CYCLOPHILIN D INHIBITORS AND USES THEREOF

20230117680 · 2023-04-20

Assignee

Inventors

Cpc classification

International classification

Abstract

Provided herein are compounds of Formula (I′) or (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing diseases and/or conditions (e.g., neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins) in a subject, as well as for reducing oxidative stress. Provided are methods of inhibiting a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject and/or biological sample.

##STR00001##

Claims

1. A compound of Formula (I′): ##STR00619## or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein: each instance of custom-character is independently a single or double C—C bond, as valency permits, wherein when is a double C—C bond adjacent to , then indicates that the adjacent C—C double bond may be in a cis or trans configuration; A is —OR.sup.5A or —N(R.sup.5).sub.2; W is an optionally substituted C.sub.1-6 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted carbocyclylene, —O—, or —N(R.sup.W)—; R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryl; X is —O—, —C(R.sup.3A).sub.2—, —C(R.sup.3A)═, or —N(R.sup.3B)—, as valency permits; Y is —C(R.sup.3A).sub.2— or —N(R.sup.3B)—, as valency permits; each instance of R.sup.3A is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN, or optionally wherein two instances of R.sup.3A are joined together with the intervening atoms to form an optionally substituted heterocyclyl or heteroaryl ring; R.sup.c1 is halogen, hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, —NH.sub.2, —N(optionally substituted alkyl).sub.2, —OH, or —O(optionally substituted alkyl); wherein each instance of R.sup.c2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; R.sup.3B is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group; R.sup.3C is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group; R.sup.4 is halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN; each instance of R.sup.5 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or a nitrogen protecting group; R.sup.5A is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or an oxygen protecting group; each of R.sup.A, R.sup.B, R.sup.C, R.sup.D, and R.sup.W is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group; x is 0 or 1; y is 0 or 1; y1 is 0 or 1; m1 is 0, 1, 2, 3, 4, 5, or 6; and n1 is 0 or 1; provided that the compound is not of formula: ##STR00620## ##STR00621## ##STR00622## ##STR00623## ##STR00624## ##STR00625## ##STR00626##

2. The compound of claim 1, wherein the compound is of Formula (I): ##STR00627## or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein: each instance of custom-character is independently a single or double C—C bond, as valency permits, wherein when is a double C—C bond adjacent to , then indicates that the adjacent C—C double bond may be in a cis or trans configuration; W is optionally substituted C.sub.1-6 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with substituted or unsubstituted phenylene, or substituted or unsubstituted carbocyclylene, —O—, or —N(R.sup.W)—; R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryl; X is —O—, —C(R.sup.3A).sub.2—, —C(R.sup.3A)═, or —N(R.sup.3B)—, as valency permits; Y is —C(R.sup.3A).sub.2— or —N(R.sup.3B)—, as valency permits; each instance of R.sup.3A is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN, or optionally wherein two instances of R.sup.3A are joined together with the intervening atoms to form an optionally substituted heterocyclyl or heteroaryl ring; R.sup.c1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; wherein each instance of R.sup.c2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; R.sup.3B is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group; R.sup.3C is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group; R.sup.4 is halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN; each instance of R.sup.5 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or a nitrogen protecting group; each of R.sup.A, R.sup.B, R.sup.C, R.sup.D, and R.sup.W is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group; x is 0 or 1; y is 0 or 1; y1 is 0 or 1; m1 is 0, 1, 2, 3, 4, 5, or 6; and n1 is 0 or 1; provided that the compound is not of formula: ##STR00628## ##STR00629## ##STR00630## ##STR00631## ##STR00632## ##STR00633## ##STR00634##

3. The compound of claim 1 or 2, wherein the compound of Formula (I′) is of formula: ##STR00635## or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein: R.sup.2 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or —CN.

4. The compound of claim 1 or 2, wherein the compound of Formula (I′) is of formula: ##STR00636## or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein: R.sup.2 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or —CN; and R.sup.5A is hydrogen or substituted or unsubstituted alkyl.

5. The compound of claim 1 or 2, wherein the compound of Formula (I′) is of formula: ##STR00637## or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein: R.sup.2 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or —CN.

6. The compound of any one of claims 1-5, wherein the compound of Formula (I′) is of formula: ##STR00638## or a pharmaceutically acceptable salt thereof, wherein: R.sup.2 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or —CN.

7. The compound of any one of claims 1-5, wherein the compound of Formula (I′) is of formula: ##STR00639## or a pharmaceutically acceptable salt thereof, wherein: R.sup.2 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or —CN; and R.sup.5A is hydrogen or substituted or unsubstituted alkyl.

8. The compound of any one of claims 1-7, wherein the compound of Formula (I′) is of formula: ##STR00640## or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein: each instance of R.sup.3a is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN; and m2 is 0, 1, 2, 3, 4, or 5.

9. The compound of any one of claims 1-8, wherein the compound is of formula: ##STR00641## or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein: each instance of R.sup.6A is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —SO.sub.2R.sup.c1, —CN, —B(OR.sup.6c1).sub.2, or —SCN; and w1 is 0, 1, 2, 3, 4, 5, or 6.

10. The compound of any one of claims 1-9, wherein the compound is of formula: ##STR00642## or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein: each instance of R.sup.6A is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —SO.sub.2R.sup.c1, —CN, —B(OH).sub.2, or —SCN; and w1 is 0, 1, 2, 3, 4, 5, or 6.

11. The compound of any one of claims 1-10, wherein the compound is of formula: ##STR00643## or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof.

12. The compound of any one of claims 1-11, wherein the compound is of formula: ##STR00644## or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof.

13. The compound of any one of claims 1-11, wherein the compound is of formula: ##STR00645## or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein: R.sup.6A is substituted or unsubstituted acyl, —C(═O)N(R.sup.6c).sub.2, ##STR00646## —NO.sub.2, —SO.sub.2R.sup.c1, —SO.sub.2N(R.sup.6c).sub.2, —B(OR.sup.6c1).sub.2, or —OR.sup.c1; each instance of R.sup.6c is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.6d, or a nitrogen protecting group; R.sup.6d is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or an oxygen protecting group; and R.sup.6w is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.6d, or a nitrogen protecting group; w2 is 0, 1, 2, 3, 4, 5, or 6.

14. The compound of any one of claims 1-11 or 13, wherein the compound is of formula: ##STR00647## or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein: R.sup.6A is substituted or unsubstituted acyl, —C(═O)N(R.sup.6c).sub.2, ##STR00648## —NO.sub.2, —SO.sub.2R.sup.c1, —SO.sub.2N(R.sup.6c).sub.2, —B(OH).sub.2, or —OR.sup.c1; each instance of R.sup.6c is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.6d, or a nitrogen protecting group; R.sup.6d is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or an oxygen protecting group; and R.sup.6w is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.6d, or a nitrogen protecting group; w2 is 0, 1, 2, 3, 4, 5, or 6.

15. The compound of claim 1 or 2, wherein W is substituted or unsubstituted C.sub.1-6 alkylene.

16. The compound of any one of claims 1, 2, or 15, wherein W is unsubstituted n-butylene.

17. The compound of claim 1 or 2, wherein W is of formula: ##STR00649##

18. The compound of claim 1 or 2, wherein W is of formula: ##STR00650##

19. The compound of any one of claims 1-8, wherein R.sup.1 is C.sub.1-6 alkyl optionally substituted with substituted or unsubstituted acyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl.

20. The compound of any one of claims 1-8 or 19, wherein R.sup.1 is methyl.

21. The compound of any one of claims 1-8 or 19, wherein R.sup.1 is ##STR00651## wherein: each instance of R.sup.1A is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —N═C(NH.sub.2).sub.2, —SR.sup.c1, —SO.sub.2, —CN, —SCN, or —OP(═O)(OH).sub.2, or optionally wherein two instances of R.sup.1A are joined together with the intervening atoms to form an optionally substituted aryl or an optionally substituted heteroaryl group; x1 is 0, 1, 2, 3, 4, 5, or 6; x2 is 0, 1, 2, 3, 4, or 5.

22. The compound of any one of claims 1-8, 19, or 21, wherein R.sup.1 is: ##STR00652## wherein: each instance of R.sup.6A is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —SO.sub.2R.sup.c1, —CN, —B(OR.sup.6c1).sub.2, or —SCN; x1 is 0, 1, 2, or 3; w1 is 0, 1, 2, 3, 4, or 5.

23. The compound of any one of claims 9-19 or 22, wherein at least one instance of R.sup.6A is ##STR00653## wherein: each instance of w1 is independently 0, 1, 2, 3, 4, 5, or 6; each instance of w2 is independently 1, 2, or 3; w3 is 1, 2, or 3; w4 is 0, 1, 2, or 3; R.sup.6B is hydrogen or substituted or unsubstituted alkyl; each instance of R.sup.6C is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OH, —O(alkyl), —NO.sub.2, —NH.sub.2, —CN, or —SCN; and each instance of R.sup.6d1 and R.sup.6d2 is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OH, —O(alkyl), —NO.sub.2, —NH.sub.2, —CN, or —SCN.

24. The compound of any one of claims 9-19 or 22, wherein at least one instance of R.sup.6A is ##STR00654## wherein: w1 is 0, 1, 2, 3, 4, 5, or 6; w3 is 1, 2, or 3; R.sup.6a and R.sup.6b are each independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OH, —O(alkyl), —NO.sub.2, —NH.sub.2, —CN, or —SCN; or optionally, R.sup.6a and R.sup.6b are joined together with the intervening atoms to form an optionally substituted carbocycle group; and each instance of R.sup.6C is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OH, —O(alkyl), —NO.sub.2, —NH.sub.2, —CN, or —SCN.

25. The compound of any one of claims 1-8 or 19, wherein R.sup.1 is ##STR00655## wherein: each instance of R.sup.1B is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN; and x2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

26. The compound of any one of claims 1-8, 19, or 21, wherein R.sup.1 is ##STR00656## wherein: each instance of R.sup.1B is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN, or nitrogen protecting group when attached to a nitrogen atom; x1 is 0, 1, 2, 3, 4, 5, or 6; and x2 is 0, 1, 2, 3, 4, 5, or 6.

27. The compound of any one of claims 1-8, 19, or 21, wherein R.sup.1 is ##STR00657## wherein: each instance of R.sup.1B is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN, or nitrogen protecting group when attached to a nitrogen atom; x1 is 0, 1, 2, 3, 4, 5, or 6; and x2 is 0, 1, 2, 3, 4, 5, or 6.

28. The compound of any one of claims 1-8, 19, or 21-27, wherein R.sup.1 is of formula: ##STR00658## ##STR00659## ##STR00660## ##STR00661## ##STR00662## ##STR00663## ##STR00664## ##STR00665## ##STR00666## ##STR00667## ##STR00668## ##STR00669## ##STR00670## ##STR00671## ##STR00672## ##STR00673## ##STR00674## ##STR00675## ##STR00676## ##STR00677## ##STR00678## ##STR00679##

29. The compound of any one of claims 1-8 or 19, wherein R.sup.1 is substituted or unsubstituted alkenyl.

30. The compound of any one of claims 1-29, wherein y is 0.

31. The compound of any one of claims 1-29, wherein y is 1.

32. The compound of any one of claims 3-6 or 15-31, wherein R.sup.2 is hydrogen.

33. The compound of any one of claims 3-7 or 15-31, wherein R.sup.2 is substituted or unsubstituted C.sub.1-6 alkyl.

34. The compound of any one of claims 1-33, wherein the moiety ##STR00680## is of formula ##STR00681##

35. The compound of any one of claims 1-33, wherein the moiety ##STR00682## is of formula: ##STR00683##

36. The compound of any one of claims 1-35, wherein at least one instance of R.sup.5 is hydrogen.

37. The compound of any one of claims 1-36, wherein at least one instance of R.sup.5 is C.sub.1-6 alkyl optionally substituted with halogen, —OR.sup.c1, or —N(R.sup.c2).sub.2; and R.sup.c1 is hydrogen or C.sub.1-6 alkyl optionally substituted with —N(R.sup.c2).sub.2, and each instance of R.sup.c2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or a nitrogen protecting group.

38. The compound of any one of claims 1-37, wherein at least one instance of R.sup.5 is methyl or of formula ##STR00684##

39. The compound of any one of claims 1-36, wherein the moiety ##STR00685## is ##STR00686##

40. The compound of any one of claims 1, 4, 7, 9, 11, 13, or 15-35, wherein R.sup.5A is hydrogen.

41. The compound of any one of claims 1, 4, 7, 9, 11, 13, or 15-35, wherein R.sup.5A is optionally substituted C.sub.1-6 alkyl.

42. The compound of any one of claims 1, 4, 7, 9, 11, 13, 15-35, or 41, wherein R.sup.5A is methyl.

43. The compound of any one of claims 1-42, wherein each of R.sup.A, R.sup.B, R.sup.C, and R.sup.D is hydrogen.

44. The compound of any one of claims 1-43, wherein x is 0.

45. The compound of any one of claims 1-44, wherein the compound is of formula: ##STR00687## ##STR00688## ##STR00689## ##STR00690## ##STR00691## ##STR00692## ##STR00693## ##STR00694## ##STR00695## ##STR00696## ##STR00697## ##STR00698## ##STR00699## ##STR00700## ##STR00701## ##STR00702## ##STR00703## ##STR00704## ##STR00705## ##STR00706## ##STR00707## ##STR00708## ##STR00709## ##STR00710## ##STR00711## ##STR00712## ##STR00713## ##STR00714## ##STR00715## ##STR00716## ##STR00717## ##STR00718## ##STR00719## ##STR00720## ##STR00721## ##STR00722## ##STR00723## ##STR00724## ##STR00725## ##STR00726## ##STR00727## ##STR00728## ##STR00729## ##STR00730## ##STR00731## or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof.

46. The compound of any one of claims 1-44, wherein the compound is of formula: ##STR00732## ##STR00733## ##STR00734## ##STR00735## ##STR00736## ##STR00737## ##STR00738## ##STR00739## ##STR00740## ##STR00741## ##STR00742## ##STR00743## ##STR00744## ##STR00745## ##STR00746## ##STR00747## ##STR00748## ##STR00749## ##STR00750## ##STR00751## ##STR00752## ##STR00753## ##STR00754## or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof.

47. A pharmaceutical composition comprising a compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, and optionally a pharmaceutically acceptable excipient.

48. The pharmaceutical composition of claim 47, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound for use in treating a disease in a subject in need thereof.

49. A method of treating a disease and/or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or a pharmaceutical composition of claim 47 or 48.

50. A method of treating a disease and/or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46, or a compound of formula: ##STR00755## ##STR00756## ##STR00757## ##STR00758## ##STR00759## ##STR00760## ##STR00761## ##STR00762## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or a pharmaceutical composition of claim 47 or 48; provided that the disease and/or condition is not a cardiovascular disease, metabolic disorder, or a disease associated with insulin-degrading enzyme (IDE).

51. The method of claim 49 or 50, wherein the disease and/or condition is associated with the mitochondria.

52. The method of one of claims 49-51, wherein the disease and/or condition is associated with regulation of the mitochondrial permeability transition pore (mPTP).

53. The method of claim 52, wherein the disease and/or condition is associated with regulation of the opening and/or closing of the mPTP.

54. The method of any one of claims 49-53, wherein the condition is associated with autophagy.

55. The method of any one of claims 49-54, wherein the condition is associated with aging.

56. The method of claim 49 or 50, wherein the disease is a neurodegenerative disease.

57. The method of claim 49 or 50, wherein the disease is a metabolic disease.

58. The method of claim 49 or 50, wherein the disease is a proliferative disease.

59. The method of claim 58, wherein the disease is cancer.

60. The method of claim 49, 50, 58, or 59, wherein the condition is associated with oxidative stress.

61. The method of claim 50, wherein the disease and/or condition is associated with the mitochondria, the condition is associated with autophagy, the condition is associated with aging, the disease is a neurodegenerative disease, the disease is a proliferative disease, or the condition is associated with oxidative stress.

62. The method of claim 49, 50, 60, or 61, wherein the condition is ischemia-reperfusion injury.

63. A method of reducing oxidative stress in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46, or a compound of formula: ##STR00763## ##STR00764## ##STR00765## ##STR00766## ##STR00767## ##STR00768## ##STR00769## ##STR00770## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or a pharmaceutical composition of claim 47 or 48.

64. A method of reducing oxidative stress in a biological sample, the method comprising: contacting the biological sample with an effective amount of a compound of any one of claims 1-46, or a compound of formula: ##STR00771## ##STR00772## ##STR00773## ##STR00774## ##STR00775## ##STR00776## ##STR00777## ##STR00778## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or a pharmaceutical composition of claim 47 or 48.

65. A method of inhibiting a cyclophilin in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46, or a compound of formula: ##STR00779## ##STR00780## ##STR00781## ##STR00782## ##STR00783## ##STR00784## ##STR00785## ##STR00786## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or a pharmaceutical composition of claim 47 or 48.

66. A method of inhibiting a cyclophilin in a biological sample, the method comprising: contacting the biological sample with an effective amount of a compound of any one of claims 1-46, or a compound of formula: ##STR00787## ##STR00788## ##STR00789## ##STR00790## ##STR00791## ##STR00792## ##STR00793## ##STR00794## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or a pharmaceutical composition of claim 47 or 48.

67. The method of claim 65 or 66, wherein the cyclophilin is cyclophilin A.

68. The method of claim 65 or 66, wherein the cyclophilin is cyclophilin B.

69. The method of claim 65 or 66, wherein the cyclophilin is cyclophilin C.

70. The method of claim 65 or 66, wherein the cyclophilin is cyclophilin D.

71. The method of any one of claims 65, 66, or 70, wherein the compound is capable of selectively inhibiting cyclophilin D over other cyclophilins.

72. The method of any one of claims 65, 66, 70, or 71, wherein the compound is capable of selectively inhibiting cyclophilin D over cyclophilin E.

73. The method of any one of claims 65, 66, 70, or 71, wherein the compound is capable of selectively inhibiting cyclophilin D over cyclophilin B.

74. The method of any one of claims 65, 66, 70, or 71-73, wherein the compound is capable of selectively inhibiting cyclophilin D over cyclophilins B and E.

75. The method of any one of claims 65, 66, or 70-74, wherein the compound is capable of binding the S2 pocket of cyclophilin D.

76. The method of any one of claims 65, 66, or 70-75, wherein the compound is capable of binding gatekeeper residues of cyclophilin D.

77. The method of any one of claims 65, 66, or 70-76, wherein the compound is capable of binding the gatekeeper residues serine and/or arginine of cyclophilin D.

78. The method of claim 77, wherein the gatekeeper residues comprise Serine 123 and/or Arginine 124.

79. The method of claim 65 or 66, wherein the cyclophilin is cyclophilin E.

80. The method of claim 65 or 66, wherein the cyclophilin is cyclophilin G.

81. The method of claim 65 or 66, wherein the cyclophilin is cyclophilin H.

82. The method of claim 65 or 66, wherein the cyclophilin is cyclophilin 40.

83. The method of claim 65 or 66, wherein the cyclophilin is PPWD1.

84. The method of claim 65 or 66, wherein the cyclophilin is PPIL1.

85. The method of claim 65 or 66, wherein the cyclophilin is NKTR.

86. The method of any one of claims 49-63, 65, or 67-82 further comprising administering to the subject a therapeutically effective amount of an additional pharmaceutical agent in combination with the compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or the pharmaceutical composition of any one of claims 47 or 48.

87. The method of any one of claims 64 or 66-82 further comprising contacting the biological sample with a therapeutically effective amount of an additional pharmaceutical agent in combination with the compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or the pharmaceutical composition of any one of claims 47 or 48.

88. The method of claim 83 or 84, wherein the additional pharmaceutical agent is an agent for treating a disease associated with cyclophilins.

89. Use of a compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or a pharmaceutical composition of claim 47 or 48 to treat a disease and/or condition in a subject in need thereof.

90. A kit comprising: a compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or a pharmaceutical composition of claim 47 or 48; and instructions for administering to a subject or contacting a biological sample with the compound, or the pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or the pharmaceutical composition of claim 47 or 48.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0109] FIG. 1 is an overview of cyclophilin (e.g., Cyclophilin D) function and activity.

[0110] FIGS. 2A-2C illustrate the design of previous Cyclophilin D inhibitors. FIGS. 2A-2C show that earlier inhibitors were reliant on either binding to a highly conserved active pocket (CsA), or dual binding into the active pocket, losing binding in conserved residues at the base of the S2 pocket, resulting in promiscuous cyclophilin inhibition. FIG. 2C shows different cyclophilins and the corresponding residues, where cyclophilin PPIA is the reference, and PPIF corresponds to CypD.

[0111] FIG. 3 shows that the adjacent S2 pocket was diversified across the Cyp family. FIG. 3 shows different cyclophilins and the corresponding residues, where cyclophilin PPIA is the reference, and PPIF corresponds to CypD.

[0112] FIG. 4 shows results of the selectivity for Cyclophilin D (CypD-5) using enrichment of the compounds of a 256,000 member DNA-templated macrocycle (DTS) library.

[0113] FIGS. 5A-5E show CypD inhibition (IC.sub.50 inhibitory data) by enriched hits from DTS library selection. ‘Cis’ and ‘trans’ refer to stereochemistry at the alkene.

[0114] FIG. 6 show dose response curves with IC.sub.50 inhibitory data by exemplary depicted compounds JOMBtrans and JOBBtransA from the inhibitory library. CypD and 10 other Cyp family members were screened against JOMBtrans. The binding curve was generated from Surface Plasmon Resonance experiments. CypD was covalently immobilized on the chip, and the macrocyclic compound was passed over the surface.

[0115] FIGS. 7A-7E show exemplary JOMBtrans derived compound structures and their IC.sub.50 inhibitory dose response data. FIGS. 7A-7E shows the structures of exemplary JOMBtrans derived compounds, and IC.sub.50 data for CypD inhibition for the depicted JOMBtrans derivatives.

[0116] FIGS. 8A-8D show relevant dose response curves of IC.sub.50 inhibition and administered compound concentration for good JOMBtrans derivatives (compounds 27, 48, 49, 63A, 64A, 65A, 66A, 68A, 70A, 71A, 74A, 75A, 76A, 77A, 78A, 79A) shown in FIGS. 8A-8D) against 11 cyclophilins (CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR).

[0117] FIGS. 9A-9C show co-crystal structures of exemplary inhibitors. CypD-compound JOMBtrans was solved at 1.8 Å and CypD-compound 49 was solved at 1.02 Å. FIG. 9B shows the binding interactions of JOMBtrans: H-bonds with the backbone of Gly72 and sidechains of Gln63 and Arg55; cation-pi interaction with Arg55 (phenyl); and hydrophobic interactions in both S2 pocket (furan) and active site (phenyl). FIG. 9C shows the binding mode of compound 49, which has the same binding interactions as JOMBtrans, plus H-bonds with the backbone of Asn102 and sidechain of Trp121. It is hypothesized that the altered conformation from benzyl group afforded these new H-bond interactions and a 75-fold increase in potency.

[0118] FIGS. 10A-10B show the IC.sub.50 inhibitory data for of the specificity analysis of the first lead inhibitor compounds. The benzyl group afforded better potency due to the conformational change in the macrocycle. This did not appear to affect the specificity profile, as compound 49 had approximately 10-fold better specificity for CypD compared to any other cyclophilins. Replacement of the benzyl group with other moieties resulted in the same trend (see dose response curves for exemplary compounds 48, 63A, 64A, 64A, 66A, 68A, 70A, 71A, 74A, 75A, 76A, 77A, 78A, and 79A). The furan on JOMBtrans/49 sits inside the S2 pocket.

[0119] FIGS. 11A-11E show the IC.sub.50 inhibitory data for the first A-Series macrocycles against the depicted cyclophilins.

[0120] FIGS. 12A-12B show the trends in the IC.sub.50 inhibitory data compared to concentration of administered compounds for the first depicted A-Series macrocycles (see FIGS. 12A-12B for administered compounds) against the depicted cyclophilins. The results show large moieties offered greater overall specificity. In particular, NKTR, CypG, PPWD1, and CypH all show reduced IC.sub.50 compared to CypD. These 4 cyclophilins have more sterically occluded S2 pockets.

[0121] FIGS. 13A-13C show the co-crystal structures of compounds A-1, A-5, and A-6. All show the same binding mode as Compound 49. As such, compounds A-1 and A-5 reach deeper into the S2 pocket, and the gatekeeper residues are shown to flip out of the pocket upon binding. Crystal structures confirm that increased specificity for CypD is dependent on deeper binding in S2 pocket. Using compound A-5, biphenyl moieties were diversified to gain interactions with gatekeeper residues of CypD (Ser81, Arg82). The crystal structures of CypD-A-1, CypD-A-5, and CypD-A-6 were solved at 1.2 Å.

[0122] FIGS. 14A-14W show a collection of further A-Series compound structures and dose response curves (IC.sub.50 inhibitory data compared to concentration of administered compounds) against the depicted cyclophilins.

[0123] FIGS. 15A-15D show the dose response curves (IC.sub.50 inhibitory data compared to concentration of administered compounds) from the A-Series derivative compounds against the depicted cyclophilins. Results show that compounds with ortho-alkyl biphenyl may offer approximately ten-fold CypE specificity.

[0124] FIG. 16 shows that the co-crystal structure of A-57 with CypD A-57 has ortho-methyl dug into S2 pocket, and flips Arg even further out of the pocket. The crystal structure was solved at 1.2 Å. Compounds with carboxylate gave specificity over almost all cyclophilins except CypE. Compounds with ortho-methyl gave approximately ten-fold specificity over CypE by pushing biphenyl closer to non-conserved CypE-Serine.

[0125] FIGS. 17A-17I show dose response curves (IC.sub.50 inhibitory data compared to concentration of the listed administered compounds) for A-Series derivative compounds against the depicted cyclophilins. Results show compounds with para carbonyl biphenyl offers varying selectivity over CypA, CypC, CypB, Cyp40, PPIL1, and PPWD1. In addition, increased potency for CypD was observed for multiple analogs compared to parent compound (A-5, 0.20 μM). FIG. 17D shows compounds with para carboxy biphenyl offered both very good potency for CypD and very good selectivity. FIGS. 17H and 17I show the compounds A-54, A-57, A-63, A-81, and A-81 have potency and specificity increases with the further extension of the carboxylate moiety.

[0126] FIG. 18A-18C show results of an analysis of the interactions between cyclophilins and the gatekeeper residues. FIG. 18A shows the co-crystal structure of a compound (A-5) and demonstrates that para-substituents can be placed near/between Ser/Arg gatekeepers. CypD specificity may derive from, but is not limited to, interactions between the carboxylate derivatives of compound A-5 and the gatekeepers. FIG. 18B shows examples of gatekeeper residue-cyclophilin interactions for the compound A-81. FIG. 18C shows results of the results of IC.sub.50 inhibitory data against the depicted cyclophilins, for the A-81 macrocycle compound.

[0127] FIGS. 19A-19U show a collection of exemplary A-Series compound structures and their corresponding dose response curves against the depicted cyclophilins, with IC.sub.50 inhibitory data compared to the concentration of the administered compounds. FIGS. 19A, 19K, 19P, and 19S show exemplary A-Series compound structures. FIGS. 19B-19J, 19L, 19M-190, 19Q, 19R, 19T, and 19U show dose response curves against the depicted cyclophilins.

[0128] FIGS. 20A-20I show the dose response curves (IC.sub.50 inhibitory data compared to concentration of the listed administered compounds) from the exemplary A-Series derivative compounds against the depicted cyclophilins.

[0129] FIG. 21 shows the co-crystal structure of A-81 with CypD A-81, which maintains the same interactions with CypD as shown in all other previous co-crystal structures in the Figures except JOMBtrans (including the co-crystal structures for compound 49 (FIGS. 9C and 10A), compound A-1 (FIG. 13A), compound A-5 (FIG. 13B), compound A-6 (FIG. 13C), and compound A-57 (FIG. 16) with regard to the active site and S2 pocket. Meanwhile, the compound A-81 also forms H-bonds with the non-gatekeeper Ser119, and a salt bridge with the non-gatekeeper Lys118.

[0130] FIGS. 22A-22B show unique exemplary structural features of A-81 binding. For example, the loop that contains the gatekeepers may flip out depending on the ligand present and the side chain of the gatekeepers may drastically change position based on the ligand. FIG. 22A shows small S2 pocket ligands, and FIG. 22B shows large S2 pocket ligands.

[0131] FIGS. 23A-23C show results of an analysis of the interactions between cyclophilins and the gatekeeper residues. FIG. 23A shows the co-crystal structure of a compound (A-81) (in the left panel) and different depicted cyclophilins (e.g., CypD, CypA, CypB) with their corresponding specified residues proximal to the ligand carboxylate (right panel), including gatekeeper residues. FIG. 23B shows exemplary residue-cyclophilin interactions for the compound A-81, and IC.sub.50 values for the depicted cyclophilins. FIG. 23C shows the IC.sub.50 inhibitory data against the depicted cyclophilins, for the macrocyclic compound A-81.

[0132] FIG. 24 shows in vitro inhibition of mPTP (via the maximum number of tolerated Ca.sup.2+ pulses over time, before full mPTP opening) in isolated mice kidney mitochondria by the depicted compounds of cyclosporin A, A-22b, A-81b, and DMSO control.

[0133] FIG. 25A shows different cyclophilins and their corresponding residues, where cyclophilin PPIA is the reference, and PPIF corresponds to CypD. FIG. 25B shows different cyclophilins and the corresponding residues, where cyclophilin PPIA is the reference, and PPIF corresponds to CypD.

[0134] FIGS. 26A-26B show the dose response curves (IC.sub.50 inhibitory data compared to concentration of the listed administered compounds) from the exemplary A-Series derivative compounds against the depicted cyclophilins. These macrocycle compounds are designed using the anchor and carboxylate hypothesis. FIGS. 26A-26B show that the inclusion of the malonate moiety in the A-series compounds provides specificity for CypD, including the compound with a dicarboxylate/malonate (A-160) which shows greatly improved potency compared to A-81.

[0135] FIGS. 27A-27C show a comparison of the dose response curves (IC.sub.50 inhibitory data compared to concentration of the listed administered cyclophilin inhibitor compounds) from the exemplary A-Series derivative compounds and cyclosporine A against the depicted cyclophilins. FIG. 27A shows that cyclosporine A shows high potency, low specificity, and binding to the active site of CypD. FIG. 27B shows that compound 49 shows low potency, low specificity, and binding to the active site of CypD. FIG. 27C shows that compound A-81 shows high potency, high specificity, and binding to the active site, S2 pocket and gatekeeper region of CypD. FIG. 27D shows that compound A-160 shows high potency, high specificity, and binding to the active site, S2 pocket, and gatekeeper region of CypD.

[0136] FIG. 28A shows a collection of exemplary A-Series cyclophilin inhibitor compound structures. FIGS. 28B-280 show dose response curves against the depicted cyclophilins, with IC.sub.50 inhibitory data compared to the concentration of the exemplary administered cyclophilin inhibitor compounds.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0137] The present disclosure provides inhibitors (e.g., selective inhibitors) of cyclophilins (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, the inventive compounds inhibit the activity of CypD. The present disclosure further provides methods of using the compounds described herein, e.g., as biological probes to study the inhibition of the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR), and as therapeutics, e.g., in the treatment and/or prevention of diseases associated with the overexpression and/or aberrant activity of the cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, the compounds covalently inhibit a cyclophilin (e.g., CypD). In certain embodiments, the diseases treated and/or prevented include, but are not limited to, neurodegenerative disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD)). The neurodegenerative diseases include, but are not limited to, Alzheimer's disease, multiple sclerosis, Parkinson's disease, and Huntington's disease. The metabolic disorders include, but are not limited to, obesity and diabetes. The proliferative diseases include, but are not limited to, cancer. Other treated conditions include conditions associated with autophagy and/or aging. The cardiovascular diseases and conditions include, but are not limited to, ischemia-reperfusion injury, stroke, coronary artery disease, and heart attack. In certain embodiments, the condition is a mitochondrial disease, for example, a condition and/or disease associated with the regulation of the mitochondrial permeability transition pore (mPTP) and/or CypD. Also provided by the present disclosure are pharmaceutical compositions, kits, methods, and uses of a compound of Formula (I′) or (I) as described herein.

Compounds

[0138] Certain aspects of the present disclosure relate to the compounds described herein. The compounds described herein may be useful in treating and/or preventing diseases and/or conditions (e.g., neurodegenerative disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD)), diseases associated with regulation of the mitochondrial permeability transition pore (mPTP), or diseases associated with the activity of a cyclophilin (e.g., CypD) in a subject, or inhibiting the activity of a cyclophilin (e.g., CypD) in a subject or biological sample. In certain embodiments, a compound described herein is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, a compound described herein is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt thereof.

[0139] In certain embodiments, a compound described herein is of Formula (I′):

##STR00194##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein:

[0140] each instance of custom-character is independently a single or double C—C bond, as valency permits, wherein when is a double C—C bond adjacent to , then indicates that the adjacent C—C double bond may be in a cis or trans configuration;

[0141] A is —OR.sup.5A or —N(R.sup.5).sub.2;

[0142] W is an optionally substituted C.sub.1-6 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted carbocyclylene, —O—, or —N(R.sup.W)—;

[0143] R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryl;

[0144] X is —O—, —C(R.sup.3A).sub.2—, —C(R.sup.3A)═, or —N(R.sup.3B)—, as valency permits; Y is —C(R.sup.3A).sub.2— or —N(R.sup.3B)—, as valency permits; [0145] each instance of R.sup.3A is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN, or optionally wherein two instances of R.sup.3A are joined together with the intervening atoms to form an optionally substituted heterocyclyl or heteroaryl ring;

[0146] R.sup.c1 is halogen, hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, —NH.sub.2, —N(optionally substituted alkyl).sub.2, —OH, or —O(optionally substituted alkyl);

[0147] wherein each instance of R.sup.c2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;

[0148] R.sup.3B is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group;

[0149] R.sup.3C is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group;

[0150] R.sup.4 is halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN;

[0151] each instance of R.sup.5 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or a nitrogen protecting group;

[0152] R.sup.5A is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or an oxygen protecting group;

[0153] each of R.sup.A, R.sup.B, R.sup.C, R.sup.D, and R.sup.W is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group;

[0154] x is 0 or 1;

[0155] y is 0 or 1;

[0156] y1 is 0 or 1;

[0157] m1 is 0, 1, 2, 3, 4, 5, or 6; and

[0158] n1 is 0 or 1;

[0159] provided that the compound is not of formula:

##STR00195## ##STR00196## ##STR00197## ##STR00198## ##STR00199## ##STR00200## ##STR00201## ##STR00202##

[0160] In certain embodiments, a compound described herein is of Formula (I′):

##STR00203##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein:

[0161] each instance of custom-character is independently a single or double C—C bond, as valency permits, wherein when is a double C—C bond adjacent to , then indicates that the adjacent C—C double bond may be in a cis or trans configuration;

[0162] W is optionally substituted C.sub.1-6 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted carbocyclylene, —O—, or —N(R.sub.W)—;

[0163] R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted aryl;

[0164] X is —O—, —C(R.sup.3A).sub.2—, —C(R.sup.3A)═, or —N(R.sup.3B)—, as valency permits;

[0165] Y is —C(R.sup.3A).sub.2— or —N(R.sup.3B)—, as valency permits;

[0166] each instance of R.sup.3A is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN, or optionally wherein two instances of R.sup.3A are joined together with the intervening atoms to form an optionally substituted heterocyclyl or heteroaryl ring;

[0167] R.sup.c1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;

[0168] wherein each instance of R.sup.c2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;

[0169] R.sup.3B is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group;

[0170] R.sup.3C is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group;

[0171] R.sup.4 is halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN;

[0172] each instance of R.sup.5 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or a nitrogen protecting group;

[0173] each of R.sup.A, R.sup.B, R.sup.C, R.sup.D, and R.sup.W is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group;

[0174] x is 0 or 1;

[0175] y is 0 or 1;

[0176] y1 is 0 or 1;

[0177] m1 is 0, 1, 2, 3, 4, 5, or 6; and

[0178] n1 is 0 or 1;

[0179] provided that the compound is not of formula:

##STR00204## ##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210## ##STR00211##

[0180] In certain embodiments, the compound of Formula (I′) or (I) is not of formula:

##STR00212## ##STR00213## ##STR00214## ##STR00215## ##STR00216## ##STR00217## ##STR00218## ##STR00219##

[0181] In certain embodiments, a compound described herein is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, a compound described herein is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt thereof.

[0182] Compounds of Formula (I′) or (I) include linker W. In certain embodiments, W is an optionally substituted C.sub.1-6 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with substituted or unsubstituted phenylene, or substituted or unsubstituted carbocyclylene, —O—, or —N(R.sup.W)—; and R.sup.W is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group. In certain embodiments, W is an optionally substituted C.sub.1-6 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with substituted or unsubstituted phenylene, or substituted or unsubstituted carbocyclylene, —O—, or —N(R.sup.W)— (e.g., —NH—). In certain embodiments, W is an optionally substituted C.sub.1-6 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with substituted or unsubstituted phenylene, —O—, or —N(R.sup.W)— (e.g., —NH—).

[0183] In certain embodiments, in linker W that is an optionally substituted C.sub.1-6 hydrocarbon chain, one or more carbon units of the hydrocarbon chain are independently optionally replaced with —N(R.sup.W)—, and R.sup.W is as defined herein. In certain embodiments, R.sup.W is hydrogen. In certain embodiments, R.sup.W is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.W is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.W is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.W is substituted or unsubstituted methyl. In certain embodiments, R.sup.W is unsubstituted methyl. In certain embodiments, R.sup.W is substituted or unsubstituted ethyl. In certain embodiments, R.sup.W is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In certain embodiments, W is an optionally substituted C.sub.1-6 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with substituted or unsubstituted phenylene or substituted or unsubstituted carbocyclylene (e.g., substituted or unsubstituted, 3- to 10-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system)). In certain embodiments, W is substituted or unsubstituted C.sub.1-6 alkylene. In certain embodiments, W is substituted or unsubstituted C.sub.1-4 alkylene. In certain embodiments, W is substituted or unsubstituted n-butylene, n-pentylene, or n-hexylene. In certain embodiments, W is substituted or unsubstituted n-butylene. In certain embodiments, W is substituted or unsubstituted n-pentylene. In certain embodiments, W is substituted or unsubstituted n-hexylene. In certain embodiments, W is substituted or unsubstituted carbocyclylene (e.g., substituted or unsubstituted, 3- to 10-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system)). In certain embodiments, W is substituted or unsubstituted, 5- to 10-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system. In certain embodiments, W is of formula:

##STR00220##

In certain embodiments, W is optionally substituted C.sub.1-6 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with substituted or unsubstituted phenylene. In certain embodiments, W is of formula:

##STR00221##

In certain embodiments, W is of formula:

##STR00222##

In certain embodiments, W is of formula:

##STR00223##

In certain embodiments, W is of formula:

##STR00224##

In certain embodiments, W is unsubstituted n-butylene, or of formula:

##STR00225##

[0184] In certain embodiments, x is 0. In certain embodiments, x is 1.

[0185] In certain embodiments, R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl (e.g., substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted butyl). In certain embodiments, R.sup.1 is C.sub.1-6 alkyl optionally substituted with substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, or —OR.sup.c1 wherein R.sup.c1 is as defined herein. In certain embodiments, R.sup.1 is C.sub.1-6 alkyl, optionally substituted with substituted or unsubstituted acyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.1 is methyl. In certain embodiments, R.sup.1 is C.sub.1-6 alkyl, optionally substituted with substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl). In certain embodiments, R.sup.1 is of formula:

##STR00226##

wherein R is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —N═C(NH.sub.2).sub.2, —SR.sup.c1, —SO.sub.2, —CN, or —SCN. In certain embodiments, R.sup.1 is of formula:

##STR00227##

wherein: each instance of R.sup.1A is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —N═C(NH.sub.2).sub.2, —SR.sup.c1, —SO.sub.2, —CN, —SCN, or —OP(═O)(OH).sub.2, or optionally wherein two instances of R.sup.1A are joined together with the intervening atoms to form an optionally substituted aryl or an optionally substituted heteroaryl group; x1 is 0, 1, 2, 3, 4, 5, or 6; and x2 is 0, 1, 2, 3, 4, or 5.

[0186] In certain embodiments, R.sup.1 is of formula:

##STR00228##

wherein: R.sup.1A is halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —N═C(NH.sub.2).sub.2, —SR.sup.c1, —SO.sub.2, —CN, —SCN, or —OP(═O)(OH).sub.2, or optionally wherein two instances of R.sup.1A are joined together with the intervening atoms to form an optionally substituted aryl group; x1 is 0, 1, 2, 3, 4, 5, or 6; and x2 is 0, 1, 2, 3, 4, or 5. In certain embodiments, R.sup.1 is of formula:

##STR00229##

##STR00230##

wherein: each instance of R.sup.1B is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN, or nitrogen protecting group when attached to a nitrogen atom; x1 is 0, 1, 2, 3, 4, 5, or 6; and x2 is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, at least one instance of R.sup.1A is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.1A is substituted or unsubstituted acyl (e.g.,
—C(═O)Me). In certain embodiments, at least one instance of R.sup.1A is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.1A is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.1A is substituted methyl (e.g., —CF.sub.3). In certain embodiments, at least one instance of R.sup.1A is unsubstituted methyl. In certain embodiments, at least one instance of R.sup.1A is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.1A is substituted ethyl (e.g., —CH.sub.2CH.sub.2OH). In certain embodiments, at least one instance of R.sup.1A is —CH.sub.2CH.sub.2OH. In certain embodiments, at least one instance of R.sup.1A is —CH.sub.2CH.sub.2OMe. In certain embodiments, at least one instance of R.sup.1A is unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.1A is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.1A is substituted or unsubstituted butyl (e.g., t-butyl, n-butyl). In certain embodiments, at least one instance of R.sup.1A is substituted or unsubstituted t-butyl. In certain embodiments, at least one instance of R.sup.1A is unsubstituted t-butyl. In certain embodiments, at least one instance of R.sup.1A is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.1A is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.1A is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 10-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.1A is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.1A is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance R.sup.1A is benzyl. In certain embodiments, at least one instance of R.sup.1A is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.1A is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.1A is —OR.sup.c1 (e.g., —OH or —OMe). In certain embodiments, at least one instance of R.sup.1A is —O(CH.sub.2)(optionally substituted aryl). In certain embodiments, at least one instance of R.sup.1A is —O(CH.sub.2)(phenyl). In certain embodiments, at least one instance of R.sup.1A is —O(optionally substituted phenyl). In certain embodiments, at least one instance of R.sup.1A is —O(optionally substituted aryl). In certain embodiments, at least one instance of R.sup.1A is —NO.sub.2. In certain embodiments, at least one instance of R.sup.1A is —N(R.sup.c2).sub.2 (e.g., —NMe.sub.2). In certain embodiments, at least one instance of R.sup.1A is —N═C(NH.sub.2).sub.2. In certain embodiments, at least one instance of R.sup.1A is —SR.sup.c1 (e.g., —SMe). In certain embodiments, at least one instance of R.sup.1A is —SO.sub.2, —CN, or —SCN. In certain embodiments, at least one instance of R.sup.1A is —OP(═O)(OH).sub.2. In certain embodiments, two instances of R.sup.1A are joined together with the intervening atoms to form an optionally substituted aryl group (e.g., substituted or unsubstituted, 6- to 10-membered aryl).

[0187] In certain embodiments, at least one instance of x1 is 0. In certain embodiments, at least one instance of x1 is 1. In certain embodiments, at least one instance of x1 is 2. In certain embodiments, at least one instance of x1 is 3. In certain embodiments, at least one instance of x1 is 4. In certain embodiments, at least one instance of x1 is 5. In certain embodiments, at least one instance of x1 is 6. In certain embodiments, at least one instance of x2 is 0. In certain embodiments, at least one instance of x2 is 1. In certain embodiments, at least one instance of x2 is 2. In certain embodiments, at least one instance of x2 is 3. In certain embodiments, at least one instance of x2 is 4. In certain embodiments, at least one instance of x2 is 5.

[0188] In certain embodiments, R.sup.1 is of formula:

##STR00231##

In certain embodiments, R.sup.1 is of formula:

##STR00232##

[0189] In certain embodiments, R.sup.1 is

##STR00233##

wherein: each instance of R.sup.6A is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —SO.sub.2R.sup.c1, —CN, —B(OR.sup.c1).sub.2, or —SCN; x1 is 0, 1, 2, or 3; and w1 is 0, 1, 2, 3, 4, or 5.

[0190] In certain embodiments, R.sup.1 is of formula:

##STR00234##

wherein: each instance of R.sup.6A is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —SO.sub.2R.sup.c1, —CN, —B(OH).sub.2, or —SCN; and w1 is 0, 1, 2, 3, 4, 5, or 6.

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

##STR00235##

there are zero or more instances of R.sup.6A. In certain embodiments, in the compound of formula:

##STR00236##

there is one instance of R.sup.6A. In certain embodiments, w1 is 0. In certain embodiments, there are one or more instances of R.sup.6A. In certain embodiments, w1 is 1. In certain embodiments, at least one instance of w1 is 2. In certain embodiments, at least one instance of w1 is 3. In certain embodiments, at least one instance of w1 is 4. In certain embodiments, at least one instance of w1 is 5. In certain embodiments, at least one instance of w1 is 6. In certain embodiments, at least one instance of R.sup.6A is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.6A is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R.sup.6A is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.6A is methyl. In certain embodiments, at least one instance of R.sup.6A is C.sub.1-6 alkyl, optionally substituted with substituted or unsubstituted acyl, —OH, —O(C.sub.1-6 alkyl), —NH.sub.2, —NH(C.sub.1-6 alkyl), —N(C.sub.1-6 alkyl).sub.2, —NO.sub.2, —CN, or —SO.sub.2H. In certain embodiments, at least one instance of R.sup.6A is —(CH.sub.2)NH.sub.2, —(CH.sub.2)NHMe, —(CH.sub.2)NMe.sub.2, —(CH.sub.2).sub.2NH.sub.2, —(CH.sub.2).sub.2NHMe, —(CH.sub.2).sub.2NMe.sub.2, or —(CH.sub.2).sub.2NO.sub.2. In certain embodiments, at least one instance of R.sup.6A is:

##STR00237##

wherein: each instance of w1 is independently 0, 1, 2, 3, 4, 5, or 6; each instance of w2 is independently 1, 2, or 3; w3 is 1, 2, or 3; w4 is 0, 1, 2, or 3; R.sup.B is hydrogen or substituted or unsubstituted alkyl; each instance of R.sup.6 is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OH, —O(alkyl), —NO.sub.2, —NH.sub.2, —CN, or —SCN; and

[0192] each instance of R.sup.6d1 and R.sup.6d2 is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OH, —O(alkyl), —NO.sub.2, —NH.sub.2, —CN, or —SCN. In certain embodiments, at least one instance of R.sup.6A is:

##STR00238##

wherein: w1, w2, w3, R.sup.6B, R.sup.6C, R.sup.6d1, and R.sup.d2 are as defined herein. In certain embodiments, at least one instance of R.sup.6A is:

##STR00239##

wherein: w1 is 0, 1, 2, 3, 4, 5, or 6; w2 is 1, 2, or 3; w3 is 1, 2, or 3; R.sup.6B is hydrogen or substituted or unsubstituted alkyl; each instance of R.sup.6C is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OH, —O(alkyl), —NO.sub.2, —NH.sub.2, —CN, or —SCN; and each instance of R.sup.6d1 and R.sup.6d2 is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OH, —O(alkyl), —NO.sub.2, —NH.sub.2, —CN, or —SCN. In certain embodiments, at least one instance of w1 is 0 or 1. In certain embodiments, at least one instance of w2 is 0 or 1. In certain embodiments, w2 is 1. In certain embodiments, at least one instance of w2 is 2. In certain embodiments, at least one instance of w2 is 3. In certain embodiments, w3 is 1. In certain embodiments, at least one instance of w3 is 2. In certain embodiments, at least one instance of w3 is 3. In certain embodiments, w4 is 1. In certain embodiments, at least one instance of R.sup.6A is:

##STR00240##

wherein each instance of w1 is independently 0, 1, 2, or 3; each instance of w2 is independently is 1, 2, or 3; w4 is 0, 1, 2, or 3; and R.sup.6B is hydrogen or alkyl. In certain embodiments, at least one instance of w1 is 0, and at least one instance of w2 is 0. In certain embodiments, each instance of w1 and w2 is 0, and w4 is 0 or 1. In certain embodiments, R.sup.1 is

##STR00241##

and at least one instance of R.sup.6A is:

##STR00242##

wherein w1, w2, w4, and R.sup.6B are as defined herein. In certain embodiments, R.sup.1 is of formula:

##STR00243##

and at least one instance of R.sup.6A is:

##STR00244##

wherein w1, w2, w4, and R.sup.6B are as defined herein. In certain embodiments, R.sup.1 is of formula:

##STR00245##

and at least one instance of R.sup.6A is:

##STR00246##

wherein w1, w2, w4, and R.sup.6B are as defined herein. In certain embodiments, at least one instance of R.sup.6A is:

##STR00247##

In certain embodiments, at least one instance of R.sup.6A is:

##STR00248##

wherein w1 is 0, 1, 2, or 3; at least one instance of R.sup.6d1 and R.sup.6d2 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, —NH.sub.2, —OH, or —O(substituted or unsubstituted alkyl); and R.sup.6B is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.6A is:

##STR00249##

In certain embodiments, at least one instance of R.sup.6A is:

##STR00250##

wherein: w3 is 1, 2, or 3; R.sup.6B is hydrogen or substituted or unsubstituted alkyl; and R.sup.6C is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, —NH.sub.2, —OH, or —O(substituted or unsubstituted alkyl). In certain embodiments, at least one instance of R.sup.6A is:

##STR00251##

In certain embodiments, at least one instance of R.sup.6A is:

##STR00252##

wherein: w1 is 0, 1, 2, 3, 4, 5, or 6; w3 is 1, 2, or 3; R.sup.6a and R.sup.6b are each independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OH, —O(alkyl), —NO.sub.2, —NH.sub.2, —CN, or —SCN; or optionally, R.sup.6a and R.sup.6b are joined together with the intervening atoms to form an optionally substituted carbocycyl group; and each instance of R.sup.6C is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OH, —O(alkyl), —NO.sub.2, —NH.sub.2, —CN, or —SCN. In certain embodiments, at least one instance of R.sup.6A is

##STR00253##

In certain embodiments, at least one instance of R.sup.6A is

##STR00254## ##STR00255##

In certain embodiments, at least one instance of R.sup.6A is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.6A is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.6A is

##STR00256##

In certain embodiments, at least one instance of R.sup.6A is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.6A is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.6A is

##STR00257##

[0193] In certain embodiments, at least one instance of R.sup.6A is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.6A is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.6A is substituted or unsubstituted cyclopropyl. In certain embodiments, at least one instance of R.sup.6A is

##STR00258##

In certain embodiments, at least one instance of R.sup.6A is

##STR00259##

In certain embodiments, at least one instance of R.sup.6A is

##STR00260##

In certain embodiments, at least one instance of R.sup.6A is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.6A is optionally substituted 2,3-dihydrobenzofuran. In certain embodiments, at least one instance of R.sup.6A is

##STR00261##

In certain embodiments, at least one instance of R.sup.6A is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.6A is optionally substituted benzyl. In certain embodiments, at least one instance of R.sup.6A is benzyl. In certain embodiments, at least one instance of R.sup.6A is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.6A is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.6A is optionally substituted tetrazole or optionally substituted benzofuran. In certain embodiments, at least one instance of R.sup.6A is

##STR00262##

In certain embodiments, R.sup.1 is of formula:

##STR00263##

wherein at least one instance of R.sup.1A is

##STR00264##

In certain embodiments, at least one instance of R.sup.1A is optionally substituted 2,3-dihydrobenzofuran. In certain embodiments, at least one instance of R.sup.1A is

##STR00265##

[0194] In certain embodiments, at least one instance of R.sup.6A is —OR.sup.c1 (e.g., —OH or —OMe). In certain embodiments, at least one instance of R.sup.6A is —O(optionally substituted alkyl). In certain embodiments, at least one instance of R.sup.6A is —O(optionally substituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.6A is

##STR00266##

for example,

##STR00267##

[0195] In certain embodiments, at least one instance of R.sup.6A is —NO.sub.2. In certain embodiments, at least one instance of R.sup.6A is —N(R.sup.c2).sub.2 (e.g., —NMe.sub.2). In certain embodiments, at least one instance of R.sup.6A is —N(R.sup.c2).sub.2, wherein at least one instance of R.sup.c2 is hydrogen. In certain embodiments, at least one instance of R.sup.6A is —N(R.sup.c2).sub.2, wherein at least one instance of R.sup.c2 is hydrogen and the other instance of R.sup.c2 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.6A is

##STR00268##

[0196] In certain embodiments, at least one instance of R.sup.6A is —SR.sup.c1 (e.g., —SMe). In certain embodiments, at least one instance of R.sup.6A is —CN. In certain embodiments, at least one instance of R.sup.6A is —B(OR.sup.c1).sub.2 (e.g., —B(OH).sub.2, —B(OMe).sub.2). In certain embodiments, at least one instance of R.sup.6A is —B(OH).sub.2. In certain embodiments, at least one instance of R.sup.6A is —B(O(optionally substituted alkyl)).sub.2. In certain embodiments, at least one instance of R.sup.6A is —B(O(optionally substituted C.sub.1-6 alkyl)).sub.2. In certain embodiments, at least one instance of R.sup.6A is —SCN.

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

##STR00269##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein: R.sup.6A is substituted or unsubstituted acyl, —C(═O)N(R.sup.6c).sub.2,

##STR00270##

—NO.sub.2, —SO.sub.2R.sup.c1, —SO.sub.2N(R.sup.6c).sub.2, —B(OR.sup.c1).sub.2, or —OR.sup.c1; each instance of R.sup.6c is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.6d, or a nitrogen protecting group; R.sup.6d is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or an oxygen protecting group; and R.sup.6w is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.6d, or a nitrogen protecting group; and w2 is 0, 1, 2, 3, 4, 5, or 6.

[0198] In certain embodiments, the compound is of formula:

##STR00271##

##STR00272##

—NO.sub.2, —SO.sub.2R.sup.c1, —SO.sub.2N(R.sup.6c).sub.2, —B(OH).sub.2, or —OR.sup.c1; each instance of R.sup.6c is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.6d, or a nitrogen protecting group; R.sup.6d is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or an oxygen protecting group; R.sup.6w is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.6d, or a nitrogen protecting group; and w2 is 0, 1, 2, 3, 4, 5, or 6.

[0199] In certain embodiments, R.sup.6A is substituted or unsubstituted acyl, —C(═O)N(R).sub.2,

##STR00273##

—NO.sub.2, —SO.sub.2R.sup.c1, —SO.sub.2N(R.sup.6c).sub.2, —B(OR.sup.c1).sub.2, or —OR.sup.c1, wherein R.sup.6c and R.sup.6c1 are as described herein. In certain embodiments, R.sup.6A is substituted or unsubstituted acyl,

##STR00274##

—NO.sub.2, —SO.sub.2R.sup.c1, —B(OR.sup.c1).sub.2, or —OR.sup.c1, wherein R.sup.6a and R.sup.6c are as described herein. In certain embodiments, at least one instance of R.sup.6c is hydrogen. In certain embodiments, R.sup.6A is substituted or unsubstituted acyl, —C(═O)N(R.sup.6c).sub.2,

##STR00275##

—NO.sub.2, —SO.sub.2R.sup.c1, —SO.sub.2N(R.sup.6c).sub.2, —B(OH).sub.2, or —OR.sup.c1, wherein R.sup.6c is as described herein. In certain embodiments, at least one instance of R.sup.6c is hydrogen. In certain embodiments, at least one instance of R.sup.6A is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.6A is —C(═O)N(R.sup.6c).sub.2 (e.g., —C(═O)NH.sub.2). In certain embodiments, R.sup.6A is not —C(═O)N(R.sup.6c).sub.2 (e.g., is not —C(═O)NH.sub.2). In certain embodiments, at least one instance of R.sup.6A is

##STR00276##

(e.g., —CH.sub.2C(═O)OMe). In certain embodiments, at least one instance of R.sup.6A is

##STR00277##

w2, w2 is 0, 1, 2, 3, 4, 5, or 6; and R.sup.c1 is halogen, optionally substituted acyl, optionally substituted alkyl, —OH, —O(optionally substituted alkyl), or —NH.sub.2. In certain embodiments, at least one instance of R.sup.6A is

##STR00278##

In certain embodiments, at least one instance of w2 is 0. In certain embodiments, at least one instance of w2 is 1. In certain embodiments, at least one instance of w2 is 2. In certain embodiments, at least one instance of w2 is 3. In certain embodiments, at least one instance of w2 is 4. In certain embodiments, at least one instance of w2 is 5. In certain embodiments, at least one instance of w2 is 6. In certain embodiments, at least one instance of R.sup.6w is hydrogen. In certain embodiments, at least one instance of R.sup.6w is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.6w is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.6w is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.6w is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.6w is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.6w is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.6w is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.6w is optionally substituted benzyl. In certain embodiments, R.sup.6w is benzyl. In certain embodiments, R.sup.6w is substituted or unsubstituted phenyl. In certain embodiments, R.sup.6w is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9 to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.6w is —OR.sup.6d (e.g., —OMe). In certain embodiments, R.sup.6w is an oxygen protecting group.

[0200] In certain embodiments, at least one instance of R.sup.6A is —SO.sub.2R.sup.c1 (e.g., —SO.sub.2Me). In certain embodiments, at least one instance of R.sup.6A is —SO.sub.2N(R.sup.6c).sub.2 (e.g., —SO.sub.2NHMe). In certain embodiments, at least one instance of R.sup.6A is —B(OH).sub.2. In certain embodiments, at least one instance of R.sup.6A is —B(O(optionally substituted alkyl)).sub.2. In certain embodiments, at least one instance of R.sup.6A is —B(O(optionally substituted C.sub.1-6 alkyl)).sub.2. In certain embodiments, at least one instance of R.sup.6A is —OR.sup.c1 (e.g., —OMe). In certain embodiments, at least one instance of R.sup.6A is —SO.sub.2R.sup.c1, and R.sup.c1 is halogen, —OH, or —O(optionally substituted alkyl). In certain embodiments, at least one instance of R.sup.6A is —SO.sub.2R.sup.c1, and R.sup.c1 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.6A is —SO.sub.2F. In certain embodiments, at least one instance of R.sup.6A is —SO.sub.2(OH).

[0201] In certain embodiments, at least one instance of R.sup.6c is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.6c is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.6c is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.6c is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.6c is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.6c is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.6c is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.6c is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.6c is optionally substituted benzyl. In certain embodiments, at least one instance of R.sup.6c is benzyl. In certain embodiments, at least one instance of R.sup.6c is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.6c is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.6c is —OR.sup.6d (e.g., —OMe). In certain embodiments, at least one instance of R.sup.6c is nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0202] In certain embodiments, R.sup.1 is of formula:

##STR00279## ##STR00280##

In certain embodiments, R.sup.1 is of formula:

##STR00281##

In certain embodiments, R.sup.1 is of formula:

##STR00282##

[0203] In certain embodiments, R.sup.1 is of formula:

##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287## ##STR00288## ##STR00289## ##STR00290## ##STR00291## ##STR00292## ##STR00293## ##STR00294## ##STR00295## ##STR00296## ##STR00297## ##STR00298## ##STR00299## ##STR00300## ##STR00301## ##STR00302## ##STR00303## ##STR00304## ##STR00305## ##STR00306## ##STR00307## ##STR00308## ##STR00309##

[0204] In certain embodiments, R.sup.1 is of formula:

##STR00310## ##STR00311## ##STR00312## ##STR00313## ##STR00314## ##STR00315## ##STR00316## ##STR00317##

[0205] In certain embodiments, R.sup.1 is of formula:

##STR00318##

##STR00319##

wherein each instance of R.sup.1B is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN, or nitrogen protecting group when attached to a nitrogen atom; x1 is 0, 1, 2, 3, 4, 5, or 6; and x2 is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, R.sup.1 is of formula:

##STR00320##

##STR00321##

In certain embodiments, at least one instance of R.sup.6A is

##STR00322##

In certain embodiments, R.sup.1 is of formula:

##STR00323##

wherein each instance of R.sup.1B is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, —SCN, or nitrogen protecting group when attached to a nitrogen atom; x1 is 0, 1, 2, 3, 4, 5, or 6; and x2 is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, R.sup.1 is of formula:

##STR00324##

##STR00325##

In certain embodiments, R.sup.1 is of formula:

##STR00326##

In certain embodiments, R.sup.1 is of formula:

##STR00327##

wherein x1 is 1, and x2 is 0. In certain embodiments, R.sup.1 is of the formula:

##STR00328##

In certain embodiments, R.sup.1 is of the formula:

##STR00329##

In certain embodiments, R.sub.1 is not of the formula:

##STR00330##

In certain embodiments, R.sup.1 is not of the formula:

##STR00331##

[0206] In certain embodiments, there are zero instances of R.sup.1B. In certain embodiments, x2 is 0. In certain embodiments, there are one or more instances of R.sup.1B. In certain embodiments, x2 is 1. In certain embodiments, at least one instance of x2 is 2. In certain embodiments, at least one instance of x2 is 3. In certain embodiments, at least one instance of x2 is 4. In certain embodiments, at least one instance of x2 is 5. In certain embodiments, at least one instance of x2 is 6. In certain embodiments, at least one instance of R.sup.1B is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.1B is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R.sup.1B is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.1B is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.1B is substituted methyl (e.g., —CF.sub.3). In certain embodiments, at least one instance of R.sup.1B is unsubstituted methyl. In certain embodiments, at least one instance of R.sup.1B is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.1B is unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.1B is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.1B is substituted or unsubstituted butyl (e.g., t-butyl, n-butyl). In certain embodiments, at least one instance of R.sup.1B is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.1B is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.1B is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 10-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.1B is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.1B is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance R.sup.1B benzyl. In certain embodiments, at least one instance of R.sup.1B is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.1B is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.1B is —OR.sup.c1 (e.g., —OH or —OMe). In certain embodiments, at least one instance of R.sup.1B is —O(CH.sub.2)(optionally substituted aryl). In certain embodiments, at least one instance of R.sup.1B is —O(CH.sub.2)(phenyl). In certain embodiments, at least one instance of R.sup.1B is —O(optionally substituted phenyl). In certain embodiments, at least one instance of R.sup.1B is —O(optionally substituted aryl). In certain embodiments, at least one instance of R.sup.1B is —NO.sub.2. In certain embodiments, at least one instance of R.sup.1B is —N(R.sup.c2).sub.2 (e.g., —NMe.sub.2). In certain embodiments, at least one instance of R.sup.1B is —SR.sup.c1 (e.g., —SMe). In certain embodiments, at least one instance of R.sup.1B is —SO.sub.2, —CN, or —SCN.

[0207] In certain embodiments, at least one instance of R.sup.1A, R.sup.1B, R.sup.3A, R.sup.3a, R.sup.4, R.sup.5, R.sup.6A, R.sup.6A, or R.sup.6B is —OR.sup.c1, —N(R.sup.c2).sub.2, or —SR.sup.c1, and R.sup.c1 and R.sup.c2 as defined herein. In certain embodiments, at least one instance of R.sup.6A is OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —SO.sub.2R.sup.c1, —CN, —B(OR.sup.c1).sub.2, or —SCN; and R.sup.c1 and R.sup.c2 are as defined herein. In certain embodiments, at least one instance of R.sup.6A is OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —SO.sub.2R.sup.c1, —CN, —B(OH).sub.2, or —SCN; and R.sup.c1 and R.sup.c2 are as defined herein.

[0208] In certain embodiments, R.sup.c1 is halogen, hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, —OH, or —O(optionally substituted alkyl). In certain embodiments, R.sup.c1 is halogen (e.g., F, Cl, Br, or I), —OH, or —O(optionally substituted alkyl).

[0209] In certain embodiments, at least one instance of R.sup.1A, R.sup.1B, R.sup.3A, R.sup.3a, R.sup.4, R.sup.5, R.sup.6A, R.sup.6A, or R.sup.6B is —OR.sup.c1, —N(R.sup.c2).sub.2, or —SR.sup.c1, and R.sup.c1 and R.sup.c2 are as defined herein. In certain embodiments, R.sup.c1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.c1 is hydrogen. In certain embodiments, R.sup.c1 is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.c1 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.c1 is substituted or unsubstituted methyl.

[0210] In certain embodiments, R.sup.c1 is substituted or unsubstituted ethyl. In certain embodiments, R.sup.c1 is substituted or unsubstituted propyl. In certain embodiments, R.sup.c1 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.c1 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.c1 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.c1 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.c1 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.c1 is benzyl. In certain embodiments, R.sup.c1 is substituted or unsubstituted phenyl. In certain embodiments, R.sup.c1 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.c1 is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.c1 is a sulfur protecting group when attached to a sulfur atom.

[0211] In certain embodiments, at least one instance of R.sup.c2 is hydrogen. In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one R.sup.c2 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sub.c2 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.c2 is benzyl. In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.c2 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0212] In certain embodiments, R.sup.1 is substituted or unsubstituted alkenyl (e.g., C.sub.2-6 alkenyl).

[0213] In certain embodiments, R.sup.1 is substituted or unsubstituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.1 is C.sub.2-6 alkenyl optionally substituted with optionally substituted aryl. In certain embodiments, R.sup.1 is C.sub.2-6 alkenyl optionally substituted with optionally substituted phenyl. In certain embodiments, R.sup.1 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 10-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.1 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).

[0214] In certain embodiments, R.sup.1 is substituted or unsubstituted phenyl. In certain embodiments, R.sup.1 is substituted or unsubstituted benzyl.

[0215] In certain embodiments, y is 0. In certain embodiments, y is 1.

[0216] In certain embodiments, in Formula (I′) or (I), X is —O—, —C(R.sup.3A).sub.2—, —C(R.sup.3A)═, or —N(R.sup.3B)—, as valency permits. In certain embodiments, X is —O—. In certain embodiments, X is —C(R.sup.3A).sub.2— (e.g., —CH.sub.2—). In certain embodiments, X is —C(R.sup.3A)═(e.g., —CH═). In certain embodiments, X is —N(R.sup.3B)— (e.g., —NH—).

[0217] In certain embodiments, in Formula (I′) or (I), Y is —C(R.sup.3A).sub.2— or —N(R.sup.3B)—, as valency permits. In certain embodiments, Y is —C(R.sup.3A).sub.2— (e.g., —CH.sub.2—). In certain embodiments, Y is —N(R.sup.3B)— (e.g., —NH—).

[0218] In certain embodiments, X is —CH.sub.2—; and Y is —NH.sub.2—. In certain embodiments, X is —NH—; and Y is —NH.sub.2—. In certain embodiments, X is —O—; and Y is —NH.sub.2—. In certain embodiments, X is —CH═; and Y is —NH.sub.2—. In certain embodiments, X is —CH.sub.2—; and Y is —CH.sub.2—. In certain embodiments, in compounds of Formula (I′) or (I), each instance of custom-character is independently a single or double C—C bond, as valency permits. In certain embodiments, in the moiety

##STR00332##

custom-character is a single bond. In certain embodiments, in the moiety

##STR00333##

custom-character is a double bond.

[0219] In certain embodiments, at least one instance of R.sup.3A is hydrogen, halogen, substituted or unsubstituted acyl (e.g., —C(═O)Me), substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN; wherein R.sup.c1 and R.sup.c2 are as defined herein. In certain embodiments, for each of X and Y, both instances of R.sup.3A are hydrogen. In certain embodiments, for X, one instance of R.sup.3A is hydrogen and the other instance of R.sup.3A is substituted or unsubstituted C.sub.1-6 alkyl, and for Y, both instances of R.sup.3A are hydrogen. In certain embodiments, X or Y is —C(R.sup.3A).sub.2—, and two instances of R.sup.3A are joined together with the intervening atoms to form an optionally substituted heterocyclyl or heteroaryl ring. In certain embodiments, at least one instance of R.sup.3A is —OR.sup.c1 (e.g., —OMe), —NO.sub.2, —N(R.sup.c2).sub.2 (e.g., —NH.sub.2), —SR.sup.c1 (e.g., —SH), —CN, or —SCN.

[0220] In certain embodiments, R.sup.3B is hydrogen. In certain embodiments, R.sup.3B is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.3B is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0221] In certain embodiments, in the moiety

##STR00334##

custom-character is a single C—C bond, as valency permits. In certain embodiments, in the moiety

##STR00335##

X is —CH═; and custom-character is a double C—C bond, as valency permits.

[0222] In certain embodiments, there are zero instances of R.sup.3C. In certain embodiments, n1 is 0. In certain embodiments, there is one instance of R.sup.3C. In certain embodiments, n1 is 1. In certain embodiments, at least one instance of R.sup.3C is hydrogen. In certain embodiments, at least one instance of R.sup.3C is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R.sup.3C is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0223] In certain embodiments, there are zero instances of R.sup.4. In certain embodiments, ml is 0. In certain embodiments, there are one or more instances of R.sup.4. In certain embodiments, m1 is 1. In certain embodiments, at least one instance of m1 is 2. In certain embodiments, at least one instance of m1 is 3. In certain embodiments, at least one instance of m1 is 4. In certain embodiments, at least one instance of m1 is 5. In certain embodiments, at least one instance of m1 is 6.

[0224] In certain embodiments, at least one instance of R.sup.4 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3 to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.4 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.4 is optionally substituted benzyl. In certain embodiments, at least one instance of R.sup.4 is benzyl. 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 substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.4 is —OR.sup.c1 (e.g., —OH or —OMe). 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 —N(R.sup.c2).sub.2 (e.g., —NMe.sub.2). In certain embodiments, at least one instance of R.sup.4 is —SR.sup.c1 (e.g., —SMe). In certain embodiments, at least one instance of R.sup.4 is —CN. In certain embodiments, at least one instance of R.sup.4 is —SCN.

[0225] In certain embodiments, the moiety

##STR00336##

is of formula:

##STR00337##

wherein R.sup.2 and R.sup.4 are as described herein. In certain embodiments, the moiety

##STR00338##

is of formula:

##STR00339##

and each instance of R.sup.3a is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN.

[0226] In certain embodiments, the moiety

##STR00340##

is of formula:

##STR00341## ##STR00342##

In certain embodiments, the moiety

##STR00343##

is of formula:

##STR00344## ##STR00345## ##STR00346##

[0227] In certain embodiments, the moiety

##STR00347##

is of formula:

##STR00348##

In certain embodiments, the moiety

##STR00349##

is of formula:

##STR00350##

In certain embodiments, the moiety

##STR00351##

is of formula:

##STR00352##

[0228] In certain embodiments, the moiety

##STR00353##

is of formula:

##STR00354##

In certain embodiments, the moiety

##STR00355##

is of formula:

##STR00356##

In certain embodiments, the moiety

##STR00357##

is of formula:

##STR00358##

[0229] In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00359##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein R.sup.2 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or —CN; and R.sup.5A is hydrogen or substituted or unsubstituted alkyl; and substituents R.sup.1, R.sup.A, R.sup.B, R.sup.C, and R.sup.D are defined as described herein.

[0230] In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00360##

or a pharmaceutically acceptable salt thereof, wherein: R.sup.2 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or —CN. In certain embodiments, R.sup.2 is hydrogen. In certain embodiments, R.sup.2 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.2 is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.2 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.2 is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is substituted or unsubstituted methyl. In certain embodiments, R.sup.2 is methyl optionally substituted with —OR.sup.c1, wherein R.sup.c1 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or oxygen protecting group. In certain embodiments, R.sup.2 is methyl optionally substituted with —OH, —O(substituted or unsubstituted C.sub.1-6 alkyl), or —O(substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.2 is substituted or unsubstituted ethyl. In certain embodiments, R.sup.2 is substituted or unsubstituted propyl. In certain embodiments, R.sup.2 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.2 is

##STR00361##

In certain embodiments, R.sup.2 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.2 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.2 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.2 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.2 is benzyl. In certain embodiments, R.sup.2 is substituted or unsubstituted benzyl. In certain embodiments, R.sup.2 is substituted or unsubstituted phenyl. In certain embodiments, R.sup.2 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.2 is —OR.sup.c1 (e.g., —OH or —OMe). In certain embodiments, R.sup.2 is —N(R.sup.c2).sub.2 (e.g., —NMe.sub.2). In certain embodiments, R.sup.2 is —SR.sup.c1 (e.g., —SMe). In certain embodiments, R.sup.2 is —CN.

[0231] In certain embodiments, the compound of Formula (I′) is of formula:

##STR00362##

or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or —CN; and R.sup.5A is hydrogen or substituted or unsubstituted alkyl; and the remaining substituents R.sup.1, R.sup.3a, R.sup.A, R.sup.B, R.sup.C, R.sup.D, and m2 are defined as described herein.

[0232] In certain embodiments, the compound of Formula (I) or (I′) is of formula:

##STR00363##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein: each instance of R.sup.3a is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —CN, or —SCN; and m2 is 0, 1, 2, 3, 4, or 5. In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00364##

or a pharmaceutically acceptable salt thereof, wherein the definitions of R.sup.3a and m2 are as provided herein.

[0233] In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00365##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein: each instance of R.sup.6A is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, —SO.sub.2R.sup.c1, —CN, —B(OR.sup.6c1).sub.2, or —SCN; and w1 is 0, 1, 2, 3, 4, 5, or 6.

[0234] In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00366##

[0235] or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof. In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00367##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof. In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00368##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof.

[0236] In certain embodiments, the compound of Formula (I) or (I′) is of formula:

##STR00369##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof.

[0237] In certain embodiments, in the moiety

##STR00370##

there are zero instances of R.sup.3a. In certain embodiments, there are zero instances of R.sup.3a. In certain embodiments, m2 is 0. In certain embodiments, there are one or more instances of R.sup.3a. In certain embodiments, m2 is 1. In certain embodiments, at least one instance of m2 is 2. In certain embodiments, at least one instance of m2 is 3. In certain embodiments, at least one instance of m2 is 4. In certain embodiments, at least one instance of m2 is 5. In certain embodiments, at least one instance of m2 is 6. In certain embodiments, at least one instance of R.sup.3a is halogen (e.g., F, Cl, Br, or I). In certain embodiments, m2 is 2 and both instances of R.sup.3a are halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.3a is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R.sup.3a is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.3a is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.3a is methyl optionally substituted with halogen. In certain embodiments, at least one instance of R.sup.3a is —CF.sub.3. In certain embodiments, at least one instance of R.sup.3a is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.3a is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.3a is substituted or unsubstituted butyl (e.g., substituted or unsubstituted n-butyl or substituted or unsubstituted t-butyl). In certain embodiments, at least one instance of R.sup.3a is substituted or unsubstituted t-butyl. In certain embodiments, at least one instance of R.sup.3a is unsubstituted t-butyl. In certain embodiments, at least one instance of R.sup.3a is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.3a is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.3a is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.3a is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.3a is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.3a is benzyl. In certain embodiments, at least one instance of R.sup.3a is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.3a is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.3a is —OR.sup.c1 (e.g., —OH or —OMe). In certain embodiments, at least one instance of R.sup.3a is —O(optionally substituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.3a is —OMe. In certain embodiments, at least one instance of R.sup.3a is —OEt. In certain embodiments, at least one instance of R.sup.3a is —O(optionally substituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.3a is

##STR00371##

In certain embodiments, at least one instance of R.sup.3a is —NO.sub.2. In certain embodiments, at least one instance of R.sup.3a is —N(R.sup.c2).sub.2 (e.g., —NMe.sub.2). In certain embodiments, at least one instance of R.sup.3a is —SR.sup.c1 (e.g., —SMe). In certain embodiments, at least one instance of R.sup.3a is —CN. In certain embodiments, at least one instance of R.sup.3a is —SCN.

[0238] In certain embodiments, y1 is 0. In certain embodiments, y1 is 1.

[0239] Compounds of Formula (I′) or (I) include substituent A that is —OR.sup.5A or —N(R.sup.5).sub.2, wherein R.sup.5A and R.sup.5 are as defined herein. In certain embodiments, A is —OR.sup.5A, wherein R.sup.5A is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or an oxygen protecting group. In certain embodiments, R.sup.5A is hydrogen. In certain embodiments, R.sup.5A is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.5A is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.5A is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.5A is substituted or unsubstituted methyl. In certain embodiments, R.sup.5A is methyl. In certain embodiments, R.sup.5A is an oxygen protecting group (e.g., methyl, methoxylmethyl (MOM), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts)).

[0240] In certain embodiments, A is —N(R.sup.5).sub.2, wherein R.sup.5 is as defined herein. In certain embodiments, A is —N(R.sup.5).sub.2, wherein each instance of R.sup.5 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or a nitrogen protecting group. In certain embodiments, at least one instance of R.sup.5 is hydrogen. In certain embodiments, both instances of R.sup.5 are hydrogen. In certain embodiments, at least one instance of R.sup.5 is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R.sup.5 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.5 is C.sub.1-6 alkyl optionally substituted with halogen, —OR.sup.c1, or —N(R.sup.c2).sub.2; and R.sup.c1 is hydrogen or C.sub.1-6 alkyl optionally substituted with —N(R.sup.c2).sub.2 and each instance of R.sup.c2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or a nitrogen protecting group. In certain embodiments, at least one instance of R.sup.5 is C.sub.1-6 alkyl optionally substituted with —OR.sup.c1, and R.sup.c1 is C.sub.1-6 alkyl optionally substituted with —N(R.sup.c2).sub.2, and each instance of R.sup.c2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or a nitrogen protecting group. In certain embodiments, at least one instance of R.sup.5 is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.5 is unsubstituted methyl. In certain embodiments, at least one instance of R.sup.5 is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.5 is ethyl optionally substituted with —OR.sup.c1, and R.sup.c1 is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.5 is ethyl optionally substituted with —OR.sup.c1, and R.sup.c1 is C.sub.1-6 alkyl optionally substituted with —NH.sub.2. In certain embodiments, at least one instance of R.sup.5 is of formula

##STR00372##

b, wherein a is 0, 1, 2, 3, 4, 5, or 6; and b is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, at least one instance of R.sup.5 is of formula:

##STR00373##

In certain embodiments, at least one instance of R.sup.5 is methyl or of formula

##STR00374##

In certain embodiments, at least one instance of R.sup.5 is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.5 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.5 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.5 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In certain embodiments, one instance of R.sup.5 is hydrogen; and the other instance of R.sup.5 is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, one instance of R.sup.5 is hydrogen; and the other instance of R.sup.5 is of formula:

##STR00375##

In certain embodiments, one instance of R.sup.5 is hydrogen; and the other instance of R.sup.5 is of formula:

##STR00376##

wherein a is 0, 1, 2, 3, 4, 5, or 6; and b is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, one instance of R.sup.5 is hydrogen; and the other instance of R.sup.5 is of formula:

##STR00377##

wherein a is 0, 1, 2, or 3; and b is 0, 1, 2, or 3.
In certain embodiments, the moiety

##STR00378##

##STR00379##

[0241] In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00380##

or a pharmaceutically acceptable salt thereof, wherein a is 0, 1, 2, 3, 4, 5, or 6; and b is 0, 1, 2, 3, 4, 5, or 6.

[0242] Each of R.sup.A, R.sup.B, R.sup.C, R.sup.D, and R.sup.W is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group. In certain embodiments, R.sup.A is hydrogen. In certain embodiments, R.sup.A is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.A is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.A is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A is substituted or unsubstituted methyl. In certain embodiments, R.sup.A is unsubstituted methyl. In certain embodiments, R.sup.A is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0243] In certain embodiments, R.sup.B is hydrogen. In certain embodiments, R.sup.B is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.B is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.B is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.B is substituted or unsubstituted methyl. In certain embodiments, R.sup.B is unsubstituted methyl. In certain embodiments, R.sup.B is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0244] In certain embodiments, R.sup.C is hydrogen. In certain embodiments, R.sup.C is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.C is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.C is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.C is substituted or unsubstituted methyl. In certain embodiments, R.sup.C is substituted or unsubstituted ethyl. In certain embodiments, R.sup.C is unsubstituted methyl. In certain embodiments, R.sup.C is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0245] In certain embodiments, R.sup.D is hydrogen. In certain embodiments, R.sup.D is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.D is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.D is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.D is substituted or unsubstituted methyl. In certain embodiments, R.sup.D is unsubstituted methyl. In certain embodiments, R.sup.D is substituted or unsubstituted ethyl. In certain embodiments, R.sup.D is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In certain embodiments, each of R.sup.A, R.sup.B, R.sup.C, and R.sup.D is hydrogen. In certain embodiments, one of R.sup.A, R.sup.B, R.sup.C, and R.sup.D is substituted or unsubstituted C.sub.1-6 alkyl and the rest of R.sup.A, R.sup.B, R.sup.C, and R.sup.D are each hydrogen. In certain embodiments, R.sup.B is substituted or unsubstituted C.sub.1-6 alkyl (e.g., methyl) and the rest of R.sup.A, R.sup.C, and R.sup.D are each hydrogen. In certain embodiments, R.sup.B is methyl and the rest of R.sup.A, R.sup.C, and R.sup.D are each hydrogen.

[0246] In certain embodiments, W is unsubstituted n-butylene or of formula:

##STR00381##

x is 1; R.sup.1 is unsubstituted straight-chain or branched C.sub.1-6 alkyl or straight-chain C.sub.1-6 alkyl substituted with —OH or —O(unsubstituted C.sub.1-6 alkyl), or of formula:

##STR00382##

x1 is 0 or 1; the moiety

##STR00383##

is of formula:

##STR00384##

m1 is 0 or 1; R.sup.2 is hydrogen, substituted or unsubstituted alkenyl, substituted or unsubstituted benzyl, or methyl optionally substituted with —OR.sup.c1, or wherein R.sup.c1 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; R.sup.4 is substituted or unsubstituted benzyl; each of R.sup.A, R.sup.B, R.sup.C, and R.sup.D is hydrogen; one instance of R.sup.5 is hydrogen and the other instance of R.sup.5 is of formula

##STR00385##

wherein a is 0, 1, 2, or 3; and b is 0, 1, 2, or 3. In certain embodiments, W is unsubstituted n-butylene; x is 1; R.sup.1 is unsubstituted straight-chain or branched C.sub.1-6 alkyl or straight-chain C.sub.1-6 alkyl substituted with —OH or —O(unsubstituted C.sub.1-6 alkyl), or of formula:

##STR00386##

x1 is 0 or 1; the moiety

##STR00387##

is of formula:

##STR00388##

##STR00389##

wherein a is 0, 1, 2, or 3; and b is 0, 1, 2, or 3. In certain embodiments, W is of formula:

##STR00390##

x is 1; R.sup.1 is unsubstituted straight-chain or branched C.sub.1-6 alkyl or straight-chain C.sub.1-6 alkyl substituted with —OH or —O(unsubstituted C.sub.1-6 alkyl), or of formula:

##STR00391##

x1 is 0 or 1; the moiety

##STR00392##

is of formula:

##STR00393##

##STR00394##

wherein a is 0, 1, 2, or 3; and b is 0, 1, 2, or 3.

[0247] In certain embodiments, W is unsubstituted n-butylene or of formula:

##STR00395##

x is 1; R.sup.1 is unsubstituted straight-chain or branched C.sub.1-6 alkyl or straight-chain C.sub.1-6 alkyl substituted with —OH or —O(unsubstituted C.sub.1-6 alkyl), or of formula:

##STR00396##

x1 is 0 or 1; the moiety

##STR00397##

is of formula:

##STR00398##

##STR00399##

wherein a is 0, 1, 2, or 3; and b is 0, 1, 2, or 3. In certain embodiments, W is unsubstituted n-butylene or of formula:

##STR00400##

x is 1; R.sup.1 is unsubstituted straight-chain or branched C.sub.1-6 alkyl or straight-chain C.sub.1-6 alkyl substituted with —OH or —O(unsubstituted C.sub.1-6 alkyl), or of formula:

##STR00401##

x1 is 0 or 1; the moiety

##STR00402##

is of formula:

##STR00403##

##STR00404##

In certain embodiments, W is unsubstituted n-butylene; x is 1; R.sup.1 is unsubstituted straight-chain or branched C.sub.1-6 alkyl or straight-chain C.sub.1-6 alkyl substituted with —OH or —O(unsubstituted C.sub.1-6 alkyl), or of formula:

##STR00405##

##STR00406##

x1 is 0 or 1; the moiety

##STR00407##

is of formula:

##STR00408##

##STR00409##

In certain embodiments, W is of formula:

##STR00410##

x is 1; R.sup.1 is unsubstituted straight-chain or branched C.sub.1-6 alkyl or straight-chain C.sub.1-6 alkyl substituted with —OH or —O(unsubstituted C.sub.1-6 alkyl), or of formula:

##STR00411##

x1 is 0 or 1; the moiety

##STR00412##

is of formula:

##STR00413##

##STR00414##

In certain embodiments, W is unsubstituted n-butylene or of formula:

##STR00415##

x is 1; R.sup.1 is unsubstituted straight-chain or branched C.sub.1-6 alkyl or straight-chain C.sub.1-6 alkyl substituted with —OH or unsubstituted C.sub.1-6

##STR00416##

x1 is 0 or 1; the moiety

##STR00417##

is of formula:

##STR00418##

m1 is 0 or 1; R.sup.2 is hydrogen, substituted or unsubstituted alkenyl, substituted or unsubstituted benzyl, or methyl optionally substituted with —OR.sup.c1, or wherein R.sup.c1 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; R.sup.4 is substituted or unsubstituted benzyl; one of R.sup.A, R.sup.B, R.sup.C, and R.sup.D is substituted or unsubstituted C.sub.1-6 alkyl; and the rest of R.sup.A, R.sup.B, R.sup.C, and R.sup.D are each hydrogen; one instance of R.sup.5 is hydrogen; and the other instance of R.sup.5 is of formula

##STR00419##

[0248] In certain embodiments, W is unsubstituted n-butylene or of formula:

##STR00420##

x is 1; R.sup.1 is unsubstituted straight-chain or branched C.sub.1-6 alkyl or straight-chain C.sub.1-6 alkyl substituted with —OH or —O(unsubstituted C.sub.1-6 alkyl), or of formula:

##STR00421##

x1 is 0 or 1; the moiety

##STR00422##

is of formula:

##STR00423##

##STR00424##

In certain embodiments, W is unsubstituted n-butylene or of formula:

##STR00425##

x is 1; R.sup.1 is unsubstituted straight-chain or branched C.sub.1-6 alkyl or straight-chain C.sub.1-6 alkyl substituted with —OH or —O(unsubstituted C.sub.1-6 alkyl), or of formula:

##STR00426##

x1 is 0 or 1; the moiety

##STR00427##

is of formula:

##STR00428##

m1 is 0 or 1; R.sup.2 is hydrogen, substituted or unsubstituted alkenyl, substituted or unsubstituted benzyl, or methyl optionally substituted with —OR.sup.c1, or wherein R.sup.c1 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; R.sup.4 is substituted or unsubstituted benzyl; one of R.sup.A, R.sup.B, R.sup.C, and R.sup.D is substituted or unsubstituted C.sub.1-6 alkyl and the rest of R.sup.A, R.sup.B, R.sup.C, and R.sup.D are each hydrogen; one instance of R.sup.5 is hydrogen and the other instance of R.sup.5 is of formula

##STR00429##

##STR00430##

x1 is 0 or 1; the moiety

##STR00431##

is of formula:

##STR00432##

##STR00433##

m1 is 0 or 1; R.sup.2 is hydrogen, substituted or unsubstituted alkenyl, substituted or unsubstituted benzyl, or methyl optionally substituted with —OR.sup.c1, or wherein R.sup.1 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; R.sup.4 is substituted or unsubstituted benzyl; one of R.sup.A, R.sup.B, R.sup.C, and R.sup.D is substituted or unsubstituted C.sub.1-6 alkyl and the rest of R.sup.A, R.sup.B, R.sup.C, and R.sup.D are each hydrogen; one instance of R.sup.5 is hydrogen and the other instance of R.sup.5 is of formula

##STR00434##

In certain embodiments, W is of formula:

##STR00435##

x is 1; R.sup.1 is unsubstituted straight-chain or branched C.sub.1-6 alkyl or straight-chain C.sub.1-6 alkyl substituted with —OH or —O(unsubstituted C.sub.1-6 alkyl), or of formula:

##STR00436##

x1 is 0 or 1; the moiety

##STR00437##

is of formula

##STR00438##

m1 is 0 or 1; R.sup.2 is hydrogen, substituted or unsubstituted alkenyl, substituted or unsubstituted benzyl, or methyl optionally substituted with —OR.sup.c1, or wherein R.sup.c1 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; R.sup.4 is substituted or unsubstituted benzyl; one of R.sup.A, R.sup.B, R.sup.C, and R.sup.D is substituted or unsubstituted C.sub.1-6 alkyl and the rest of R.sup.A, R.sup.B, R.sup.C, and R.sup.D are each hydrogen; one instance of R.sup.5 is hydrogen and the other instance of R.sup.5 is of

##STR00439##

In certain embodiments, W is unsubstituted n-butylene or of formula:

##STR00440##

x is 1; R.sup.1 is unsubstituted straight-chain or branched C.sub.1-6 alkyl or straight-chain C.sub.1-6 alkyl substituted with —OH or —O(unsubstituted C.sub.1-6 alkyl), or of formula:

##STR00441##

x1 is 0 or 1; the moiety

##STR00442##

is of formula:

##STR00443##

m1 is 0 or 1; R.sup.2 is hydrogen, substituted or unsubstituted alkenyl, substituted or unsubstituted benzyl, or methyl optionally substituted with —OR.sup.c1, or wherein R.sup.c1 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; R.sup.4 is substituted or unsubstituted benzyl; one of R.sup.A, R.sup.B, R.sup.C, and R.sup.D is substituted or unsubstituted C.sub.1-6 alkyl and the rest of R.sup.A, R.sup.B, R.sup.C, and R.sup.D are each hydrogen; one instance of R.sup.5 is hydrogen and the other instance of R.sup.5 is of formula

##STR00444##

##STR00445##

x1 is 0 or 1; the moiety

##STR00446##

is of formula:

##STR00447##

m1 is 0 or 1; R.sup.2 is hydrogen, substituted or unsubstituted alkenyl, substituted or unsubstituted benzyl, or methyl optionally substituted with —OR.sup.c1, or wherein R.sup.c1 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; R.sup.4 is substituted or unsubstituted benzyl; one of R.sup.A, R.sup.B, R.sup.C, and R.sup.D is substituted or unsubstituted C.sub.1-6 alkyl; and the rest of R.sup.A, R.sup.B, R.sup.C, and R.sup.D are each hydrogen; one instance of R.sup.5 is hydrogen; and the other instance of R.sup.5 is of formula

##STR00448##

In certain embodiments, W is of formula:

##STR00449##

x is 1; R.sup.1 is unsubstituted straight-chain or branched C.sub.1-6 alkyl or straight-chain C.sub.1-6 alkyl substituted with —OH or —O(unsubstituted C.sub.1-6 alkyl), or of formula:

##STR00450##

x1 is 0 or 1; the moiety

##STR00451##

is of formula:

##STR00452##

m1 is 0 or 1; R.sup.2 is hydrogen, substituted or unsubstituted alkenyl, substituted or unsubstituted benzyl, or methyl optionally substituted with —OR.sup.c1, or wherein R.sup.c1 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; R.sup.4 is substituted or unsubstituted benzyl; one of R.sup.A, R.sup.B, R.sup.C, and R.sup.D is substituted or unsubstituted C.sub.1-6 alkyl and the rest of R.sup.A, R.sup.B, R.sup.C, and R.sup.D are each hydrogen; one instance of R.sup.5 is hydrogen and the other instance of R.sup.5 is of formula

##STR00453##

[0249] In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00454## ##STR00455## ##STR00456##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof.

[0250] In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00457## ##STR00458## ##STR00459## ##STR00460## ##STR00461## ##STR00462## ##STR00463## ##STR00464## ##STR00465##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof.

[0251] In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00466## ##STR00467##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof.

[0252] In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00468##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof.

[0253] In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00469##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof.

[0254] In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00470##

or a pharmaceutically acceptance salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein each instance of R.sup.6A is independently optionally substituted acyl, substituted or unsubstituted C.sub.1-6 alkyl, or substituted or unsubstituted C.sub.2-6 alkenyl, or —O(substituted or unsubstituted C.sub.1-6 alkyl).

[0255] In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00471## ##STR00472## ##STR00473## ##STR00474##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein n2 is 0, 1, 2, 3, 4, 5, or 6; and wherein the remaining substituents are defined as described herein.

[0256] In certain embodiments, the compound of Formula (I) or (I′) is of formula:

##STR00475## ##STR00476## ##STR00477## ##STR00478##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein n2 is 0, 1, 2, 3, 4, 5, or 6.

[0257] In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00479## ##STR00480## ##STR00481## ##STR00482##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein n2 is 0, 1, 2, 3, 4, 5, or 6.

[0258] In certain embodiments, the compound of Formula (I′) or (I) is of formula:

##STR00483## ##STR00484## ##STR00485## ##STR00486##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein n2 is 0 or 1.

[0259] In certain embodiments, the compound of Formula (I′) or (I) is of the formula:

##STR00487## ##STR00488## ##STR00489## ##STR00490## ##STR00491## ##STR00492## ##STR00493## ##STR00494## ##STR00495## ##STR00496## ##STR00497## ##STR00498## ##STR00499## ##STR00500## ##STR00501## ##STR00502## ##STR00503## ##STR00504## ##STR00505## ##STR00506## ##STR00507## ##STR00508## ##STR00509## ##STR00510## ##STR00511## ##STR00512## ##STR00513## ##STR00514## ##STR00515## ##STR00516## ##STR00517## ##STR00518## ##STR00519## ##STR00520## ##STR00521## ##STR00522## ##STR00523## ##STR00524## ##STR00525## ##STR00526## ##STR00527## ##STR00528## ##STR00529## ##STR00530## ##STR00531## ##STR00532## ##STR00533## ##STR00534## ##STR00535## ##STR00536## ##STR00537## ##STR00538## ##STR00539## ##STR00540## ##STR00541## ##STR00542## ##STR00543##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof.

[0260] In certain embodiments, the compound of Formula (I′) or (I) is of the formula:

##STR00544## ##STR00545## ##STR00546## ##STR00547## ##STR00548## ##STR00549## ##STR00550## ##STR00551## ##STR00552## ##STR00553## ##STR00554## ##STR00555## ##STR00556## ##STR00557## ##STR00558## ##STR00559## ##STR00560## ##STR00561## ##STR00562## ##STR00563## ##STR00564## ##STR00565## ##STR00566##

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof.

[0261] In certain embodiments, the compound of Formula (I′) or (I) is a compound provided in any one of the Examples below. In certain embodiments, a compound described herein is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt thereof.

[0262] Certain compounds described herein bind, covalently modify, and/or inhibit a cyclophilin. In certain embodiments, the compounds described herein irreversibly inhibit a cyclophilin. In certain embodiments, the compounds described herein reversibly inhibit a cyclophilin. In certain embodiments, the cyclophilin is a cyclophilin A. In certain embodiments, the cyclophilin is cyclophilin B. In certain embodiments, the cyclophilin is cyclophilin C. In certain embodiments, the cyclophilin is cyclophilin D (CypD). In certain embodiments, the cyclophilin is cyclophilin E. In certain embodiments, the cyclophilin is cyclophilin G. In certain embodiments, the cyclophilin is cyclophilin H. In certain embodiments, the cyclophilin is cyclophilin 40. In certain embodiments, the cyclophilin is PPWD1. In certain embodiments, the cyclophilin is PPIL1. In certain embodiments, the cyclophilin is NKTR. In certain embodiments, the compounds described herein covalently bind to the cyclophilin (e.g., CypD)). In certain embodiments, the compounds described herein reversibly bind to the cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, the compounds described herein non-reversibly bind to the cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, the compounds described herein modulate the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, the compounds described herein inhibit the cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, the compounds described herein reversibly inhibit the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR).

[0263] The binding affinity of a compound described herein to a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) may be measured by the dissociation constant (K.sub.d) value of an adduct of the compound and the cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) using methods known in the art (e.g., isothermal titration calorimetry (ITC)). In certain embodiments, the K.sub.d value of the adduct is not more than about 100 μM, not more than about 10 μM, not more than about 1 μM, not more than about 100 nM, not more than about 10 nM, or not more than about 1 nM.

[0264] In certain embodiments, the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) is inhibited by a compound described herein. The inhibition of the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) by a compound described herein may be measured by determining the half maximal inhibitory concentration (IC.sub.50) of the compound when the compound, or a pharmaceutical composition thereof, is contacted with the cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). The IC.sub.50 values may be obtained using methods known in the art (e.g., by a competition binding assay). In certain embodiments, the IC.sub.50 value of a compound described herein is not more than about 1 mM, not more than about 100 μM, not more than about 10 μM, not more than about 1 μM, not more than about 100 nM, not more than about 10 nM, or not more than about 1 nM.

[0265] The compounds described herein may selectively modulate the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, the compounds selectively increase the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, the compounds selectively inhibit the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) over other cyclophilins. In certain embodiments, the compounds inhibit the activity of two or more cyclophilins (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) to the same extent.

[0266] The selectivity of a compound described herein in inhibiting the activity of a first cyclophilin (e.g., CypD) over a second cyclophilin may be measured by the quotient of the IC.sub.50 value of the compound in inhibiting the activity of the second cyclophilin over the IC.sub.50 value of the compound in inhibiting the activity of the first cyclophilin. The selectivity of a compound described herein in modulating the activity of a first cyclophilin over a second cyclophilin may also be measured by the quotient of the K.sub.d value of an adduct of the compound and the second cyclophilin over the K.sub.d value of an adduct of the compound and the first cyclophilin (e.g., CypD). In certain embodiments, the selectivity is at least about 1-fold, at least about 3-fold, at least about 10-fold, at least about 30-fold, at least about 100-fold, at least about 300-fold, at least about 1,000-fold, at least about 3,000-fold, at least about 10,000-fold, at least about 30,000-fold, or at least about 100,000-fold. In certain embodiments, the selectivity is at least about 1 at least 2-fold, 5-fold, 10-fold, or more. In certain embodiments, the compounds of Formula (I′) or (I) are selective for cyclophilin D compared to other cyclophilins (e.g., at least 2-fold, 5-fold, 10-fold, or more selective for cyclophilin D). In certain embodiments, the compounds of Formula (I′) or (I) are selective for cyclophilin D compared to cyclophilin E (e.g., at least 2-fold, 5-fold, 10-fold, or more selective for cyclophilin D). In certain embodiments, the compounds of Formula (I′) or (I) are selective for cyclophilin D compared to cyclophilin B (e.g., at least 2-fold, 5-fold, 10-fold, or more selective for cyclophilin D). In certain embodiments, the compounds of Formula (I′) or (I) are selective for cyclophilin D compared to cyclophilins B and/or E (e.g., at least 2-fold, 5-fold, 10-fold, or more selective for cyclophilin D). In certain embodiments, selectivity for inhibiting a first cyclophilin over other cyclophilins is measured by in vitro inhibition (IC.sub.50) assays using a chymotrypsin coupled PPIase assay with Suc-AAPF-AMC as the peptide substrate was used, whereby isomerization of a peptide substrate Suc-AAPF-AMC from the cis to trans conformation allowed for proteolysis via excess a-chymotrypsin, releasing the C-terminal coumarin fluorophoreas, as disclosed in the Examples (e.g., Examples 1-3). In certain embodiments, selectivity for inhibiting a first cyclophilin over other cyclophilins is measured by Surface Plasmon Resonance (SPR) assays as disclosed in the Examples.

[0267] It is expected that the compounds described herein may be useful in treating and/or preventing diseases associated with aberrant activity (e.g., increased activity, undesired activity, abnormal activity) of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). It is known in the art that cyclophilins are implicated in a wide range of diseases and conditions, such as neurological (e.g., neurodegenerative) diseases, metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), and conditions associated with regulation of the mitochondrial permeability transition pore (mPTP), autophagy, aging; and oxidative stress. Therefore, the compounds described herein are expected to be useful in treating and/or preventing diseases (e.g., neurological (e.g., neurodegenerative) diseases, metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), and conditions associated with regulation of the mitochondrial permeability transition pore (mPTP), autophagy, aging; and oxidative stress).

Pharmaceutical Compositions, Kits, and Administration

[0268] The present disclosure also provides pharmaceutical compositions comprising a compound described herein and optionally a pharmaceutically acceptable excipient. In certain embodiments, a compound described herein is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, a compound described herein in a pharmaceutical composition for treating the diseases and/or conditions described herein is a compound of Formula (I′) or (I), a compound of Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0269] In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, a therapeutically effective amount is an amount effective for inhibiting the aberrant activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, a therapeutically effective amount is an amount effective for treating a disease (e.g., neurological (e.g., neurodegenerative) disease, metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), and conditions associated with regulation of the mitochondrial permeability transition pore (mPTP), autophagy, aging; and oxidative stress; and other diseases associated with cyclophilins (e.g., CypD)). In certain embodiments, a therapeutically effective amount is an amount effective for inhibiting the aberrant activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) and treating a disease (e.g., a disease associated with aberrant activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, a therapeutically effective amount is an amount effective for inducing apoptosis of a cell (e.g., cell in vivo or in vitro). In certain embodiments, a prophylactically effective amount is an amount effective for inhibiting the aberrant activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, a prophylactically effective amount is an amount effective for preventing or keeping a subject in need thereof in remission of a disease (e.g., a disease associated with aberrant activity of a cyclophilin (e.g., neurological (e.g., neurodegenerative) disease, metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), and conditions associated with regulation of the mitochondrial permeability transition pore (mPTP), autophagy, aging; and oxidative stress; and other diseases associated with cyclophilins (e.g., CypD)). In certain embodiments, a prophylactically effective amount is an amount effective for inhibiting the aberrant activity of a cyclophilin, and preventing or keeping a subject in need thereof in remission of a disease (e.g., a disease associated with aberrant activity of a cyclophilin (e.g., neurological (e.g., neurodegenerative) disease, metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), and conditions associated with regulation of the mitochondrial permeability transition pore (mPTP), autophagy, aging; and oxidative stress; and other diseases associated with cyclophilins (e.g., CypD)). In certain embodiments, a compound of Table 1 is used for treating diseases and/or conditions disclosed herein, provided that the compound is not used for treating cardiovascular disease, a metabolic disorder (e.g., obesity, diabetes), or a disease associated with insulin-degrading enzyme (IDE).

[0270] In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%.

[0271] 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 described herein is a human. 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 animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0272] In certain embodiments, the cell being contacted with a compound or composition described herein is in vitro. In certain embodiments, the cell being contacted with a compound or composition described herein is in vivo.

[0273] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “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.

[0274] 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.

[0275] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0276] 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 composition.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0286] 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.

[0287] 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, German® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] Liquid dosage forms foral 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 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 described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0292] 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.

[0293] 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 compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0294] 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.

[0295] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein 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.

[0296] Solid dosage forms foral 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.

[0297] Solid 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 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 compositions which can be used include polymeric substances and waxes. Solid 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 polethylene glycols and the like.

[0298] 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 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.

[0299] Dosage forms for topical and/or transdermal administration of a compound described herein 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.

[0300] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal 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 compound in powder form through the outer layers of the skin to the dermis are suitable.

[0301] 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 described herein.

[0302] A pharmaceutical composition described herein 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 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 compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0303] 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 composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the 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).

[0304] Pharmaceutical compositions described herein 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.

[0305] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. 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.

[0306] 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 described herein. A pharmaceutical composition described herein 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 composition and, optionally, one or more of the additional ingredients described herein. 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 described herein.

[0307] A pharmaceutical composition described herein 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 described herein. Other ophthalmically-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.

[0308] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such 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 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.

[0309] Compounds provided herein 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 compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject 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 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.

[0310] The compounds and compositions provided herein 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 compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0311] The exact amount of a 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 compound described herein. 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, tissue, 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, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 μg and 1 μg, 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 compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0312] Dose ranges as described herein 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.

[0313] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compounds or 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, in inhibiting the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject, biological sample, tissue, or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject, biological sample, tissue, 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 described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.

[0314] The compound or 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 therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. 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 (e.g., neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD)). In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating diseases associated with cyclophilins (e.g., CypD)). 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 the compound or composition described herein 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 compound described herein 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.

[0315] The additional pharmaceutical agents include, but are not limited to, anti-proliferative 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 certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent (e.g., anti-cancer agent). In certain embodiments, the additional pharmaceutical agent is an anti-leukemia agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ADE, Adriamycin RDF (doxorubicin hydrochloride), Ambochlorin (chlorambucil), ARRANON (nelarabine), ARZERRA (ofatumumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicin hydrochloride), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine), CLOLAR (clofarabine), CVP, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), ERWINAZE (Asparaginase Erwinia chrysanthemi), FLUDARA (fludarabine phosphate), FOLEX (methotrexate), FOLEX PFS (methotrexate), GAZYVA (obinutuzumab), GLEEVEC (imatinib mesylate), Hyper-CVAD, ICLUSIG (ponatinib hydrochloride), IMBRUVICA (ibrutinib), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), MARQIBO (vincristine sulfate liposome), METHOTREXATE LPF (methorexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), mitoxantrone hydrochloride, MUSTARGEN (mechlorethamine hydrochloride), MYLERAN (busulfan), NEOSAR (cyclophosphamide), ONCASPAR (Pegaspargase), PURINETHOL (mercaptopurine), PURIXAN (mercaptopurine), Rubidomycin (daunorubicin hydrochloride), SPRYCEL (dasatinib), SYNRIB O (omacetaxine mepesuccinate), TARABINE PFS (cytarabine), TASIGNA (nilotinib), TREANDA (bendamustine hydrochloride), TRISENOX (arsenic trioxide), VINCASAR PFS (vincristine sulfate), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-lymphoma agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC, ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), AMBOCHLORIN (chlorambucil), AMBOCLORIN (chlorambucil), ARRANON (nelarabine), BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR (tositumomab and iodine I 131 tositumomab), BICNU (carmustine), BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide), COPP, COPP-ABV, CVP, CYTOXAN (cyclophosphamide), DEPOCYT (liposomal cytarabine), DTIC-DOME (dacarbazine), EPOCH, FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLOTYN (pralatrexate), HYPER-CVAD, ICE, IMBRUVICA (ibrutinib), INTRON A (recombinant interferon alfa-2b), ISTODAX (romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), Lomustine, MATULANE (procarbazine hydrochloride), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MOPP, MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (denileukin diftitox), OPPA, R-CHOP, REVLIMID (lenalidomide), RITUXAN (rituximab), STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VINCASAR PFS (vincristine sulfate), ZEVALIN (ibritumomab tiuxetan), ZOLINZA (vorinostat), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is REVLIMID (lenalidomide), DACOGEN (decitabine), VIDAZA (azacitidine), CYTOSAR-U (cytarabine), IDAMYCIN (idarubicin), CERUBIDINE (daunorubicin), LEUKERAN (chlorambucil), NEOSAR (cyclophosphamide), FLUDARA (fludarabine), LEUSTATIN (cladribine), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABRAXANE (paclitaxel albumin-stabilized nanoparticle formulation), AC, AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITOR DISPERZ (everolimus), ALDARA (imiquimod), ALIMTA (pemetrexed disodium), AREDIA (pamidronate disodium), ARIMIDEX (anastrozole), AROMASIN (exemestane), AVASTIN (bevacizumab), BECENUM (carmustine), BEP, BICNU (carmustine), BLENOXANE (bleomycin), CAF, CAMPTOSAR (irinotecan hydrochloride), CAPDX, CAPRELSA (vandetanib), CARBOPLATIN-TAXOL, CARMUBRIS (carmustine), CASODEX (bicalutamide), CEENU (lomustine), CERUBIDINE (daunorubicin hydrochloride), CERVARIX (recombinant HPV bivalent vaccine), CLAFEN (cyclophosphamide), CMF, COMETRIQ (cabozantinib-s-malate), COSMEGEN (dactinomycin), CYFOS (ifosfamide), CYRAMZA (ramucirumab), CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), DACOGEN (decitabine), DEGARELIX, DOXIL (doxorubicin hydrochloride liposome), DOXORUBICIN HYDROCHLORIDE, DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME (dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicin hydrochloride), ELOXATIN (oxaliplatin), ERBITUX (cetuximab), ERIVEDGE (vismodegib), ETOPOPHOS (etoposide phosphate), EVACET (doxorubicin hydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant), FEC, FEMARA (letrozole), FLUOROPLEX (fluorouracil), FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, GARDASIL (recombinant human papillomavirus (HPV) quadrivalent vaccine), GEMCITABINE-CISPLATIN, GEMCITABINE-OXALIPLATIN, GEMZAR (gemcitabine hydrochloride), GILOTRIF (afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustine implant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab), HYCAMTIN (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (axitinib), INTRON A (recombinant interferon alfa-2b), IRESSA (gefitinib), IXEMPRA (ixabepilone), JAKAFI (ruxolitinib phosphate), JEVTANA (cabazitaxel), KADCYLA (ado-trastuzumab emtansine), KEYTRUDA (pembrolizumab), KYPROLIS (carfilzomib), LIPODOX (doxorubicin hydrochloride liposome), LUPRON (leuprolide acetate), LUPRON DEPOT (leuprolide acetate), LUPRON DEPOT-3 MONTH (leuprolide acetate), LUPRON DEPOT-4 MONTH (leuprolide acetate), LUPRON DEPOT-PED (leuprolide acetate), MEGACE (megestrol acetate), MEKINIST (trametinib), METHAZOLASTONE (temozolomide), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MITOXANTRONE HYDROCHLORIDE, MITOZYTREX (mitomycin c), MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR (azacitidine), NAVELBINE (vinorelbine tartrate), NEOSAR (cyclophosphamide), NEXAVAR (sorafenib tosylate), NOLVADEX (tamoxifen citrate), NOVALDEX (tamoxifen citrate), OFF, PAD, PARAPLAT (carboplatin), PARAPLATIN (carboplatin), PEG-INTRON (peginterferon alfa-2b), PEMETREXED DISODIUM, PERJETA (pertuzumab), PLATINOL (cisplatin), PLATINOL-AQ (cisplatin), POMALYST (pomalidomide), prednisone, PROLEUKIN (aldesleukin), PROLIA (denosumab), PROVENGE (sipuleucel-t), REVLIMID (lenalidomide), RUBIDOMYCIN (daunorubicin hydrochloride), SPRYCEL (dasatinib), STIVARGA (regorafenib), SUTENT (sunitinib malate), SYLATRON (peginterferon alfa-2b), SYLVANT (siltuximab), SYNOVIR (thalidomide), TAC, TAFINLAR (dabrafenib), TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA (nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), TEMODAR (temozolomide), THALOMID (thalidomide), TOPOSAR (etoposide), TORISEL (temsirolimus), TPF, TRISENOX (arsenic trioxide), TYKERB (lapatinib ditosylate), VECTIBIX (panitumumab), VEIP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VEPESID (etoposide), VIADUR (leuprolide acetate), VIDAZA (azacitidine), VINCASAR PFS (vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVORIN (leucovorin calcium), XALKORI (crizotinib), XELODA (capecitabine), XELOX, XGEVA (denosumab), XOFIGO (radium 223 dichloride), XTANDI (enzalutamide), YERVOY (ipilimumab), ZALTRAP (ziv-aflibercept), ZELBORAF (vemurafenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid), ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate), ENMD-2076, PCI-32765, AC.sub.220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC.sub.0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethyl melamine, or a combination thereof. In certain embodiments, the additional pharmaceutical agent is ibrutinib. In certain embodiments, the additional pharmaceutical agent is a protein kinase inhibitor (e.g., tyrosine protein kinase inhibitor). In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of Bruton's tyrosine kinase (BTK). In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with a pharmaceutical agent useful for treating and/or preventing a neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease). In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with a pharmaceutical agent for treating and/or preventing Parkinson's disease that is levodopa, carbidopa, or a dopamine agonist. In certain embodiments, the additional pharmaceutical agent is an agent for treating Alzheimer's disease (e.g., cholinesterase inhibitors, memantine). In certain embodiments, the additional pharmaceutical agent is an agent for treating Huntington's disease (e.g., tetrabenazine). In certain embodiments, the additional pharmaceutical agent is an agent for treating amyotrophic lateral sclerosis (ALS) (e.g., glutamate blockers, edaravone). In certain embodiments, the additional pharmaceutical agent is an agent for treating multiple sclerosis (e.g., interferon beta, glatiramer acetate, CD52 antibody, sphingosine-1-phospate receptor modulators, dihydroorotate dehydrogenase (DHODH) inhibitors). In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with a pharmaceutical agent useful for treating and/or preventing oxidative stress. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with a pharmaceutical agent useful for treating and/or preventing a mitochondrial disease (e.g., condition associated with modulating (e.g., regulating) the mPTP, condition related to autophagy autophagy (e.g., neurodegenerative disease, infection, cancer, aging, heart disease)). In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with a pharmaceutical agent useful for treating and/or preventing a cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack. In certain embodiments, the additional pharmaceutical agent is an agent for treating ischemia-reperfusion injury (e.g., blood thinners, arterial dilators).

[0316] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0317] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., proliferative disease, metabolic disorder, autoimmune disease, or neurological disease) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD)) in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting the activity (e.g., aberrant or unwanted activity, such as increased activity) of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject, biological sample, tissue, or cell.

[0318] In certain embodiments, a kit described herein further includes instructions for using the compound or pharmaceutical composition included in the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD)) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD)) in a subject in need thereof. In certain embodiments, the kits and instructions provide for modulating (e.g., inhibiting) the activity (e.g., aberrant activity, such as increased activity) of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject, biological sample, tissue, or cell. In certain embodiments, the kits and instructions provide for reducing oxidative stress in a subject in need thereof or in a biological sample. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

Methods of Treatment and Uses

[0319] The present disclosure provides methods of modulating (e.g., inhibiting or increasing) the activity (e.g., aberrant activity, such as increased or decreased activity) of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). The present disclosure provides methods of modulating (e.g., inhibiting or increasing) the activity (e.g., aberrant activity, such as increased or decreased activity) of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject, biological sample, or cell. The present disclosure provides methods of reducing oxidative stress in a subject, biological sample, or cell. The present disclosure also provides methods for the treatment of a wide range of diseases, such as diseases associated with the aberrant activity (e.g., increased activity) of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR), e.g., neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD) in a subject in need thereof. The present disclosure provides methods for the treatment and/or prevention of a neurological disease (e.g., neurodegenerative) (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD).

[0320] The present disclosure also provides a compound of Formula (I′) or (I), a compound of Table 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, for use in the treatment of a disease, such as neurological disease (e.g., neurodegenerative) (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, ischemia-reperfusion injury, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD), in a subject in need thereof. The present disclosure also provides a compound of Formula (I′) or (I), a compound of Table 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, for use in the treatment of a disease, such as neurological disease (e.g., neurodegenerative) (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, ischemia-reperfusion injury, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD), in a subject in need thereof. In certain embodiments, the disease and/or condition treated with a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, is not a cardiovascular disease, metabolic disorder, or a disease associated with insulin-degrading enzyme (IDE).

[0321] The present disclosure also provides uses of a compound of Formula (I′) or (I), a compound of Table 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, in the manufacture of a medicament for the treatment of a disease, such as neurological disease (e.g., neurodegenerative) (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD), in a subject in need thereof. The present disclosure also provides uses of a compound of Formula (I′) or (I), a compound of Table 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, in the manufacture of a medicament for the treatment of a disease, such as neurological disease (e.g., neurodegenerative) (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, ischemia-reperfusion injury, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD), in a subject in need thereof.

[0322] In another aspect, the present disclosure provides treating a disease, such as neurological disease (e.g., neurodegenerative) (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD), the methods comprising administering to the subject an effective amount of a compound of Formula (I′) or (I), or a compound of formula:

##STR00567## ##STR00568## ##STR00569## ##STR00570## ##STR00571## ##STR00572## ##STR00573## ##STR00574##

[0323] In another aspect, the present disclosure provides methods of modulating the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject, biological sample, or cell. In certain embodiments, provided are methods of inhibiting a cyclophilin in a subject. In certain embodiments, provided are methods of inhibiting a cyclophilin in a cell. In certain embodiments, provided are methods of inhibiting the activity of a cyclophilin in a subject. In certain embodiments, provided are methods of inhibiting the activity of a cyclophilin in a cell. The compounds described herein may exhibit cyclophilin inhibitory activity; the ability to inhibit a cyclophilin; the ability to inhibit CypB, without inhibiting another cyclophilin; the ability to inhibit CypC, without inhibiting another cyclophilin; the ability to inhibit CypD, without inhibiting another cyclophilin; the ability to inhibit CypE, without inhibiting another cyclophilin; the ability to inhibit CypG, without inhibiting another cyclophilin; the ability to inhibit CypH, without inhibiting another cyclophilin; the ability to inhibit Cyp40, without inhibiting another cyclophilin; the ability to inhibit PPWD1, without inhibiting another cyclophilin; the ability to inhibit PPIL1, without inhibiting another cyclophilin; the ability to inhibit NKTR, without inhibiting another cyclophilin; a therapeutic effect and/or preventative effect in the treatment of neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD)) in a subject in need thereof. In certain embodiments, the compound being administered or used inhibits a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject or cell, treats and/or prevents a disease (e.g., neurodegenerative disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilin (e.g., CypD); and/or a therapeutic profile (e.g., optimum safety and curative effect) that is superior to existing chemotherapeutic agents, or agents for treating neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins (e.g., CypD)) in a subject in need thereof. In certain embodiments, the compound being administered or used inhibits a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject or cell, treats and/or prevents a disease (e.g., neurodegenerative disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilin (e.g., CypD).

[0324] In certain embodiments, provided are methods of decreasing the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject or biological sample (e.g., cell, tissue) by a method described herein by at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In certain embodiments, the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject or cell is decreased by a method described herein by at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject or cell is selectively inhibited by the method. In some embodiments, the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject or cell is selectively decreased by the method.

[0325] Without wishing to be bound by any particular theory, the compounds described herein are able to bind (e.g., covalently modify) the cyclophilin being inhibited. In certain embodiments, a compound described herein is able to bind (e.g., covalently modify) the cyclophilin. In certain embodiments, the compound described herein is able to covalently bind a central pocket of the cyclophilin. In certain embodiments, the compound is capable of covalently binding the S2 pocket of CyPD. In certain embodiments, the compound is capable of binding (e.g., covalently binding) the gatekeeper residues of CypD (serine and/or arginine). In certain embodiments, the compound is capable of covalently binding the gatekeeper residues of CypD (Ser81, Arg82). In certain embodiments, the compound is capable of binding (e.g., covalently binding) the gatekeeper residues of CypD (Ser81, Arg82, Serine 123, and/or Arginine 124). In certain embodiments, the compound is capable of binding (e.g., covalently binding) the gatekeeper residues of CypD (Serine 123 and/or Arginine 124). In some embodiments, the compound is capable of binding (e.g., covalently binding) the gatekeeper residues of CypD (Serine 123 and Arginine 124). In certain embodiments, the compound is capable of binding (e.g., covalently binding) the gatekeeper region of CypD (e.g., the gatekeeper residues of CypD including Serine 123 and Arginine 124). In certain embodiments, the compound is capable of binding (e.g., covalently binding) the active site, the S2 pocket, and/or the gatekeeper region of CypD (e.g., the gatekeeper residues of CypD including Serine 123 and Arginine 124). In certain embodiments, the compound is capable of binding (e.g., covalently binding) the active site, the S2 pocket, and the gatekeeper region of CypD (e.g., the gatekeeper residues of CypD including Serine 123 and Arginine 124). In certain embodiments, the compound described herein is able to selectively bind CypD over other cyclophilins. In certain embodiments, the compound described herein is able to selectively inhibit CypD over other cyclophilins. In certain embodiments, the compound is capable of covalently binding CyPD. In certain embodiments, the compound is capable of covalently modifying CypD (e.g., S2 pocket of CypD). In certain embodiments, the compound is capable of covalently modifying the S2 pocket of CyPD. In certain embodiments, the compound is capable of covalently binding CypB, In certain embodiments, the compound is capable of covalently binding CypC, In certain embodiments, the compound is capable of covalently modifying CypE. In certain embodiments, the compound is capable of covalently binding CypG. In certain embodiments, the compound is capable of covalently binding CypH. In certain embodiments, the compound is capable of covalently binding Cyp40. In certain embodiments, the compound is capable of covalently binding PPWD1. In certain embodiments, the compound is capable of covalently binding PPIL1. In certain embodiments, the compound is capable of covalently binding NKTR. In certain embodiments, the compound is capable of covalently binding CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, or NKTR.

[0326] In certain embodiments, the compound is capable of covalently binding CypB. In certain embodiments, the compound is capable of covalently binding CypC, In certain embodiments, the compound is capable of covalently modifying CypE. In certain embodiments, the compound is capable of covalently modifying CypG. In certain embodiments, the compound is capable of covalently modifying CypH. In certain embodiments, the compound is capable of covalently modifying Cyp40. In certain embodiments, the compound is capable of covalently modifying PPWD1. In certain embodiments, the compound is capable of covalently modifying PPIL1. In certain embodiments, the compound is capable of covalently modifying NKTR. In certain embodiments, the compound is capable of covalently modifying CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, or NKTR.

[0327] In certain embodiments, the compound is capable of non-covalently modifying CypD. In certain embodiments, the compound is capable of non-covalently inhibiting CypD. In certain embodiments, the compound is capable of non-covalently modifying CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, or NKTR. In certain embodiments, the compound is capable of non-covalently inhibiting CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, or NKTR.

[0328] In another aspect, the present disclosure provides methods of inhibiting the activity of a cyclophilin in a subject, the methods comprising administering to the subject an effective amount (e.g., therapeutically effective amount) of a compound, or pharmaceutical composition thereof, as described herein. In another aspect, the present disclosure provides methods of inhibiting the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a biological sample, the methods comprising contacting the biological sample with an effective amount of a compound, or pharmaceutical composition thereof, as described herein. In another aspect, the present disclosure provides methods of inhibiting the activity of a cyclophilin in a biological sample (e.g., tissue or cell), the methods comprising contacting the biological sample (e.g., tissue or cell) with an effective amount of a compound, or pharmaceutical composition thereof, as described herein.

[0329] In another aspect, the present disclosure provides methods of inhibiting the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a biological sample (e.g., tissue or cell), the methods comprising contacting the biological sample (e.g., tissue or cell) with an effective amount of a compound, or pharmaceutical composition thereof, as described herein. In another aspect, the present disclosure provides methods of inhibiting (e.g., inhibiting the activity of) a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject or biological sample, the methods comprising administering to the subject or contacting the biological sample (e.g., tissue or cell) with an effective amount of a compound of Formula (I′) or (I), or a compound of formula:

##STR00575## ##STR00576## ##STR00577## ##STR00578## ##STR00579## ##STR00580## ##STR00581## ##STR00582##

[0330] In another aspect, the present disclosure provides methods of reducing oxidative stress in a subject or biological sample, the methods comprising administering to the subject or contacting the biological sample (e.g., tissue or cell) with an effective amount of a compound, or pharmaceutical composition thereof, as described herein. In another aspect, the present disclosure provides methods of reducing oxidative stress in a subject or biological sample, the methods comprising administering to the subject or contacting the biological sample (e.g., tissue or cell) with an effective amount of a compound of Formula (I′), (I), or a compound of formula:

##STR00583## ##STR00584## ##STR00585## ##STR00586## ##STR00587## ##STR00588## ##STR00589##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, or pharmaceutical composition thereof, as described herein. In another aspect, the present disclosure provides methods of reducing oxidative stress in a biological sample (e.g., tissue or cell), the methods comprising contacting the biological sample (e.g., tissue or cell) with an effective amount of a compound, or pharmaceutical composition thereof, as described herein.

[0331] In certain embodiments, the subject being treated is a mammal. In certain embodiments, the subject is a human. 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, dog, or non-human primate. In certain embodiments, the subject is a non-human transgenic animal such as a transgenic mouse or transgenic pig.

[0332] In certain embodiments, the biological sample being contacted with the compound or composition is breast tissue, bone marrow, lymph node, lymph tissue, spleen, or blood. In certain embodiments, the biological sample being contacted with the compound or composition is a tumor cancerous tissue. In certain embodiments, the biological sample being contacted with the compound or composition is serum, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.

[0333] In certain embodiments, the cell or tissue being contacted with the compound or composition is present in vitro. In certain embodiments, the cell or tissue being contacted with the compound or composition is present in vivo. In certain embodiments, the cell or tissue being contacted with the compound or composition is present ex vivo. In certain embodiments, the cell or tissue being contacted with the compound or composition is a malignant cell (e.g., malignant blood cell). In certain embodiments, the cell being contacted with the compound or composition is a malignant hematopoietic stem cell (e.g., malignant myeloid cell or malignant lymphoid cell). In certain embodiments, the cell being contacted with the compound or composition is a malignant lymphocyte (e.g., malignant T-cell or malignant B-cell). In certain embodiments, the cell being contacted with the compound or composition is a malignant white blood cell. In certain embodiments, the cell being contacted with the compound or composition is a malignant neutrophil, malignant macrophage, or malignant plasma cell. In certain embodiments, the cell being contacted with the compound or composition is a carcinoma cell. In certain embodiments, the cell being contacted with the compound or composition is a breast carcinoma cell. In certain embodiments, the cell being contacted with the compound or composition is a sarcoma cell. In certain embodiments, the cell being contacted with the compound or composition is a sarcoma cell from breast tissue.

[0334] The disease (e.g., neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases) to be treated or prevented using the compounds described herein may be associated with increased activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). The disease (e.g., neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases) to be treated or prevented using the compounds described herein may be associated with the overexpression of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR).

[0335] In certain embodiments, the disease (e.g., neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases) to be treated or prevented using the compounds described herein may be associated with the overexpression of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). A disease (e.g., neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases) may be associated with aberrant activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). Aberrant activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) may be elevated and/or inappropriate or undesired activity of the cyclophilin. The compounds described herein, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof, may inhibit the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) and be useful in treating and/or preventing diseases (e.g., neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases). The compounds described herein, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof, may inhibit the activity of a cyclophilin and be useful in treating and/or preventing diseases (e.g., neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases). The compounds described herein, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof, may inhibit the activity of a cyclophilin and be useful in treating and/or preventing diseases (e.g., neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases).

[0336] All types of biological samples described herein or known in the art are contemplated as being within the scope of the invention. In certain embodiments, the neurological disease to be treated or prevented using the compounds described herein is a neurodegenerative disease. In certain embodiments, the neurodegenerative disease is Alzheimer's disease. In certain embodiments, the neurodegenerative disease is multiple sclerosis. In certain embodiments, the neurological disease is Parkinson's disease. In certain embodiments, the neurological disease is Huntington's disease. In certain embodiments, the neurological disease is amyotrophic lateral sclerosis. In certain embodiments, the metabolic disorder to be treated or prevented using the compounds described herein is diabetes (e.g., Type I diabetes, Type II diabetes, gestational diabetes). In some embodiments, the metabolic disorder is hyperglycemia. In some embodiments, the metabolic disorder is hyperinsulinemia. In some embodiments, the metabolic disorder is insulin resistance. In some embodiments, the metabolic disorder is obesity.

[0337] In certain embodiments, the proliferative disease to be treated or prevented using the compounds described herein is cancer. All types of cancers disclosed herein or known in the art are contemplated as being within the scope of the invention. In certain embodiments, the proliferative disease is a hematological malignancy. In certain embodiments, the proliferative disease is a blood cancer. In certain embodiments, the proliferative disease is a hematological malignancy. In certain embodiments, the proliferative disease is leukemia. In certain embodiments, the proliferative disease is chronic lymphocytic leukemia (CLL). In certain embodiments, the proliferative disease is acute lymphoblastic leukemia (ALL). In certain embodiments, the proliferative disease is T-cell acute lymphoblastic leukemia (T-ALL). In certain embodiments, the proliferative disease is chronic myelogenous leukemia (CML). In certain embodiments, the proliferative disease is acute myeloid leukemia (AML). In certain embodiments, the proliferative disease is acute monocytic leukemia (AMoL). In certain embodiments, the proliferative disease is Waldenström's macroglobulinemia. In certain embodiments, the proliferative disease is Waldenström's macroglobulinemia associated with the MYD88 L265P somatic mutation. In certain embodiments, the proliferative disease is myelodysplastic syndrome (MDS). In certain embodiments, the proliferative disease is a carcinoma. In certain embodiments, the proliferative disease is lymphoma. In certain embodiments, the proliferative disease is T-cell lymphoma. In some embodiments, the proliferative disease is Burkitt's lymphoma. In certain embodiments, the proliferative disease is a Hodgkin's lymphoma. In certain embodiments, the proliferative disease is a non-Hodgkin's lymphoma. In certain embodiments, the proliferative disease is multiple myeloma. In certain embodiments, the proliferative disease is melanoma. In certain embodiments, the proliferative disease is colorectal cancer. In certain embodiments, the proliferative disease is colon cancer. In certain embodiments, the proliferative disease is breast cancer. In certain embodiments, the proliferative disease is recurring breast cancer. In certain embodiments, the proliferative disease is mutant breast cancer. In certain embodiments, the proliferative disease is HER2+ breast cancer. In certain embodiments, the proliferative disease is HER2− breast cancer. In certain embodiments, the proliferative disease is triple-negative breast cancer (TNBC). In certain embodiments, the proliferative disease is a bone cancer. In certain embodiments, the proliferative disease is osteosarcoma. In certain embodiments, the proliferative disease is Ewing's sarcoma. In some embodiments, the proliferative disease is a brain cancer. In some embodiments, the proliferative disease is neuroblastoma. In some embodiments, the proliferative disease is a lung cancer. In some embodiments, the proliferative disease is small cell lung cancer (SCLC). In some embodiments, the proliferative disease is non-small cell lung cancer. In some embodiments, the proliferative disease is liver cancer. In some embodiments, the proliferative disease is pancreatic cancer. In some embodiments, the proliferative disease is gastric cancer. In some embodiments, the proliferative disease is ovarian cancer. In some embodiments, the proliferative disease is ovarian cancer. In some embodiments, the proliferative disease is a benign neoplasm. All types of benign neoplasms disclosed herein or known in the art are contemplated as being within the scope of the invention. In some embodiments, the proliferative disease is associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are contemplated as being within the scope of the invention.

[0338] In certain embodiments, the disease and/or condition to be treated or prevented using the compounds described herein is a condition associated with the mitochondria (e.g., a mitochondrial disease). In certain embodiments, the mitochondrial disease and/or condition to be treated or prevented is associated with regulation of the mitochondrial permeability transition pore (mPTP). In certain embodiments, the mitochondrial disease and/or condition to be treated or prevented is associated with regulation of the opening and/or closing of the mPTP. In certain embodiments, the condition to be treated or prevented using the compounds described herein is a condition associated with autophagy and/or aging. In certain embodiments, the condition to be treated or prevented using the compounds described herein is a cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases). In certain embodiments, the cardiovascular condition is ischemia-reperfusion injury. In certain embodiments, the cardiovascular condition is stroke or heart attack.

[0339] In certain embodiments, the condition associated with autophagy to be treated or prevented using the compounds described herein is neurodegenerative disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), infection (e.g., infection by a bacteria, virus, or other microbes), cancer, condition associated with aging, or heart disease.

[0340] One aspect of the disclosure relates to methods of reducing oxidative stress subject or in a biological sample, the method comprising administering to the subject or contacting the biological sample with a therapeutically effective amount of compounds described herein.

[0341] Another aspect of the disclosure relates to methods of inhibiting the activity of a cyclophilin in a biological sample (e.g., tissue, cell), or subject. In certain embodiments, the cyclophilin is a CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR. In certain embodiments, the activity of the cyclophilin is aberrant activity of the cyclophilin. In certain embodiments, the activity of the cyclophilin is increased activity of the cyclophilin. In certain embodiments, the inhibition of the activity of the cyclophilin is irreversible. In other embodiments, the inhibition of the activity of the cyclophilin is reversible. In certain embodiments, the methods of inhibiting the activity of the cyclophilin include attaching a compound described herein to the cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, the methods comprise covalently inhibiting a cyclophilin In certain embodiments, the methods comprise covalently inhibiting a cyclophilin (e.g., CypD). In certain embodiments, the methods comprise reversibly inhibiting a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR).

[0342] In certain embodiments, the methods described herein include administering to a subject or contacting a biological sample with an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the methods described herein include administering to a subject or contacting a biological sample with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the compound is contacted with a biological sample. In certain embodiments, the compound is administered to a subject. In certain embodiments, the compound is administered in combination with one or more additional pharmaceutical agents described herein. The additional pharmaceutical agent may be an agent for treating a neurological (e.g., neurodegenerative) disease. The additional pharmaceutical agent may be an agent for treating a metabolic disorder. The additional pharmaceutical agent may be an anti-aging agent. The additional pharmaceutical agent may be an agent for treating a cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases). The additional pharmaceutical agent may be an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. The additional pharmaceutical agent may also be a cyclophilin inhibitor. In certain embodiments, the additional pharmaceutical agent is an inhibitor of CypD. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, the additional pharmaceutical agent is a selective inhibitor of cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, the additional pharmaceutical agent is a non-selective inhibitor of cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR)

[0343] 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 some embodiments, the additional pharmaceutical agent is etoposide, obatoclax, navitoclax, JQ1, 4-(((5′-chloro-2′-(((1R,4R)-4-(((R)-1-methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4′-bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile, JIB04, or cisplatin. Exemplary chemotherapeutic agents include alkylating agents such as nitrogen mustards, ethylenimines, methylmelamines, alkyl sulfonates, nitrosuoureas, and triazenes; antimetabolites such as folic acid analogs, pyrimidine analogs, in particular fluorouracil and cytosine arabinoside, and purine analogs; natural products such as vinca alkaloids epi-podophyllotoxins, antibiotics, enzymes, and biological response modifiers; and miscellaneous products such as platinum coordination complexes, anthracenedione, substituted urea such as hydroxyurea, methyl hydrazine derivatives, and adrenocorticoid suppressant. Exemplary chemotherapeutic agents also include anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, paclitaxel, colchicine, cytochalasin B, emetine, maytansine, amsacrine, cisplatin, carboplatin, mitomycin, altretamine, cyclophosphamide, lomustine, and carmustine. In certain embodiments, a pharmaceutical composition described herein further comprises a combination of the additional pharmaceutical agents described herein.

[0344] The inventive compounds or compositions may synergistically augment inhibition of cyclophilins induced by the additional pharmaceutical agent(s) in the biological sample or subject. Thus, the combination of the inventive compounds or compositions and the additional pharmaceutical agent(s) may be useful in treating proliferative diseases resistant to a treatment using the additional pharmaceutical agent(s) without the inventive compounds or compositions.

[0345] In some embodiments, the activity of a cyclophilin is non-selectively inhibited by the compounds or pharmaceutical compositions described herein. In some embodiments, the activity of the cyclophilin being inhibited is selectively inhibited by the compounds or pharmaceutical compositions described herein, compared to the activity of a cyclophilin (e.g., a different cyclophilin). In certain embodiments, the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) is selectively inhibited by a compound or pharmaceutical composition described herein, compared to the activity of a different protein. In certain embodiments, the activity of CypD is selectively inhibited by a compound or pharmaceutical composition described herein, compared to the activity of another cyclophilin (e.g., CypB, CypC, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR). In certain embodiments, the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) is selectively inhibited by a compound or pharmaceutical composition described herein, compared to the activity of another cyclophilin.

[0346] The selectivity of a compound or pharmaceutical composition described herein in inhibiting the activity of a cyclophilin over a different protein (e.g., a different cyclophilin) may be measured by the quotient of the IC.sub.50 value of the compound or pharmaceutical composition in inhibiting the activity of the different protein over the IC.sub.50 value of the compound or pharmaceutical composition in inhibiting the activity of the cyclophilin. The selectivity of a compound or pharmaceutical composition described herein for a cyclophilin over a different protein may also be measured by the quotient of the K.sub.d value of an adduct of the compound or pharmaceutical composition and the different protein over the K.sub.d value of an adduct of the compound or pharmaceutical composition and the cyclophilin. In certain embodiments, the selectivity is at least 2-fold, at least 3-fold, at least 5-fold, at least 10-fold, at least 30-fold, at least 100-fold, at least 300-fold, at least 1,000-fold, at least 3,000-fold, at least 10,000-fold, at least 30,000-fold, or at least 100,000-fold. In certain embodiments, the selectivity is not more than 100,000-fold, not more than 10,000-fold, not more than 1,000-fold, not more than 100-fold, not more than 10-fold, or not more than 2-fold. Combinations of the above-referenced ranges (e.g., at least 2-fold and not more than 10,000-fold) are also within the scope of the disclosure.

[0347] In certain embodiments, a kit described herein includes a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, a kit described herein is useful in treating and/or preventing a disease, such as a neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilins, in a subject in need thereof, inhibiting the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject, biological sample, tissue, or cell, and/or reducing oxidative stress in a subject or in a biological sample.

[0348] In certain embodiments, a kit described herein further includes instructions for using the compound or pharmaceutical composition included in the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a proliferative disease in a subject in need thereof, preventing a disease, such as a neurological (e.g., neurodegenerative) disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), metabolic disorder (e.g., obesity, diabetes), proliferative disease (e.g., cancers), condition associated with autophagy (e.g., neurodegenerative disease, infection, cancer, condition associated with aging, heart disease), condition associated with aging, condition associated with modulating (e.g., regulating) the mPTP, cardiovascular condition (e.g., ischemia-reperfusion injury), stroke, heart attack, conditions associated with oxidative stress, mitochondrial diseases), or other diseases associated with cyclophilinsin a subject in need thereof, inhibiting the activity of a cyclophilin (e.g., CypB, CypC, CypD, CypE, CypG, CypH, Cyp40, PPWD1, PPIL1, NKTR) in a subject, biological sample, tissue, or cell, and/or reducing oxidative stress in a subject or in a biological sample. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

EXAMPLES

[0349] In order that the present disclosure 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 compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures or methods known in the art. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures.

[0350] Compounds of Formula (I′) or (I) and/or Table 1 (shown above) may be prepared using synthetic schemes and procedures recognized by one of ordinary skill in the art.

Example 1. Synthesis of Exemplary Cyclophilin Inhibitor Compounds

[0351] Compounds of Formula (I′) or (I) and/or Table 1 (shown above) may be prepared using the following synthetic schemes. Disclosed below is are general synthetic scheme for preparing macrocycles disclosed herein via solid phase peptide synthesis (Scheme 1), for preparing Fmoc-protected and Alloc-protected amino acids (Scheme 2), for synthesizing biphenyl building blocks or compound 49-derivatives (A-series compounds) (Scheme 3), and for synthesizing piperidine analogs (Scheme 4).

##STR00590##

##STR00591##

##STR00592##

##STR00593##

Example 2. Biological Assays of Compounds

[0352] Novel cyclophilin inhibitors were discovered from a DNA-templated library of 256,000 macrocycles. Lead macrocycle scaffolds from the library were synthetically modified to increase both potency and specificity for CypD. The 3D structures and binding of lead hits to CypD were determined via X-ray crystallography, which were utilized to develop further improvements. Good hits from this series possessed the most specific inhibition profile for CypD over other cyclophilin family members in the reported literature while retaining very high potency.

Results

[0353] Selection on CypD and screening of library hits: To find novel CypD inhibitors, a selection was conducted with a DNA-templated library (DTS) of 256,000 macrocycles by incubating the library with immobilized His6-CypD on Ni-NTA functionalized beads. After washing away non-binders, the protein was eluted thus carrying any bound library members. This elution fraction was PCR amplified, barcoded, and submitted for high throughput sequencing to generate enrichment plots. Each data point in FIG. 4 represents enrichment of one macrocycle-barcode in the library compared to the original pre-selection library. Upon two replicate experiments, two families of macrocycles with good structure-activity relationships (SAR) were enriched, the HO**/HJ** and the JO** families.

[0354] Following the synthesis of the indicated library members, in vitro inhibition (IC.sub.50) assays of these hits were conducted to obtain IC.sub.50 inhibitory data. For the IC.sub.50 assays, a chymotrypsin coupled PPIase assay using Suc-AAPF-AMC as the peptide substrate was used, whereby isomerization of a peptide substrate Suc-AAPF-AMC from the cis to trans conformation allowed for proteolysis via excess a-chymotrypsin, releasing the C-terminal coumarin fluorophore. Of the tested compounds, two macrocycles showed inhibition profiles, JOMBtrans and JOBBtrans, both of which have 10-40 uM IC.sub.50 values and contain a conserved 3-carboxy-piperidine structure in the 3.sup.rd building block. The weaker inhibition profile was further validated through Surface Plasmon Resonance experiments that garnered similar K.sub.d values. Other non-inhibitor library members were also checked for binding via SPR, but produced the same profile as the prolyl isomerase assay.

TABLE-US-00004 TABLE 1 Exemplary compounds from DTS Library with inhibitory activity against cyclophilins [00594] embedded image (JOGJ) [00595] (HOJJ) [00596] (HJJJ) [00597] (JOBB_A) [00598] (JOMB_A) [00599] (JOGB_A) [00600] (JOGC_A) [00601] (JOGD_A) [00602] (JOGA_A) [00603] (JOID_A) [00604] (JOGA) [00605] (JOBB) [00606] (JOMB) [00607] (JOCD_A) [00608] (JOMD_A) [00609] (JOBD_A) [00610] (JOGJ_A) [00611] (JOGK_A) [00612] embedded image (JOCB_A) [00613] (CNIV_A) [00614] (JOMA) [00615] (JOMC) [00616] (JOME) [00617] (JOMF) [00618] (JOMI)

[0355] Derivatization of JOMBtrans and analysis of binding modes from co-crystal structures: Using JOMBtrans as a basis for derivatization, a variety of analogs were synthesized in an attempt to garner further CypD potency. Several trends were elucidated including retention of the phenyl ring of the 1J building block, defined 22-23 atom macrocycle backbone, the trans conformation at the alkene, strict stereochemical requirements at each stereocenter, and modulatory of the furan at the 2.sup.nd building block. One of the very good analogs involved substituting a benzyl group at the tertiary carbon on the piperidine ring, increasing potency to 200 nM (compound 49). Substitutions at this position with other functionalities also improved potency compared to JOMBtrans, but none to a greater degree than compound 49.

[0356] Subsequently, to determine if the compounds could both access the S2 pocket and display CypD specificity, JOMBtrans and compound 49 were screened against the 10 other cyclophilins with reported prolyl isomerase activity. Promiscuous inhibition was observed, exhibiting at most a ten-fold decrease in inhibition against other family members compared to CypD. Co-crystal structures of JOMBtrans and 49 were solved with CypD. JOMBtrans exhibits a dual-binding mode with CypD, where the phenyl ring on the 1J building block is buried in the active side and the furan sits at the precipice of the S2 pocket. Three further H-bonds with the macrocycle's backbone and CypD were observed along with a cation-n interaction. Compound 49 displayed a similar but optimized binding mode with CypD. The benzyl group on the piperidine ring altered the conformation of the macrocycle to open up two new hydrogen bonding interactions with CypD. This conformational shift can be attributed to the 75-fold increase in potency for 49 compared to JOMBtrans. Both compounds showed very promiscuous cyclophilin inhibition, which was attributed to the furan not accessing the S2 pocket and gatekeepers, most of its binding interactions occurring around the structurally conserved active pocket. A quick screen of an alternate JOMBtrans derivative (compound 27), which replaces the furan with a larger benzophenone, showcased an improvement in specificity for CypD. Almost complete ablation of inhibition profiles for NKTR, CypG, PPWD1, CypH, was observed along with decreased potency for other cyclophilins. This improvement in specificity compared to JOMBtrans signified that more CypD specific compounds can be garnered by derivatization into the S2 pocket.

[0357] Initial A-Series derivatives and co-crystal structures: Using conclusions from solved co-crystal structures and specificity profiles, a new series of macrocycles (A-series) was created that utilized the increased potency from the benzyl-piperidine of 49 coupled with moieties that replaced its furan group. The initial series of A-series macrocycles displayed a variety of specificity profiles. Macrocycles with large functionalities (benzophenone, biphenyl, tertbutyl-Phe for compounds A-1, A-5, and A-9 respectively) abolished inhibition for NKTR, CypG, PPWD1, CypH, mimicking the profile of compound 27, albeit with much better potency. To confirm that these larger substituents reached deeper in the S2 pocket and could access the gatekeeper residues, co-crystal structures of compounds A-1 and A-5 were solved with CypD, along with compound A-6 which has a comparatively smaller substitution. Co crystal structures of these three compounds showed the same binding mode as compound 49. However, as larger moieties were introduced, both deeper binding into the S2 pocket as well as a greater degree of ‘flipping’ the gatekeeper residues out of the pocket was observed. For example, A-1's benzophenone completely removed the gatekeeper residues from the pocket while the 3-methyl-phenylalanine of compound A-6 allowed retention of the gatekeeper residues in the pocket. A-5 represented a middle-ground, whereby it still reached deep into the S2 pocket while also retaining close proximity to the gatekeeper residues.

[0358] A-Series derivatization to gain access to CypD specific inhibitors: From the co-crystal structure of compound A-5 with CypD, biphenyl derivatives containing moieties designed to interact with CypD gatekeeper residues, Ser81 and Arg82, were synthesized. Hydrogen-bond acceptor functional groups were incorporated at the para position of the biphenyl group, as the crystal structure suggested that would be the most efficient way to access interactions with gatekeeper residues. A variety of functional groups were incorporated, including carbonyl, alkyl, alkoxy, and alcohol substituents along with various biphenyl heterocycles. Just like compound A-5, these derivatives all showed significant reduction in potency for NKTR, CypG, PPWD1, and CypH. CypC, CypE, CypA, CypB, Cyp40, and PPIL1 all had varying degrees of selectivity profiles depending on the substituent on the biphenyl group.

[0359] The A-series of macrocycles exhibited two trends from diversification. First, compounds with ortho-alkyl-biphenyl moieties showed a consistent 10-fold decrease in potency for CypE when compared to CypD. Second, p compounds with ara-substitutions with carbonyl like moieties, including ketones, amides, sulfones, esters, hydroxamic esters, and carboxylates exhibited varying drops in potency for CypC, CypA, CypB, Cyp40, and PPIL1. In particular, compounds with carboxylate substituted biphenyl groups showcased the best specificity profiles, as shown in compounds A-54 and A-57. Extension of the carboxylate via a methyl, ethyl or vinyl linker drastically increased the potency of these compounds for CypD and eliminated significant inhibition profiles for the other tested cyclophilins. A very good compound, A-81, contained a para-ethylcarboxy functionality that provides 2.5 nM potency and a drastic preference for inhibition of CypD.

[0360] Binding modes for inhibitors with improved specificity profiles: A Co-crystal structure of A-57 with CypD showed both ortho-alkyl biphenyl and para-carboxy biphenyl moieties, which explained the increased selectivity profile. Ortho-alkyl substituents slightly altered the binding mode of the biphenyl group, whereby the methyl group of A-57 buried itself in the base of the S2 pocket, thereby pushing the biphenyl group further out of the pocket. It was consistently observed that this alkyl substitution afforded around a 10-fold decrease in potency for CypE. Pushing the biphenyl group closer with an ortho-alkyl group created a repulsive interaction in CypE that would normally be a hydrophobic interaction in CypD.

[0361] Although ortho-alkyl biphenyl groups occupy a slightly different binding mode than regular biphenyl groups, the co-crystal structure of A-57 showed that para-carboxy biphenyl groups are placed near the gatekeeper residues of CypD. In this particular instance, the carboxylate fully flipped the Arg gatekeeper out of the S2 pocket while positioned near the Ser gatekeeper. Due to having a negatively charged carboxylate near the gatekeeper residues, a marked decrease in potency was observed for many cyclophilins compared to CypD, explained below.

[0362] Drawing conclusions from cyclophilin gatekeeper residues and inhibitor functional groups: As exhibited by compounds A-54, A-57, A-63, A-81, and A-82, para-carboxy biphenyl moieties placed within the S2 pocket provided cyclophilin selectivity profiles showing preference for CypD. Upon analysis and modeling into CypD, it was hypothesized that the family of tested cyclophilins fell into three broad categories based on their potency against the compound A-81. The first group of cyclophilins included NKTR, CypG, PPWD1, and CypH which contain relatively occluded S2 pockets from the gatekeeper residues or a combination of the gatekeepers with nearby residues. Nearly total ablation of inhibition was achieved for these cyclophilins by building sterically bulky moieties into the compounds. The second group included Cyp40 and CypC, which have sterically accessible S2 pockets just like CypD but have acidic moieties that repulse the carboxylates built into the compounds. The third group encompassed CypB, CypE, CypA, and PPIL1 which have varying degrees of selectivity compared to CypD. The variety of potencies was owed to gatekeeper residues that are similar to CypD (such as CypB) or that contain a varying number of positively charged regions that can interact with the carboxylate of the inhibitors.

[0363] Design inhibitors specific to other cyclophilins: Derivatization of compound 49 into the ‘A-series’ macrocycles provided a scaffold by which functional groups that bind in the S2 pocket and interact with gatekeeper residues were diversified. These new inhibitors can target disease models by which the mPTP has been implicated through oxidative damage. Given the ubiquity of oxidative damage in the mechanism of cell necrosis, offering an inhibitor that can target this mechanism via the mPTP-CypD interaction serves as a treatment method for multiple diseases. These inhibitors can be applied in animal models of neurodegeneration, as oxidative stress can cause irreversible damage to cells in the nervous system.

Example 3. Additional Biological Assays of Compounds

Further Exemplary A-Series Macrocycle Compounds

[0364] Using conclusions from solved co-crystal structures and specificity profiles, an additional A-series of macrocycles were created (see FIGS. 19A-19U). Further evidence was found showing that the carboxylate inhibitors engender CypD selectivity and high potency (see FIGS. 20A-20B). It was determined that placement of the carboxylate is important for potency. It was further determined that conversion of the carboxylate to amine appears to eliminate potency and shift selectivity, where a (−) charge on carboxylate appears to engender specificity and potency, and a (+) charge on amine flips selectivity to CypC/PPWD1/CypB, albeit at lower potency (see FIGS. 20C-20D). Nitriles provide similar potency, but have reduced selectivity for CypD, and just like carboxylates, need optimal geometry and placement (see FIGS. 20E-20F). The core compound scaffold can still support a variety of moieties on 4th building block tail, the site of DNA attachment in the compound library (see FIGS. 20G-20H).

Co-Crystal Structure of A-81 Bound to CypD

[0365] The co-crystal structure of A-81 maintains the same interactions as the previous crystal structure scaffolds in active site and S2 pocket (see FIG. 21). There are H-bonds with non-gatekeeper Ser119, and a salt bridge with non-gatekeeper Lys118.

[0366] There are unique structural features of A81-binding. There are small S2 pocket ligands (see FIG. 22A) and large S2 pocket ligands (see FIG. 22B). There is a loop that contains gatekeepers and flips out depending on the ligand present. There is also a side chain of gatekeepers that drastically changes position based on the ligand (see FIGS. 22A-22B).

Phenotypic Analysis of CypD Inhibitors in Cell Culture and Isolated Mitochondria Inhibition of mPtP in Isolated Mitochondria

[0367] In isolated mice kidney mitochondria, the maximum number of Ca.sup.2+ pulses that could be tolerated before full mPTP opening was measured (see FIG. 24). Administration of exemplary CypD inhibitors extended the number of tolerated pulses. CsA, a positive control CypD inhibitor doubled the pulse number. A-22b and A-81b extended pulse number, with A-81b almost as potent as CsA. The in vitro inhibition data translates to phenotypic CypD inhibition in isolated mitochondria (see FIG. 24).

Inhibition of mPtP in In Vitro Cell Culture Using Exemplary CypD Inhibitors

[0368] As disclosed herein, macrocycle inhibitors of cyclophilin D have been discovered and designed with previously unparalleled specificity. An active site binder displaying weak inhibition (IC.sub.50=15 uM) and no selectivity profile was initially optimized to 200 nM. CypD specificity was designed by building into S2 pocket residues. Bi-phenyl para-carboxylates provided the greatest level of potency (<2-30 nM) and selectivity for CypD. Co-crystal structures of these macrocycles bound to CypD were solved, and a dual binding mode was determined between active site and S2 pocket. MD simulations of co-crystal structures were conducted to observe dynamic interactions of carboxylate with S2 pocket. Initial proof of target engagement was determined via inhibition of the mPTP. Exemplary compounds A-81 and A-22 can extend Ca.sup.2+ loading in isolated mitochondria before mPTP opening occurs. Compound A-81 appears to not rescue mPTP in cell culture. Alternate macrocycle A-22 shows minimal rescue and can be optimized for cell permeability by modification of its tail region.

EQUIVALENTS AND SCOPE

[0369] 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 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 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.

[0370] Furthermore, the 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 disclosure, or aspects described herein, is/are referred to as comprising particular elements and/or features, certain embodiments described herein or aspects described herein 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 described herein, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0371] 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 disclosure 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 described herein can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0372] 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 disclosure, as defined in the following claims.

CYCLOPHILIN D INHIBITORS AND USES THEREOF

Assignee

Inventors

Cpc classification

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C07K7/56

CHEMISTRY; METALLURGY

Classification Explorer

C07K7/06

CHEMISTRY; METALLURGY

International classification

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C07K7/56

CHEMISTRY; METALLURGY

Abstract

Claims

Description