Polyamine sulfonamides and uses thereof

Abstract

Cancer is a disease for which there remains a great unmet medical need, and therefore the discovery and development of new antineoplastic agents is critically important. The present invention relates in part to new therapeutic compounds with antineoplastic activity. Provided herein are polyamine sulfonamides such as compounds of Formula (I), or pharmaceutically acceptable salts thereof, which may be used in the treatment and/or prevention of diseases such as cancer. Also provided herein are pharmaceutical compositions and kits comprising the inventive compounds. Furthermore, the present invention provides methods of treating and/or preventing diseases (e.g., cancer) using compounds of Formula (I), or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof. Other methods provided include methods for inducing apoptosis of a cell, as well as methods for inhibiting alpha-enolase enzymatic activity in vivo and in vitro.

Claims

1. A compound of Formula (I): ##STR00130## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl; R.sup.3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; and R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted acyl; or optionally R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; provided that neither R.sup.1 nor R.sup.2 is substituted or unsubstituted benzyl.

2. The compound of claim 1, wherein R.sup.3 is optionally substituted aryl.

3. The compound of claim 1, wherein the compound of Formula (I) is of Formula (II): ##STR00131## or a pharmaceutically acceptable salt thereof, wherein: each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.4a, —N(R.sup.4b).sub.2, or —SR.sup.4c; each instance of R.sup.4ais independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.4b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.4b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.4c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; and n is 0, 1, 2, 3, 4, or 5.

4. The compound of claim 3, wherein the compound of Formula (II) is of Formula (II-a): ##STR00132## or a pharmaceutically acceptable salt thereof.

5. The compound of claim 3, wherein n is 1.

6. The compound of claim 3, wherein at least one instance of R.sup.4 is halogen.

7. The compound of claim 3, wherein at least one instance of R.sup.4 is optionally substituted C.sub.1-6 alkyl.

8. The compound of claim 3, wherein the compound is selected from the group consisting of: ##STR00133## and pharmaceutically acceptable salts thereof.

9. The compound of claim 3, wherein the compound is of Formula (II-b) or (II-c): ##STR00134## or a pharmaceutically acceptable salt thereof.

10. The compound of claim 3, wherein the compound is of Formula (II-d) or (II-e): ##STR00135## or a pharmaceutically acceptable salt thereof.

11. The compound of claim 3, wherein the compound is of Formula (II-f): ##STR00136## or a pharmaceutically acceptable salt thereof.

12. The compound of claim 3, wherein the compound is of Formula (II-g): ##STR00137## or a pharmaceutically acceptable salt thereof.

13. The compound of claim 3, wherein the compound is of Formula (II-h) or (II-i): ##STR00138## or a pharmaceutically acceptable salt thereof.

14. The compound of claim 3, wherein the compound is of Formula (II-j) or (II-k): ##STR00139## or a pharmaceutically acceptable salt thereof.

15. The compound of claim 3, wherein at least one instance of R.sup.4 is —I.

16. The compound of claim 3, wherein at least one instance of R.sup.4 is tert-butyl.

17. The compound of claim 3, wherein the compound is the following: ##STR00140## or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein the compound of Formula (I) is of Formula (III): ##STR00141## or a pharmaceutically acceptable salt thereof, wherein: each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.4a, —N(R.sup.4b).sub.2, or —SR.sup.4c; each instance of R.sup.4ais independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.4b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.4b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.4c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; and m is 1, 2, 3, 4, 5, 6, or 7.

19. The compound of claim 18, wherein the compound of Formula (III) is of Formula (III-a): ##STR00142## or a pharmaceutically acceptable salt thereof.

20. The compound of claim 18, wherein the compound is selected from the group consisting of: ##STR00143## and pharmaceutically acceptable salts thereof.

21. The compound of claim 18, wherein the compound is of Formula (III-b) or (III-c): ##STR00144## or a pharmaceutically acceptable salt thereof.

22. The compound of claim 18, wherein the compound is of Formula (III-d) or (III-e): ##STR00145## or a pharmaceutically acceptable salt thereof.

23. The compound of claim 18, wherein the compound is of Formula (III-f) or (III-g): ##STR00146## or a pharmaceutically acceptable salt thereof.

24. The compound of claim 18, wherein m is 0.

25. The compound of claim 1, wherein R.sup.1 is optionally substituted C.sub.1-6 alkyl.

26. The compound of claim 1, wherein R.sup.2 is optionally substituted C.sub.1-6 alkyl.

27. The compound of claim 1, wherein R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are hydrogen.

28. The compound of claim 1, wherein R.sup.1 is unsubstituted C.sub.1-6 alkyl.

29. The compound of claim 1, wherein R.sup.1 is selected from the group consisting of methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CH(OH)CH.sub.3, —CH.sub.2CH(OH)CH.sub.3, —CH.sub.2SH, —CH.sub.2CH.sub.2SCH.sub.3, —CH.sub.2NH.sub.2, CH.sub.2(CH.sub.2).sub.1-4NH.sub.2 ##STR00147##

30. The compound of claim 1, wherein R.sup.1 is selected from the group consisting of methyl, iso-propyl, and —CH.sub.2CH.sub.2OH.

31. The compound of claim 1, wherein R.sup.2 is unsubstituted C.sub.1-6 alkyl.

32. The compound of claim 1, wherein R.sup.2 is selected from the group consisting of methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CH(OH)CH.sub.3, —CH.sub.2CH(OH)CH.sub.3, —CH.sub.2SH, —CH.sub.2CH.sub.2SCH.sub.3, —CH.sub.2NH.sub.2, —CH.sub.2(CH.sub.2).sub.1-4NH.sub.2, ##STR00148##

33. The compound of claim 1, wherein R.sup.2 is iso-propyl or iso-butyl.

34. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

35. A kit comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; and optionally instructions for administering the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.

36. A method of treating a proliferative disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

37. The method of claim 36, wherein the proliferative disease is cancer.

38. The method of claim 37, wherein the cancer is a hematological cancer.

39. The method of claim 37, wherein the cancer is selected from the group consisting of leukemias, myeloproliferative neoplasms, lymphomas, and multiple myeloma.

40. The method of claim 37, wherein the cancer is leukemia.

41. The method of claim 37, wherein the cancer is acute myeloid leukemia (AML).

42. A method for inducing apoptosis of a cell in a subject or biological sample, the method comprising administering to the subject or biological sample a compound of claim 1, or a pharmaceutically acceptable salt thereof.

43. A method for inhibiting the enzymatic activity of an alpha-enolase protein, the method comprising contacting an alpha-enolase protein with a compound of claim 1, or a pharmaceutically acceptable salt thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

(2) FIG. 1. Comparing average AML-LSC toxicity vs. AML total toxicity. Fresh human primary leukemia bone marrow mononuclear cells were treated with single doses of compounds 2470-23 and 2470-51 at a single time point and the killing of the leukemia stem cell (LSC) population (defined as CD34+CD38-CD123+) was quantified versus the total AML cell population. This demonstrates that both compounds selectively kills the AML LSC fraction, which is responsible for cancer refractoriness and relapse.

(3) FIG. 2. Comparison of average AML-LSC toxicity vs. Jurkat toxicity. The 2470-23 and 2470-51 single-dose treatments were compared on lymphoid (CD4+ Jurkat) versus myeloid (AML LSC) leukemias to demonstrate the specificity of these compounds for AML.

(4) FIG. 3. Comparison of average AML-LSC toxicity vs. cord blood stem cell toxicity. The single-dose treatments of 2470-23 and 2470-51 on normal healthy blood stem cells (sourced from fresh umbilical cord blood) and AML LSC were compared. The compounds do not deplete healthy stem cells while they do deplete the leukemia stem cells. These results indicate selectivity for diseased cells and suggest sparing of normal cells.

(5) FIG. 4. Schematic of high throughput screening assay. AML cells are cultured on bone marrow derived endothelial cells. After 24 hours of exposure to compound treatment, the AML cells and endothelial cells are analyzed for viability using flow cytometry for 7-AAD and annexin. The phase contrast micrographs in the bottom portion of this figure are representative of untreated control and drug treated conditions. In the control situation, spindle shaped endothelial cells appear under the round shaped AML cells. In the drug treated conditions, some compounds disrupt the spindle shaped endothelial cells and lead to their detachment and death. While other compounds leave the endothelial layer intact but cause AML cells to appear picnotic due to apoptotic death, compounds of the present invention caused AML cell death while leaving the endothelial cell layer intact and viable. This is optimal because of the high toxicity to the malignant cells and low toxicity to stromal cells. Stromal cell viability represents safety.

(6) FIG. 5A. Primary human AML specimens (824, 872, 874) treated with 2470-51 for 24 hours at 50 ng/mL significantly reduced AML cell viability compared to vehicle-treated controls (*** P<0.05). FIG. 5B. Compound 2470-51 did not reduce cell viability of bone marrow cells from healthy adults compared to vehicle control. FIG. 5C. Effect of compound 2470-51 on viability of four cell lines (HL-60, THP-1, MV4-11, and K562).

(7) FIG. 6. This schematic illustrates the proteomics work flow in identifying protein targets for the compounds. AML cells (KG-1, AML 1:816, AML 2:LPP4) and health hematopoietic stem/progenitor cells (CD34+) were lysed and then mixed with either vehicle or a compound (e.g., 2470-51). Following compound-protein binding, pronase was used to cleave the proteins. Where the compound bound to proteins, this site was protected from pronase digestion. The peptides were then analyzed via gel-based target identification and label-free mass spectrometry.

(8) FIG. 7A. Using mass spectometry/mass spectometry (MS/MS) techniques, an alpha-enolase peptide was identified as covalently bound to compound 2470-51. FIG. 7B. Computational docking using SWISS identified an active site binding pocket within alpha-enolase that the 2470-51 compound fit into.

(9) FIG. 8A. Enolase protein expression. AML cells showed higher protein expression of enolase compared to healthy human hematopoietic stem/progenitor cells (CD34+ cord blood (CB)). However, compound 2470-51 (denoted by D) did not change protein expression relative to vehicle (denoted by V) treatment. Thus, enolase correlates with malignant transformation, but is not changed by applying compounds of the present invention. FIG. 8B. Effect of compounds on enolase enzyme activity. Although protein expression did not change, enolase enzymatic activity was reduced in a dose-dependent fashion by compound 2470-51.

(10) FIG. 9. Compound 2470-51 significantly reduced AML engraftment. Immunocompromised NRGS (NOD.CG-Rag1.sup.tm1MomIl2rg.sup.tm1Wjl (CMV-IL3, CSF2, KITLG) 1Eav/J) mice were given sub-lethal irradiation (200 cGy), followed by tail vein injection of primary human AML cells. At the end of four week, the animals were randomized into two-week treatment groups: vehicle-treated (PBS treatment control), cytarabine-treated 100 mg/kg IP TIW (positive treatment control), and 2470-51 20 mg/kg IP TIW. Bone marrows were examined for the presence of human CD45+ (green) and DAPI).

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

(11) Effective treatment of acute myeloid leukemia (AML) and related diseases constitute an unmet medical need, and therefore the discovery and development of new anti-proliferative agents is critically important. Human AML cells functionally integrate within blood vessels, occasionally fusing with endothelial cells (ECs), and consequently can become more resistant to existing antineoplastic agents. The present invention relates in part to new therapeutic compounds with anti-neoplastic activity. Provided herein are polyamine sulfonamides such as compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, which may be used in the treatment and/or prevention of diseases such as cancer and other proliferative diseases. Also provided herein are pharmaceutical compositions and kits comprising the inventive compounds. Furthermore, the present invention provides methods of treating diseases (e.g., hematological cancers such as AML) using compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof, or pharmaceutical compositions thereof. Also provided herein are methods of inhibiting the enzymatic activity of alpha-enolase proteins and inducing apoptosis of cells using compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof, or pharmaceutical compositions thereof. The following describes in detail several embodiments of the invention.

(12) Compounds

(13) One aspect of the present invention relates to polyamine sulfonamides, which may be useful in the treatment and/or prevention of diseases or conditions. In certain embodiments, the polyamine sulfonamides of the present invention are of Formula (I). Provided herein are compounds of Formula (I):

(14) ##STR00007##
and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein: R.sup.1 is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl; R.sup.2 is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl; R.sup.3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; and R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, or a nitrogen protecting group; or optionally R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; optionally wherein R.sup.2 and either R.sup.N3 or R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl; or optionally wherein R.sup.1 and R.sup.N2 are joined together with the intervening atoms to form optionally substituted heterocyclyl; or optionally wherein R.sup.3 and R.sup.N1 are joined together with the intervening atoms to form optionally substituted heterocyclyl; provided that at least one of R.sup.1 and R.sup.2 is a non-hydrogen group; and provided that neither R.sup.1 or R.sup.2 is benzyl.

(15) Also provided herein are compounds of Formula (I):

(16) ##STR00008##
and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein: R.sup.1 is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl; R.sup.2 is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl; R.sup.3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; and R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, or a nitrogen protecting group; or optionally R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; provided that at least one of R.sup.1 and R.sup.2 is a non-hydrogen group; and provided that neither R.sup.1 or R.sup.2 is benzyl.

(17) As described herein, at least one of R.sup.1 and R.sup.2 is not hydrogen (i.e., either or both R.sup.1 are R.sup.2 are a non-hydrogen substituent). In certain embodiments, R.sup.1 is hydrogen, and R.sup.2 is a non-hydrogen substituent. In certain embodiments, R.sup.2 is hydrogen, and R.sup.1 is a non-hydrogen substituent. In certain embodiments, both R.sup.1 and R.sup.2 are not hydrogen (i.e., both R.sup.1 and R.sup.2 are non-hydrogen substituents).

(18) As described herein, both R.sup.1 and R.sup.2 are not benzyl (i.e., neither R.sup.1 nor R.sup.2 is benzyl). As generally defined herein, benzyl is —CH.sub.2Ph.

(19) In certain embodiments of Formula (I), R.sup.2 and either R.sup.N3 or R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.1 and R.sup.N2 are joined together with the intervening atoms to form optionally substituted heterocyclyl. In other embodiments, R.sup.3 and R.sup.N1 are joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, a compound of Formula (I) is of one of the following formulae:

(20) ##STR00009##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: p is 0, 1, or 2.

(21) In certain embodiments, a compound of Formula (I) is of one of the following formulae:

(22) ##STR00010##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(23) Formula (I) includes substituents R.sup.3, R.sup.1, R.sup.2, R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4. In certain embodiments, R.sup.3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; and R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H. In certain embodiments, R.sup.3 is optionally substituted alkyl; R.sup.1 is optionally substituted C.sub.1-6alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; and R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H. In certain embodiments, R.sup.3 is optionally substituted heteroaryl; R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; and R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H. In certain embodiments, R.sup.3 is optionally substituted carbocyclyl; R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; and R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H. In certain embodiments, R.sup.3 is optionally substituted heterocyclyl; R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; and R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H. In certain embodiments, R.sup.3 is optionally substituted heteroaryl; R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; and R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H. In certain embodiments, R.sup.3 is optionally substituted aryl; R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; and R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H. In certain embodiments, R.sup.3 is optionally substituted phenyl; R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; and R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H. In certain embodiments, R.sup.3 is optionally substituted naphthyl; R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; and R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H.

(24) In certain embodiments, the compound of Formula (I) is of the following formula:

(25) ##STR00011##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(26) In certain embodiments, the compound of Formula (I) is of one of the following formulae:

(27) ##STR00012##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(28) In certain embodiments, the compound of Formula (I) is of the following formula:

(29) ##STR00013##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(30) In certain embodiments, the compound of Formula (I) is of one of the following formulae:

(31) ##STR00014##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(32) In certain embodiments, the compound of Formula (I) is of the following formula:

(33) ##STR00015##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(34) In certain embodiments, the compound of Formula (I) is of one of the following formulae:

(35) ##STR00016##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(36) In certain embodiments, the compound of Formula (I) is of the following formula:

(37) ##STR00017##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(38) In certain embodiments, a compound of Formula (I) is of one of the following formulae:

(39) ##STR00018##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(40) In certain embodiments, the compound of Formula (I) is of the following formula:

(41) ##STR00019##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(42) In certain embodiments, the compound of Formula (I) is of one of the following formulae:

(43) ##STR00020##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(44) In certain embodiments, the compound of Formula (I) is of the following formula:

(45) ##STR00021##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(46) In certain embodiments, the compound of Formula (I) is of one of the following formulae:

(47) ##STR00022##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(48) In certain embodiments, the compound of Formula (I) is of the following formula:

(49) ##STR00023##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(50) In certain embodiments, the compound of Formula (I) is of one of the following formulae:

(51) ##STR00024##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(52) In certain embodiments, the compound of Formula (I) is of the following formula:

(53) ##STR00025##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(54) In certain embodiments, the compound of Formula (I) is of one of the following formulae:

(55) ##STR00026##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(56) In certain embodiments, R.sup.3 and R.sup.N1 are joined together with the intervening atoms to form optionally substituted heterocyclyl; and a compound of Formula (I) is of the following formula:

(57) ##STR00027##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(58) In certain embodiments, the compound of Formula (I) is of one of the following formulae:

(59) ##STR00028##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(60) In certain embodiments, a compound of Formula (I) is of the following formula:

(61) ##STR00029##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(62) In certain embodiments, the compound of Formula (I) is of one of the following formulae:

(63) ##STR00030##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(64) In certain embodiments, a compound of Formula (I) is of the following formula:

(65) ##STR00031##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(66) In certain embodiments, the compound of Formula (I) is of one of the following formulae:

(67) ##STR00032##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(68) In certain embodiments, a compound of Formula (I) is of the following formula:

(69) ##STR00033##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(70) In certain embodiments, the compound of Formula (I) is of one of the following formulae:

(71) ##STR00034##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(72) In certain embodiments, R.sup.2 and R.sup.N3 are joined together with the intervening atoms to form optionally substituted heterocyclyl; and the compound of Formula (I) is of the formula:

(73) ##STR00035##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(74) In certain embodiments, the compound of Formula (I) is of one of the following formulae:

(75) ##STR00036##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(76) In certain embodiments, the compound of Formula (I) is of the formula:

(77) ##STR00037##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(78) In certain embodiments, the compound of Formula (I) is of one of the following formulae:

(79) ##STR00038##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(80) In certain embodiments, R.sup.1 and R.sup.N2 are joined together to form optionally substituted heterocyclyl; and the compound of Formula (I) is of the following formula:

(81) ##STR00039##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer isotopically labeled derivative, or prodrug thereof.

(82) In certain embodiments, the compound of Formula (I) is of one of the following formula:

(83) ##STR00040##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(84) In certain embodiments, R.sup.1 and R.sup.N2 are joined together to form optionally substituted heterocyclyl; and the compound of Formula (I) is of the following formula:

(85) ##STR00041##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(86) In certain embodiments, the compound of Formula (I) is of one of the following formula:

(87) ##STR00042##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(88) In certain embodiments, R.sup.3 is optionally substituted phenyl; and the compound of Formula (I) is of Formula (II):

(89) ##STR00043##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R.sup.1 is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl; R.sup.2 is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, or a nitrogen protecting group; or optionally R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.4a, —N(R.sup.4b).sub.2, or —SR.sup.4c; each instance of R.sup.4a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.4b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.3b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.4c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; and n is 0, 1, 2, 3, 4, or 5; optionally wherein R.sup.2 and either R.sup.N3 or R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl; or optionally wherein R.sup.1 and R.sup.N2 are joined together with the intervening atoms to form optionally substituted heterocyclyl; or optionally wherein R.sup.3 and R.sup.N1 are joined together with the intervening atoms to form optionally substituted heterocyclyl; provided that at least one of R.sup.1 and R.sup.2 is a non-hydrogen group; and provided that neither R.sup.1 or R.sup.2 is benzyl.

(90) In certain embodiments, a compound of Formula (I) is of Formula (II):

(91) ##STR00044##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R.sup.1 is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl; R.sup.2 is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, or a nitrogen protecting group; or optionally R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.4a, —N(R.sup.4b).sub.2, or —SR.sup.4c; each instance of R.sup.4a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.4b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.3b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.4c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; and n is 0, 1, 2, 3, 4, or 5; provided that at least one of R.sup.1 and R.sup.2 is a non-hydrogen group; and provided that neither R.sup.1 or R.sup.2 is benzyl.

(92) In certain embodiments of Formula (II), R.sup.2 and either R.sup.N3 or R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.1 and R.sup.N2 are joined together with the intervening atoms to form optionally substituted heterocyclyl. In other embodiments, R.sup.3 and R.sup.N1 are joined together with the intervening atoms to form optionally substituted heterocyclyl.

(93) In certain embodiments, a compound of Formula (II) is of one of the following formulae:

(94) ##STR00045##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorp, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: p is 0, 1, or 2.

(95) In certain embodiments, a compound of Formula (II) is of one of the following formulae:

(96) ##STR00046##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(97) Formula (II) includes the substituents R.sup.1, R.sup.2, R.sup.4, R.sup.N1, R.sup.N2, R.sup.N3, R.sup.N4 and the variable n. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, R.sup.N4 are H; n is 1, 2, 3, 4, or 5; and each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.4a, N(R.sup.4b).sub.2, or —SR.sup.4c, wherein R.sup.4a, R.sup.4b, and R.sup.4c are as defined herein. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is as defined herein. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is halogen. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; R.sup.4 is halogen; and R.sup.4 is para to the point of attachment of the sulfonamide group to the benzenoid ring. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-3 alkyl; R.sup.2 is optionally substituted C.sub.1-3 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is halogen. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-3 alkyl; R.sup.2 is unsubstituted C.sub.1-3 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is halogen. In certain embodiments, R.sup.1 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl; R.sup.2 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is halogen. In certain embodiments, R.sup.1 is iso-propyl; R.sup.2 is iso-propyl; R.sup.N, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is halogen. In certain embodiments, R.sup.1 is iso-propyl; R.sup.2 is iso-propyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is iodo (I). In certain embodiments, R.sup.1 is iso-propyl; R.sup.2 is iso-propyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; R.sup.4 is iodo (I); and R.sup.4 is para to the point of attachment of the sulfonamide group to the benzenoid ring.

(98) In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is optionally substituted alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is unsubstituted C.sub.1-6 alkyl.

(99) In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3 and R.sup.N4 are H; n is 1; R.sup.4 is unsubstituted C.sub.1-6 alkyl; and R.sup.4 is para to the point of attachment of the sulfonamide group to the benzenoid ring. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-3 alkyl; R.sup.2 is optionally substituted C.sub.1-3 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-3 alkyl; R.sup.2 is unsubstituted C.sub.1-3 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl; R.sup.2 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is methyl; R.sup.2 is iso-propyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is methyl; R.sup.2 is iso-propyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is methyl; R.sup.2 is iso-propyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is methyl; R.sup.2 is iso-propyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.1 is methyl; R.sup.2 is iso-propyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; n is 1; and R.sup.4 is tert-butyl. In certain embodiments, R.sup.1 is methyl; R.sup.2 is iso-propyl; R.sup.N1, R.sup.N2R.sup.N3, and R.sup.N4 are H; n is 1; R.sup.4 is tert-butyl; and R.sup.4 is para to the point of attachment of the sulfonamide group to the benzenoid ring.

(100) In certain embodiments, the compound of Formula (II) is of the following formula:

(101) ##STR00047##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(102) In certain embodiments, the compound of Formula (II) is of one of the following formulae:

(103) ##STR00048##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(104) In certain embodiments, the compound of Formula (II) is of the following formula:

(105) ##STR00049##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(106) In certain embodiments, the compound of Formula (II) is of one of the following formulae:

(107) ##STR00050##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(108) In certain embodiments, R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are hydrogen; and the compound of Formula (II) is of Formula (II-a):

(109) ##STR00051##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(110) In certain embodiments, a compound of Formula (II-a) is of one of the following formulae:

(111) ##STR00052##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(112) In certain embodiments, the compound of Formula (II) is of Formula (II-b) or (II-c):

(113) ##STR00053##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(114) In certain embodiments, the compound of Formula (II-b) is of one of the following formulae:

(115) ##STR00054##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(116) In certain embodiments, the compound of Formula (II-c) is of one of the following formulae:

(117) ##STR00055##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(118) In certain embodiments, R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are hydrogen; and the compound of Formula (II-a) is of Formula (II-d) or (II-e):

(119) ##STR00056##

(120) In certain embodiments, a compound of Formula (II-d) is of one of the following formulae:

(121) ##STR00057##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(122) In certain embodiments, a compound of Formula (II-e) is of one of the following formulae:

(123) ##STR00058##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(124) In certain embodiments, the compound of Formula (II) is of the following formula:

(125) ##STR00059##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(126) In certain embodiments, the compound of Formula (II) is of one of the following formulae:

(127) ##STR00060##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(128) In certain embodiments, the compound of Formula (II) is of the following formula:

(129) ##STR00061##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(130) In certain embodiments, the compound of Formula (II) is of one of the following formulae:

(131) ##STR00062##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(132) In certain embodiments, the compound of Formula (II) is of the following formula:

(133) ##STR00063##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(134) In certain embodiments, the compound of Formula (II) is of one of the following formulae:

(135) ##STR00064##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(136) In certain embodiments, n is 1; and the compound of Formula (II) is of Formula (II-f):

(137) ##STR00065##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(138) In certain embodiments, a compound of Formula (II-f) is of one of the following formulae:

(139) ##STR00066##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(140) In certain embodiments, the compound of Formula (II) is of Formula (II-g):

(141) ##STR00067##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(142) In certain embodiments, the compound of Formula (II-g) is of one of the following formulae:

(143) ##STR00068##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(144) In certain embodiments, the compound of Formula (II) is of Formula (II-h) or (II-i):

(145) ##STR00069##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(146) In certain embodiments, a compound of Formula (II-h) is of one of the following formulae:

(147) ##STR00070##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(148) In certain embodiments, a compound of Formula (II-i) is of one of the following formulae:

(149) ##STR00071##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(150) In certain embodiments, the compound of Formula (II) is of Formula (II-j), (II-k), (II-l), or (II-m):

(151) ##STR00072##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(152) In certain embodiments, a compound of Formula (II-l) is of one of the following formulae:

(153) ##STR00073##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(154) In certain embodiments, a compound of Formula (II-m) is of one of the following formulae:

(155) ##STR00074##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(156) In certain embodiments of the invention, a compound of Formula (I) is of one of the following formulae:

(157) ##STR00075##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(158) In a particular embodiment, a compound of Formula (I) is of the following formula:

(159) ##STR00076##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(160) In certain embodiments, R.sup.3 is optionally substituted naphthyl; and the compound of Formula (I) is of Formula (III):

(161) ##STR00077##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R.sup.1 is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl; R.sup.2 is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, or a nitrogen protecting group; or optionally R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.4a, —N(R.sup.4b).sub.2, or —SR.sup.4c; each instance of R.sup.4a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.4b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.3b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.4c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; and m is 1, 2, 3, 4, 5, 6, or 7; optionally wherein R.sup.2 and either R.sup.N3 or R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl; or optionally wherein R.sup.1 and R.sup.N2 are joined together with the intervening atoms to form optionally substituted heterocyclyl; or optionally wherein R.sup.3 and R.sup.N1 are joined together with the intervening atoms to form optionally substituted heterocyclyl; provided that at least one of R.sup.1 and R.sup.2 is a non-hydrogen group; and provided that neither R.sup.1 or R.sup.2 is benzyl. In certain embodiments, the compound of Formula (I) is of Formula (III):

(162) ##STR00078##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R.sup.1 is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl; R.sup.2 is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, or a nitrogen protecting group; or optionally R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.4a, —N(R.sup.4b).sub.2, or —SR.sup.4c; each instance of R.sup.4a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.4b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.3b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.4c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; and m is 1, 2, 3, 4, 5, 6, or 7; provided that at least one of R.sup.1 and R.sup.2 is a non-hydrogen group; and provided that neither R.sup.1 or R.sup.2 is benzyl.

(163) In certain embodiments of Formula (III), R.sup.2 and either R.sup.N3 or R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.1 and R.sup.N2 are joined together with the intervening atoms to form optionally substituted heterocyclyl. In other embodiments, R.sup.3 and R.sup.N1 are joined together with the intervening atoms to form optionally substituted heterocyclyl.

(164) In certain embodiments, a compound of Formula (III) is of one of the following formulae:

(165) ##STR00079##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: p is 0, 1, or 2.

(166) In certain embodiments, a compound of Formula (III) is of one of the following formulae:

(167) ##STR00080##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(168) Formula (III) includes the substituents R.sup.1, R.sup.2, R.sup.4, R.sup.N1, R.sup.N2, R.sup.N3, R.sup.N4 and the variable m. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; m is 1, 2, 3, 4, 5, 6, or 7; and each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.4a, N(R.sup.4b).sub.2, or —SR.sup.4c, wherein R.sup.4aR.sup.4b, and R.sup.4c are as defined herein. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is unsubstituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is substituted C.sub.1-6 alkyl; R.sup.2 is unsubstituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is C.sub.1-6 alkyl substituted with oxygen; R.sup.2 is unsubstituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is C.sub.1-6 alkyl substituted with —OH; R.sup.2 is unsubstituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is —CH.sub.2(CH.sub.2).sub.0-4OR.sup.O, wherein R.sup.O is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted acyl, or an oxygen protecting group; R.sup.2 is unsubstituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is —CH.sub.2(CH.sub.2).sub.0-4 OR.sup.O, wherein R.sup.O is optionally substituted C.sub.1-6 alkyl; R.sup.2 is unsubstituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is —CH.sub.2(CH.sub.2).sub.0-4OR.sup.O, wherein R.sup.O is hydrogen; R.sup.2 is unsubstituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is —CH.sub.2(CH.sub.2).sub.0-4OR.sup.O, wherein R.sup.O is hydrogen; R.sup.2 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is —CH.sub.2(CH.sub.2).sub.0-4 OH; R.sup.2 is iso-butyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is —CH.sub.2CH.sub.2OH; R.sup.2 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is —CH.sub.2CH.sub.2OH; R.sup.2 is iso-butyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is —CH.sub.2CH.sub.2OH; R.sup.2 is iso-butyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; m is 1, 2, 3, 4, 5, 6, or 7; and R.sup.4 is as defined herein.

(169) In certain embodiments, R.sup.1 is optionally substituted C.sub.1-3 alkyl; R.sup.2 is optionally substituted C.sub.1-6alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-3 alkyl; R.sup.2 is unsubstituted C.sub.1-6 alkyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl; R.sup.2 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is methyl; R.sup.2 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl; R.sup.2 is iso-butyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is methyl; R.sup.2 is iso-butyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; and m is 0. In certain embodiments, R.sup.1 is methyl; R.sup.2 is iso-butyl; R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are H; m is 1, 2, 3, 4, 5, 6, or 7; and R.sup.4 is as defined herein.

(170) In certain embodiments, the compound of Formula (III) is of the following formula:

(171) ##STR00081##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(172) In certain embodiments, the compound of Formula (III) is of one of the following formulae:

(173) ##STR00082##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(174) In certain embodiments, the compound of Formula (I) is of Formula (III). In certain embodiments, R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are hydrogen, and the compound of Formula (III) is of Formula (III-a):

(175) ##STR00083##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(176) In certain embodiments, a compound of Formula (III-a) is of one of the following formulae:

(177) ##STR00084##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(178) In certain embodiments, the compound of Formula (III) is of Formula (III-b) or (III-c):

(179) ##STR00085##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(180) In certain embodiments, a compound of Formula (III-b) is of one of the following formulae:

(181) ##STR00086##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(182) In certain embodiments, a compound of Formula (III-c) is of one of the following formulae:

(183) ##STR00087##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(184) In certain embodiments, the compound of Formula (III) is of Formula (III-d) or (III-e):

(185) ##STR00088##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(186) In certain embodiments, a compound of Formula (III-d) is of one of the following formulae:

(187) ##STR00089##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(188) In certain embodiments, a compound of Formula (III-e) is of one of the following formulae:

(189) ##STR00090##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(190) In certain embodiments, the compound of Formula (III) is of Formula (III-f) or (III-g):

(191) ##STR00091##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(192) In certain embodiments, a compound of Formula (III-f) is of one of the following formulae:

(193) ##STR00092##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(194) In certain embodiments, a compound of Formula (III-g) is of one of the following formulae:

(195) ##STR00093##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(196) In certain embodiments, a compound of Formula (III) is of one of the following formulae:

(197) ##STR00094##
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
R Group Definitions

(198) The following definitions apply to all formulae recited herein, including, but not limited to, Formulae (I), (II) and (III).

(199) Groups R.sup.1 and R.sup.2

(200) As generally defined herein, R.sup.1 and R.sup.2 are independently hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or optionally substituted heteroaralyl.

(201) In certain embodiments, R.sup.1 is hydrogen. In certain embodiments, R.sup.1 is optionally substituted carbocyclyl. In certain embodiments, R.sup.1 is optionally substituted heterocyclyl. In certain embodiments, R.sup.1 is optionally substituted heterocyclylalkyl. In certain embodiments, R.sup.1 is optionally substituted heteroaralkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is selected from the group consisting of methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-3alkyl. In certain embodiments, R.sup.1 is substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is selected from the group consisting of methyl, ethyl, propyl, and iso-propyl. In certain embodiments, R.sup.1 is methyl. In certain embodiments, R.sup.1 is iso-propyl. In certain embodiments, R.sup.1 is iso-butyl.

(202) In certain embodiments, R.sup.1 is C.sub.1-6 alkyl substituted with a nitrogen-, oxygen-, or sulfur-containing moiety. In certain embodiments, R.sup.1 is selected from the group consisting of —CH.sub.2(CH.sub.2).sub.0-4OR.sup.O, —CH(OR.sup.O)CH.sub.3, —(CH.sub.2).sub.1-4CH(OR.sup.O)CH.sub.3, —CH.sub.2(CH.sub.2).sub.0-4SR.sup.S, and —CH.sub.2(CH.sub.2).sub.0-4N(R.sup.N).sub.2, wherein R.sup.O is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted acyl, or an oxygen protecting group; R.sup.S is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted acyl, or a sulfur protecting group; and R.sup.N is optionally substituted C.sub.1-6 alkyl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.N are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted aryl. In certain embodiments, R.sup.1 is —CH.sub.2(CH.sub.2).sub.1-4OR.sup.O, and R.sup.O is optionally substituted C.sub.1-6alkyl. In certain embodiments, R.sup.1 is —CH.sub.2(CH.sub.2).sub.1-4OR.sup.O, and R.sup.O is hydrogen. In certain embodiments, R.sup.1 is selected from the group consisting of —CH.sub.2CH.sub.2OH, —CH.sub.2CH.sub.2CH.sub.2OH, —CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH, or —CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH. In certain embodiments, R.sup.1 is —CH.sub.2CH.sub.2OH.

(203) In certain embodiments, R.sup.1 is selected from the group consisting of —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CH(OH)CH.sub.3, —CH.sub.2CH(OH)CH.sub.3, —CH.sub.2SH, —CH.sub.2CH.sub.2SCH.sub.3, —CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2, and —CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2.

(204) In certain embodiments, R.sup.1 is optionally substituted heterocyclyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.1 is optionally substituted five-membered heterocyclyl. In certain embodiments, R.sup.1 is optionally substituted pyrrolidine. In certain embodiments, R.sup.1 is of the formula:

(205) ##STR00095##
In certain embodiments, R.sup.1 is of the formula:

(206) ##STR00096##

(207) In certain embodiments, R.sup.1 is optionally substituted heterocyclylalkyl. In certain embodiments, R.sup.1 is optionally substituted —C.sub.1-6 alkyl-heterocyclyl. In certain embodiments, R.sup.1 is optionally substituted —CH.sub.2-heterocyclyl. In certain embodiments, R.sup.1 is optionally substituted —CH.sub.2—C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.1 is optionally substituted —CH.sub.2—C.sub.5 heterocyclyl. In certain embodiments, R.sup.1 is optionally substituted —CH.sub.2— pyrrolidine. In certain embodiments, R.sup.1 is of the formula:

(208) ##STR00097##
In certain embodiments, R.sup.1 is optionally substituted heteroaralkyl. In certain embodiments, R.sup.1 is optionally substituted —C.sub.1-6 alkyl-heterocyclyl. In certain embodiments, R.sup.1 is optionally substituted —CH.sub.2— heterocyclyl. In certain embodiments, R.sup.1 is optionally substituted —CH.sub.2—C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.1 is optionally substituted —CH.sub.2—C.sub.5 heterocyclyl. In certain embodiments, R.sup.1 is of the formula:

(209) ##STR00098##
In certain embodiments, R.sup.1 is optionally substituted —CH.sub.2—C.sub.7-10 heterocyclyl. In certain embodiments, R.sup.1 is of the formula:

(210) ##STR00099##
In certain embodiments, R.sup.1 is any amino acid side chain, provided that the amino acid is not phenylalanine or tyrosine.

(211) In certain embodiments, R.sup.2 is hydrogen. In certain embodiments, R.sup.2 is optionally substituted carbocyclyl. In certain embodiments, R.sup.2 is optionally substituted heterocyclyl. In certain embodiments, R.sup.2 is optionally substituted heterocyclylalkyl. In certain embodiments, R.sup.2 is optionally substituted heteroaralkyl. In certain embodiments, R.sup.2 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is selected from the group consisting of methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.2 is optionally substituted C.sub.1-3alkyl. In certain embodiments, R.sup.2 is substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.2 is selected from the group consisting of methyl, ethyl, propyl, and iso-propyl. In certain embodiments, R.sup.2 is methyl. In certain embodiments, R.sup.2 is iso-propyl. In certain embodiments, R.sup.2 is iso-butyl.

(212) In certain embodiments, R.sup.2 is C.sub.1-6alkyl substituted with a nitrogen-, oxygen-, or sulfur-containing moiety. In certain embodiments, R.sup.2 is selected from the group consisting of —CH.sub.2(CH.sub.2).sub.0-4OR.sup.O, —CH(OR.sup.O)CH.sub.3, —(CH.sub.2).sub.1-4CH(OR.sup.O)CH.sub.3, —CH.sub.2(CH.sub.2).sub.0-4SR.sup.S, —CH.sub.2(CH.sub.2).sub.0-4N(R.sup.N).sub.2, wherein R.sup.O is hydrogen, optionally substituted C.sub.1-6alkyl, optionally substituted acyl, or an oxygen protecting group; R.sup.S is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted acyl, or a sulfur protecting group; and R.sup.N is optionally substituted C.sub.1-6alkyl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.N are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted aryl. In certain embodiments, R.sup.2 is —CH.sub.2(CH.sub.2).sub.1-4OR.sup.O, and R.sup.O is optionally substituted C.sub.1-6alkyl. In certain embodiments, R.sup.2 is —CH.sub.2(CH.sub.2).sub.1-4OR.sup.O, and R.sup.O is hydrogen. In certain embodiments, R.sup.2 is selected from the group consisting of —CH.sub.2CH.sub.2OH, —CH.sub.2CH.sub.2CH.sub.2OH, —CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH, or —CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH. In certain embodiments, R.sup.2 is —CH.sub.2CH.sub.2OH.

(213) In certain embodiments, R.sup.2 is selected from the group consisting of —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CH(OH)CH.sub.3, —CH.sub.2CH(OH)CH.sub.3, —CH.sub.2SH, —CH.sub.2CH.sub.2SCH.sub.3, —CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2, and —CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2.

(214) In certain embodiments, R.sup.2 is optionally substituted heterocyclyl. In certain embodiments, R.sup.2 is optionally substituted C.sub.3-6heterocyclyl. In certain embodiments, R.sup.2 is optionally substituted five-membered heterocyclyl. In certain embodiments, R.sup.2 is optionally substituted pyrrolidine. In certain embodiments, R.sup.2 is of the formula:

(215) ##STR00100##
In certain embodiments, R.sup.2 is of the formula:

(216) ##STR00101##
In certain embodiments, R.sup.2 is optionally substituted heterocyclylalkyl. In certain embodiments, R.sup.2 is optionally substituted —C.sub.1-6alkyl-heterocyclyl. In certain embodiments, R.sup.2 is optionally substituted —CH.sub.2-heterocyclyl. In certain embodiments, R.sup.2 is optionally substituted —CH.sub.2—C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.2 is optionally substituted —CH.sub.2—C.sub.5 heterocyclyl. In certain embodiments, R.sup.2 is optionally substituted —CH.sub.2-pyrrolidine. In certain embodiments, R.sup.2 is of the formula:

(217) ##STR00102##
In certain embodiments, R.sup.2 is optionally substituted heteroaralkyl. In certain embodiments, R.sup.2 is optionally substituted —C.sub.1-6 alkyl-heterocyclyl. In certain embodiments, R.sup.2 is optionally substituted —CH.sub.2-heterocyclyl. In certain embodiments, R.sup.2 is optionally substituted —CH.sub.2—C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.2 is optionally substituted —CH.sub.2—C.sub.5heterocyclyl. In certain embodiments, R.sup.2 is of the formula:

(218) ##STR00103##
In certain embodiments, R.sup.2 is optionally substituted —CH.sub.2—C.sub.7-10 heterocyclyl. In certain embodiments, R.sup.2 is of the formula:

(219) ##STR00104##
In certain embodiments, R.sup.2 is any amino acid side chain, provided that the amino acid is not phenylalanine or tyrosine.

(220) In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; and R.sup.2 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl; and R.sup.2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-3 alkyl; and R.sup.2 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-3alkyl; and R.sup.2 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, both R.sup.1 and R.sup.2 are independently selected from the group consisting of methyl, ethyl, propyl, and iso-propyl. In certain embodiments, R.sup.1 is methyl; and R.sup.2 is iso-propyl. In certain embodiments, R.sup.1 is ethyl; and R.sup.2 is iso-propyl. In certain embodiments, R.sup.1 is n-propyl; and R.sup.2 is iso-propyl. In certain embodiments, R.sup.2 is methyl; and R.sup.1 is iso-propyl. In certain embodiments, R.sup.2 is ethyl; and R.sup.1 is iso-propyl. In certain embodiments, R.sup.2 is n-propyl; and R.sup.1 is iso-propyl. In certain embodiments, both R.sup.1 and R.sup.2 are methyl. In certain embodiments, both R.sup.1 and R.sup.2 are ethyl.

(221) In certain embodiments, both R.sup.1 and R.sup.2 are n-propyl. In certain embodiments, both R.sup.1 and R.sup.2 are iso-propyl.

(222) In certain embodiments, R.sup.1 is substituted C.sub.1-6 alkyl; and R.sup.2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is —CH.sub.2(CH.sub.2).sub.0-4OR.sup.O, wherein R.sup.O is hydrogen, optionally substituted C.sub.1-6 alkyl, optionally substituted acyl, or an oxygen protecting group; and R.sup.2 is unsubstituted C.sub.1-6alkyl. In certain embodiments, R.sup.1 is —CH.sub.2(CH.sub.2).sub.0-4OH; and R.sup.2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is selected from the group consisting of —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CH.sub.2CH.sub.2CH.sub.2OH, —CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH, or —CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH; and R.sup.2 is selected from the group consisting of methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, and sec-butyl. In certain embodiments, R.sup.1 is —CH.sub.2CH.sub.2OH; and R.sup.2 is iso-butyl.

(223) Group R.sup.3

(224) As generally defined herein, R.sup.3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.

(225) In certain embodiments, R.sup.3 is optionally substituted alkyl. In certain embodiments, R.sup.3 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.3 is optionally substituted C.sub.1-3 alkyl.

(226) In certain embodiments, R.sup.3 is optionally substituted heteroaryl. In certain embodiments, R.sup.3 is optionally substituted five-membered heteroaryl. In certain embodiments, R.sup.3 is optionally substituted six-membered heteroaryl. In certain embodiments, R.sup.3 is optionally substituted five- to seven-membered heteroaryl. In certain embodiments, R.sup.3 is optionally substituted nine-membered heteroaryl. In certain embodiments, R.sup.3 is optionally substituted ten-membered heteroaryl.

(227) In certain embodiments, R.sup.3 is optionally substituted carbocyclyl. In certain embodiments, R.sup.3 is optionally substituted C.sub.3carbocyclyl. In certain embodiments, R.sup.3 is optionally substituted C.sub.4carbocyclyl. In certain embodiments, R.sup.3 is optionally substituted C.sub.5carbocyclyl. In certain embodiments, R.sup.3 is optionally substituted C.sub.6carbocyclyl. In certain embodiments, R.sup.3 is optionally substituted C.sub.7 carbocyclyl. In certain embodiments, R.sup.3 is optionally substituted C.sub.8 carbocyclyl. In certain embodiments, R.sup.3 is optionally substituted C.sub.9 carbocyclyl. In certain embodiments, R.sup.3 is optionally substituted C.sub.10 carbocyclyl.

(228) In certain embodiments, R.sup.3 is optionally substituted heterocyclyl. In certain embodiments, R.sup.3 is optionally substituted three-membered heterocyclyl. In certain embodiments, R.sup.3 is optionally substituted four-membered heterocyclyl. In certain embodiments, R.sup.3 is optionally substituted five-membered heterocyclyl. In certain embodiments, R.sup.3 is optionally substituted six-membered heterocyclyl. In certain embodiments, R.sup.3 is optionally substituted seven-membered heterocyclyl.

(229) In certain embodiments, R.sup.3 is optionally substituted aryl. In certain embodiments, R.sup.3 is optionally substituted C.sub.6-10 aryl. In certain embodiments, R.sup.3 is optionally substituted phenyl. In certain embodiments, R.sup.3 is unsubstituted phenyl. In certain embodiments, R.sup.3 is substituted phenyl. In certain embodiments, R.sup.3 is phenyl substituted with 0, 1, 2, 3, 4, or 5 instances of R.sup.4, wherein R.sup.4 is as defined herein. In certain embodiments, R.sup.3 is of the formula:

(230) ##STR00105##
wherein R.sup.4 is as defined herein; and n is 0, 1, 2, 3, 4, or 5.

(231) In certain embodiments, R.sup.3 is of one of the following formulae:

(232) ##STR00106##

(233) In certain embodiments, n is 1, and R.sup.3 is of the following formula:

(234) ##STR00107##
In certain embodiments, n is 1; and R.sup.3 is of the formula:

(235) ##STR00108##
In certain embodiments, n is 1; and R.sup.3 is of the formula:

(236) ##STR00109##
In certain embodiments, n is 1; and R.sup.3 is of the formula:

(237) ##STR00110##
In certain embodiments, R.sup.3 is of the following formula:

(238) ##STR00111##
In certain embodiments, R.sup.3 is of the formula:

(239) ##STR00112##
In certain embodiments, R.sup.3 is of the formula:

(240) ##STR00113##
In certain embodiments, R.sup.3 is of the formula:

(241) ##STR00114##

(242) In certain embodiments, R.sup.3 is of one of the following formulae:

(243) ##STR00115##

(244) In certain embodiments, R.sup.3 is of the following formula:

(245) ##STR00116##
In certain embodiments, R.sup.3 is of the formula:

(246) ##STR00117##
In certain embodiments, R.sup.3 is of the formula:

(247) ##STR00118##
In certain embodiments, R.sup.3 is of the formula:

(248) ##STR00119##

(249) In certain embodiments, R.sup.3 is of one of the following formulae:

(250) ##STR00120##

(251) In certain embodiments, R.sup.3 is optionally substituted naphthyl. In certain embodiments, R.sup.3 is substituted naphthyl. In certain embodiments, R.sup.3 is unsubstituted naphthyl. In certain embodiments, R.sup.3 is substituted with 0, 1, 2, 3, 4, 5, 6, or 7, instances of R.sup.4, wherein R.sup.4 is as defined herein. In certain embodiments, R.sup.3 is of one of the following formulae:

(252) ##STR00121##
wherein R.sup.4 is as defined herein and m is 0, 1, 2, 3, 4, 5, 6, or 7. In certain embodiments, m is 0 and R.sup.3 is of one of the following formulae:

(253) ##STR00122##
In certain embodiments, R.sup.3 is of the following formula:

(254) ##STR00123##

(255) As generally defined herein, n is 0, 1, 2, 3, 4, or 5. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5.

(256) As generally defined herein, m is 0, 1, 2, 3, 4, 5, 6, or 7. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7.

(257) Groups R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4

(258) As generally defined herein, R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, or a nitrogen protecting group; or optionally R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, R.sup.N3 and R.sup.N4 are taken together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.N3 and R.sup.N4 are taken together with the intervening atoms to form optionally substituted heteroaryl.

(259) As generally defined herein, R.sup.N1 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, or a nitrogen protecting group. In certain embodiments, R.sup.N1 is optionally substituted alkyl. In certain embodiments, R.sup.N1 is optionally substituted C.sub.1-6alkyl. In certain embodiments, R.sup.N1 is substituted C.sub.1-6alkyl. In certain embodiments, R.sup.N1 is unsubstituted C.sub.1-6alkyl. In certain embodiments, R.sup.N1 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.N1 is substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.N1 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.N1 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiment, R.sup.N1 is methyl. In certain embodiments, R.sup.N1 is ethyl. In certain embodiments, R.sup.N1 is optionally substituted aryl. In certain embodiments, R.sup.N1 is substituted aryl. In certain embodiments, R.sup.N1 is unsubstituted aryl. In certain embodiments, R.sup.N1 is optionally substituted phenyl. In certain embodiments, R.sup.N1 is substituted phenyl. In certain embodiments, R.sup.N1 is unsubstituted phenyl. In certain embodiments, R.sup.N1 is optionally substituted naphthyl. In certain embodiments, R.sup.N1 is substituted naphthyl. In certain embodiments, R.sup.N1 is unsubstituted naphthyl. In certain embodiments, R.sup.N1 is optionally substituted acyl. In certain embodiments, R.sup.N1 is substituted acyl. In certain embodiments, R.sup.N1 is unsubstituted acyl. In certain embodiments, R.sup.N1 is a nitrogen protecting group. In certain embodiments, R.sup.N1 is hydrogen.

(260) As generally defined herein, R.sup.N2 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, or a nitrogen protecting group. In certain embodiments, R.sup.N2 is optionally substituted alkyl. In certain embodiments, R.sup.N2 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N2 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N2 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.N2 is substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.N2 is unsubstituted C.sub.1-3alkyl. In certain embodiments, R.sup.N2 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiment, R.sup.N2 is methyl. In certain embodiments, R.sup.N2 is ethyl. In certain embodiments, R.sup.N2 is optionally substituted aryl. In certain embodiments, R.sup.N2 is substituted aryl. In certain embodiments, R.sup.N2 is unsubstituted aryl. In certain embodiments, R.sup.N2 is optionally substituted phenyl. In certain embodiments, R.sup.N2 is substituted phenyl. In certain embodiments, R.sup.N2 is unsubstituted phenyl. In certain embodiments, R.sup.N2 is optionally substituted naphthyl. In certain embodiments, R.sup.N2 is substituted naphthyl. In certain embodiments, R.sup.N2 is unsubstituted naphthyl. In certain embodiments, R.sup.N2 is optionally substituted acyl. In certain embodiments, R.sup.N2 is substituted acyl. In certain embodiments, R.sup.N2 is unsubstituted acyl. In certain embodiments, R.sup.N2 is a nitrogen protecting group. In certain embodiments, R.sup.N2 is hydrogen.

(261) As generally defined herein, R.sup.N3 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, or a nitrogen protecting group. In certain embodiments, R.sup.N3 is optionally substituted alkyl. In certain embodiments, R.sup.N3 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N3 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N3 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.N3 is substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.N3 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.N3 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiment, R.sup.N3 is methyl. In certain embodiments, R.sup.N3 is ethyl. In certain embodiments, R.sup.N3 is optionally substituted aryl. In certain embodiments, R.sup.N3 is substituted aryl. In certain embodiments, R.sup.N3 is unsubstituted aryl. In certain embodiments, R.sup.N3 is optionally substituted phenyl. In certain embodiments, R.sup.N3 is substituted phenyl. In certain embodiments, R.sup.N3 is unsubstituted phenyl. In certain embodiments, R.sup.N3 is optionally substituted naphthyl. In certain embodiments, R.sup.N3 is substituted naphthyl. In certain embodiments, R.sup.N3 is unsubstituted naphthyl. In certain embodiments, R.sup.N3 is optionally substituted acyl. In certain embodiments, R.sup.N3 is substituted acyl. In certain embodiments, R.sup.N3 is unsubstituted acyl. In certain embodiments, R.sup.N3 is a nitrogen protecting group. In certain embodiments, R.sup.N1 is hydrogen.

(262) As generally defined herein, R.sup.N4 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, or a nitrogen protecting group. In certain embodiments, R.sup.N4 is optionally substituted alkyl. In certain embodiments, R.sup.N4 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N4 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N4 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N4 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.N4 is substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.N4 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.N4 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiment, R.sup.N4 is methyl. In certain embodiments, R.sup.N4 is ethyl. In certain embodiments, R.sup.N4 is optionally substituted aryl. In certain embodiments, R.sup.N4 is substituted aryl. In certain embodiments, R.sup.N4 is unsubstituted aryl. In certain embodiments, R.sup.N4 is optionally substituted phenyl. In certain embodiments, R.sup.N4 is substituted phenyl. In certain embodiments, R.sup.N4 is unsubstituted phenyl. In certain embodiments, R.sup.N4 is optionally substituted naphthyl. In certain embodiments, R.sup.N4 is substituted naphthyl. In certain embodiments, R.sup.N4 is unsubstituted naphthyl. In certain embodiments, R.sup.N4 is optionally substituted acyl. In certain embodiments, R.sup.N4 is substituted acyl. In certain embodiments, R.sup.N4 is unsubstituted acyl. In certain embodiments, R.sup.N1 is an oxygen protecting group. In certain embodiments, R.sup.N4 is hydrogen.

(263) In certain embodiments, R.sup.N1, R.sup.N2, R.sup.N3, and R.sup.N4 are all hydrogen.

(264) In certain embodiments, R.sup.2 and either R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.2 and either R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form optionally substituted pyrrolidine. In certain embodiments, R.sup.2 and either R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form unsubstituted pyrrolidine. In certain embodiments, R.sup.2 and either R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form optionally substituted azetidine. In certain embodiments, R.sup.2 and either R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form unsubstituted azetidine. In certain embodiments, R.sup.2 and either R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form optionally substituted piperidine. In certain embodiments, R.sup.2 and either R.sup.N3 and R.sup.N4 are joined together with the intervening atoms to form unsubstituted piperidine.

(265) In certain embodiments, R.sup.1 and R.sup.N2 are joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.1 and R.sup.N2 are joined together with the intervening atoms to form optionally substituted pyrrolidine. In certain embodiments, R.sup.1 and R.sup.N2 are joined together with the intervening atoms to form unsubstituted pyrrolidine. In certain embodiments, R.sup.1 and R.sup.N2 are joined together with the intervening atoms to form optionally substituted azetidine. In certain embodiments, R.sup.1 and R.sup.N2 are joined together with the intervening atoms to form unsubstituted azetidine. In certain embodiments, R.sup.1 and R.sup.N2 are joined together with the intervening atoms to form optionally substituted piperidine. In certain embodiments, R.sup.1 and R.sup.N2 are joined together with the intervening atoms to form unsubstituted piperidine.

(266) In certain embodiments, R.sup.3 and R.sup.N1 are joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.3 and R.sup.N1 are joined together with the intervening atoms to form optionally substituted pyrrolidine. In certain embodiments, R.sup.3 and R.sup.N1 are joined together with the intervening atoms to form unsubstituted pyrrolidine. In certain embodiments, R.sup.3 and R.sup.N1 are joined together with the intervening atoms to form optionally substituted azetidine. In certain embodiments, R.sup.3 and R.sup.N1 are joined together with the intervening atoms to form unsubstituted azetidine. In certain embodiments, R.sup.3 and R.sup.N1 are joined together with the intervening atoms to form optionally substituted piperidine. In certain embodiments, R.sup.3 and R.sup.N1 are joined together with the intervening atoms to form unsubstituted piperidine.

(267) As generally defined herein, p is 0, 1, or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2.

(268) Group R.sup.4

(269) As generally defined herein, each instance of R.sup.4 is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.4a, N(R.sup.4b).sub.2, or —SR.sup.4c. In certain embodiments, at least one instance of R.sup.4 is hydrogen. 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 —NO.sub.2. In certain embodiments, at least one instance of R.sup.4 is —N.sub.3. In certain embodiments, at least one instance of R.sup.4 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.4 is —OR.sup.4a, wherein R.sup.4a is as defined herein. In certain embodiments, at least one instance of R.sup.4 is —N(R.sup.4b).sub.2, wherein R.sup.4b is as defined herein. In certain embodiments, at least one instance of R.sup.4 is —SR.sup.4c, wherein R.sup.4c is as defined herein. In certain embodiments, at least one instance of R.sup.4 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.4 is substituted alkyl. In certain embodiments, at least one instance of R.sup.4 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted C.sub.1-6alkyl. In certain embodiments, at least one instance of R.sup.4 is substituted C.sub.1-6alkyl. In certain embodiments, at least one instance of R.sup.4 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted C.sub.1-3alkyl. In certain embodiments, at least one instance of R.sup.4 is substituted C.sub.1-3alkyl. In certain embodiments, at least one instance of R.sup.4 is unsubstituted C.sub.1-3alkyl. In certain embodiments, at least one instance of R.sup.4 is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, at least one instance of R.sup.4 is tert-butyl. In certain embodiments, one instance of R.sup.4 is tert-butyl. In certain embodiments, at least one instance of R.sup.4 is halogen. In certain embodiments, at least one instance of R.sup.4 is selected from the group consisting of Cl, Br, F, and I. In certain embodiments, at least one instance of R.sup.4 is Cl. In certain embodiments, one instance of R.sup.4 is Cl. In certain embodiments, at least one instance of R.sup.4 is Br. In certain embodiments, one instance of R.sup.4 is Br. In certain embodiments, at least one instance of R.sup.4 is F. In certain embodiments, one instance of R.sup.4 is F. In certain embodiments, at least one instance of R.sup.4 is I. In certain embodiments, one instance of R.sup.4 is I.

(270) As generally defined herein, each instance of R.sup.4a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, at least one instance of R.sup.4a is hydrogen. In certain embodiments, at least one instance of R.sup.4a is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.4a is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.4a is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.4a is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.4a is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.4a is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.4a is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.4a is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.4a is an oxygen protecting group.

(271) As generally defined herein, each instance of R.sup.4b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R.sup.4b are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.4b is hydrogen. In certain embodiments, at least one instance of R.sup.4b is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.4b is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.4b is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.4b is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.4b is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.4b is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.4b is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.4b is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.4b is a nitrogen protecting group. In certain embodiments, two R.sup.4b are joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, two R.sup.4b are joined together with the intervening atoms to form optionally substituted heteroaryl.

(272) As generally defined herein, each instance of R.sup.4c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group. In certain embodiments, at least one instance of R.sup.4c is hydrogen. In certain embodiments, at least one instance of R.sup.4c is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.4c is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.4b is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.4c is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.4c is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.4c is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.4c is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.4c is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.4c is a nitrogen protecting group.

(273) Pharmaceutical Compositions, Kits, and Administration

(274) The present disclosure provides pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

(275) 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, the effective amount is an amount effective for treating a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a proliferative disease in a subject in need thereof. Exemplary proliferative diseases include, but are not limited to, cancer, benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, and autoimmune diseases. In certain embodiments, the effective amount is an amount effective for treating a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating cancer (e.g., leukemia, such as AML) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing the recurrence of a hematological cancer in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease (e.g., proliferative disease, hematological cancer) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for inducing apoptisis of a cell in a subject or biological sample. In certain embodiments, the effective amount is an amount effective for inhibiting alpha-enolase enzymatic activity in a subject or biological sample.

(276) 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.

(277) 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.

(278) 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.

(279) 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.

(280) 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.

(281) 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.

(282) 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.

(283) 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.

(284) 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.

(285) 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.

(286) 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.

(287) 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.

(288) Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

(289) 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.

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

(291) 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.

(292) 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.

(293) 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, eveninu nrimrnse 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.

(294) Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral 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.

(295) 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.

(296) 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.

(297) 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.

(298) 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.

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

(300) 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 polyethylene glycols and the like.

(301) 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.

(302) 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.

(303) 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.

(304) 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.

(305) 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.

(306) 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 or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific 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.

(307) 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.

(308) 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 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 tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the 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 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 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 tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a 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.

(309) 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.

(310) 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 reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject 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.

(311) 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.

(312) 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 such as cancer) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., proliferative disease such as cancer) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease (e.g., proliferative disease such as cancer) in a subject in need thereof.

(313) In certain embodiments, a kit described herein further includes instructions for using 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., proliferative disease such as cancer) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., proliferative disease such as cancer) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g., proliferative disease such as cancer) in a subject in need thereof. In certain embodiments, the kits and instructions provide for inhibiting the activity (e.g., aberrant activity, such as increased activity) of an alpha-enolase protein in a subject or cell. In certain embodiments, the kits and instructions provide for inducing apoptosis of a cell in a subject or biological sample. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

(314) Methods of Treatment and Use

(315) The present invention also provides methods of using the compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, e.g., for the treatment and/or prevention of diseases or conditions, for the inhibition of alpha-enolase enzymatic activity, and for the induction of apoptosis of cells.

(316) Provided herein are methods of treating and/or preventing a disease or condition in a subject, the methods comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. The compounds provided herein may be used to treat any disease or condition. In certain embodiments, the disease or conditions is a proliferative disease, genetic disease, disease associated with angiogenesis, inflammatory disease, cardiovascular disease, hepatic disease, spleen disease, pulmonary disease, painful condition, hematological disease, neurological disease, psychiatric disorder, autoimmune disease, infectious disease, metabolic disease, gastrointestinal disorder, or endocrine disease.

(317) In certain embodiments, the disease is a proliferative disease. Examples of proliferative diseases include, but are not limited to, benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, and autoimmune diseases. In certain embodiments, the disease is cancer. In certain embodiments, the disease is an FLT3 mutant cancer. In certain embodiments, the disease is a hematological cancer. In certain embodiments, the disease is leukemia. In certain embodiments, the disease is acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or chronic lymphocytic leukemia (CLL)). In certain embodiments, the disease is a myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), myelofibrosis (MF), or some combination of a hematological cancer. In certain embodiments, the disease is lymphoma. In certain embodiments, the disease is Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL). In certain embodiments, the disease is non-Hodgkin lymphoma (NHL). Examples of non-Hodgkin lymphoma include, but are not limited to, B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM). In certain embodiments, the disease is multiple myeloma. In certain embodiments, the disease is AML. In certain embodiments, the disease is FLT3 mutant AML. In certain embodiments, the disease is a disease associated with aberrant alpha-enolase activity. In certain embodiments, the disease is a cancer associated with aberrant alpha-enolase activity. In certain embodiments, the disease is a disease associated with increased alpha-enolase activity. In certain embodiments, the disease is a cancer associated with increased alpha-enolase activity.

(318) The present invention also provides uses of compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the treatment and/or prevention of diseases described herein.

(319) Additionally, the present invention provides uses of compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for the treatment of diseases described herein.

(320) Also provided herein are methods of inducing apoptosis of a cell in a subject or biological sample, the methods comprising administering to the subject or biological sample a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the methods of inducing apoptosis in a cell involve contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cell is a hematopoietic cancer cell (e.g., AML cell). In certain embodiments, the cell is an AML cancer cell.

(321) The present invention also provides uses of compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the induction of apoptosis in a cell of a subject or biological sample.

(322) Additionally, the present invention provides uses of compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for the induction of apoptosis of a cell in a subject or biological sample.

(323) Furthermore, provided herein are methods of modulating the enzymatic activity of (i.e., inhibiting) an alpha-enolase protein, the methods comprising contacting the alpha-enolase with a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the alpha-enolase protein is inhibited in a cell. In certain embodiments, the alpha-enolase protein is inhibited in vitro. In certain embodiments, the alpha-enolase protein is inhibitited in the cell of a subject (e.g., in vivo). As described herein, alpha-enolase overexpression is associated with several cancers and tumors (e.g., hemotological cancers, gliomas, neuroendocrine tumors, neuroblastomas, prostate cancer, pancreatic cancer, cholangiocarcinoma, thyroid cancer, lung cancer, breast cancer, etc.). In untreated cancers (e.g., hemotolocial cancers such as AML), for example, enolase activity is increased due to increased protein expression. Enolase provides ATP as an energy source via its role in glycolysis. Enolase also supports microtubule polymerization and re-organization, which are required for cell cycling. Without wishing to be bound by a particular theory, compounds of the present invention can inhibit alpha-enolase enzymatic activity, thereby reducing ATP for microtubule polymerization and leading to apoptotic cell death.

(324) The present invention also provides uses of compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the inhibition of enzymatic activity of an alpha-enolase protein.

(325) Additionally, the present invention provides uses of compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for the inhibition of an alpha-enolase protein.

(326) In certain embodiments, the methods described herein comprise administering to a subject a therapeutically effective amount compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, wherein “therapeutically effective amount” is as defined herein.

(327) In certain embodiments, the methods described herein comprise administering to a subject a prophylactically effective amount compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, wherein “prophylactically effective amount” is as defined herein.

(328) A compound or composition provided herein may be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. It will further be appreciated that the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved. In general, it is expected that additional therapeutically active agents utilized 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. In certain embodiments, the additional therapeutic agent is an anti-proliferative agent, wherein “anti-proliferative” agent is as defined herein. In certain embodiments, the additional therapeutic agent is an anti-cancer agent, wherein “anti-cancer” agent is as defined herein.

(329) In certain embodiments, the compounds or pharmaceutical compositions described herein 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.

(330) 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.

(331) In certain embodiments, the provided methods comprise contacting a cell with an effective amount of a compound or a pharmaceutical composition as described herein. The cell may be contacted in vitro or in vivo. In certain embodiments, the contacting is in vivo. In certain embodiments, the contacting is in vitro. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cell is a leukemia cell. In certain embodiments, the cell is an acute myeloid leukemia cell (AML cell). In certain embodiments, the cell is a cancer stem cell such as a leukemia stem cell.

(332) In certain embodiments, the methods described herein include contacting a biological sample with an effective amount of a compound of Formula (I), 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 biological sample is contacted in vitro. In certain embodiments, the biological sample is obtained from a subject.

EXAMPLES

(333) These and other aspects of the present invention will be further appreciated upon consideration of the following Examples, which are intended to illustrate certain particular embodiments of the invention but are not intended to limit its scope, as defined by the claims.

(334) Synthesis of Compounds

(335) General Synthesis

(336) Compounds of Formula (I) were prepared as shown in Scheme 1. The mBHA (4-methylbenzhydrylamine) resin-bound Boc-protected dipeptide 1 was made using standard Boc (tert-butyloxycarbonyl) chemistry. Reagents and conditions for Scheme 1 are as follows: (a) 55% TFA/DCM (trifluoroacetic acid/dichloromethane), 30 min; 3×5% DIEA (N,N-diisopropylethylamine); (b) Sulfonyl chloride (e.g., Cl—SO.sub.2R.sup.3) (8 equiv 0.1M anhydrous DCM), DIEA (10 equiv), room temperature, overnight; (c) BH.sub.3-THF (borane-tetrahydrofuran), 65° C., 100 hours; (d) piperidine, 65° C., 24 hours; (e) HF (hydrofluoric acid), 0° C., 7 hours. In all cases the final products were extracted from their HF vessels with 95% acetic acid and then underwent three successive rounds of freezing, lyophilizing, and resuspending with 50% acetonitrile/water.

(337) ##STR00124##
Purification and Characterization
Instrumentation

(338) All purification were carried out using a Shimadzu Semi-preparative HPLC (high performance liquid chromatography). The HPLC system consisting of LC-6AD binary pumps, a DGU-20A 3R degassing unit, a CBM-20A communication bus module, a SIL-10AP auto sampler, and a FRC-10A fraction collector. All chromatographic peak detections were performed by using a SPD-20A diode array detector set to detect 214 nm absorbance. All chromatographic separations were performed using a Phenomenex Luna C18 preparative column (5 m, 150×21.20 mm i.d.). The inlet of the column was protected by a Phenomenex C18 Prep security guard cartridge (15×21.2 mm i.d.).

(339) Chemicals and Reagents

(340) All samples were reconstituted in 2000/3000 uL of a 50/50 mixture of HPLC grade or higher acetonitrile/water mixture obtained through Sigma Aldrich. The samples were then filtered through a Spartan 30, 0.45 μm syringe filter before injecting onto the HPLC for separation. The mobile phases consisted of deionized water and HPLC grade acetonitrile with 0.1% LCMS (liquid chromatography-mass spectrometry) grade formic acid obtained from Sigma Aldrich and Fisher Scientific.

(341) HPLC Conditions

(342) The initial setting for the HPLC was 95% water. The gradient was linearly increased to 20% acetonitrile (v/v) over 6 minutes. The gradient was again linearly increased to 60% acetonitrile (v/v) over 39 minutes. The gradient was then linearly increased to 95% acetonitrile (v/v) over 3 minutes and then held for an additional 4 minutes. Finally the gradient was linearly decreased to 5% acetonitrile (v/v) over 1 minute and held until stop. The total run time was equal to 58 minutes. The total flow rate used was 12 mL per minute and peak divide time was set at 0.75 minutes. A slope of 1,000,000uV/sec was set for this unit along with a level of 1,004,500uV, a slope override was also set for 5,510uV. Sample volume injected were based upon crude material yields with either 2000 uL or 3000 uL being injected 1×.

(343) LCMS Analysis

(344) Samples analyzed on Shimadzu Prominence liquid chromatograph (Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with 0.1% formic acid), Shimadzu Prominence UV (ultraviolet light) Detector (wavelength 214 and 254 nm) and Shimadzu LCMS-2010 (positive mode scanning 175-1000 m/z). Samples are run in reverse phase mode with a flow rate of 0.5 mL/min and a gradient of 5-95% over 6 minutes on a Phenomenex Luna C18 5μ 100 A 50×4.60 mm column.

(345) Exemplary compound 2470-15 was made utilizing the general procedure outlined in Scheme 1. R.sup.2 was incorporated from Boc-Val; R.sup.1 from Boc-Ala; and R.sup.3 from 4-tert-butylbenzene-1-sulfonyl chloride. LCMS Retention Time at 3.74 minutes found [M+H].sup.+ 356.

(346) Exemplary compound 2470-23 was made utilizing the general procedure outlined in Scheme 1. R.sup.2 was incorporated from Boc-Val; R.sup.1 from Boc-Val; and R.sup.3 from 4-iodobenzene-1-sulfonyl chloride. LCMS Retention Time at 3.71 minutes found [M+H].sup.+454.

(347) Exemplary compound 2470-40 was made utilizing the general procedure outlined in Scheme 1. R.sup.2 was incorporated from Boc-D-leu; R.sup.1 from Boc-Asp(OBzl)-OH; and R.sup.3 from naphthalene-2-sulfonyl chloride. LCMS Retention Time at 3.30 minutes found [M+H].sup.+ 394.

(348) Exemplary compound 2470-49 was made utilizing the general procedure outlined in Scheme 1. R.sup.2 was incorporated from Boc-D-val; R.sup.1 from Boc-Ala; and R.sup.3 from naphthalene-2-sulfonyl chloride. LCMS Retention Time at 3.32 minutes found [M+H].sup.+ 350.

(349) Exemplary compound 2470-51 was made utilizing the general procedure outlined in Scheme 1. R.sup.2 was incorporated from Boc-D-val; R.sup.1 from Boc-Ala; and R.sup.3 from 4-tert-butylbenzene-1-sulfonyl chloride. LCMS Retention Time at 3.67 minutes found [M+H].sup.+ 356.

(350) In Vitro and In Vivo Studies

(351) Compounds of Formula (I) were found to have significant toxicity in KG-1 cell lines (human acute myeloid leukemia cells) with minimal BMEC disruption at 50 μg/mL (see Table 1). The values given for percent toxicity to KG-1 cells is normalized to DMF. To compare the average AML-LSC toxicity vs. AML total toxicity, fresh human primary leukemia bone marrow mononuclear cells were treated with single doses of compounds, 2470-23 and 2470-51, at a single time point, and the killing of the AML leukemia stem cell (LSC) population versus the total AML cell population was quantified (FIG. 1). This demonstrates that both 2470 compounds were selectively toxic to the AML LSC fraction. Next, AML-LSC toxicity versus T lymphocyte (Jurkat) toxicity was investigated. The single-dose treatments 2470-23 and 2470-51 were compared on lymphoid (CD4+ Jurkat) versus myeloid (AML LSC) leukemia cells to demonstrate the specificity of these compounds for AML (FIG. 2). The single-dose treatments of 2470-23 and 2470-51 on normal healthy blood stem cells (sourced from fresh umbilical cord blood) versus AML LSC were also compared. As shown in FIG. 3, the inventive compounds do not deplete healthy stem cells while they do deplete the leukemia stem cells. These results indicate the specificity of action on diseased cells, with relative sparing of normal cells.

(352) TABLE-US-00001 TABLE 1 Exemplary compounds with AML cell (KG1) toxicity and no BMEC disruption KG1 toxicity Exact tPSA Compound Structure (50 μg/mL) Mass LogP (Å.sup.2) CLogP 2470-40 37.4% 393.21 2.25 104.45 2.3137 2470-49 46.7% 349.18 2.5   84.22 2.5647 2470-51 93.2% 355.23 3.26  84.22 3.2167 2470-15 38.4% 355.23 3.26  84.22 3.2167 2470-23 45.9% 453.09 3.34  84.22 3.7441

(353) Pharmacologic and ADME (absorption, distribution, metabolism, excretion) data for compound 2570-51 is shown in Table 2. Additional biological data for compounds of the present invention can be found in in the Figures and the Brief Description of the Drawings.

(354) TABLE-US-00002 TABLE 2 Pharmacologic characteristics and ADME data for compound 2470-51 Aqueous Microsomal Human plasma CYP450 Plasma protein Solubility Stability, t.sub.1/2 half-life inhibition binding PAMPA >100 μM mouse: 8 min >200 min 2C9 > 20 μM 80.5% 1 × 10.sup.−6 cm/s rat: 9 min 2D6 = 10.8 μM (moderate) human: 33 min 3A4 > 20 μM

EQUIVALENTS AND SCOPE

(355) 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 invention 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 invention 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.

(356) Furthermore, the invention 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 invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

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

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