In certain embodiments, Y is C(R.sup.8).sub.2. In certain embodiments, Y is CH.sub.2. In certain embodiments, Y is NR.sup.9. In certain embodiments, Y is NH. In certain embodiments, Y is N(unsubstituted C.sub.1-6 alkyl).

[0157] In certain embodiments, at least one instance of R.sup.8 is hydrogen. In certain embodiments, each instance of R.sup.8 is hydrogen. In certain embodiments, at least one instance of R.sup.8 is halogen. In certain embodiments, at least one instance of R.sup.8 is F. In certain embodiments, each R.sup.8 is F. In certain embodiments, at least one instance of R.sup.8 is Cl. In certain embodiments, at least one instance of R.sup.8 is Br. In certain embodiments, at least one instance of R.sup.8 is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, at least one instance of R.sup.8 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.8 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.8 is Me. In certain embodiments, each R.sup.8 is Me. In certain embodiments, at least one instance of R.sup.8 is Et, Pr, or Bu. In certain embodiments, at least one instance of R.sup.8 is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.8 is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of R.sup.8 is substituted ethyl, substituted propyl, or substituted butyl.

[0158] In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted, C.sub.2-6 alkynyl (e.g., substituted or unsubstituted ethynyl). In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.8 is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R.sup.8 is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.8 is —OR.sup.a (e.g., —OH, —O(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —OMe, —OCF.sub.3, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, at least one instance of R.sup.8 is —O(substituted or unsubstituted alkyl). In certain embodiments, at least one instance of R.sup.8 is —O(alkyl substituted with at least one -OH). In certain embodiments, at least one instance of R.sup.8 is —OCH.sub.2CH(OH)CH.sub.2OH. In certain embodiments, at least one instance of R.sup.8 is —O(unsubstituted alkyl). In certain embodiments, at least one instance of R.sup.8 is —OMe. In certain embodiments, at least one instance of R.sup.8 is -SR.sup.a (e.g., —SH, -S(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —SMe, —SCF.sub.3, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g., —SPh)). In certain embodiments, at least one instance of R.sup.8 is —N(R.sup.a).sub.2 (e.g., —NH.sub.2, —NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHMe), or —N(substituted or unsubstituted, C.sub.1-6 alkyl)-(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NMe.sub.2)). In certain embodiments, at least one instance of R.sup.8 is —CN or —SCN. In certain embodiments, at least one instance of R.sup.8 is —NO.sub.2. In certain embodiments, at least one instance of R.sup.8 is —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, or —C(═NR.sup.a)N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.8 is —C(═O)R.sup.a (e.g., —C(═O)(substituted or unsubstituted alkyl) (e.g., —C(═O)Me) or —C(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.8 is —C(═O)OR.sup.a (e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), or —C(═O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.8 is —C(═O)N(R.sup.a).sub.2 (e.g., —C(═O)NH.sub.2, —C(═O)NH(substituted or unsubstituted alkyl) (e.g., —C(═O)NHMe), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R.sup.8 is —NR.sup.aC(═O)R.sup.a (e.g., —NHC(═O)(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)Me) or —NHC(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.8 is —NR.sup.aC(═O)OR.sup.a. In certain embodiments, at least one instance of R.sup.8 is —NR.sup.aC(═O)N(R.sup.a).sub.2 (e.g., —NHC(═O)NH.sub.2, —NHC(═O)NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)NHMe)). In certain embodiments, at least one instance of R.sup.8 is —OC(═O)R.sup.a (e.g., —OC(═O)(substituted or unsubstituted alkyl) or —OC(═O)(substituted or unsubstituted phenyl)), —OC(═O)OR.sup.a (e.g., —OC(═O)O(substituted or unsubstituted alkyl) or —OC(═O)O(substituted or unsubstituted phenyl)), or —OC(═O)N(R.sup.a).sub.2 (e.g., —OC(═O)NH.sub.2, —OC(═O)NH(substituted or unsubstituted alkyl), —OC(═O)NH(substituted or unsubstituted phenyl), —OC(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or —OC(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R.sup.8 is —NR.sup.aS(═O).sub.2R.sup.a (e.g., —NHS(═O).sub.2R.sup.a, —NHS(═O).sub.2(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.8 is —NR.sup.aS(═O).sub.2OR.sup.a (e.g., —NHS(═O).sub.2OR.sup.a, —NHS(═O).sub.2OH, —NHS(═O).sub.2O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.8 is —NR.sup.aS(═O).sub.2N(R.sup.a).sub.2 (e.g., —NHS(═O).sub.2N(R.sup.a).sub.2, —NHS(═O).sub.2NH.sub.2, —NHS(═O).sub.2NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), —NHS(═O).sub.2N(substituted or unsubstituted alkyl).sub.2, —NHS(═O).sub.2N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.8 is —OS(═O).sub.2R.sup.a (e.g., —OS(═O).sub.2(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.8 is —OS(═O).sub.2OR.sup.a (e.g., —OS(═O).sub.2OH, —OS(═O).sub.2O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.8 is —OS(═O).sub.2N(R.sup.a).sub.2 (e.g., —OS(═O).sub.2NH.sub.2, —OS(═O).sub.2NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), —OS(═O).sub.2N(substituted or unsubstituted alkyl).sub.2, —OS(═O).sub.2N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.8 is —S(═O).sub.2R.sup.a (e.g., —S(═O).sub.2(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.8 is —S(═O).sub.2OR.sup.a (e.g., —S(═O).sub.2OH, —S(═O).sub.2O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). or In certain embodiments, at least one instance of R.sup.8 is —S(═O).sub.2N(R.sup.a).sub.2 (e.g., —S(═O).sub.2NH.sub.2, —S(═O).sub.2NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), —S(═O).sub.2N(substituted or unsubstituted alkyl).sub.2, —S(═O).sub.2N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certain embodiments, two R.sup.8 on the same carbon atom are joined with the intervening carbon atom to form C═O.

[0159] In certain embodiments, one R.sup.8 is hydrogen, and the other R.sup.8 is unsubstituted C.sub.1-6 alkyl (e.g., Me). In certain embodiments, one R.sup.8 is hydrogen, and the other R.sup.8 is halogen (e.g., F).

[0160] In certain embodiments, R.sup.9 is hydrogen. In certain embodiments, R.sup.9 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted, C.sub.1-6 alkyl). In certain embodiments, R.sup.9 is Me. In certain embodiments, R.sup.9 is Et, Pr, Bu, substituted methyl (e.g., fluorinated methyl or Bn), substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R.sup.9 is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0161] In certain embodiments, m is 2. In certain embodiments, m is 3.

[0162] In certain embodiments,

##STR00347##

(“Ring C”) is aryl. In certain embodiments, Ring C is phenyl. In certain embodiments,

##STR00348##

is unsubstituted phenyl. In certain embodiments,

##STR00349##

##STR00350##

##STR00351##

In certain embodiments,

##STR00352##

##STR00353##

##STR00354##

##STR00355##

##STR00356##

##STR00357##

##STR00358##

In certain embodiments,

##STR00359##

##STR00360##

In certain embodiments,

##STR00361##

##STR00362##

In certain embodiments,

##STR00363##

##STR00364##

In certain embodiments,

##STR00365##

##STR00366##

In certain embodiments,

##STR00367##

##STR00368##

wherein each R.sup.7 is independently halogen or substituted or unsubstituted alkyl (e.g., unsubstituted C.sub.1-6 alkyl). In certain embodiments,

##STR00369##

##STR00370##

wherein each R.sup.7 is independently substituted or unsubstituted alkyl (e.g., unsubstituted C.sub.1-6 alkyl). In certain embodiments,

##STR00371##

##STR00372##

In certain embodiments,

##STR00373##

##STR00374##

##STR00375##

##STR00376##

##STR00377##

##STR00378##

##STR00379##

certain embodiments,

##STR00380##

##STR00381##

##STR00382##

In certain embodiments,

##STR00383##

##STR00384##

##STR00385##

In certain embodiments,

##STR00386##

##STR00387##

In certain embodiments,

##STR00388##

##STR00389##

In certain embodiments,

##STR00390##

##STR00391##

##STR00392##

In certain embodiments,

##STR00393##

##STR00394##

##STR00395##

[0163] In certain embodiments, Ring C is heteroaryl. In certain embodiments, Ring C is 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring C is pyrimidinyl, thienyl, pyrazolyl, tetrazolyl, isoxazolyl, or

##STR00396##

In certain embodiments, Ring C is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In certain embodiments, Ring C is pyridinyl. In certain embodiments,

##STR00397##

##STR00398##

##STR00399##

##STR00400##

In certain embodiments,

##STR00401##

##STR00402##

##STR00403##

##STR00404##

In certain embodiments,

##STR00405##

##STR00406##

##STR00407##

##STR00408##

In certain embodiments,

##STR00409##

##STR00410##

In certain embodiments,

##STR00411##

##STR00412##

In certain embodiments,

##STR00413##

##STR00414##

In certain embodiments,

##STR00415##

##STR00416##

##STR00417##

##STR00418##

##STR00419##

In certain embodiments,

##STR00420##

##STR00421##

In certain embodiments,

##STR00422##

##STR00423##

In certain embodiments,

##STR00424##

##STR00425##

In certain embodiments,

##STR00426##

##STR00427##

certain embodiments,

##STR00428##

##STR00429##

In certain embodiments,

##STR00430##

##STR00431##

In certain embodiments,

##STR00432##

##STR00433##

In certain embodiments,

##STR00434##

##STR00435##

. In certain embodiments,

##STR00436##

##STR00437##

In certain embodiments,

##STR00438##

##STR00439##

In certain embodiments,

##STR00440##

##STR00441##

##STR00442##

In certain embodiments,

##STR00443##

##STR00444##

##STR00445##

##STR00446##

[0164] In certain embodiments,

##STR00447##

##STR00448##

##STR00449##

##STR00450##

certain embodiments,

##STR00451##

##STR00452##

In certain embodiments,

##STR00453##

##STR00454##

##STR00455##

In certain embodiments,

##STR00456##

##STR00457##

##STR00458##

##STR00459##

In certain embodiments,

##STR00460##

##STR00461##

In certain embodiments,

##STR00462##

##STR00463##

##STR00464##

##STR00465##

##STR00466##

In certain embodiments,

##STR00467##

##STR00468##

certain embodiments,

##STR00469##

##STR00470##

##STR00471##

In certain embodiments,

##STR00472##

##STR00473##

In certain embodiments,

##STR00474##

##STR00475##

In certain embodiments,

##STR00476##

##STR00477##

[0165] In certain embodiments, Ring C is phenyl fused with monocyclic or bicyclic, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein bond c is attached to the phenyl. In certain embodiments, Ring C is naphthyl. In certain embodiments, Ring C is phenyl fused with naphthyl, wherein bond c is attached to the phenyl. In certain embodiments, Ring C is phenyl fused with 5- to 6-membered, monocyclic heteroaryl, wherein bond c is attached to the phenyl. In certain embodiments, Ring C is phenyl fused with 8-14 membered, bicyclic heteroaryl, wherein bond c is attached to the phenyl. In certain embodiments, Ring C is phenyl fused with 4- to 7-membered, monocyclic carbocyclyl, wherein bond c is attached to the phenyl. In certain embodiments, Ring C is phenyl fused with 6- to 13-membered, bicyclic carbocyclyl, wherein bond c is attached to the phenyl. In certain embodiments, Ring C is phenyl fused with 4- to 7-membered, monocyclic heterocyclyl, wherein bond c is attached to the phenyl. In certain embodiments, Ring C is phenyl fused with 6- to 13-membered, bicyclic heterocyclyl, wherein bond c is attached to the phenyl.

[0166] In certain embodiments, Ring C is 5- or 6-membered monocyclic heteroaryl fused with monocyclic or bicyclic, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein bond c is attached to the 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring C is 5- or 6-membered monocyclic heteroaryl fused with phenyl, wherein bond c is attached to the 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring C is 5- or 6-membered monocyclic heteroaryl fused with naphthyl, wherein bond c is attached to the 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring C is 5- or 6-membered monocyclic heteroaryl fused with another 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, Ring C is 5- or 6-membered monocyclic heteroaryl fused with 8-14 membered, bicyclic heteroaryl, wherein bond c is attached to the 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring C is 5- or 6-membered monocyclic heteroaryl fused with 4- to 7-membered, monocyclic carbocyclyl, wherein bond c is attached to the 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring C is 5- or 6-membered monocyclic heteroaryl fused with 6- to 13-membered, bicyclic carbocyclyl, wherein bond c is attached to the 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring C is 5- or 6-membered monocyclic heteroaryl fused with 4- to 7-membered, monocyclic heterocyclyl, wherein bond c is attached to the 5- or 6-membered monocyclic heteroaryl. In certain embodiments, Ring C is 5- or 6-membered monocyclic heteroaryl fused with 6- to 13-membered, bicyclic heterocyclyl, wherein bond c is attached to the 5- or 6-membered monocyclic heteroaryl.

[0167] In certain embodiments,

##STR00478##

##STR00479##

##STR00480##

##STR00481##

##STR00482##

##STR00483##

##STR00484##

##STR00485##

##STR00486##

##STR00487##

[0168] In certain embodiments, the molecular weight of each R.sup.7 is less than 200 g/mol. In certain embodiments, the molecular weight of each R.sup.7 is less than 150 g/mol. In certain embodiments, the molecular weight of each R.sup.7 is less than 100 g/mol.

[0169] This paragraph applies when R.sup.7 is attached to a carbon atom. In certain embodiments, at least one instance of R.sup.7 is halogen. In certain embodiments, at least one instance of R.sup.7 is F. In certain embodiments, at least one instance of R.sup.7 is Cl. In certain embodiments, at least one instance of R.sup.7 is Br. In certain embodiments, at least one instance of R.sup.7 is unsubstituted alkyl (e.g., unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.7 is Me. In certain embodiments, at least one instance of R.sup.7 is Et, Pr, or Bu. In certain embodiments, at least one instance of R.sup.7 is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, at least one instance of R.sup.7 is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.7 is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of R.sup.7 is —CF.sub.3. In certain embodiments, at least one instance of R.sup.7 is —CHF.sub.2 or —CH.sub.2F. In certain embodiments, at least one instance of R.sup.7 is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted, C.sub.2-6 alkynyl (e.g., substituted or unsubstituted ethynyl). In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.7 is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.7 is —OR.sup.a (e.g., —OH, —O(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —OMe, —OCF.sub.3, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, at least one instance of R.sup.7 is —O(substituted or unsubstituted alkyl). In certain embodiments, at least one instance of R.sup.7 is —O(alkyl substituted with at least one -OH). In certain embodiments, at least one instance of R.sup.7 is —OCH.sub.2CH(OH)CH.sub.2OH. In certain embodiments, at least one instance of R.sup.7 is —O(unsubstituted alkyl). In certain embodiments, at least one instance of R.sup.7 is —OMe. In certain embodiments, at least one instance of R.sup.7 is —SR.sup.a (e.g., —SH, -S(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —SMe, —SCF.sub.3, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g., —SPh)). In certain embodiments, at least one instance of R.sup.7 is —N(R.sup.a).sub.2 (e.g., —NH.sub.2, -NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHMe), or —N(substituted or unsubstituted, C.sub.1-6 alkyl)-(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NMe.sub.2)). In certain embodiments, at least one instance of R.sup.7 is —CN or —SCN. In certain embodiments, at least one instance of R.sup.7 is —NO.sub.2. In certain embodiments, at least one instance of R.sup.7 is —C(═NR.sup.a)R.sup.a, —C(═NR.sup.a)OR.sup.a, or —C(═NR.sup.a)N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.7 is —C(═O)R.sup.a (e.g., —C(═O)(substituted or unsubstituted alkyl) (e.g., —C(═O)Me) or —C(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —C(═O)OR.sup.a (e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), or —C(═O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —C(═O)N(R.sup.a).sub.2 (e.g., —C(═O)NH.sub.2, —C(═O)NH(substituted or unsubstituted alkyl) (e.g., —C(═O)NHMe), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R.sup.7 is —NR.sup.aC(═O)R.sup.a (e.g., —NHC(═O)(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)Me) or —NHC(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —NR.sup.aC(═O)OR.sup.a. In certain embodiments, at least one instance of R.sup.7 is —NR.sup.aC(═O)N(R.sup.a).sub.2 (e.g., —NHC(═O)NH.sub.2, —NHC(═O)NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)NHMe)). In certain embodiments, at least one instance of R.sup.7 is —OC(═O)R.sup.a (e.g., —OC(═O)(substituted or unsubstituted alkyl) or —OC(═O)(substituted or unsubstituted phenyl)), —OC(═O)OR.sup.a (e.g., —OC(═O)O(substituted or unsubstituted alkyl) or —OC(═O)O(substituted or unsubstituted phenyl)), or —OC(═O)N(R.sup.a).sub.2 (e.g., —OC(═O)NH.sub.2, —OC(═O)NH(substituted or unsubstituted alkyl), —OC(═O)NH(substituted or unsubstituted phenyl), —OC(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or —OC(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R.sup.7 is —NR.sup.aS(═O).sub.2R.sup.a (e.g., —NHS(═O).sub.2R.sup.a, —NHS(═O).sub.2(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —NR.sup.aS(═O).sub.2OR.sup.a (e.g., —NHS(═O).sub.2OR.sup.a, —NHS(═O).sub.2OH, —NHS(═O).sub.2O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —NR.sup.aS(═O).sub.2N(R.sup.a).sub.2 (e.g., —NHS(═O).sub.2N(R.sup.a).sub.2, —NHS(═O).sub.2NH.sub.2, —NHS(═O).sub.2NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), —NHS(═O).sub.2N(substituted or unsubstituted alkyl).sub.2, —NHS(═O).sub.2N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —OS(═O).sub.2R.sup.a (e.g., —OS(═O).sub.2(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —OS(═O).sub.2OR.sup.a (e.g., —OS(═O).sub.2OH, —OS(═O).sub.2O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —OS(═O).sub.2N(R.sup.a).sub.2 (e.g., —OS(═O).sub.2NH.sub.2, —OS(═O).sub.2NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), —OS(═O).sub.2N(substituted or unsubstituted alkyl).sub.2, —OS(═O).sub.2N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —S(═O).sub.2R.sup.a (e.g., —S(═O).sub.2(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —S(═O).sub.2OR.sup.a (e.g., —S(═O).sub.2OH, —S(═O).sub.2O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). or In certain embodiments, at least one instance of R.sup.7 is —S(═O).sub.2N(R.sup.a).sub.2 (e.g., —S(═O).sub.2NH.sub.2, —S(═O).sub.2NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), —S(═O).sub.2N(substituted or unsubstituted alkyl).sub.2, —S(═O).sub.2N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —P(═O)(R.sup.a).sub.2 (e.g., —P(═O)(substituted or unsubstituted phenyl).sub.2). In certain embodiments, at least one instance of R.sup.7 is ═O. In certain embodiments, at least one R.sup.7 is halogen, substituted or unsubstituted alkyl, —OR.sup.a, or —CN. In certain embodiments, at least one R.sup.7 is halogen, unsubstituted C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with one or more halogen, —O(unsubstituted C.sub.1-6 alkyl), or —CN. In certain embodiments, at least one R.sup.7 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl, substituted or unsubstituted phenyl, —OR.sup.a, —CN, or —N(R.sup.a).sub.2. In certain embodiments, each R.sup.7 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl, substituted or unsubstituted phenyl, —OR.sup.a, —CN, or —N(R.sup.a).sub.2. In certain embodiments, at least one R.sup.7 is chloro, fluoro, —CH.sub.3, —CF.sub.3, unsubstituted benzyl, unsubstituted C.sub.2-6 alkyl, —OCH.sub.3, —O(unsubstituted C.sub.2-6 alkyl), —OCH.sub.2CH.sub.2OCH.sub.3, —CN, —NHCH.sub.3, or —N(CH.sub.3).sub.2. In certain embodiments, at least one R.sup.7 is halogen, unsubstituted C.sub.1-6 alkyl, -O(unsubstituted C.sub.1-6 alkyl), or —CN. In certain embodiments, each R.sup.7 is independently halogen, substituted or unsubstituted alkyl, —OR.sup.a, or —CN. In certain embodiments, each R.sup.7 is independently halogen, unsubstituted C.sub.1-6 alkyl, -O(unsubstituted C.sub.1-6 alkyl), or —CN. In certain embodiments, at least one R.sup.7 is halogen or substituted or unsubstituted alkyl (e.g., unsubstituted C.sub.1-6 alkyl). In certain embodiments, each R.sup.7 is independently halogen or substituted or unsubstituted alkyl. In certain embodiments, each R.sup.7 is independently halogen or unsubstituted C.sub.1-6 alkyl. In certain embodiments, each R.sup.7 is independently Cl or Me.

[0170] This paragraph applies when R.sup.7 is attached to a nitrogen atom. In certain embodiments, at least one instance of R.sup.7 is unsubstituted alkyl (e.g., unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.7 is Me. In certain embodiments, at least one instance of R.sup.7 is Et, Pr, or Bu. In certain embodiments, at least one instance of R.sup.7 is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, at least one instance of R.sup.7 is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.7 is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of R.sup.7 is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted, C.sub.2-6 alkynyl (e.g., substituted or unsubstituted ethynyl). In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R.sup.7 is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.7 is —C(═O)R.sup.a (e.g., —C(═O)(substituted or unsubstituted alkyl) (e.g., —C(═O)Me) or —C(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —C(═O)OR.sup.a(e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), or —C(═O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —C(═O)N(R.sup.a).sub.2 (e.g., —C(═O)NH.sub.2, —C(═O)NH(substituted or unsubstituted alkyl) (e.g., —C(═O)NHMe), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R.sup.7 is —S(═O).sub.2R.sup.a (e.g., —S(═O).sub.2(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —S(═O).sub.2OR.sup.a (e.g., —S(═O).sub.2OH, —S(═O).sub.2O(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl)). or In certain embodiments, at least one instance of R.sup.7 is —S(═O).sub.2N(R.sup.a).sub.2 (e.g., —S(═O).sub.2NH.sub.2, —S(═O).sub.2NH(substituted or unsubstituted alkyl or substituted or unsubstituted phenyl), —S(═O).sub.2N(substituted or unsubstituted alkyl).sub.2, —S(═O).sub.2N(substituted or unsubstituted alkyl)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.7 is —P(═O)(R.sup.a).sub.2 (e.g., —P(═O)(substituted or unsubstituted phenyl).sub.2). In certain embodiments, at least one instance of R.sup.7 is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, at least one instance of R.sup.7 is ═O.

[0171] In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 1 or 2. In certain embodiments, n is such an integer between 1 and 13, inclusive, that Ring C is fully substituted.

[0172] In certain embodiments, the compound is of the formula:

##STR00488##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0173] In certain embodiments, the compound is of the formula:

##STR00489##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0174] In certain embodiments, the compound is of the formula:

##STR00490##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0175] In certain embodiments, the compound is of the formula:

##STR00491##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0176] In certain embodiments, the compound is of the formula:

##STR00492##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0177] In certain embodiments, the compound is of the formula:

##STR00493##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0178] In certain embodiments, the compound is of the formula:

##STR00494##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0179] In certain embodiments, the compound is of the formula:

##STR00495##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0180] In certain embodiments, the compound is of the formula:

##STR00496##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0181] In certain embodiments, the compound is of the formula:

##STR00497##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0182] In certain embodiments, the compound is of the formula:

##STR00498##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0183] In certain embodiments, the compound is of the formula:

##STR00499##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0184] In certain embodiments, the compound is of the formula:

##STR00500##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0185] In certain embodiments, the compound is of the formula:

##STR00501##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0186] In certain embodiments, the compound is of the formula:

##STR00502##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0187] In certain embodiments, the compound is of the formula:

##STR00503##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0188] In certain embodiments, the compound is of the formula:

##STR00504##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0189] In certain embodiments, the compound is of the formula:

##STR00505##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0190] In certain embodiments, the compound is of the formula:

##STR00506##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0191] In certain embodiments, the compound is of the formula:

##STR00507##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0192] In certain embodiments, the compound is of the formula:

##STR00508##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0193] In certain embodiments, the compound is of the formula:

##STR00509##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0194] In certain embodiments, the compound is of the formula:

##STR00510##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0195] In certain embodiments, the compound is of the formula:

##STR00511##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0196] In certain embodiments, the compound is of the formula:

TABLE-US-00001 No. Formula 1190 [00512]embedded image 1209 [00513]embedded image 1210 [00514]embedded image 1212 [00515]embedded image 1331 [00516]embedded image 1974 [00517]embedded image 1975 [00518]embedded image 1976 [00519]embedded image 1989 [00520]embedded image 1992 [00521]embedded image 1994 [00522]embedded image 2058 [00523]embedded image 2075 [00524]embedded image 2080 [00525]embedded image 2085 [00526]embedded image 2090 [00527]embedded image 2096 [00528]embedded image 2135 [00529]embedded image 2167 [00530]embedded image 2172 [00531]embedded image 2173 [00532]embedded image 2174 [00533]embedded image 2175 [00534]embedded image 2179 [00535]embedded image 2180 [00536]embedded image 2181 [00537]embedded image 2184 [00538]embedded image 2187 [00539]embedded image 2190 [00540]embedded image 2191 [00541]embedded image 2192 [00542]embedded image 2194 [00543]embedded image 2197 [00544]embedded image 2198 [00545]embedded image 2199 [00546]embedded image 2200 [00547]embedded image 2202 [00548]embedded image 2206 [00549]embedded image 2209 [00550]embedded image 2210 [00551]embedded image 2213 [00552]embedded image 2215 [00553]embedded image 2219 [00554]embedded image 2221 [00555]embedded image 2222 [00556]embedded image 2224 [00557]embedded image 2226 [00558]embedded image 2227 [00559]embedded image 2228 [00560]embedded image 2230 [00561]embedded image 2234 [00562]embedded image 2236 [00563]embedded image 2240 [00564]embedded image 2241 [00565]embedded image 2242 [00566]embedded image 2245 [00567]embedded image 2248 [00568]embedded image 2249 [00569]embedded image 2254 [00570]embedded image 2257 [00571]embedded image 2258 [00572]embedded image 2261 [00573]embedded image 2264 [00574]embedded image 2265 [00575]embedded image 2268 [00576]embedded image 2275 [00577]embedded image 2280 [00578]embedded image 2286 [00579]embedded image 2288 [00580]embedded image 2290 [00581]embedded image 2291 [00582]embedded image 2294 [00583]embedded image 2295 [00584]embedded image 2296 [00585]embedded image 2299 [00586]embedded image 2305 [00587]embedded image 2317 [00588]embedded image 2323 [00589]embedded image 2334 [00590]embedded image 2337 [00591]embedded image 2339 [00592]embedded image 2343 [00593]embedded image 2344 [00594]embedded image 2345 [00595]embedded image 2351 [00596]embedded image 2375 [00597]embedded image 2377 [00598]embedded image

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof).

[0197] In certain embodiments, the compound is of the formula:

TABLE-US-00002 No. Formula 2355 [00599]embedded image 2362 [00600]embedded image 2388 [00601]embedded image 2398 [00602]embedded image 2402 [00603]embedded image 2410 [00604]embedded image 2417 [00605]embedded image 2423 [00606]embedded image 2433 [00607]embedded image 2439 [00608]embedded image 2443 [00609]embedded image 2449 [00610]embedded image 2451 [00611]embedded image 2458 [00612]embedded image 2462 [00613]embedded image 2472 [00614]embedded image 2473 [00615]embedded image 2494 [00616]embedded image 2495 [00617]embedded image 2503 [00618]embedded image 2510 [00619]embedded image 2513 [00620]embedded image 2514 [00621]embedded image 2515 [00622]embedded image 2516 [00623]embedded image

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof).

[0198] In certain embodiments, the compound is Compound 1331, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the compound is Compound 1331, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is Compound 2058, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the compound is Compound 2058, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is Compound 2173, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the compound is Compound 2173, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is Compound 2339, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the compound is Compound 2339, or a pharmaceutically acceptable salt thereof.

[0199] In certain embodiments, a provided compound (a compound of the present disclosure) is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled compound thereof. In certain embodiments, a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, a provided compound is a mixture (e.g., a racemic mixture) of enantiomers and/or diastereomers.

[0200] In certain embodiments, a provided compound is electrically neutral. In certain embodiments, a provided compound further comprises one or more counterions so that the provided compound is electrically neutral.

[0201] In certain embodiments, the molecular weight of a provided compound that is not in the form of a salt, solvate, hydrate, co-crystal, or prodrug is lower than 1,000, lower than 800, lower than 600, lower than 500, or lower than 400 g/mol. In certain embodiments, the molecular weight of a provided compound that is not in the form of a salt, solvate, hydrate, co-crystal, or prodrug is lower than 600 g/mol. In certain embodiments, the molecular weight of a provided compound that is not in the form of a salt, solvate, hydrate, co-crystal, or prodrug is lower than 500 g/mol.

[0202] In certain embodiments, a provided compound is a TRAP1 modulator. In certain embodiments, a provided compound modulates the function of TRAP1. In certain embodiments, a provided compound is a TRAP1 activator. In certain embodiments, a provided compound increases the expression and/or activity of TRAP1. In certain embodiments, a provided compound increases the activity of TRAP1. In certain embodiments, the activity of TRAP1 is ATPase activity of TRAP1. In certain embodiments, a provided compound increases the expression and/or activity of TRAP1 in an in vitro assay (e.g., an in vitro assay described herein). In certain embodiments, a provided compound increases the expression and/or activity of TRAP1 in a cellular assay (e.g., a cellular assay described herein). In certain embodiments, a provided compound increases the expression and/or activity of TRAP1 (e.g., as measured by E.sub.max (maximal percent activation)) by at least 10%, at least 20%, at least 30%, at least 50%, at least 70%, at least 100%, at least 300%, or at least 1,000%. In certain embodiments, the TRAP1 is a human TRAP1. In certain embodiments, the TRAP1 is a non-human mammal TRAP1. In certain embodiments, the TRAP1 is a wild type TRAP1. In certain embodiments, the TRAP1 is a mutant TRAP1. In certain embodiments, a provided compound is selective for increasing the expression and/or activity of TRAP1 over a different protein (e.g., a protein kinase or a heat shock protein (e.g., a HSP90 (e.g., HSP90B, GRP94))). In certain embodiments, the selectivity is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 7-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 300-fold, or at least 1,000-fold. For example, if a provided compound’s TRAP1 EC.sub.50 is 1 .Math.M, and the provided compound’s EC.sub.50 regarding a different protein is 10 .Math.M, then the selectivity is (10 .Math.M)/(1 .Math.M)=10 folds. In certain embodiments, a provided compound reversibly binds to TRAP1.

[0203] It has also been reported that TRAP1 may protect against mitochondrial apoptosis (Altieri et al., Biochim Biophys Acta 2012, 1823: 767-73). In certain embodiments, a provided compound increases the quality, health, function, quantity, and/or activity of mitochondria by at least 10%, at least 20%, at least 30%, at least 50%, at least 70%, at least 100%, at least 300%, or at least 1,000%.

[0204] In certain embodiments, the increase is obtained with an assay described herein.

[0205] The provided compounds may be advantageous over known compounds. In certain embodiments, the provided compounds are more soluble and/or permeable than known compounds. In certain embodiments, the provided compounds show higher brain penetration than known compounds. In certain embodiments, the provided compounds show more desirable absorption, distribution, metabolism, excretion, and/or liberation than known compounds. In certain embodiments, the provided compounds show higher bioavailability than known compounds. In certain embodiments, the provided compounds are more physically, chemically, and/or metabolically stable than known compounds. In certain embodiments, the provided compounds are more potent than known compounds. In certain embodiments, the provided compounds show less frequent and/or less severe side effects than known compounds. In certain embodiments, the provided compounds show less frequent and/or less severe off-target effects than known compounds. In certain embodiments, the provided compounds are less toxic than known compounds. In certain embodiments, the provided compounds are more efficacious than known compounds. In certain embodiments, the provided compounds show wider therapeutic window than known compounds. In certain embodiments, the provided compounds show better subject (e.g., a human in need of treatment or prevention of a disease) compliance than known compounds.

Pharmaceutical Compositions and Administration

[0206] In another aspect, the present disclosure provides pharmaceutical compositions comprising a provided compound and optionally a pharmaceutically acceptable excipient.

[0207] In certain embodiments, the pharmaceutical composition comprises an effective amount of the provided compound. In certain embodiments, an effective amount is an amount effective for increasing the expression of TRAP1 in a subject, biological sample, tissue, or cell. In certain embodiments, an effective amount is an amount effective for increasing the activity of TRAP1 in a subject, biological sample, tissue, or cell. In certain embodiments, an effective amount is an amount effective for increasing the health, quality, function, quantity, and/or activity of mitochondria in a subject, biological sample, tissue, or cell. In certain embodiments, the effective amount increases the expression and/or activity of TRAP1 in a subject, biological sample, tissue, or cell by at least 10%, at least 20%, at least 30%, at least 50%, at least 70%, at least 100%, at least 300%, or at least 1,000%. In certain embodiments, the effective amount increases the health, quality, function, quantity, and/or activity of mitochondria in a subject, biological sample, tissue, or cell by at least 10%, at least 20%, at least 30%, at least 50%, at least 70%, at least 100%, at least 300%, or at least 1,000%.

[0208] In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is effective in treating (e.g., therapeutically treating) a disease in a subject in need thereof. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is effective in preventing a disease in a subject in need thereof.

[0209] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject is a human (e.g., an adult, juvenile, or child). In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the subject is a genetically engineered animal. In certain embodiments, the subject is a transgenic animal (e.g., transgenic mice, transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0210] In certain embodiments, the biological sample, tissue, or cell (e.g., the biological sample, tissue, or cell being contacted with a provided compound or pharmaceutical composition) is in vitro. In certain embodiments, the biological sample, tissue, or cell is in vivo. In certain embodiments, the biological sample, tissue, or cell is ex vivo. In certain embodiments, the cell is a neuron (e.g., dysfunctional neuron).

[0211] Pharmaceutical compositions can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the provided compound (“active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.

[0212] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0213] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the pharmaceutical composition is to be administered. The pharmaceutical composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0214] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the pharmaceutical composition.

[0215] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0216] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0217] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

[0218] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

[0219] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0220] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0221] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0222] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0223] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0224] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0225] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0226] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[0227] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0228] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0229] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0230] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0231] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0232] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0233] Pharmaceutical compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0234] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0235] Solid pharmaceutical compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a pharmaceutical composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating pharmaceutical compositions which can be used include polymeric substances and waxes. Solid pharmaceutical compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0236] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a pharmaceutical composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0237] Dosage forms for topical and/or transdermal administration of a provided compound may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.

[0238] Suitable devices for use in delivering intradermal pharmaceutical compositions include short needle devices. Intradermal pharmaceutical compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the provided compound in powder form through the outer layers of the skin to the dermis are suitable.

[0239] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients.

[0240] A pharmaceutical composition can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such pharmaceutical compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder pharmaceutical compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0241] Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the pharmaceutical composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the pharmaceutical composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0242] Pharmaceutical compositions formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0243] Formulations as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0244] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients. A pharmaceutical composition can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable pharmaceutical composition and, optionally, one or more of the additional ingredients. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients.

[0245] A pharmaceutical composition can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

[0246] Although the descriptions of the pharmaceutical compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such pharmaceutical compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the pharmaceutical compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

[0247] The provided compounds are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the pharmaceutical compositions will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific pharmaceutical composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0248] The provided compounds and pharmaceutical compositions can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the provided compound or pharmaceutical composition is suitable for topical administration to the eye of a subject.

[0249] The exact amount of a provided compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, any two doses of the multiple doses include different or substantially the same amounts of a provided compound. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) includes independently between 0.1 .Math.g and 1 .Math.g, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a provided compound. In certain embodiments, a dose includes independently between 1 mg and 3 mg, inclusive, of a provided compound. In certain embodiments, a dose includes independently between 3 mg and 10 mg, inclusive, of a provided compound. In certain embodiments, a dose includes independently between 10 mg and 30 mg, inclusive, of a provided compound. In certain embodiments, a dose includes independently between 30 mg and 100 mg, inclusive, of a provided compound.

[0250] Dose ranges as provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0251] In certain embodiments, the pharmaceutical composition further comprises an additional pharmaceutical agent. The additional pharmaceutical agent is different from the provided compound. In certain embodiments, the additional pharmaceutical agent is an additional therapeutically active agent. In certain embodiments, the additional pharmaceutical agent is an additional prophylactically active agent. A provided compound or pharmaceutical composition can be administered in combination with one or more additional pharmaceutical agents. The provided compounds or pharmaceutical compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject, biological sample, or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition including a provided compound and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the provided compound and the additional pharmaceutical agent, but not both.

[0252] The provided compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease or premalignant condition. Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with a provided compound or pharmaceutical composition in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the provided compound with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0253] The additional pharmaceutical agents include, but are not limited to, cytotoxic chemotherapeutic agents, epigenetic modifiers, glucocorticoids, immunotherapeutic agents, antiproliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, and a combination thereof. In some embodiments, the additional pharmaceutical agent is a topoisomerase inhibitor, a MCL1 inhibitor, a BCL-2 inhibitor, a BCL-xL inhibitor, a BRD4 inhibitor, a BRCA1 inhibitor, BRCA2 inhibitor, HER1 inhibitor, HER2 inhibitor, a CDK9 inhibitor, a Jumonji histone demethylase inhibitor, or a DNA damage inducer. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a kinase (e.g., tyrosine kinase). In certain embodiments, the additional pharmaceutical agent is an antibody or a fragment thereof (e.g., monoclonal antibody). In certain embodiments, the additional therapy is an immunotherapy (e.g., an immunotherapeutic monoclonal antibody). In certain embodiments, the additional pharmaceutical agent is an immunosuppressor. In certain embodiments, the additional pharmaceutical agent is an immunoactivator. In certain embodiments, the additional pharmaceutical agent is an immune checkpoint inhibitor. In certain embodiments, the additional pharmaceutical agent is a programmed cell death 1 protein (PD-1) inhibitor. In certain embodiments, the additional pharmaceutical agent is a programmed cell death 1 protein ligand 1 (PD-L1) inhibitor. In certain embodiments, the additional pharmaceutical agent is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor. In certain embodiments, the additional pharmaceutical agent is a T-cell immunoglobulin domain and mucin domain 3 (TIM3) inhibitor, lymphocyte activation gene-3 (LAG3) inhibitor, V-set domain-containing T-cell activation inhibitor 1 (VTCN1 or B7-H4) inhibitor, cluster of differentiation 276 (CD276 or B7-H3) inhibitor, B and T lymphocyte attenuator (BTLA) inhibitor, galectin-9 (GAL9) inhibitor, checkpoint kinase 1 (Chk1) inhibitor, adenosine A2A receptor (A2AR) inhibitor, indoleamine 2,3-dioxygenase (IDO) inhibitor, killer-cell immunoglobulin-like receptor (KIR) inhibitor, or V-domain Ig suppressor of T cell activation (VISTA) inhibitor. In certain embodiments, the additional pharmaceutical agent is metformin. In certain embodiments, the additional pharmaceutical agent is approved for human and/or veterinarian administration by a regulatory agency, such as the U.S. Food and Drug Administration (FDA) or the European Agency for the Evaluation of Medicinal Products (EMA). In certain embodiments, the provided compounds or pharmaceutical compositions can be administered in combination with surgery, radiation therapy, and/or transplantation (e.g., stem cell transplantation, bone marrow transplantation).

Kits

[0254] In another aspect, the present disclosure provides kits comprising a provided compound or pharmaceutical composition, and instructions for using the provided compound or pharmaceutical composition. In certain embodiments, the kit comprises a first container, wherein the first container comprises the provided compound or pharmaceutical composition. In some embodiments, the kit further comprises a second container. In certain embodiments, the second container includes an excipient (e.g., an excipient for dilution or suspension of the provided compound or pharmaceutical composition). In certain embodiments, the second container includes an additional pharmaceutical agent. In some embodiments, the kit further comprises a third container. In certain embodiments, the third container includes an additional pharmaceutical agent. In some embodiments, the provided compound or pharmaceutical composition included in the first container and the excipient or additional pharmaceutical agent included in the second container are combined to form one unit dosage form. In some embodiments, the provided compound or pharmaceutical composition included in the first container, the excipient included in the second container, and the additional pharmaceutical agent included in the third container are combined to form one unit dosage form. In certain embodiments, each of the first, second, and third containers is independently a vial, ampule, bottle, syringe, dispenser package, tube, or inhaler.

[0255] In certain embodiments, the first container, second container, and third container do not comprise the instructions. In certain embodiments, the instructions are for administering the provided compound or pharmaceutical composition to a subject (e.g., a subject in need of treatment or prevention of a disease). In certain embodiments, the instructions are for contacting a biological sample, tissue, or cell with the provided compound or pharmaceutical composition. In certain embodiments, the instructions comprise information required by a regulatory agency, such as the FDA or EMA. In certain embodiments, the instructions comprise prescribing information.

Methods of Use and Uses

[0256] The present disclosure also provides methods of using the provided compounds and pharmaceutical compositions. In another aspect, the present disclosure provides methods of increasing the expression and/or activity of TRAP1 in a subject in need thereof, the methods comprising administering to the subject in need thereof an effective amount of a provided compound or pharmaceutical composition. In certain embodiments, the activity of TRAP1 is the ATPase activity of TRAP1.

[0257] In another aspect, the present disclosure provides methods of increasing the health, quality, function, quantity, and/or activity of mitochondria in a subject in need thereof, the methods comprising administering to the subject in need thereof an effective amount of a provided compound or pharmaceutical composition.

[0258] In another aspect, the present disclosure provides methods of increasing the expression and/or activity of TRAP1 in a cell, tissue, or biological sample, the methods comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition.

[0259] In another aspect, the present disclosure provides methods of increasing the health, quality, function, quantity, and/or activity of mitochondria in a cell, tissue, or biological sample, the methods comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition.

[0260] The provided compounds and pharmaceutical compositions may also be useful for treating or preventing a disease in a subject in need thereof. It has been reported that that PINK1 may protect against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria, and this protective action of PINK1 may depend on its kinase activity to phosphorylate TRAP1 (Pridgeon et al., PLoS Biol., 2007, 5, e172). Moreover, the ability of PINK1 to promote TRAP1 phosphorylation and cell survival may be impaired by of Parkinson’s disease linked PINK1 G309D, L347P, and W437X mutations. See, id. PINK1 may phosphorylate downstream effector TRAP1 to prevent oxidative-stress-induced apoptosis. See, id.

[0261] It has been reported that that TRAP1 may work downstream of PINK1 and in parallel with parkin in Drosophila, and that enhancing its function may ameliorate mitochondrial dysfunction and rescue neurodegeneration in Parkinson’s disease (Costa et al., Cell Death and Disease (2013) 4, e467).

[0262] It has been reported that in certain human cell models, TRAP1 overexpression may be protective, rescuing HTRA2 and PINK1-associated mitochondrial dysfunction, that TRAP1 may act downstream of HTRA2 and PINK1, and that TRAP1 loss of function may lead to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential (Fitzgerald et al., Brain 2017: 140; 2444-2459).

[0263] It has been reported that that [A53T]α-Synuclein toxicity may be intimately connected to mitochondrial dysfunction, and that toxicity reduction in fly and rat primary neurons and human cell lines may be achieved using overexpression of the mitochondrial chaperone TRAP1 (Butler et al., PLoS Genetics, 2012, volume 8, issue 2, e1002488). α -Synuclein may be a causal factor in Parkinson’s disease pathogenesis. See id.

[0264] It has been reported that mitochondria are intimately involved in the regulation of calcium homeostasis, stress response, and cell death pathways, that an impairment of mitochondrial function results in cellular damage and is linked to aging and neurodegeneration, that mitochondrial dysfunction plays a central role in the pathogenesis of Parkinson’s disease, and that several Parkinson’s disease-associated genes interface with pathways regulating mitochondrial function, morphology, and dynamics (Winklhofer et al., Biochimica et Biophysica Acta, 1802 (2010) 29-44).

[0265] It has been reported that there is overwhelming evidence of impaired mitochondrial function as a causative factor in neurodegenerative diseases, that evidence has emerged for impaired mitochondrial dynamics (e.g., shape, size, fission-fusion, distribution, movement etc.) in neurodegenerative diseases such as Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease, and Friedreich’s ataxia.

[0266] It has been reported that mitochondrial dysfunction is not only observed in monogenic mitochondrial disorders but is also associated with more common pathologic conditions, such as Alzheimer’s disease, Parkinson’s disease, cancer, cardiac disease, diabetes, epilepsy, Huntington’s disease, and obesity (Koopman et al., The New England Journal of Medicine, 2012, 366, 1132-1141).

[0267] It has been reported that some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON]), many other mitochondrial disorders involve multiple organ systems and often present with prominent neurologic and myopathic features (Chinnery PF. Mitochondrial Disorders Overview. 2000 Jun 8 [Updated 2014 Aug 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020). Chinnery also discloses that many individuals with a mutation of mtDNA display a cluster of clinical features that fall into a discrete clinical syndrome, such as the Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers fibers fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS). Chinnery also discloses that considerable clinical variability exists, and many individuals do not fit neatly into one particular category, which is well-illustrated by the overlapping spectrum of disease phenotypes (including mitochondrial recessive ataxia syndrome (MIRAS)). Chinnery also discloses that common clinical features of mitochondrial disease – whether involving a mitochondrial or nuclear gene – include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Common central nervous system findings are fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity.

[0268] Ng et al., J Neurol (2016) 263:179-191 discloses the genetics and management of mitochondrial diseases, e.g., mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); myoclonic epilepsy with ragged red fibres (MERRF); mitochondrial neuro-gastrointestinal involvement and encephalopathy (MNGIE); neuropathy, ataxia, and retinitis pigmentosa (NARP); chronic progressive external ophthalmoplegia (CPEO); Alpers disease; Pearson syndrome; Leigh disease; Sengers syndrome; and Kearns-Sayre syndrome.

[0269] It has been reported that three very-highly conserved variants, p.Ile253Val, p.Glu192Lys, and p.Arg128His, in the ATPase domain of the TRAP1 gene may be associated with a statistically-significant, several-fold increased, prevalence of common chronic functional conditions, including at least pain, fatigue, and GI dysmotility (Boles et al., Mitochondrion 23 (2015) 64-70). These variants may be an important factor in the etiology of functional symptomatology. See, id.

[0270] It has been reported that mutations in TRAP1 may cause congenital abnormalities of the kidney and urinary tract (CAKUT) CAKUT or VACTERL association with CAKUT (Saisawat et al., Kidney International (2014) 85, 1310-1317).

[0271] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the methods comprising administering to the subject in need thereof an effective amount of a provided compound or pharmaceutical composition.

[0272] In another aspect, the present disclosure provides methods of preventing a disease in a subject in need thereof, the methods comprising administering to the subject in need thereof an effective amount of a provided compound or pharmaceutical composition.

[0273] In certain embodiments, the disease is a disease described herein. In certain embodiments, the disease is associated with decreased expression and/or activity of TRAP1. In certain embodiments, the disease is associated with decreased activity of TRAP1. In certain embodiments, the disease is associated with a mutation in the gene encoding TRAP1. In certain embodiments, the effective amount is effective in increasing the expression and/or activity of TRAP1. In certain embodiments, the effective amount is effective in increasing the activity of TRAP1.

[0274] In certain embodiments, the disease is associated with decreased expression and/or activity of PTEN induced putative kinase 1 (PINK1). In certain embodiments, the disease is associated with a mutation in the gene encoding PINK1. In certain embodiments, the effective amount is effective in increasing the expression and/or activity of PINK1.

[0275] In certain embodiments, the disease is associated with increased production of reactive oxygen species.

[0276] In certain embodiments, the disease is associated with decreased health, quality, function, quantity, and/or activity of mitochondria. In certain embodiments, the effective amount is effective in increasing the health, quality, function, quantity, and/or activity of mitochondria.

[0277] In certain embodiments, the disease is a mitochondrial disease, disease associated with oxidative stress, neurodegenerative disease, or kidney disease.

[0278] In certain embodiments, the disease is a mitochondrial disease. In certain embodiments, the disease is Alpers-Huttenlocher syndrome, Barth syndrome, Friedreich ataxia, Kearns-Sayre syndrome, Leigh disease, mitochondrial encephalomyopathy (e.g., MELAS syndrome, MERRF syndrome, or MNGIE syndrome), mitochondrial injury, mitochondrial myopathy (e.g., Kearns-Sayre syndrome or mitochondrial encephalomyopathy (e.g., MELAS syndrome, MERRF syndrome, or MNGIE syndrome)), multiple symmetric lipomatosis, Pearson marrow-pancreas syndrome, or Sengers syndrome. In certain embodiments, the disease is diabetes mellitus and deafness (DAD); Leber’s hereditary optic neuropathy (LHON); neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP); or mitochondrial DNA depletion syndrome. In certain embodiments, the disease is Leigh disease.

[0279] In certain embodiments, the disease is a neurological disease. In certain embodiments, the disease is a neurodegenerative disease. In certain embodiments, the disease is Parkinson’s disease (e.g., Guamanian parkinsonism-dementia or X-linked dystonia parkinsonism). In certain embodiments, the disease is Parkinson’s disease associated with a mutation in the gene encoding PINK1. In certain embodiments, the disease is Huntington’s disease. In certain embodiments, the disease is Alzheimer’s disease. In certain embodiments, the disease is dementia. In certain embodiments, the disease is frontotemporal dementia. In certain embodiments, the disease is amyotrophic lateral sclerosis. In certain embodiments, the disease is Friedreich’s ataxia.

[0280] In certain embodiments, the disease is associated with increased protein misfolding and/or protein aggregation. In certain embodiments, the disease is a proteopathy. In certain embodiments, the disease is pathological protein aggregation (e.g., synucleinopathy (e.g., (Lewy body dementia, multiple system atrophy, or Parkinson’s disease)); or trinucleotide repeat disorder (e.g., polyglutamine disease (e.g., dentatorubral-pallidoluysian atrophy, Huntington disease, Machado-Joseph disease, spinal-bulbar muscular atrophy, or spinocerebellar ataxia)).

[0281] In certain embodiments, the disease is a psychiatric disease. In certain embodiments, the disease is bipolar disorder. In certain embodiments, the disease is schizophrenia. In certain embodiments, the disease is anxiety disorder. In certain embodiments, the disease is a learning disability.

[0282] In certain embodiments, the disease is autonomic dysfunction.

[0283] In certain embodiments, the disease is a lysosomal storage disease. In certain embodiments, the disease is aspartylglucosaminuria; Danon disease; Farber disease; fucosidosis; galactosialidosis; Hermansky-Pudlak syndrome; mannosidase deficiency disorder (e.g., α-mannosidosis or β-mannosidosis); mucolipidosis; mucopolysaccharidosis (e.g., Di Ferrante syndrome, Hunter syndrome, Hurler syndrome, Hurler-Sheie syndrome, Maroteaux-Lamy syndrome, Morquio syndrome type A, Morquio syndrome type B, Natowicz syndrome, Sanfilippo syndrome, or Scheie syndrome); neuronal ceroid lipofuscinosis (e.g., adult neuronal ceroid lipofuscinosis, infantile neuronal ceroid lipofuscinosis (e.g., late infantile neuronal ceroid lipofuscinosis or variant late infantile neuronal ceroid lipofuscinosis), juvenile neuronal ceroid lipofuscinosis, or Northern epilepsy); Salla disease; Schindler disease; or sphingolipidosis (e.g., Fabry disease, gangliosidosis (e.g., GM1 gangliosidosis, GM2 gangliosidoses, GM2 gangliosidosis AB variant, Sandhoff disease, or Tay-Sachs disease), Gaucher’s disease, Krabbe disease, metachromatic leukodystrophy, or Niemann-Pick disease. In certain embodiments, the disease is Niemann-Pick disease, Fabry disease, Farber disease, Wolman disease, Gaucher’s disease, Krabbe disease, mucopolysaccharidosis type VII, neuronal ceroid lipofuscinosis type 2, or Pompe disease. In certain embodiments, the disease is (1) sphingolipidose (e.g., Fabry disease; Farber lipogranulomatosis; Gaucher disease types I, II, or III; Niemann-Pick disease types A or B; GM1 gangliosidosis; GM2-gangliosidosis (Sandhoff); GM2-gangliosidosis (Tay-Sachs); GM2-gangliosidosis (GM2-activator deficiency); GM3-gangliosidosis; metachromatic leukodystrophy; or sphingolipid-activator deficiency); (2) mucopolysaccharidose (e.g., MPS I (Schele, Hurler-Schele, or Hurler disease); MPS II (Hunter); MPS IIIA (Sanfilippo A); MPS IIIB (Sanfilippo B); MPS IIIC (Sanfilippo C); MPS IIID (Sanfilippo D); MPS IVA (Morquio syndrome A); MPS IVB (Morquio syndrome B); MPS VI (Maroteaux-Lamy); MPS VII (Sly disease); or MPS IX); (3) oligosaccharidose (e.g., α-mannosidosis; P-mannosidosis; fucosidosis; aspartylglucosaminuria; Schindler disease; sialidosis; galactosialidosis; mucolipidosis II (I-cell disease); or mucolipidosis III); (4) glycogen storage disease (e.g., Pompe disease); or (5) integral membrane protein disorder (e.g., cystinosis; Danon disease; action myoclonus-renal failure syndrome; Sailia disease; Niemann-Pick disease type C1; or Mucolipidosis IV). In certain embodiments, the disease is Haitia-Santavuori; Jansky-Bielschowsky; Spielmeyer-Sjogren; Parry; Hermansky-Pudlak diseases types 1-8; Griscelli 1, 2, or 3; or Chediak-Higashi disease. In certain embodiments, the disease is Tay-Sachs disease. In certain embodiments, the disease is Sandhoff disease. In certain embodiments, the disease is Niemann-Pick disease. In certain embodiments, the disease is Fabry disease. In certain embodiments, the disease is Gaucher’s disease.

[0284] In certain embodiments, the disease is chronic pain, fatigue, gastrointestinal dysmotility, congenital abnormality of the kidney and urinary tract, VACTERL association, or cardiac hypertrophy. In certain embodiments, the disease is a painful condition (e.g., chronic pain). In certain embodiments, the disease is fatigue (e.g., chronic fatigue syndrome). In certain embodiments, the disease is a kidney disease. In certain embodiments, the disease is autoimmune kidney disease (e.g., autoimmune nephritis); Bartter syndrome; cardiorenal syndrome; chronic kidney disease (e.g., chronic nephritis, chronic obstructive nephropathy, or chronic renal failure); diabetes insipidus (e.g., genetic diabetes insipidus (e.g., X-linked nephrogenic diabetes insipidus), nephrogenic diabetes insipidus (e.g., X-linked nephrogenic diabetes insipidus), or neurogenic diabetes insipidus); diabetic nephropathy (e.g., diabetic glomerulopathy); Gitelman syndrome; glomerular kidney disease (e.g., diabetic glomerulopathy, glomerular hypertrophy, glomerular kidney injury, glomerulitis, glomerulonephritis (e.g., Heymann nephritis, mesangial proliferative glomerulonephritis, or minimal change glomerulonephritis), glomerulosclerosis (e.g., focal segmental glomerulosclerosis), Goodpasture syndrome, kidney mesangial injury, or renal glomerular thrombosis); HANAC syndrome; hemolytic-uremic syndrome; hemorrhagic fever with renal syndrome; hepatorenal syndrome; hydronephrosis; idiopathic membranous nephropathy; Kelley-Seegmiller syndrome; kidney cyst; kidney failure; kidney infection; kidney injury (e.g., acute kidney injury, glomerular kidney injury, kidney mesangial injury, or kidney tubule injury); kidney interstitial fibrosis; kidney ischemia; kidney lesion; kidney necrosis (e.g., kidney tubular necrosis); kidney neoplasm (e.g., nephroblastoma, renal cell carcinoma (e.g., papillary renal cell carcinoma, renal adenocarcinoma, or renal clear cell carcinoma), renal epithelioid leiomyoma, renal pelvis neoplasm, or Wilms tumor (e.g., Denys-Drash syndrome); kidney tubule disease (e.g., Dent disease, Fanconi syndrome, kidney tubular necrosis, kidney tubule injury, kidney tubulointerstitial disease, or renal tubular acidosis ); Lesch-Nyhan syndrome; Lowe oculocerebrorenal syndrome; Mainzer-Saldino syndrome; nephritis (e.g., autoimmune nephritis, chronic nephritis, glomerulitis, immune complex nephritis (e.g., immune complex glomerulonephritis), interstitial nephritis, nephronophthisis (e.g., familial juvenile nephronophthisis), nephrotoxic nephritis, pyelitis, pyelonephritis, or Senior-Loken syndrome); nephrosclerosis; nephrotic syndrome; obstructive nephropathy; oligomeganephronic hypoplasia; polycystic kidney disease (e.g., autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease); primary hyperoxaluria type I; primary hyperoxaluria type II; renal amyloidosis; renal anemia; renal artery spasm; renal calculi; renal embolism; renal hypertrophy; renal infarction; renal-coloboma syndrome; Schinzel-Giedion midface retraction syndrome; ureteropelvic junction obstruction; or Zellweger syndrome. In certain embodiments, the disease is polycystic kidney disease. In certain embodiments, the disease is autosomal dominant polycystic kidney disease. In certain embodiments, the disease is autosomal recessive polycystic kidney disease. Polycystic kidney disease is an inherited genetic disorder that is characterized by the formation of renal cysts that block normal tubular function and thereby cause a progressive decline in kidney function with age, typically leading to end-stage renal disease (ESRD) by the sixth decade of life. See, e.g., Booij et al., SLAS Discovery, 2017, Vol. 22(8), 974-984.

[0285] In certain embodiments, the disease is a heart disease.

[0286] In certain embodiments, the disease is a gastrointestinal disease.

[0287] In certain embodiments, the disease is a liver disease.

[0288] In certain embodiments, the disease is a respiratory disease.

[0289] In certain embodiments, the disease is a cardiovascular disease.

[0290] In certain embodiments, the disease is sarcopenia.

[0291] In certain embodiments, the disease is a central nervous system (CNS) disease. In certain embodiments, the disease is a brain disease.

[0292] In certain embodiments, the disease is a hematological disease.

[0293] In certain embodiments, the disease is a metabolic disease. In certain embodiments, the disease is diabetes. In certain embodiments, the disease is obesity.

[0294] In certain embodiments, the disease is a genetic disease.

[0295] In certain embodiments, the disease is an inflammatory disease.

[0296] In certain embodiments, the disease is an autoimmune disease.

[0297] In certain embodiments, the disease is an autoinflammatory disease.

[0298] In certain embodiments, the disease is a proliferative disease. In certain embodiments, the disease is a cancer.

[0299] In certain embodiments, the effective amount, subject, biological sample, tissue, and cell are as described in the present disclosure.

[0300] In certain embodiments, the provided method further comprises administering to the subject in need thereof an additional therapy. In certain embodiments, the additional therapy is an additional pharmaceutical agent. In certain embodiments, the additional pharmaceutical agent is as described in the present disclosure. In certain embodiments, a provided method that further comprises administering to the subject in need thereof the additional therapy is synergistic as compared to a provided method that does not comprise administering to the subject in need thereof the additional therapy and as compared to a method comprises administering to the subject in need thereof the additional therapy as the only active therapy. In certain embodiments, the subject is a subject that has been administered the additional therapy. In certain embodiments, the subject is resistant to the additional therapy. In certain embodiments, the effective amount of a provided compound or pharmaceutical composition is effective in decreasing the resistance to the additional therapy. The additional therapy may be administered to the subject concurrently with, prior to, or subsequent to the administration of the provided compound or pharmaceutical composition.

[0301] In another aspect, the present disclosure provides compounds and pharmaceutical compositions for use in increasing the expression and/or activity of TRAP1 in a subject in need thereof.

[0302] In another aspect, the present disclosure provides compounds and pharmaceutical compositions for use in increasing the health, quality, function, quantity, and/or activity of mitochondria in a subject in need thereof.

[0303] In another aspect, the present disclosure provides compounds and pharmaceutical compositions for use in increasing the expression and/or activity of TRAP1 in a cell, tissue, or biological sample.

[0304] In another aspect, the present disclosure provides compounds and pharmaceutical compositions for use in increasing the health, quality, function, quantity, and/or activity of mitochondria in a cell, tissue, or biological sample.

[0305] In another aspect, the present disclosure provides compounds and pharmaceutical compositions for use in the treatment of a disease.

[0306] In another aspect, the present disclosure provides compounds and pharmaceutical compositions for use in the prevention of a disease.

[0307] In another aspect, the present disclosure provides use of compounds and pharmaceutical compositions in increasing the expression and/or activity of TRAP1 in a subject in need thereof.

[0308] In another aspect, the present disclosure provides use of compounds and pharmaceutical compositions in increasing the health, quality, function, quantity, and/or activity of mitochondria in a subject in need thereof.

[0309] In another aspect, the present disclosure provides use of compounds and pharmaceutical compositions in increasing the expression and/or activity of TRAP1 in a cell, tissue, or biological sample.

[0310] In another aspect, the present disclosure provides use of compounds and pharmaceutical compositions in increasing the health, quality, function, quantity, and/or activity of mitochondria in a cell, tissue, or biological sample.

[0311] In another aspect, the present disclosure provides use of compounds and pharmaceutical compositions in the treatment of a disease.

[0312] In another aspect, the present disclosure provides use of compounds and pharmaceutical compositions in the prevention of a disease.

[0313] In another aspect, the present disclosure provides use of compounds and pharmaceutical compositions in the manufacture of a medicament for increasing the expression and/or activity of TRAP1 in a subject in need thereof.

[0314] In another aspect, the present disclosure provides use of compounds and pharmaceutical compositions in the manufacture of a medicament for increasing the health, quality, function, quantity, and/or activity of mitochondria in a subject in need thereof.

[0315] In another aspect, the present disclosure provides use of compounds and pharmaceutical compositions in the manufacture of a medicament for increasing the expression and/or activity of TRAP1 in a cell, tissue, or biological sample.

[0316] In another aspect, the present disclosure provides use of compounds and pharmaceutical compositions in the manufacture of a medicament for increasing the health, quality, function, quantity, and/or activity of mitochondria in a cell, tissue, or biological sample.

[0317] In another aspect, the present disclosure provides use of compounds and pharmaceutical compositions in the manufacture of a medicament for the treatment of a disease.

[0318] In another aspect, the present disclosure provides use of compounds and pharmaceutical compositions in the manufacture of a medicament for the prevention of a disease.

EXAMPLES

[0319] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the methods and uses provided herein and are not to be construed in any way as limiting their scope. Certain known compounds are disclosed in U.S. Pat. Application Publication No. US 2018/0044286, which is incorporated by reference in its entirety.

Example 1. Preparation of Exemplary Compounds of the Present Disclosure

Methods and Materials

Cyclic Sulfonamide Synthetic Preparations

[0320] Scheme-1:

##STR00624##

##STR00625##

##STR00626##

[0321] Conditions: a. ClSO.sub.3H, 0° C.-110° C., 16 h. b. 4-chloroaniline, CH.sub.2Cl.sub.2, DMAP, pyridine, 0° C.-rt, 16 h. c. 2-bromoethan-1-ol, NaI, K.sub.2CO.sub.3, DMF, 80° C., 16 h. d. Fe, NH.sub.4Cl, EtOH, H.sub.2O, 80° C., 2 h. e. 4-methylnicotinic acid, HATU, DIPEA, DMF, 0° C.-rt, 16 h.

General Experimental Procedures

Scheme-1, Step-1 (Method-A)

[0322] To a stirred solution of corresponding 1 (1.0 eq.) was added chlorosulfonic acid (3.0 eq.) at 0° C. The resulting mixture was then heated to 110° C. for 16 h. The reaction mixture was cooled to room temperature, poured over ice cold water, extracted with EtOAc (2x 300 mL), combined organic layers were washed with water, brine solution, dried over Na.sub.2SO.sub.4 and concentrated to obtained crude compound. The crude compound was purified by combi-flash, eluting with EtOAc: hexanes to obtain corresponding sulfonylchloride

Scheme-1, Step-2 (Method-B)

[0323] To a stirred solution of corresponding amine (1.2 eq.), pyridine (3.0 eq.) and DMAP (0.1 eq.) in dichloromethane was added the corresponding sulfonylchloride (1.0 eq.) at 0° C. The resulting reaction mixture was stirred at room temperature for 16 h and monitored by TLC. The reaction mixture was quenched with water and extracted with dichloromethane (2 x 30 mL). The organic layer was washed with 1N HCl (20 mL) and dried over anhydrous sodium sulphate, the solvent was concentrated under reduced pressure to provide crude compound. The crude compound was purified by combi-flash column chromatography using EtOAc in hexanes as eluent to obtain corresponding sulfonamide.

Scheme-1, Step-3 (Method-C)

[0324] To a stirred solution of corresponding sulfonamide (1.0 eq.) in DMF were added K.sub.2CO.sub.3 (2.0 eq.), NaI (2.0 eq.) and bromoethanol (2.0 eq.) at room temperature. The resulting reaction mixture was allowed to stir at 80° C. for 16 h and was monitored by TLC. The mixture was diluted with ice water and extracted with EtOAc and the combined organic extracts were washed with brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude compound was purified by combi-flash, eluting with EtOAc: hexanes to obtain the corresponding cyclic sulfonamide.

Scheme-1, Step-4 (Method-D)

[0325] To a stirred solution of corresponding cyclic sulfonamide nitro compound (1.0 eq.) in EtOH and water, were added NH.sub.4Cl (10.0 eq.) and Fe (5.0 eq.) at room temperature. The resulting mixture was stirred at 90° C. for 2 h. After completion of the reaction (monitored by TLC) the mixture was cooled to room temperature, diluted with EtOAc, and filtered through a celite pad. The filtrate was washed with water and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. Crude compound was purified by combi-flash to obtain corresponding cyclic sulfonamide amine.

Scheme-1, Step-5 (Method-E)

[0326] To a stirred solution of corresponding acid (1.0 eq.) in DMF were added DIPEA (3.0 eq.) and HATU (1.5 eq.) at 0° C. and the resulting mixture stirred for 15 minutes. The corresponding cyclic sulfonamide amine (1.0 eq.) was then added and the resulting reaction mixture was stirred at room temperature for 12 h. After completion of reaction (monitored by TLC), the mixture was poured on ice cold water and the solid that separated was filtered and dried under reduced pressure. The crude compound was purified by combi-flash to obtain corresponding cyclic sulfonamide amide.

Experimental Procedures for Scheme-1

[0327] Scheme-1, Step-1: Preparation of 2-fluoro-5-nitrobenzenesulfonyl chloride (2)

##STR00627##

[0328] To a stirred solution of 1-fluoro-4-nitrobenzene (1, 10.0 g, 70.87 mmol, 1.0 eq.) was added chlorosulfonic acid (24.77 g, 212.61 mmol, 3.0 eq.) at 0° C. The resulting mixture was then heated to 110° C. for 16 h. The reaction mixture was cooled to room temperature, poured over ice cold water and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with water, brine solution, dried over Na.sub.2SO.sub.4, and concentrated to obtain crude compound. The crude compound was purified by combi-flash, eluting with EtOAc: hexanes (40:60) to afford a brown liquid 2 (4.00 g, 16.69 mmol, 23 % yield).

[0329] Scheme-1, Step-2: Preparation of N-(4-chlorophenyl)-2-fluoro-5-nitrobenzenesulfonamide (3)

##STR00628##

[0330] To a stirred solution of 4-chloroaniline (3.44 g, 27.13 mmol, 1.3 eq.) in dichloromethane (100 mL) were added pyridine (5.05 mL, 62.61 mmol, 3.0 eq.) and DMAP (0.254 g, 2.09 mmol, 0.1 eq.) at 0° C. and the reaction was stirred for 15 minutes. To the above solution, 2-fluoro-5-nitrobenzenesulfonyl chloride (2, 5.0 g, 20.87 mmol, 1.0 eq.) was added portion-wise. The resulting reaction mixture was allowed to stir at room temperature for 16 h. After completion of the reaction (monitored by TLC) the mixture was diluted with water and extracted with dichloromethane (2 x 300 mL). The combined organic extracts were washed with 2 N HCl (2 x 170 mL) and water (170 mL) followed by brine (200 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude compound was purified by combi-flash, eluting with EtOAc: hexanes (20:80) to afford a pale brown solid 3 (3.50 g, 10.58 mmol, 51 % yield). LC-MS: m/z 329.0 ([M-H].sup.-).

[0331] Scheme-1, Step-3: Preparation of 2-(4-chlorophenyl)-8-nitro-3, 4-dihydro-2H-benzo[b][1,4,5] oxathiazepine 1,1-dioxide (4)

##STR00629##

[0332] To a stirred solution of N-(4-chlorophenyl)-2-fluoro-5-nitrobenzenesulfonamide (3, 3.00 g, 9.07 mmol, 1.0 eq.) in DMF (50 mL) were added K.sub.2CO.sub.3 (2.507 g, 18.142 mmol, 2.0 eq.), NaI (2.719 g, 18.142 mmol, 2.0 eq.) and bromoethanol (2.27 g, 18.142 mmol, 2.0 eq.) at room temperature. The resulting reaction mixture was allowed to stir at 80° C. for 16 h, monitoring by TLC. The reaction was diluted with ice water and extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with brine (150 mL) and the organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude compound was purified by combi-flash, eluting with EtOAc: hexanes (20:80) to afford an off-white solid 4 (1.4 g, 3.950 mmol, 43% yield). LC-MS: m/z 353.0 ([M-H].sup.-).

[0333] Scheme-1, Step-4: Preparation of 8-amino-2-(4-chlorophenyl)-3, 4-dihydro-2H-benzo[b][1,4,5] oxathiazepine 1,1-dioxide (1184)

##STR00630##

[0334] To a solution of 2-(4-chlorophenyl)-8-nitro-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-1,1-dioxide (4, 1.4 g, 3.946 mmol, 1.0 eq.) in a mixture of EtOH/water (4:1) (24.0 mL) was added iron powder (1.102 g, 19.730 mmol, 5.0 eq.) followed by NH.sub.4Cl (2.110 g, 39.460 mmol, 10.0 eq.). The reaction mixture was heated with stirring at 80° C. and maintained for 2 h. The reaction mixture was cooled to room temperature, filtered through a celite pad and washed with EtOH (70 mL). The filtrate was concentrated, diluted with water (70 mL) and extracted with EtOAc (2 x 120 mL). The combined organic extracts were washed with brine (70 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude compound was purified by combi-flash, eluting with EtOAc: hexanes (20:80) to afford 1184 as a brown solid (0.90 g, 2.77 mmol, 70% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.42 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 2.8 Hz, 1H), 6.75-6.72 (m, 1H), 5.41 (s, 2H), 4.11-4.01 (m, 4H). LC-MS: m/z 325.1 ([M+H].sup.+).

Scheme-1, Step-5: Preparation of N-(2-(4-chlorophenyl)-1,1-Dioxido-3,4-Dihydro-2H-Benzo[b][1,4,5] Oxathiazepin-8-yl)-4-Methylnicotinamide (1209)

[0335] To a stirred solution of 4-methylnicotinic acid (0.063 g, 0.460 mmol, 1.5 eq.) in DMF (3.0 mL) were added HATU (0.351 g, 0.921 mmol, 3.0 eq.), DIPEA (0.16 mL, 0.921 mmol, 3.0 eq.) and 8-amino-2-(4-chlorophenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-1,1-dioxide (1184, 0.1 g, 0.307 mmol, 1.0 eq.) and the mixture was allowed to stir at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (2 x 70 mL). The combined organic extracts were washed with brine (50 mL) and the organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude compound was purified by combi-flash, eluting with EtOAc: hexanes (30:70) to afford 1209 as a pale brown solid (0.030 g, 0.067 mmol, 22% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.75 (s, 1H), 8.66 (s, 1H), 8.54 (d, J = 4.8 Hz, 1H), 8.17 (s, 1H), 7.94 (d, J = 7.2 Hz, 1H),7.44-7.33 (m, 4H), 7.22 (d, J = 8.0 Hz, 2H), 4.33 (s, 2H), 4.09 (s, 2H), 2.41(s, 3H). LC-MS: m/z 444.1 ([M+H].sup.+).

Analogous Compounds Were Prepared by Using the General Experimental Procedures

Preparation of N-(2-(4-chlorophenyl)-1, 1-Dioxido-3,4-Dihydro-2H-Benzo[b][1,4,5]Oxathiazepin-8-yl)-4-Methyloxazole-5-Carboxamide (1210)

[0336] Prepared by Method-E by reacting 8-amino-2-(4-chlorophenyl)-3,4-dihydro-2H-benzo[b] [1, 4, 5] oxathiazepine 1,1-dioxide (1184) with 4-methyloxazole-5-carboxylic, to afford a pale brown solid (37% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.59 (s, 1H), 8.55 (s, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.00 (dd, J.sub.1 = 8.8 Hz, J.sub.2 = 2.4 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 4.31 (s, 2H), 4.09 (s, 2H), 2.32 (s, 3H). LC-MS: m/z 434.1 ([M+H].sup.+).

[0337] Preparation of 2-fluoro-5-nitro-N-(4-(trifluoromethyl) phenyl)benzenesulfonamide (5)

##STR00631##

[0338] Prepared by Method-B by reacting 2-fluoro-5-nitrobenzenesulfonyl chloride (2) with 4-(trifluoromethyl) aniline, to afford a pale brown solid (46% yield). LC-MS: m/z 363.0 ([M-H].sup.-).

[0339] Preparation of 8-nitro-2-(4-(trifluoromethyl) phenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (6)

##STR00632##

[0340] Prepared by Method-C by reacting 2-fluoro-5-nitro-N-(4-(trifluoromethyl) phenyl)benzenesulfonamide (5) with 2-bromoethan-1-ol, to afford an off white solid (25% yield). LC-MS: m/z 388.0 ([M-H].sup.-).

[0341] Preparation of 8-amino-2-(4-(trifluoromethyl) phenyl)-3, 4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (1177)

##STR00633##

[0342] Prepared by following Method-D to afford a brown solid (81% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.74 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz,1H), 6.91 (d, J = 3.2 Hz, 1H), 6.76-6.73 (m, 1H), 5.45 (s, 2H), 4.12-4.10 (m, 4H). LC-MS: m/z 359.0 ([M+H].sup.+).

Preparation of N-(1,1-Dioxido-2-(4-(Trifluoromethyl)Phenyl)-3,4-Dihydro-2H-benzo[b][1,4,5]Oxathiazepin-8-yl)-4-Methyloxazole-5-Carboxamide (1190)

[0343] Prepared by Method-E by reacting 8-amino-2-(4-(trifluoromethyl) phenyl)-3,4-dihydro-2H-benzo[b][1,4,5] oxathiazepine-1,1-dioxide (1177) with 4-methyloxazole-5-carboxylic acid, to afford an off-white solid (38% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.60 (s, 1H), 8.56 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.01 (dd, J.sub.1 = 8.8 Hz, J.sub.2 = 2.8 Hz,1H), 7.74 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 9.2 Hz,1H), 4.33-4.31 (m, 2H), 4.20-4.18 (m, 2H), 2.42 (s, 3H). LC-MS: m/z 468.1 ([M+H].sup.+).

Preparation of N-(1,1-Dioxido-2-(4-(Trifluoromethyl)Phenyl)-3,4-Dihydro-2H-Benzo[b][1,4,5]Oxathiazepin-8-yl)-4-Methylnicotinamide (1212)

[0344] Prepared by Method-E by reacting 8-amino-2-(4-(trifluoromethyl) phenyl)-3,4-dihydro-2H-benzo[b][1,4,5] oxathiazepine-1,1-dioxide (1177) with 4-methylnicotinic acid, to afford a pale brown solid (32% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.77 (s, 1H), 8.67 (s, 1H), 8.54 (d, J = 4.8 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H), 7.94 (dd, J.sub.1 = 9.2 Hz, J.sub.2 = 2.4 Hz,1H), 7.75 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.37-7.34 (m, 2H), 4.34 (d, J = 4.4 Hz, 2H), 4.20 (d, J = 4.0 Hz, 2H), 2.41 (s, 3H). LC-MS: m/z 478.1 ([M+H].sup.+).

Preparation of n-(1, 1-Dioxido-2-(4-(Trifluoromethyl) Phenyl)-3, 4-Dihydro-2H-Benzo[b][1,4,5]Oxathiazepin-8-yl)Oxazole-5-Carboxamide (1994)

[0345] Prepared by Method-E by reacting 8-amino-2-(4-(trifluoromethyl) phenyl)-3,4-dihydro-2H-benzo[b][1,4,5] oxathiazepine-1,1-dioxide (1177) with oxazole-5-carboxylic acid, to afford an off-white solid (30% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.87 (s, 1H), 8.66 (s, 1H), 8.14 (d, J = 2.4 Hz, 1H), 8.05 (dd, J.sub.1 = 8.8 Hz, J.sub.2 = 6.4 Hz,1H), 7.99 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz,2H), 7.36 (d, J = 8.4 Hz,1H), 4.33 (d, J = 4.4 Hz, 2H), 4.20 (d, J = 3.6 Hz, 2H). LC-MS: m/z 454.0 ([M+H].sup.+).

Preparation of N-(1,1-Dioxido-2-(4-(trifluoromethyl)Phenyl)-3,4-Dihydro-2H-Benzo[b][1,4,5]Oxathiazepin-8-yl)-2-Methyloxazole-4-Carboxamide (1992)

[0346] Prepared by Method-E by reacting 8-amino-2-(4-(trifluoromethyl) phenyl)-3,4-dihydro-2H-benzo[b][1,4,5] oxathiazepine-1,1-dioxide (1177) with 2-methyloxazole-4-carboxylic acid, to afford an off-white solid (31% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 2.50 (s, 3H), 4.20-4.19 (m, 2H), 4.31-4.30 (m, 2H), 7.33-7.31 (m,1H), 7.44-7.42 (m, 2H), 7.75-7.73 (m, 2H), 8.05-8.02 (m, 1H), 8.34-8.33 (m, 1H), 8.65 (s, 1H), 10.50 (s, 1H). LC-MS: m/z 468.1 ([M+H].sup.+).

Preparation of N-(1,1-Dioxido-2-(4-(Trifluoromethyl)Phenyl)-3,4-Dihydro-2H-Benzo[b][1,4,5]Oxathiazepin-8-yl)Oxazole-4-Carboxamide (1976)

[0347] Prepared by Method-E by reacting 8-amino-2-(4-(trifluoromethyl) phenyl)-3,4-dihydro-2H-benzo[b][1,4,5] oxathiazepine-1,1-dioxide (1177) with oxazole-4-carboxylic acid, to afford a pale yellow solid (15% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.57 (s, 1H), 8.83 (s, 1H), 8.63 (s, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.06 (dd, J.sub.1 = 9.2, J.sub.2 =2.8 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 8.8 Hz, 1H), 4.31 (s, 2H), 4.20 (d, J = 3.2 Hz, 2H). LC-MS: m/z 454.1 ([M+H].sup.+).

Preparation of N-(1,1-Dioxido-2-(4-(Trifluoromethyl)Phenyl)-3,4-Dihydro-2H-Benzo[b][1,4,5]Oxathiazepin-8-yl)-5-Methyloxazole-4-Carboxamide (1975)

[0348] Prepared by Method-E by reacting 8-amino-2-(4-(trifluoromethyl) phenyl)-3,4-dihydro-2H-benzo[b][1,4,5] oxathiazepine-1,1-dioxide (1177) with 5-methyloxazole-4-carboxylic acid, to afford an off-white solid (65% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.58 (s, 1H), 8.46 (s, 1H), 8.39 (d, J = 4.0, 2H), 8.03-8.0 (m, 1H), 7.75-7.73 (m, 2H), 7.44-7.41 (m, 2H), 7.32-7.31 (m, 2H), 4.32-4.30 (m, 2H), 4.19-4.18 (m, 2H), 2.62 ( s, 3H). LC-MS: m/z 468.1 ([M+H].sup.+).

Preparation of N-(1,1-Dioxido-2-(4-(Trifluoromethyl)Phenyl)-3,4-Dihydro-2H-Benzo[b][1,4,5]Oxathiazepin-8-yl)-2,4-Dimethyloxazole-5-Carboxamide (1974)

[0349] Prepared by Method-E by reacting 8-amino-2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5] oxathiazepine-1,1-dioxide (1177) with 2,4-dimethyloxazole-5-carboxylic acid, to afford an off-white solid (69% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.15 (dd, J.sub.1 = 6.0 Hz, J.sub.2 = 2.8 Hz,1H), 7.88 (s, 1H), 7.70 (d, J = 2.8 Hz,1H), 7.57 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 4.44 (d, J = 9.6 Hz, 2H), 4.18 (t, J = 9.2 Hz, 2H), 2.51-2.50 (m, 6H). LC-MS: m/z 482.05 ([M+H].sup.+).

Preparation of N-(1,1-Dioxido-2-(4-(Trifluoromethyl)Phenyl)-3,4-Dihydro-2H-Benzo[b][1,4,5]Oxathiazepin-8-yl)-4-Methylthiazole-5-Carboxamide (2058)

[0350] Prepared by Method-E by reacting 8-amino-2-(4-(trifluoromethyl) phenyl)-3,4-dihydro-2H-benzo[b][1,4,5] oxathiazepine-1,1-dioxide (1177) with 4-methylthiazole-5-carboxylic acid, to afford a pale brown solid (35% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.47 (s, 1H), 9.14 (s, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.95 (dd, J.sub.1 = 8.4 Hz, J.sub.2 = 2.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.8 Hz, 1H), 4.33 (bs, 2H), 4.20 (d, J = 3.6 Hz, 2H), 2.62 (s, 3H). LC-MS: m/z 484.1 ([M+H].sup.+).

Preparation of N-(1, 1-Dioxido-2-(4-(Trifluoromethyl) Phenyl)-3,4-Dihydro-2H-Benzo [b] [1,4,5] Oxathiazepin-8-yl)-1H-Imidazole-5-Carboxamide (2075)

[0351] Prepared by Method-E by reacting 8-amino-2-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4,5] oxathiazepine-1,1-dioxide (1177) with 1H-imidazole-5-carboxylic acid, to afford an off-white solid (58% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.65 (bs, 1H), 10.23 (bs, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.04-8.03 (m, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.8 Hz, 1H), 4.28-4.27 (d, J = 4.4 Hz, 2H), 4.16-4.15 (d, J = 4.4 Hz, 2H). LC-MS: m/z 453.0 ([M+H].sup.+).

Preparation of N-(1,1-Dioxido-2-(4-(Trifluoromethyl)Phenyl)-3,4-Dihydro-2H-Benzo[b][1,4,5]Oxathiazepin-8-yl)-4-Isopropylthiazole-5-Carboxamide (2080)

[0352] Prepared by Method-E by reacting 8-amino-2-(4-(trifluoromethyl) phenyl)-3,4-dihydro-2H-benzo[b][1,4,5] oxathiazepine-1,1-dioxide (1177) with 4-isopropylthiazole-5-carboxylic acid, to afford an off-white solid (14% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.35 (s, 1H), 9.12 (s, 1H), 8.152-8.147 (m, 1H), 7.958-7.931 (m, 1H), 7.76-7.73 (m, 2H), 7.45-7.43 (m, 2H), 7.34-7.32 (m, 1H), 4.33 (s, 2H), 4.19 (s, 2H), 3.68-3.65 (m, 1H), 1.33-1.17 (m, 6H). LC-MS: m/z 512.0 ([M+H].sup.+).

Preparation of N-(1,1-Dioxido-2-(4-(Trifluoromethyl)phenyl)-3,4-Dihydro-2H-Benzo[b][1,4,5]Oxathiazepin-8-yl)-5-Isopropylthiazole-4-Carboxamide (2085)

[0353] Prepared by Method-E by reacting 8-amino-2-(4-(trifluoromethyl) phenyl)-3,4-dihydro-2H-benzo[b][1,4,5] oxathiazepine-1,1-dioxide (1177) with 5-isopropylthiazole-4-carboxylic acid, to afford an off-white solid (40% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.62 (bs, 1H), 9.06 (bs, 1H), 8.42 (d, J = 2.8 Hz, 1H), 8.02 (dd, J.sub.1 = 2.4 Hz, J.sub.2= 8.8 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.8 Hz, 1H), 4.32-4.18 (m, 5H), 1.30 (s, 3H), 1.29 (s, 3H). LC-MS: m/z 512.2 ([M+H].sup.+).

Preparation of N-(1,1-Dioxido-2-(4-(Trifluoromethyl)Phenyl)-3,4-Dihydro-2H-Benzo[b][1,4,5]Oxathiazepin-8-yl)-1-Methyl-1H-Imidazole-2-Carboxamide (2090)

[0354] Prepared by Method-E by reacting 8-amino-2-(4-(trifluoromethyl) phenyl)-3,4-dihydro-2H-benzo[b][1,4,5] oxathiazepine-1,1-dioxide (1177) with 1-methyl-1H-imidazole-2-carboxylic acid, to afford an off-white solid (42% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.58 (s, 1H), 8.46 (s, 1H), 8.0-7.9 (m, 1H), 7.77-7.75 (m, 2H), 7.74-7.73 (m, 2H ),7.33-7.31(m, 1H), 7.09 (s, 1H), 4.32-4.30 ( m, 2H), 4.19-4.18 (m, 2H), 3.98 (s, 3H). LC-MS: m/z 481.1 ([M+H].sup.+).

[0355] Preparation of N-(4-bromophenyl)-2-fluoro-5-nitrobenzenesulfonamide (7)

##STR00634##

[0356] Prepared by Method-B by reacting 2-fluoro-5-nitrobenzenesulfonyl chloride (2) with 4-bromoaniline, to afford a pale brown solid (63% yield). LC-MS: m/z 374.80 ([M-H].sup.-).

[0357] Preparation of 2-(4-bromophenyl)-8-nitro-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-1,1-dioxide (8)

##STR00635##

[0358] Prepared by Method-C by reacting N-(4-bromophenyl)-2-fluoro-5-nitrobenzenesulfonamide with 2-bromoethan-1-ol, to afford an off-white solid (52% yield). LC-MS: m/z 396.85 ([M-H].sup.-).

[0359] Preparation of 8-amino-2-(4-bromophenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (9)

##STR00636##

[0360] Was prepared by following Method-D to afford a pale brown solid (64% yield). LC-MS: m/z 371.0 ([M+H].sup.+).

Preparation of N-(2-(4-bromophenyl)-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-8-yl)-2-phenyl-1H-imidazole-5-carboxamide (1331)

[0361] Prepared by Method-E by reacting 8-amino-2-(4-bromophenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (9) with sodium 2-phenyl-1H-imidazole-5-carboxylate (26) to afford a pale brown solid (13% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 13.16 (s, 1H), 10.18 (s, 1H), 8.31 (d, J = 2.8 Hz,1H), 8.13-8.06 (m, 3H), 7.96 (d, J = 2.4 Hz, 1H), 7.57-7.41 (m, 5H), 7.32 (d, J = 8.8 Hz, 1H), 7.16-7.13 (m, 2H), 4.29 (t, J = 8.4 Hz, 2H), 4.10 (t, J = 8.0 Hz, 2H). LC-MS: m/z 540.90 ([M+H].sup.+).

[0362] Preparation of 2-fluoro-5-nitro-N-phenylbenzenesulfonamide (10)

##STR00637##

[0363] Prepared by Method-B by reacting 2-fluoro-5-nitrobenzenesulfonyl chloride (2) with aniline, to afford a brown solid (61% yield).

[0364] Preparation of 8-nitro-2-phenyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (11)

##STR00638##

[0365] Prepared by Method-C by reacting 2-fluoro-5-nitro-N-phenylbenzenesulfonamide (10) with 2-bromoethan-1-ol, to afford a pale yellow solid (62% yield).

[0366] Preparation of 8-amino-2-phenyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (2131)

##STR00639##

[0367] Was prepared by Method-D to afford a yellow solid (27% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.37-7.27 (m, 3H), 7.76 (dd J.sub.1 = 8.8 Hz, J.sub.2 = 8.4 Hz, 2H), 6.99 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 2.8 Hz, 1H), 6.73 (dd J.sub.1 = 8.4 Hz, J.sub.2 = 2.8 Hz, 1H), 5.40 (s, 2H), 4.11-4.09 (m, 2H), 4.03-4.01 (m, 2H). LC-MS: m/z 291.0 ([M+H].sup.+).

Preparation of N-(1,1-dioxido-2-phenyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-8-yl)-5-methyloxazole-4-carboxamide (2135)

[0368] Prepared by Method-E by reacting 8-amino-2-phenyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-1,1-dioxide (2131) with 5-methyloxazole-4-carboxylic acid, to afford an off-white solid (81% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.42 (s, 1H), 8.46 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.00 (dd J.sub.1 = 8.8 Hz, J.sub.2 = 2.4 Hz, 1H), 7.37-7.27 (m, 4H), 7.16 (d, J = 7.2 Hz, 2H), 4.29 (t, J = 3.6 Hz, 2H), 4.09 (t, J = 4.4 Hz, 2H), 2.67 (s, 3H). LC-MS: m/z 400.1 ([M+H].sup.+)

[0369] Preparation of 2-fluoro-5-nitro-N-(o-tolyl)benzenesulfonamide (12)

##STR00640##

[0370] Prepared by Method-B by reacting 2-fluoro-5-nitrobenzenesulfonyl chloride (2) with with o-toluidine, to afford a pale brown solid (59% yield).

[0371] Preparation of 8-nitro-2-(o-tolyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (13)

##STR00641##

[0372] Prepared by Method-C by reacting 2-fluoro-5-nitro-N-(o-tolyl)benzenesulfonamide (12) with 2-bromoethan-1-ol, to afford a pale yellow solid (64% yield).

[0373] Preparation of 8-amino-2-(o-tolyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (2094)

##STR00642##

[0374] Prepared by following Method-D to afford a pale brown solid (66% yield). LC-MS: m/z 305.0 ([M-H].sup.+).

Preparation of N-(1,1-dioxido-2-(o-tolyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-8-yl)-5-methyloxazole-4-carboxamide (2096)

[0375] Prepared by Method-E by reacting 8-amino-2-(o-tolyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-1,1-dioxide (2094) with 5-methyloxazole-4-carboxylic acid, to afford an off-white solid (40% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.42 (s, 1H), 8.45 (s, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.01 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H) 7.37-7.31 (m, 2H), 7.24 (t, J = 7.2 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 4.46-4.32 (m, 2H), 4.15-4.09 (m, 1H), 3.51-3.48 (m, 1H), 2.61 (s, 3H), 2.34 (s, 3H). LC-MS: m/z 414.2 ([M+H].sup.+)

[0376] Preparation of 2-fluoro-N-(4-methoxyphenyl)-5-nitrobenzenesulfonamide (14)

##STR00643##

[0377] Prepared by Method-B by reacting 2-fluoro-5-nitrobenzenesulfonyl chloride (2) with 4-methoxvaniline. to afford a brown solid (40% vield). LC-MS: m/z 325.1 ([M-H].sup.-).

[0378] Preparation of 2-(4-methoxyphenyl)-8-nitro-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (15)

##STR00644##

[0379] Prepared by Method-C by reacting 2-fluoro-N-(4-methoxyphenyl)-5-nitrobenzenesulfonamide (15) with 2-bromoethan-1-ol, to afford a yellow solid (52% yield).

[0380] Preparation of 8-amino-2-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (2158)

##STR00645##

[0381] Prepared by following Method-D to afford an off white solid (82% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.00 (t, J = 8.4 Hz, 3H), 6.88 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 2.4 Hz, 1H), 6.73 (dd, J.sub.1 = 8.8 Hz, J.sub.2 = 2.8 Hz, 1H), 5.37 (s, 2H), 4.10 (d, J = 4.0 Hz, 2H), 3.93 (d, J = 3.2 Hz, 2H), 3.71 (s, 3H). LC-MS: m/z 321.1 ([M+H].sup.+).

Preparation of N-(2-(4-methoxyphenyl)-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-8-yl)-5-methyloxazole-4-carboxamide (2167)

[0382] Prepared by Method-E by reacting 8-amino-2-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (2158) with 5-methyloxazole-4-carboxylic acid, to afford an off-white solid (37% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.40 (bs, 1H), 8.44 (bs, 1H), 8.31 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.29 (bs, 2H), 4.00 (bs, 2H), 3.70 (s, 3H), 2.50 (s, 3H). LC-MS: m/z 430.1 ([M+H].sup.+).

[0383] Preparation of 2-fluoro-N-(4-fluorophenyl)-5-nitrobenzenesulfonamide (16)

##STR00646##

[0384] Prepared by Method-B by reacting 2-fluoro-5-nitrobenzenesulfonyl chloride (2) with 4-fluoroaniline, to afford a pale yellow solid (76% yield). LC-MS: m/z 313 ([M-H].sup.-).

[0385] Preparation of 2-(4-fluorophenyl)-8-nitro-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (17)

##STR00647##

[0386] Prepared by Method-C by reacting 2-fluoro-N-(4-fluorophenyl)-5-nitrobenzenesulfonamide (16) with 2-bromoethan-1-ol, to afford a yellow solid (83% yield).

[0387] Preparation of 8-amino-2-(4-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (18)

##STR00648##

[0388] Prepared by following Method-D to afford a pale yellow (73% yield). LC-MS: m/z 307.0 ([M-H].sup.+).

Preparation of N-(2-(4-fluorophenyl)-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-8-yl)-5-methyloxazole-4-carboxamide (2375)

[0389] Prepared by Method-E by reacting 8-amino-2-(4-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (18) with 5-methyloxazole-4-carboxylic acid, to afford a pale yellow solid (81% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.39 (s, 1H), 8.44 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.0 (dd, J.sub.1 = 2.4 Hz, J.sub.2 = 6.4 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 6.8 Hz, 4H), 4.3 (d, J = 4.0 Hz, 2H), 4.06 (d, J = 4.0 Hz, 2H), 2.61 (s, 3H). LC-MS: m/z 416.0 ([M+H].sup.+)

[0390] Preparation of N-(4-cyanophenyl)-2-fluoro-5-nitrobenzenesulfonamide (19)

##STR00649##

[0391] Prepared by Method-B by reacting 2-fluoro-5-nitrobenzenesulfonyl chloride (2) with 4-aminobenzonitrile, to afford a yellow solid (45% yield). LC-MS: m/z 320.0 ([M-H].sup.-).

[0392] Preparation of 4-(8-nitro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)benzonitrile (20)

##STR00650##

[0393] Prepared by Method-C by reacting N-(4-cyanophenyl)-2-fluoro-5-nitrobenzenesulfonamide (19) with 2-bromoethan-1-ol, to afford a yellow solid (39% yield). LC-MS: m/z 344.0 ([M-H].sup.-).

[0394] Preparation of 4-(8-amino-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)benzonitrile (21)

##STR00651##

[0395] Prepared by following Method-D to afford an off-white solid (27% yield).

Preparation of N-(2-(4-cyanophenyl)-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-8-yl)-5-methyloxazole-4-carboxamide (2377)

[0396] Prepared by Method-E by reacting 4-(8-amino-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)benzonitrile (21) with 5-methyloxazole-4-carboxylic acid, to afford an off-white solid (23% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.55 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.02-8.00 (m, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 4.31-4.30 (m, 2H), 4.22-4.21 (m, 2H), 2.50 (s, 3H). LC-MS: m/z 425.1 ([M+H].sup.+).

[0397] Preparation of 2-methoxy-5-nitro-N-(6-(trifluoromethyl) pyridin-2-yl)benzenesulfonamide (22)

##STR00652##

[0398] Prepared by Method-B by reacting 2-methoxy-5-nitrobenzenesulfonylchloride with 6-(trifluoromethyl) pyridin-2-amine, to afford a brown solid (37% yield). LC-MS: m/z 377.95 ([M+H].sup.-).

[0399] Preparation of 2-hydroxy-5-nitro-N-(6-(trifluoromethyl) pyridin-2-yl)benzenesulfonamide (23)

##STR00653##

[0400] To a stirred solution of 2-methoxy-5-nitro-N-(6-(trifluoromethyl) pyridin-3-yl)benzenesulfonamide (22, 2.20 g, 5.830 mmol, 1.0 eq.) in dichloromethane (20 mL) was added BBr3 (1 M in dichloromethane, 17.5 mL 17.49 mmol, 3.0 eq.) at 0° C. The resulting reaction mixture was allowed to stir at room temperature for 1 h. The mixture was diluted with ice water and extracted with dichloromethane (2 x 300 mL). The combined organic extracts were washed with sodium bicarbonate solution (2 x 200 mL) followed by saturated sodium chloride (200 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a brown solid 23. LC-MS: m/z 364.0 ([M+H].sup.-).

[0401] Preparation of 8-nitro-2-(6-(trifluoromethyl) pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (24)

##STR00654##

[0402] Prepared by Method-C by reacting 2-hydroxy-5-nitro-N-(6-(trifluoromethyl) pyridin-2-yl)benzenesulfonamide (23) with dibromoethane, to afford a brown solid (35% yield). LC-MS: m/z 390.0 ([M-H].sup.-).

[0403] Preparation of 9-nitro-2-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide (25)

##STR00655##

[0404] Prepared by Method-C by reacting 2-fluoro-5-nitro-N-(4-(trifluoromethyl) phenyl)benzenesulfonamide) (5) with 3-bromo propanol. The crude product was used for the next step.

[0405] Preparation of 9-amino-2-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide (1996)

##STR00656##

[0406] Prepared by following Method-D to afford a brown solid. LC-MS: m/z 373.0 ([M+H].sup.+).

Preparation of N-(1, 1-Dioxido-2-(4-(Trifluoromethyl) Phenyl)-2,3,4,5-Tetrahydrobenzo[b][1,4,5]Oxathiazocin-9-yl)-4-Methyloxazole-5-Carboxamide (1989)

[0407] Prepared by Method-E by reacting 9-amino-2-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[b][1,4,5] oxathiazocine-1,1-dioxide (1996) with 4-methyloxazole-5-carboxylic acid, to afford a white solid (31% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 1.85-1.82 (m, 2H), 2.44(s,3H) 4.08-4.05 (m, 2H), 4.34-4.31 (m, 2H), 7.35-7.33 (m, 2H), 7.46-7.44 (m, 1H), 7.73-7.71 (m, 2H), 8.11-8.08 (m, 1H), 8.40-8.39 (m, 1H), 8.57 (s, 1H), 10.63 (s, 1H). LC-MS: m/z 482.1 ([M+H].sup.+).

Synthesis of Sodium 2-Phenyl-1H-Imidazole-5-carboxylAte (26)

[0408] Scheme-2:

##STR00657##

Step-1: Preparation of 2-Phenyl-5-(Trifluoromethyl)-1H-Imidazole

[0409] 1,1-dibromo-3,3,3-trifluoro acetone (15.5 g, 0.057 mol, 1.11 eq.) was dissolved in aqueous sodium acetate solution (8.5 g, 0.0104 mol, 1.0 eq.) in 26 mL of water. The mixture was stirred at 90° C. for 30 minutes and then cooled to ambient temperature. Benzaldehyde (5.5 g, 0.052 mol,1.0 eq.) dissolved in a mixture of 160 mL methanol and 53 mL aqueous ammonia was then added to the mixture. The reaction mixture was stirred overnight at room temperature. After completion of the reaction (monitored by TLC), the excess of methanol was evaporated under reduced pressure and ice water was added to the remaining aqueous phase. The solid that separated was filtered, washed with water (20 mL) and dried, to obtain an off-white solid (9.0 g, 0.0424 mol, 74% yield). LC-MS: m/z 212.7 ([M+H].sup.+).

Step-2: Preparation of Sodium 2-Phenyl-1H-Imidazole-5-Carboxylate (26)

[0410] To a solution of 2-phenyl-5-(trifluoromethyl)-1H-imidazole (9.0 g, 0.0424 mol, 1.0 eq.) in water (25 mL) was added sodium hydroxide (2.3 g, 0.0572 mol, 1.35 eq.) at 0° C. The resulting reaction mixture was gradually warmed to room temperature and then heated to 95° C. for 12 h. The reaction mixture was cooled to room temperature and diluted with water (10 mL). The contents were transferred to a separatory funnel, washed with dichloromethane (2 x 30 mL) and the layers were separated. The aqueous layer was neutralized with concentrated HCl and the aqueous solvent was removed by lyophilization for 16 h to obtain the crude compound 26 as a pale yellow solid (6.5 g crude). LC-MS: m/z 186.9 ([M-H].sup.-).

[0411] Additional General Procedures to Prepare Left-Hand Side Variants

##STR00658##

General Procedure 1

[0412] To a mixture of 1177 (21.4 mg, 0.06 mmol, 1.0 eq.), carboxylic acid (0.072 mmol, 1.2 eq.) and triethylamine (0.3 mmol, 5.0 eq.) in ACN (0.5 mL) was added propanephosphonic acid anhydride (T.sub.3P, 0.08 mL) and the mixture heated at 100° C. for 16 h. LC-MS showed 1177 was consumed completely. The reaction mixtures were concentrated by Speedvac. The residues were purified by preparative HPLC (basic condition) to give Final Products.

General Procedure 2

[0413] To a mixture of 1177 (21.4 mg, 0.06 mmol, 1.0 eq.), carboxylic acid (0.072 mmol, 1.2 eq.), pyridine (0.1 mL) and triethylamine (0.1 mL) in THF (0.1 mL) was added propanephosphonic acid anhydride (T.sub.3P, 0.1 mL) and the mixture heated at 80° C. for 16 h. LC-MS showed 1177 was consumed completely. The reaction mixtures were concentrated by Speedvac. The residues were purified by preparative HPLC (basic condition) to give Final Products.

General Procedure 3

[0414] To a mixture of 1177 (21.4 mg, 0.06 mmol, 1.0 eq.), carboxylic acid (0.072 mmol, 1.2 eq.) and K.sub.2CO.sub.3 (0.12 mmol, 2 eq.) in DMF (0.5 mL) was added HATU (0.063 mmol, 1.05 eq.) and the mixture heated at 30° C. for 16 h. LC-MS showed 1177 was consumed completely. The reaction mixtures were concentrated by Speedvac. The residues were purified by preparative HPLC (basic condition) to give Final Products.

[0415] The following compounds were prepared using the above general procedures by reacting compound 1177 with a variety of carboxylic acids. All products gave mass spectral and/or .sup.1H-NMR data consistent with the structure.

TABLE-US-00003 Exemplary general procedures for preparing select compounds Compound No. General Procedure No. Compound No. General Procedure No. 2172 1 2241 2 2173 1 2242 1 2174 1 2245 1 2175 1 2248 2 2179 2 2249 2 2180 2 2254 2 2181 2 2257 2 2184 2 2258 2 2187 3 2261 1 2190 3 2264 1 2191 1 2265 2 2192 2 2268 1 2194 3 2275 1 2197 1 2280 3 2198 1 2286 1 2199 1 2288 1 2200 1 2290 3 2202 2 2291 1 2206 1 2294 2 2209 1 2295 2 2210 1 2296 3 2213 2 2299 3 2215 1 2305 3 2219 2 2317 2 2221 1 2323 1 2222 2 2334 3 2224 1 2337 1 2226 2 2339 2 2227 2 2343 2 2234 1 2344 1 2230 1 2345 2 2236 1 2351 2 2240 1

Example 2. ADP Glo Assay

[0416] Potency of test compounds to modulate the ATPase activity of TRAP1 enzyme was evaluated using ADP Glo assay. The assay is based on quantification of the ADP generated from ATP in the ATPase reaction. The assay is performed in two steps; first, after the ATPase reaction, an equal volume of ADP-Glo™ Reagent is added to terminate the ATPase reaction and deplete the remaining ATP. Second, the Kinase Detection Reagent is added to simultaneously convert ADP to ATP and allow the newly synthesized ATP to be measured using a luciferase/luciferin reaction.

[0417] All the assays were carried out in a 384-well Proxiplate. The buffer used was 25 mM Pipes pH-7.5, 40 mM KCl, 0.05 mM MgCl.sub.2, 0.025 % BSA, 0.316 mM EGTA, 0.003% Empigen, 0.01% Igepal. 150 nM Trap1 enzyme was incubated with various concentrations of the test compound (0.79 .Math.M - 100 .Math.M) at 37° C. for 30 mins (except in blank wells). 20 .Math.M ATP was added to each well to start the reaction. The plate was spun for 1 min at 1200 rpm and then incubated at 37° C. for 60 mins. 5 .Math.l of ADP Glo reagent was added to all the wells and spun the plate for 1 min at 1200 rpm and kept it on a shaker at ambient temperature for 60 mins. 10 .Math.l of kinase detection mix was added to all the wells and the plate was read for Luminescence at 495 nm. The amount of ADP released was estimated from ATP/ADP standard curve generated at the same experimental conditions. E.sub.max (Maximal percent activation) and EC.sub.50 (concentration for half maximal activation ) were estimated by fitting the dose response data to a sigmoidal curve fitting equation using Graphpad Prism software V. 8. Exemplary results are shown in Table 2.

TABLE-US-00004 Exemplary biochemical data of select compounds Compound No. ADP GLO DRC: GeoMean EC.sub.50 (.Math.M) ADP GLO DRC: Mean E.sub.max 1190 A B 1209 C B 1210 C A 1212 B B 1331 A B 1974 B B 1975 A C 1976 C B 1989 C A 1992 B B 1994 C A 2058 A B 2075 B B 2080 B C 2085 C B 2090 A C 2096 C B 2135 C B 2167 C B 2172 B B 2173 A B 2174 B C 2175 A C 2179 B B 2180 B B 2181 A C 2184 A C 2187 C A 2190 C A 2191 A B 2192 B C 2194 A C 2197 C C 2198 B B 2199 B B 2200 C B 2202 C B 2206 C B 2209 B C 2210 A B 2213 A B 2215 C C 2219 C A 2221 C B 2222 A B 2224 C B 2226 C B 2227 A C 2228 B C 2230 B B 2234 B B 2236 C B 2240 C B 2241 B B 2242 C A 2245 B C 2248 C B 2249 C B 2254 A C 2257 C B 2258 B C 2261 C B 2264 B C 2265 A B 2268 A B 2275 C B 2280 C B 2286 C A 2288 A B 2290 C A 2291 A B 2294 A B 2295 C A 2296 A B 2299 C A 2305 B C 2317 A C 2323 B B 2334 A B 2337 C B 2339 A C 2343 C B 2344 A B 2345 C B 2351 C A 2355 A A 2362 C B 2375 C B 2377 C B 2388 C B 2398 A C 2402 C B 2410 C B 2417 C B 2423 A C 2433 C A 2439 B B 2443 C B 2449 C B 2451 A C 2458 A C 2462 B B 2472 C B 2473 C A 2494 C C 2495 B A 2503 C C 2510 C B 2513 C A 2514 B C 2515 B A 2516 C A

[0418] In Table 2, for EC.sub.50: “A” refers to < 20 .Math.M; “B” refers to 20-30 .Math.M, inclusive; and “C” refers to 30-100 .Math.M, exclusive; and for E.sub.max: “A” refers to > 200%; “B” refers to 150-200%, inclusive; and “C” refers to 129-149%, inclusive.

Example 3. Effects of Compounds on ROS Production in Primary Rat Dopaminergic TH-Positive Neurons

Primary Culture of Mesencephalic Neurons

[0419] All experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and followed current European Union regulations (Directive 2010/63/EU). Agreement number: A1301310.

[0420] Rat dopaminergic neurons were cultured as described by Visanji et al., 2008. Briefly, pregnant female rat of 15 days of gestation are sacrificed using a deep anesthesia with CO.sub.2 chamber and a cervical dislocation. The midbrains obtained from 15-day-old rat embryos are dissected under a microscope. The embryonic midbrains are removed and placed in ice-cold medium of Leibovitz (L15) containing 2% of Penicillin- Streptomycin (PS) and 1% of bovine serum albumin (BSA). The ventral portion of the mesencephalic flexure, a region of the developing brain rich in dopaminergic neurons, is used for the cell preparations.

[0421] The midbrains are dissociated by trypsinisation for 20 min at 37° C. (solution at a final concentration of 0.05% trypsin and 0.02% EDTA). The reaction is stopped by the addition of Dulbecco’s modified Eagle’s medium (DMEM) containing DNAase I grade II (0.5 mg/mL) and 10% of foetal calf serum (FCS). Cells are then mechanically dissociated by 3 passages through a 10 mL pipette. Cells are then centrifuged at 180 x g for 10 min at +4° C. on a layer of BSA (3.5%) in L15 medium. The supernatant is discarded and the cell pellets re-suspended in a defined culture medium consisting of Neurobasal supplemented with B27 (2%), L-glutamine (2 mM) and 2% of PS solution and 10 ng/mL of Brain-derived neurotrophic factor (BDNF) and 1 ng/mL of Glial-Derived Neurotrophic Factor (GDNF). Viable cells are counted in a Neubauer cytometer using the trypan blue exclusion test. The cells are seeded at a density of 40,000 cells/well in 96 well-plates (pre-coated with poly-L-lysine) and maintained in a humidified incubator at 37° C. in 5% CO2/95% air atmosphere. Half of the medium is changed every 2 days with fresh medium. To avoid any edge effect, the first and last columns as well as first and last lines of culture plates are not used in the study. Briefly, on day 4 of culture, the medium is removed, and fresh medium added, without or with compounds, as well as ferulic acid. On day 6 the toxin is added for 4 h or 24 h diluted in control medium, in presence of the compounds. Six wells per condition are assessed.

Test Compounds and 6OHDA and MPP+ Exposure

[0422] Pre-incubation: On day 4 of culture, the compounds and the reference compound (ferulic acid) are dissolved in culture medium and then pre-incubated with mesencephalic neurons for 48 hours before the toxin application (plate 1 and plate 2). Ferulic acid (10 .Math.M) is used as a reference positive control for its anti-oxidative properties. Injury: 48 hours after the application of the test compounds (on day 6), 6OHDA (20 .Math.M) is diluted in culture medium, in presence of the compounds and added to the culture for 4 hours (plate 1) or 24 hours (plate 2). For plate 1, the culture is stopped after the 4-hour injury. For plate 2, the culture medium is removed after 24 hours and replaced with fresh medium, without 6-OHDA and without the compounds, for an additional 24 hours.

End Point Evaluation

Immunostaining: TH and ROS - Plate 1

[0423] 4 hours (plate 1) after injury, the cell culture supernatant is removed, and the live cells are incubated with CellROX green reagent (marker of ROS production) for 30 min at 37° C. The CellROX reagent is cell-penetrant and will become fluorescent once oxidized by ROS. Then, cells are fixed by a solution of 4% paraformaldehyde in PBS, pH =7.3 for 20 min at room temperature. The cells are washed twice in PBS, and then are permeabilized and non-specific sites are blocked with a solution of PBS containing 0.1% of saponin and 1% FCS for 15 min at room temperature. Then, the cultures are incubated with a monoclonal Anti-Tyrosine Hydroxylase (TH) antibody produced in mouse at dilution of 1/10000 in PBS containing 1% FCS, 0.1 % saponin, for 2 hours at room temperature. This antibody will be revealed with Alexa Fluor 568 goat anti-mouse IgG at the dilution 1/800 in PBS containing 1% FCS, 0.1 % saponin, for 1 h at room temperature.

Immunostaining: TH and Caspase 3 - Plate 2

[0424] 48 hours (24 h injury + 24 h recovery) after the injury, the cell culture supernatant is removed, and cells are fixed by a solution of 4% paraformaldehyde in PBS, pH =7.3 for 20 min at room temperature. The cells are washed twice in PBS, and then are permeabilized and non-specific sites blocked with a solution of PBS containing 0.1% of saponin and 1% FCS for 15 min at room temperature. Then, the cultures are incubated with i) a monoclonal Anti-Tyrosine Hydroxylase (TH) antibody produced in mouse at dilution of 1/10000 and ii) a rabbit polyclonal antibody anti-activated caspase 3 at dilution of 1/500 in PBS containing 1% fetal calf serum and 0.1% of saponin, for 2 hours at room temperature. These antibodies will be revealed with Alexa Fluor 488 goat anti-mouse IgG and Alexa fluor 568 goat anti-rabbit IgG at the dilution 1/400 in PBS containing 1% FCS, 0.1% saponin, for 1 hour at room temperature.

Automatic Computer Analysis

[0425] For each condition, 20 pictures at 10x magnification (plate 1) or 30 pictures at 20x magnification (representing the whole well area) were automatically taken using ImageXpress®. All images were generated by ImageXpress® using the same acquisition parameters. From images, analyses were directly and automatically performed by Custom Module Editor®. The following read-outs were measured: Analysis of total number of TH neurons (TH positive neuron number), Analysis of the ROS into TH positive neurons, Analysis of caspase 3 positive TH neurons, and Analysis of total neurite network of TH positive neurons (in .Math.m).

Statistical Analysis

[0426] All values are expressed as mean +/- SEM (standard error of the mean). Statistical analysis was performed by one-way ANOVA, followed by a Dunnett’s or a PLSD Fisher’s test. p<0.05 is considered significant.

Example 4. In-Cell Target Engagement Assay

[0427] In-cell target engagement assays were performed as described in Robers M.B. et al. (2019) Quantitative, Real-Time Measurements of Intracellular Target Engagement Using Energy Transfer. In: Ziegler S., Waldmann H. (eds) Systems Chemical Biology. Methods in Molecular Biology, vol 1888. Humana Press, New York, NY; Machleidt et al., ACS Chem. Biol. 2015, 10, 8, 1797-1804; or Vasta et al., Cell Chemical Biology 25, 206-214, Feb. 15, 2018; or as described herein.

Transient Transfection of SHSY5Y Cells With NanoLuc® Fusions

[0428] Below is a protocol for transient transfection of SHSY5Y cells with NanoLuc® fusions. [0429] 1. Cultivate SHSY5Y cells appropriately prior to assay in MEM w NEAA supplemented with 10% FBS. [0430] 2. Remove medium from cell flask via aspiration, trypsinize, and allow cells to dissociate from the flask. [0431] 3. Neutralize trypsin using growth medium and pellet cells via centrifugation at 200 g for 5 minutes. [0432] 4. Aspirate medium and re-suspend cells into a single cell suspension using complete cell culture medium. [0433] 5. Adjust the cell density to 300 K/mL in cell culture medium in a sterile, conical tube. [0434] 6. Prepare lipid:DNA complexes as follows (this covers two assay plates, adjust numbers for more plates) [0435] a. Prepare a 10 .Math.g/mL solution of DNA in Opti-MEM without serum. This solution should contain the following ratios of carrier DNA and DNA encoding NanoLuc® fusion. [0436] i. 5.0 .Math.g/mL of Transfection Carrier DNA (pGEM) [0437] ii. 5.0 .Math.g/mL of NanoLuc® fusion DNA [0438] iii. 1 mL of Opti-MEM without phenol red [0439] b. Mix thoroughly. [0440] c. Add 30 .Math.L of FuGENE® HD into each mL of DNA mixture to form lipid:DNA complex and mix by inversion. [0441] d. Incubate at room temperature for 20 minutes to allow complexes to form, prepare cells while waiting for complex formation [0442] 7. Mix 1 part (e.g. 1 mL) of lipid:DNA complex with 20 parts (e.g. 20 mL) of SHSY5Y cells in suspension at 300 K/mL. Mix gently by inversion 5 times in a sterile, conical tube (Again, this covers two plates, adjust for more plates) Note: Larger or smaller bulk transfections should be scaled accordingly, using this ratio. [0443] 8. Dispense cells + lipid:DNA complex into 96-well white tissue culture treated plates (0.1 mL (30 K cells)/well) [0444] 9. Incubate at 37° C. in 5% CO.sub.2 at least 20 hours to allow expression to occur.

NanoBRET™ Target Engagement Assay Protocol

[0445] Below is a preparation of 20X NanoBRET tracer in tracer dilution buffer: [0446] 1) Prepare a 100X solution of serially diluted NanoBRET Tracer in 100% DMSO. Note: For displacement test, prepare ten 2-fold serial dilutions of Tracer from the top concentration 200 .Math.M. For competition test, prepare 100 .Math.M concentration of Tracer. [0447] 2) Add 1 part of 100X tracer to 4 parts NanoBRET Tracer Dilution Buffer to generate 20X NanoBRET Tracer Dilution Buffer.

[0448] Below is a preparation of unlabeled ‘cold’ parental compound: [0449] 1) Prepare unlabeled parental compound at 1000X final concentration in 100% DMSO. Note: For tracer dose response, prepare 1000X (20 mM) concentration in 100% DMSO. For matrix experiments, prepare 1000X serial dilutions in 100% DMSO and then dilute to 10X in Opti-MEM without serum or phenol red. [0450] 2) Dilute it to 10X final concentration in Opti-MEM without serum or phenol red.

[0451] Below is a preparation of permeabilizing reagent: 1) Prepare 10X final concentration 500 .Math.g/mL Digitonin in OptiMEM without serum or phenol red

[0452] Below is an assay procedure: Prior additions of tracer and compound remove growth media and add 0.1 mL/well Opti-MEM without serum or phenol red. [0453] 1) Remove Opti-MEM without serum or phenol red and add new 85 .Math.L (testing in live cells) or 75 .Math.L (testing in permeabilized cells) Opti-MEM [0454] 2) Add 5 pL/well 10X Digitonin (only if testing in permeabilized cells), mix 15 sec at 700 rpm [0455] 3) Add 5 pL/well 20X Tracer in NanoBret Dilution Buffer, mix 15 sec at 700 rpm [0456] 4) Add 10 .Math.L/well 1% DMSO in Opti-MEM or 10X ‘cold’ compound, mix 15 sec at 700 rpm [0457] 5) Incubate 120 min in tissue culture incubator

[0458] Below is a protocol for the NanoBRET™ measurement: [0459] 1) Immediately prior to BRET measurements, prepare 3X Complete NanoBRET™ Nano-Glo® Substrate in OptiMEM without serum or phenol red. This solution consists of a 1:166 dilution of NanoBRET™ Nano-Glo® Substrate plus a 1:500 dilution of Extracellular NanoLuc Inhibitor in OptiMEM without serum or phenol red. Mix gently by inversion 5-10 times in a conical tube. [0460] Note: The final concentration of Extracellular NanoLuc inhibitor in the 3X solution is 60 .Math.M, for a working concentration of 20 .Math.M. [0461] Note: 3X solutions should be used within 2 hours of preparation. [0462] Note: Do not add inhibitor to permeabilized assays. [0463] 2) Add 50 .Math.L per well of 3X Complete NanoBRET™ Nano-Glo® Substrate for a 96-well plate. Incubate 2-3 minutes at RT. [0464] Note: For optimal performance, BRET measurements should occur within 10 minutes of substrate addition. [0465] 3) Following addition of NanoBRET™ Nano-Glo® Substrate, measure donor emission (e.g. 450 nm) and acceptor emission (e.g. 610 nm or 630 nm) using a NanoBRET™-compatible luminometer.

[0466] Below is a protocol for BRET ratio determinations and data processing: [0467] 1) To generate raw BRET ratio values, divide the acceptor emission value (e.g. 610 nm) by the donor emission value (e.g. 450 nm) for each sample. [0468] 2) Convert raw BRET units to milli-BRET units (mBBET) by multiplying each raw BRET value by 1000.

[0469] NanoBRET equation, including optional background correction: [(Acceptor.sub.sample / Donor.sub.sample)] x 1000.

NanoBRET™ Target Engagement Assay Formats

[0470] Displacement was performed by titration of Tracer +/- 20 .Math.M compound.

[0471] Competition was performed by using 1 .Math.M Tracer +/- titration of compound.

Example 5. Mouse Cell Derived Cyst Assay

[0472] Mouse cell derived cyst assays were performed as described in Booij, Tijmen H et al., SLAS discovery: advancing life sciences R & D vol. 22,8 (2017): 974-984, or as described below.

[0473] Murine inner medullary collecting duct cell line (mIMCD3 Pkd1.sup.-/- cells) [0474] mIMCD3 Pkd1 KO cells were seeded in 384 wells plates in extracellular matrix. [0475] 4 days after seeding, cultures were co-exposed to treatments and stimuli (2.5 .Math.M forskolin); [0476] After 72 h, cultures were fixed, stained for nuclei and actin cytoskeleton and imaged with 4x magnification; and [0477] Image analysis of the 3D stack was done using Ominer™ image analysis software.

TABLE-US-00005 List of abbreviations aq. Aqueous CH.sub.2Cl.sub.2 Dichloromethane DMAP 4-(dimethylamino)pyridine DIPEA N,N-Diisopropylethylamine DMF N, N-dimethylformamide DMSO-d.sub.6 Deuterated dimethyl sulfoxide d Doublet dd Doublet of doublets EtOAc Ethyl acetate EtOH Ethanol eq. Equivalent g Gram h Hour Hz Hertz HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide Hexafluorophosphate LC-MS Liquid chromatography-mass spectrometry m Multiplet mg Milligram mL Millilitre min Minute(s) mmol Millimole MeOH Methanol m/z Mass-to-charge ratio NMR Nuclear magnetic resonance py pyridine s Singlet t Triplet THF Tetrahydrofuran TLC Thin layer chromatography

References

[0478] 1. Abou-Sleiman PM, Muqit MM & Wood NW (2006) Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci, 7, 207-19. [0479] 2. Bayir H, Kapralov AA, Jiang J, Huang Z, Tyurina YY, Tyurin VA, Zhao Q, Belikova NA, Vlasova II, Maeda A, Zhu J, Na HM, Mastroberardino PG, Sparvero LJ, Amoscato AA, Chu CT, Greenamyre JT & Kagan VE (2009) Peroxidase mechanism of lipid-dependent crosslinking of synuclein with cytochrome C: protection against apoptosis versus delayed oxidative stress in Parkinson disease. J Biol Chem, 284, 15951-69. [0480] 3. Giordano S, Lee J, Darley-Usmar VM & Zhang J (2012) Distinct effects of rotenone, 1-methyl-4-phenylpyridinium and 6-hydroxydopamine on cellular bioenergetics and cell death. PLoS One, 7, e44610. [0481] 4. Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry,79, 368-76. [0482] 5. Martin I, Dawson VL, & Dawson TM (2010) The impact of genetic research on our understanding of Parkinson’s disease. Prog Brain Res, 183, 21-41. [0483] 6. Vila, M. & Przedborski, S. (2004). Genetic clues to the pathogenesis of Parkinson’s disease. Nat. Med., 10 Suppl, S58-S62. [0484] 7. Visanji NP, Orsi A, Johnston TH, Howson PA, Dixon K, Callizot N, Brotchie JM and Rees DD. PYM50028, a novel, orally active, nonpeptide neurotrophic factor inducer, prevents and reverses neuronal damage induced by MPP+ in mesencephalic neurons and by MPTP in a mouse model of Parkinson’s disease. FASEB J. 2008; 22(7):2488-97. [0485] 8. Vogiatzi T, Xilouri M, Vekrellis K & Stefanis L (2008) Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem, 283, 23542-56.

EQUIVALENTS AND SCOPE

[0486] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0487] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0488] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0489] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.