Activators of class I histone deacetylases (HDACs) and uses thereof

Abstract

The present invention provides compounds of Formulae (A), (B), (C), and (D), pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, pharmaceutical compositions thereof, and kits thereof. The present invention further provides methods of using the compounds to treat or prevent neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis), traumatic brain injury, ischemic brain injury, stroke, frontal temporal dementia, Pick's disease, corticobasal degeneration, supra cerebral palsy, prion diseases (e.g., Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia, and Kuru), Nieman Pick type C, spinal cerebellar ataxia, spinal muscular dystrophy, ataxia telangiectasia, hippocampal sclerosis, Cockayne syndrome, Werner syndrome, xeroderma pigmentosaum, and Bloom syndrome. In one aspect, the methods include administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of DAC-001, DAC-002, DAC-003, DAC-009, or DAC-012, or a compound of Formula (A), (B), (C), or (D). ##STR00001##

Claims

1. A method for therapeutically treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (C-III): ##STR00060## or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: each instance of R.sup.C1 and R.sup.C2 is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.C2a, —N(R.sup.C2b).sub.2, —SR.sup.C2a, —C(═O)R.sup.C2a, —C(═O)OR.sup.C2a, —C(═O)SR.sup.C2a, —C(═O)N(R.sup.C2b).sub.2, —OC(═O)R.sup.C2b, —OC(═O)OR.sup.C2a, —OC(═O)SR.sup.C2b, —OC(═O)N(R.sup.C2b).sub.2, —NR.sup.C2bC(═O)R.sup.C2b, —NR.sup.C2bC(═O)OR.sup.C2a, —NR.sup.C2bC(═O)SR.sup.C2a, —NR.sup.C2bC(═O)N(R.sup.C2b).sub.2, —SC(═O)R.sup.C2a, —SC(═O)OR.sup.C2a, —SC(═O)SR.sup.C2b, —SC(═O)N(R.sup.C2b).sub.2, —C(═NR.sup.C2b)R.sup.C2a, —C(═NR.sup.C2b)OR.sup.C2a, —C(═NR.sup.C2b)SR.sup.C2a, —C(═NR.sup.C2b)N(R.sup.C2b).sub.2, —OC(═NR.sup.C2b)R.sup.C2a, —OC(═NR.sup.C2b)OR.sup.C2a, —OC(═NR.sup.C2b)SR.sup.C2a, —OC(═NR.sup.C2b)N(R.sup.C2b).sub.2, —NR.sup.C2bC(═NR.sup.C2b)R.sup.C2b, —NR.sup.C2bC(═NR.sup.C2b)OR.sup.C2a, —NR.sup.C2bC(═NR.sup.C2b)SR.sup.C2a, —NR.sup.C2bC(═NR.sup.C2b)N(R.sup.C2b).sub.2, —SC(═NR.sup.C2b)R.sup.C2a, —SC(═NR.sup.C2b)OR.sup.C2a, —SC(═NR.sup.C2b)SR.sup.C2a, —SC(═NR.sup.C2b)N(R.sup.C2b).sub.2, —C(═S)R.sup.C2a, —C(═S)OR.sup.C2a, —C(═S)SR.sup.C2a, —C(═S)N(R.sup.C2b).sub.2, —OC(═S)R.sup.C2a, —OC(═S)OR.sup.C2a, —OC(═S)SR.sup.C2a, —OC(═S)N(R.sup.C2b).sub.2, —NR.sup.C2bC(═S)R.sup.C2b, —NR.sup.C2bC(═S)OR.sup.C2a, —NR.sup.C2bC(═S)SR.sup.C2a, —NR.sup.C2bC(═S)N(R.sup.C2b).sub.2, —SC(═S)R.sup.C2a, —SC(═S)OR.sup.C2b, —SC(═S)SR.sup.C2a, —SC(═S)N(R.sup.C2b).sub.2, —S(═O)R.sup.C2a, —SO.sub.2R.sup.C2a, —NR.sup.C2bSO.sub.2R.sup.C2a, —SO.sub.2N(R.sup.C2b).sub.2, —CN, —SCN, and —NO.sub.2, wherein each occurrence of R.sup.C2a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R.sup.C2b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.C2b groups are joined to form an optionally substituted heterocyclic ring; q is 0, 1, 2, 3, or 4; and r is 0, 1, 2, 3, 4, or 5.

2. The method in claim 1, wherein the therapeutically effective amount is further effective in activating class I histone deacetylase.

3. The method in claim 1, wherein the therapeutically effective amount is further effective in activating histone deacetylase 1.

4. The method in claim 1, wherein the compound is: ##STR00061## or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

5. The method of claim 1, wherein the neurological disorder is Alzheimer's disease.

6. The method of claim 1, wherein the neurological disorder is Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic brain injury, stroke, Pick's disease, corticobasal degeneration, supra cerebral palsy, prion disease, Niemann Pick disease type C, spinal muscular dystrophy, ataxia telangiectasia, hippocampal sclerosis, Cockayne syndrome, Werner syndrome, xeroderma pigmentosum, or Bloom syndrome.

7. The method of claim 1, wherein the neurological disorder is frontal temporal dementia.

8. The method of claim 1, wherein the neurological disorder is Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, or Kuru.

9. The method of claim 1, wherein the neurological disorder is spinal cerebellar ataxia.

10. The method of claim 1, wherein the compound is not: ##STR00062## or a pharmaceutically acceptable salt thereof.

11. The method of claim 1, wherein the compound is: ##STR00063## or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

12. The method of claim 1, wherein the compound is: ##STR00064## or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

13. The method of claim 1, wherein the compound is: ##STR00065## or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: each instance of R.sup.C3 and R.sup.C4 is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.C4a, —N(R.sup.C4b).sub.2, —SR.sup.C4a, —C(═O)R.sup.C4a, —C(═O)OR.sup.C4a, —C(═O)SR.sup.C4a, —C(═O)N(R.sup.C4b).sub.2, OC(═O)R.sup.C4a, —OC(═O)OR.sup.C4a, OC(═O)SR.sup.C4a, —OC(═O)N(R.sup.C4b).sub.2, —NR.sup.C4bC(═O)R.sup.C4b, —NR.sup.C4bC(═O)OR.sup.C4a, —NR.sup.C4bC(═O)SR.sup.C4a, —NR.sup.C4bC(═O)N(R.sup.C4b).sub.2, —SC(═O)R.sup.C4a, —SC(═O)OR.sup.C4a, —SC(═O)SR.sup.C4a, —SC(═O)N(R.sup.C4b).sub.2, —C(═NR.sup.C4b)R.sup.C4a, —C(═NR.sup.C4a)OR.sup.C4a, —C(═NR.sup.C4b)SR.sup.C4a, —C(═NR.sup.C4b)N(R.sup.C4b).sub.2, —OC(NR.sup.C4b)R.sup.C4a, —OC(═NR.sup.C4b)OR.sup.C4a, —OC(═NR.sup.C4bSR.sup.C4a, —OC(═NR.sup.C4b)N(R.sup.C4b).sub.2, —NR.sup.C4bC(═NR.sup.C4b)R.sup.C4b, —NR.sup.C4bC(═NR.sup.C4b)OR.sup.C4a, —NR.sup.C4bC(═NR.sup.C4b)SR.sup.C4a, —NR.sup.C4bC(═NR.sup.C4b)N(R.sup.C4b).sub.2, —SC(═NR.sup.C4b)R.sup.C4a, —SC(═NR.sup.C4b)OR.sup.C4a, —SC(═NR.sup.C4b)SR.sup.C4a, —SC(═NR.sup.C4b)N(R.sup.C4b).sub.2, —C(═S)R.sup.C4a, —C(═S)OR.sup.C4a, —C(═S)SR.sup.C4a, —C(═S)N(R.sup.C4b).sub.2, —OC(═S)R.sup.C4a, —OC(═S)OR.sup.C4a, —OC(═S)SR.sup.C4a, —OC(═S)N(R.sup.C4b).sub.2, —NR.sup.C4bC(═S)R.sup.C4b, —NR.sup.C4bC(═S)OR.sup.C4a, —NR.sup.C4bC(═S)SR.sup.C4a, —NR.sup.C4bC(═S)N(R.sup.C4b).sub.2, —SC(═S)R.sup.C4a, —SC(═S)OR.sup.C4a, —SC(═S)SR.sup.C4a, —SC(═S)N(R.sup.C4b).sub.2, —S(═O)R.sup.C4a, —SO.sub.2R.sup.C4a, —NR.sup.C4bSO.sub.2R.sup.C4a, —SO.sub.2N(R.sup.C4b).sub.2, —CN, —SCN, and —NO.sub.2, wherein each occurrence of R.sup.C4a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R.sup.C4b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.C4b groups are joined to form an optionally substituted heterocyclic ring; and v is 0, 1, 2, and 3.

14. The method of claim 13, wherein the compound is: ##STR00066## or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

15. The method of claim 13, wherein the compound is: ##STR00067## or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

16. The method of claim 13, wherein the compound is: ##STR00068## or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

17. The method of claim 1, wherein the compound is: ##STR00069## or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

18. The method of claim 1, wherein the compound is: ##STR00070## or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

19. The method of claim 1, wherein the compound is: ##STR00071## or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

20. The method of claim 1, wherein in the compound of Formula (C-III), at least one instance of R.sup.C1 is optionally substituted alkyl.

21. The method of claim 1, wherein in the compound of Formula (C-III), at least one instance of R.sup.C2 is —OR.sup.C2a.

22. The method of claim 1, wherein the neurological disorder is Parkinson's disease.

23. The method of claim 1, wherein the neurological disorder is Huntington's disease.

24. The method of claim 1, wherein the neurological disorder is amyotrophic lateral sclerosis.

25. The method of claim 1, wherein the neurological disorder is stroke.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows an overview of small molecule modulators of class I HDACs and relevance to response to DNA damage, DNA repair, and neuroprotection. HDAC1, HDAC2, HDAC3, and HDAC8 are zinc-dependent hydrolases that remove acetyl groups from the ε-amino group of lysine side chains. Class I HDACs have also been found to have other enzymatic activities, including esterase activity.

(2) FIGS. 2A to 2B show HDAC1 microfluidics. FIG. 2A shows an assay control data of 7,080 negative control samples (DMSO). FIG. 2B shows 580 ginkgetin positive controls (50 μM).

(3) FIGS. 3A to 3B show HDAC1 microfluidics high-throughput screening data. FIG. 3A depicts a primary microfluidic fluorescence reader trace for ginkgetin (positive control, for its structure, see FIG. 6A) showing increased conversion of the peptidic substrate FAM-TSRHKacKL to the deacetylated product FAM-TSRHKKL (illustrated with arrows). FIG. 3B depicts a primary microfluidic fluorescence reader trace for DAC-001, showing increased conversion of the peptidic substrate FAM-TSRHKacKL to the deacetylated product FAM-TSRHKKL (illustrated with arrows).

(4) FIG. 4 shows that DAC compounds reduce histone acetylation. DAC compounds were added to HEK293T cells for 20 h. Vehicle was DMSO. Histones were acid-extracted and analyzed by Western blot for Ac-H3K56, Ac-H4K12, Ac-H3K14 and Ac-H2B. Histone 3 was used as the loading control.

(5) FIGS. 5A to 5C show that DAC compounds protect cells from stress-induced cell death. FIG. 5A shows that DAC compounds protect cells against oxidative stress, 10 μM DAC-003 can significantly protect cells from oxidative insults (*p<0.05, compound versus vehicle treatment, student's t-test). FIG. 5B shows that DAC compounds protect cells from DNA damage-induced stress. Cells were treated with etoposide, a topoisomerase II inhibitor, to generate DNA double strand breaks (DSB). It was found that DAC-001, DAC-002, DAC-003. DAC-009, and DAC-012 significantly protect cells from DSB-induced cell death (***p<0.001, compound versus vehicle treatment, student's t-test). FIG. 5C shows that DAC compounds have minimal effects on cell proliferation and survival at their working concentration (5 μM for DAC-001 and DAC-003; 10 μM for the others).

(6) FIGS. 6A to 6C show the twenty-one (21) hit structures from the high throughput HDAC1 activator screen.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

(7) The present invention provides compounds that activate Class I histone deacetlyases (HDACs), and pharmaceutical compositions thereof, for the treatment of human disease. The present invention further provides methods of using the compounds described herein, e.g., as biological probes to study the activation of HDACs, and as therapeutics, e.g. in the treatment of neurological disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease. ALS (Amyotrophic lateral sclerosis), traumatic brain injury, ischemic brain injury, stroke, frontal temporal dementia, Pick's disease, corticobasal degeneration, supra cerebral palsy, prion diseases (e.g., Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome. Fatal Familial Insomnia, and Kuru). Nieman Pick type C, spinal cerebellar ataxia, spinal muscular dystrophy, ataxia telangiectasia, hippocampal sclerosis, Cockayne syndrome, Werner syndrome, xeroderma pigmentosaum, or Bloom syndrome.

(8) Compounds

(9) 47,144 compounds were screened for hit compounds, which enhance the enzymatic activity of class I HDAC, especially, HDAC1. Of the hit compounds, multiple common structural frameworks were identified, suggesting the existence of a defined structure-activity-relationship for HDAC1 activation.

(10) The compounds depicted below and herein may be prepared by conventional chemical transformations (including protecting group methodologies), e.g., those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. The compounds can also be synthesized in manners similar to those described with necessary modifications as recognized by those skilled in the art.

(11) In one aspect, provided is a compound of Formula (A):

(12) ##STR00007##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein

(13) each instance of X.sup.A1, X.sup.A2, and X.sup.A3 is independently oxygen or sulfur:

(14) each instance of R.sup.A1 and R.sup.A2 is independently hydrogen, a nitrogen protecting group, or C.sub.1-6 alkyl;

(15) Ar is optionally substituted aryl or optionally substituted heteroaryl;

(16) each instance of R.sup.A3 and R.sup.A4 is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.A3a, —N(R.sup.A3b).sub.2, —SR.sup.A3a, —C(═O)R.sup.A3a, —C(═O)OR.sup.A3a, —C(═O)SR.sup.A3a, —C(═O)N(R.sup.A3b).sub.2, —OC(═O)R.sup.A3b, —OC(═O)OR.sup.A3a, —OC(═O)SR.sup.A3a, —OC(═O)N(R.sup.A3b).sub.2, —NR.sup.A3bC(═O)R.sup.A3b, —NR.sup.A3bC(═O)OR.sup.A3a, —NR.sup.A3bC(═O)SR.sup.A3a, —NR.sup.A3bC(═O)N(R.sup.A3b).sub.2, —SC(═O)R.sup.A3a, —SC(═O)OR.sup.A3a, —SC(═O)SR.sup.A3a, —SC(═O)N(R.sup.A3b).sub.2, —C(═NR.sup.A3b)R.sup.A3a, —C(═NR.sup.A3b)OR.sup.A3a, —C(═NR.sup.A3b)SR.sup.A3a, —C(═NR.sup.A3b)N(R.sup.A3b).sub.2, —OC(═NR.sup.A3b)R.sup.A3a, —OC(═NR.sup.A3b)OR.sup.A3a, —OC(═NR.sup.A3b)SR.sup.A3a, —OC(═NR.sup.A3b)N(R.sup.A3b).sub.2, —NR.sup.A3bC(═NR.sup.A3b)R.sup.A3b, —NR.sup.A3bC(═NR.sup.A3b)OR.sup.A3a, —NR.sup.A3bC(═NR.sup.A3b)SR.sup.A3a, —NR.sup.A3bC(═NR.sup.A3b)N(R.sup.A3b).sub.2, —SC(═NR.sup.A3b)R.sup.A3a, —SC(═NR.sup.A3b)OR.sup.A3a, —SC(═NR.sup.A3b)SR.sup.A3a, —SC(═NR.sup.A3b)N(R.sup.A3b).sub.2, —C(═S)R.sup.A3a, —C(═S)OR.sup.A3a, —C(═S)SR.sup.A3a, —C(═S)N(R.sup.A3b).sub.2, —OC(═S)R.sup.A3a, —OC(═S)OR.sup.A3a, —OC(═S)SR.sup.A3a, —OC(═S)N(R.sup.A3b).sub.2, —NR.sup.A3bC(═S)R.sup.A3b, —NR.sup.A3bC(═S)OR.sup.A3a, —NR.sup.A3bC(═S)SR.sup.A3a, —NR.sup.A3bC(═S)N(R.sup.A3b).sub.2, —SC(═S)R.sup.A3a, —SC(═S)OR.sup.A3a, —SC(═S)SR.sup.A3a, —SC(═S)N(R.sup.A3b).sub.2, —S(═O)R.sup.A3a, —SO.sub.2R.sup.A3a, —NR.sup.A3bSO.sub.2R.sup.A3a, —SO.sub.2N(R.sup.A3b).sub.2, —CN, —SCN, and —NO.sub.2, wherein each occurrence of R.sup.A3a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R.sup.A3b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.A3b groups are joined to form an optionally substituted heterocyclic ring;

(17) m is 0, 1, 2, 3, or 4; and

(18) n is 0, 1, 2, or 3.

(19) In certain embodiments, X.sup.A1, X.sup.A2, and X.sup.A3 are oxygen. In certain embodiments, X.sup.A1 and X.sup.A2 are oxygen, and X.sup.A3 is sulfur. In certain embodiments, X.sup.A1 and X.sup.A3 are oxygen, and X.sup.A2 is sulfur. In certain embodiments, X.sup.A2 and X.sup.A3 are oxygen, and X.sup.A1 is sulfur. In certain embodiments, X.sup.A1 and X.sup.A2 are sulfur, and X.sup.A3 is oxygen. In certain embodiments, X.sup.A1 and X.sup.A3 are sulfur, and X.sup.A2 is oxygen. In certain embodiments, X.sup.A2 and X.sup.A3 are sulfur, and X.sup.A1 is oxygen. In certain embodiments, X.sup.A1, X.sup.A2, and X.sup.A3 are sulfur.

(20) In certain embodiments, R.sup.A1 is hydrogen. In certain embodiments. R.sup.A1 is a nitrogen protecting group. In certain embodiments, R.sup.A1 is C.sub.1-6 alkyl. In certain embodiments, R.sup.A1 is methyl.

(21) In certain embodiments, R.sup.A2 is hydrogen. In certain embodiments, R.sup.A2 is a nitrogen protecting group. In certain embodiments, R.sup.A2 is C.sub.1-6 alkyl. In certain embodiments, R.sup.A2 is methyl.

(22) In certain embodiments, R.sup.A1 and R.sup.A2 are both hydrogen.

(23) In certain embodiments, X.sup.A1 and X.sup.A3 are oxygen, X.sup.A2 is sulfur, and R.sup.A1 and R.sup.A2 are hydrogen.

(24) In certain embodiments, Ar is aryl. In certain embodiments, Ar is substituted aryl. In certain embodiments, Ar is heteroaryl. In certain embodiments, Ar is substituted heteroaryl.

(25) In certain embodiments, each instance of R.sup.A3 is independently optionally substituted alkyl. In certain embodiments, each instance of R.sup.A3 is independently optionally substituted C.sub.1-6 alkyl. In certain embodiments, each instance of R.sup.A3 is independently optionally substituted methyl. In certain embodiments, each instance of R.sup.A3 is independently methyl.

(26) In certain embodiments, each instance of R.sup.A4 is independently optionally substituted alkyl. In certain embodiments, each instance of R.sup.A4 is independently optionally substituted C.sub.1-6 alkyl. In certain embodiments, each instance of R.sup.A4 is independently optionally substituted methyl. In certain embodiments, each instance of R.sup.A4 is independently optionally substituted hydroxyl-substituted alkyl. In certain embodiments, each instance of R.sup.A4 is independently optionally substituted hydroxyl-substituted C.sub.1-6 alkyl. In certain embodiments, each instance of R.sup.A4 is independently substituted hydroxymethyl. In certain embodiments, each instance of R.sup.A4 is independently hydroxymethyl.

(27) 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.

(28) In certain embodiments. X.sup.A1 and X.sup.A3 are oxygen, X.sup.A1 is sulfur, R.sup.A1 and R.sup.A2 are hydrogen, and m is 0.

(29) In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.

(30) In certain embodiments, wherein Ar is optionally substituted phenyl, provided is a compound of Formula (A-I):

(31) ##STR00008##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein

(32) X.sup.A1, X.sup.A2, X.sup.A3, R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4, m, and n are as defined herein:

(33) each instance of R.sup.AI is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.AIa, —N(R.sup.AIb).sub.2, —SR.sup.AIa, —C(═O)R.sup.AIa, —C(═O)OR.sup.AIa, —C(═O)SR.sup.AIa, —C(═O)N(R.sup.AIb).sub.2, —OC(═O)R.sup.AIa, —OC(═O)OR.sup.AIa, —OC(═O)SR.sup.AIa, —OC(═O)N(R.sup.AIb).sub.2, —NR.sup.AIbC(═O)R.sup.AIb, —NR.sup.AIbC(═O)OR.sup.AIb, —NR.sup.AIbC(═O)SR.sup.AIa, —NR.sup.AIb, —C(═O)N(R.sup.AIb).sub.2, —SC(═O)R.sup.AIa, —SC(═O)OR.sup.AIa, —SC(═O)SR.sup.AIa, —SC(═O)N(R.sup.AIb).sub.2, —C(═NR.sup.AIb)R.sup.AIa, C(═NR.sup.AIb)OR.sup.AIa, —C(═NR.sup.AIb)SR.sup.AIb, —C(═NR.sup.AIb)N(R.sup.AIa).sub.2, —OC(═NR.sup.AIb)R.sup.AIa, —OC(═NR.sup.AIb)OR.sup.AIa, —OC(═NR.sup.AIb)SR.sup.AIa, —OC(═NR.sup.AIb)N(R.sup.AIb).sub.2, —NR.sup.AIbC(═NR.sup.AIb)R.sup.AIb, —NR.sup.AIbC(R.sup.AIb)OR.sup.AIa, —NR.sup.AIbC(═NR.sup.AIb)SR.sup.AIa, —NR.sup.AIbC(═NR.sup.AIb)N(R.sup.AIb).sub.2, —SC(═NR.sup.AIb)R.sup.AIa, —SC(═NR.sup.AIb)OR.sup.AIa, —SC(═NR.sup.AIb)SR.sup.AIa, —SC(═NR.sup.AIb)N(R.sup.AIb).sub.2, —C(═S)R.sup.AIa, —C(═S)OR.sup.AIa, —C(═S)SR.sup.AIa, —C(═S)N(R.sup.AIb).sub.2, —OC(═S)R.sup.AIa, —OC(═S)OR.sup.AIa, —OC(═S)SR.sup.AIa, —OC(═S)N(R.sup.AIb).sub.2, —NR.sup.AIbC(═S)R.sup.AIb, —NR.sup.AIbC(═S)OR.sup.AIa, —NR.sup.AIbC(═S)SR.sup.AIa, —NR.sup.AIbC(═S)N(R.sup.AIb).sub.2, —SC(═S)R.sup.AIa, —SC(═S)OR.sup.AIa, —SC(═S)SR.sup.AIa, —SC(═S)N(R.sup.AIb).sub.2, —S(═O)R.sup.AIa, —SO.sub.2R.sup.AIa, —NR.sup.AIbSO.sub.2R.sup.AIa, —SO.sub.2N(R.sup.AIb).sub.2, —CN, —SCN, and —NO.sub.2, wherein each occurrence of R.sup.AIa is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or each occurrence of R.sup.AIb is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.AIb groups are joined to form a heterocyclic ring; and

(34) j is 0, 1, 2, 3, 4, or 5.

(35) In certain embodiments of Formula (A-I), j is 0. In certain embodiments, j is 1. In certain embodiments, j is 2. In certain embodiments, j is 3. In certain embodiments, j is 4. In certain embodiments, j is 5.

(36) In certain embodiments, provided is a compound of any of the formulae:

(37) ##STR00009##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein X.sup.A1, X.sup.A2, X.sup.A3, R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4, R.sup.AI, m, and n are as defined herein.

(38) In certain embodiments, provided is a compound of any of the formulae:

(39) ##STR00010##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.A3, R.sup.A4, R.sup.AI, m, and n are as defined herein.

(40) In certain embodiments. R.sup.AI is C.sub.1-6 alkyl. In certain embodiments, R.sup.AI is methyl. In certain embodiments, R.sup.AI is ethyl. In certain embodiments. R.sup.AI is propyl. In certain embodiments, R.sup.AI is butyl.

(41) In certain embodiments, provided is a compound of any of the formulae:

(42) ##STR00011##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein X.sup.A1, X.sup.A2, X.sup.A3, Ar, R.sup.A1, R.sup.A2, and R.sup.A4 are as defined herein.

(43) In certain embodiments, provided is a compound of any of the formulae:

(44) ##STR00012##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein X.sup.A1, X.sup.A2, X.sup.A3, Ar, R.sup.A1, R.sup.A2, and R.sup.A3 are as defined herein.

(45) In certain embodiments, wherein Ar is a optionally substituted thiophenyl, provided is a compound of Formula (A-VI):

(46) ##STR00013##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein

(47) X.sup.A1, X.sup.A2, X.sup.A3, R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4, m, and n are as defined herein:

(48) each instance of R.sup.AII is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.AIIa, —N(R.sup.AIIb).sub.2, —SR.sup.AIIa, —C(═O)R.sup.AIIa, —C(═O)OR.sup.AIIa, —C(═O)SR.sup.AIIa, —C(═O)N(R.sup.AIIb).sub.2, —OC(═O)R.sup.AIIa, —OC(═O)OR.sup.AIIa, —OC(═O)SR.sup.AIIa, —OC(═O)N(R.sup.AIIb).sub.2, —NR.sup.AIIbC(═O)R.sup.AIIb, —NR.sup.AIIbC(═O)OR.sup.AIIb, —NR.sup.AIIbC(═O)SR.sup.AIIa, —NR.sup.AIIb, —C(═O)N(R.sup.AIIb).sub.2, —SC(═O)R.sup.AIIa, —SC(═O)OR.sup.AIIa, —SC(═O)SR.sup.AIIa, —SC(═O)N(R.sup.AIIb).sub.2, —C(═NR.sup.AIIb)R.sup.AIIa, C(═NR.sup.AIIb)OR.sup.AIIa, —C(═NR.sup.AIIb)SR.sup.AIIb, —C(═NR.sup.AIIb)N(R.sup.AIIa).sub.2, —OC(═NR.sup.AIIb)R.sup.AIIa, —OC(═NR.sup.AIIb)OR.sup.AIIa, —OC(═NR.sup.AIIb)SR.sup.AIIa, —OC(═NR.sup.AIIb)N(R.sup.AIIb).sub.2, —NR.sup.AIIbC(═NR.sup.AIIb)R.sup.AIIb, —NR.sup.AIIbC(R.sup.AIIb)OR.sup.AIIa, —NR.sup.AIIbC(═NR.sup.AIIb)SR.sup.AIIa, —NR.sup.AIIbC(═NR.sup.AIIb)N(R.sup.AIIb).sub.2, —SC(═NR.sup.AIIb)R.sup.AIIa, —SC(═NR.sup.AIIb)OR.sup.AIIa, —SC(═NR.sup.AIIb)SR.sup.AIIa, —SC(═NR.sup.AIIb)N(R.sup.AIIb).sub.2, —C(═S)R.sup.AIIa, —C(═S)OR.sup.AIIa, —C(═S)SR.sup.AIIa, —C(═S)N(R.sup.AIIb).sub.2, —OC(═S)R.sup.AIIa, —OC(═S)OR.sup.AIIa, —OC(═S)SR.sup.AIIa, —OC(═S)N(R.sup.AIIb).sub.2, —NR.sup.AIIbC(═S)R.sup.AIIb, —NR.sup.AIIbC(═S)OR.sup.AIIa, —NR.sup.AIIbC(═S)SR.sup.AIIa, —NR.sup.AIIbC(═S)N(R.sup.AIIb).sub.2, —SC(═S)R.sup.AIIa, —SC(═S)OR.sup.AIIa, —SC(═S)SR.sup.AIIa, —SC(═S)N(R.sup.AIIb).sub.2, —S(═O)R.sup.AIIa, —SO.sub.2R.sup.AIIa, —NR.sup.AIIbSO.sub.2R.sup.AIIa, —SO.sub.2N(R.sup.AIIb).sub.2, —CN, —SCN, and —NO.sub.2, wherein each occurrence of R.sup.AIIa is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and each occurrence of R.sup.AIIb is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.AIIb groups are joined to form a heterocyclic ring; and

(49) k is 0, 1, 2, or 3.

(50) In certain embodiments of Formula (A-VI), k is 0. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3.

(51) In certain embodiments of Formula (A-VI), wherein k is 1, provided is a compound of any of the formulae:

(52) ##STR00014##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein X.sup.A1, X.sup.A2, X.sup.A3, R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4, R.sup.AII, m, and n are as defined herein.

(53) In certain embodiments of Formula (A-VI), wherein n is 1, provided is a compound of any of the formulae:

(54) ##STR00015##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein X.sup.A1, X.sup.A2, X.sup.A3, R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4, R.sup.AII, k, and mare as defined herein.

(55) In certain embodiments of Formula (A-VI), provided is a compound of any of the formulae:

(56) ##STR00016##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein X.sup.A1, X.sup.A2, X.sup.A3, R.sup.A1, R.sup.A2, R.sup.A3, R.sup.AII, k, and mare as defined herein.

(57) In certain embodiments, provided is a compound of any of the formulae:

(58) ##STR00017##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.A3, R.sup.AII, k, and m are as defined herein.

(59) In a certain embodiment, the compound of Formula (A) is not of the formula:

(60) ##STR00018##
or a pharmaceutically acceptable salt thereof.

(61) Another hit from the library was identified with a structural framework as shown in

(62) ##STR00019##
Therefore, in certain embodiments, provided is a compound of Formula (B), and pharmaceutically acceptable salts, solvates hydrates, polymorphs, co-crystals tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein

(63) each instance of X.sup.B1, X.sup.B3, and X.sup.B4 is independently oxygen, sulfur. NR.sup.B4a, or C(R.sup.B1b).sub.2, wherein R.sup.B4a is hydrogen, a nitrogen protecting group, or C.sub.1-6 alkyl, and each occurrence of R.sup.B4b is hydrogen, halogen, or C.sub.1-6 alkyl, or two R.sup.B4b groups are joined to form an optionally substituted carbocyclic or heterocyclic ring;

(64) X.sup.B2 is nitrogen or CR.sup.B2a, wherein R.sup.B2a is hydrogen, halogen, or C.sub.1-6 alkyl;

(65) each instance of R.sup.B1 is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.B1a, —N(R.sup.B1b).sub.2, —SR.sup.B1a, —C(═O)R.sup.B1a, —C(═O)OR.sup.B1a, —C(═O)SR.sup.B1a, —C(═O)N(R.sup.B1b).sub.2, —OC(═O)R.sup.B1a, —OC(═O)OR.sup.B1a, —OC(═O)SR.sup.B1a, —OC(═O)N(R.sup.B1b).sub.2, —NR.sup.B1bC(═O)R.sup.B1b, —NR.sup.B1bC(═O)OR.sup.B1a, —NR.sup.B1bC(═O)SR.sup.B1a, NR.sup.B1bC(═O)N(R.sup.B1b).sub.2, —SC(═O)R.sup.B1a, —SC(═O)OR.sup.B1a, —SC(═O)SR.sup.B1a, —SC(═O)N(R.sup.B1b).sub.2, —C(═NR.sup.B1b)R.sup.B1a, —C(═NR.sup.B1b)OR.sup.B1a, C(═NR.sup.B1b)SR.sup.B1a, —C(═NR.sup.B1b)N(R.sup.B1b).sub.2, —OC(═NR.sup.B1b)R.sup.B1a, —OC(═NR.sup.B1b)OR.sup.B1a, —OC(═NR.sup.B1b)SR.sup.B1a, —OC(═NR.sup.B1b)N(R.sup.B1b).sub.2, NR.sup.B1bC(═NR.sup.B1b)R.sup.B1b, —NR.sup.B1bC(═NR.sup.B1b)OR.sup.B1a, —NR.sup.B1bC(═NR.sup.B1b)SR.sup.B1a, NR.sup.B1bC(═NR.sup.B1b)N(R.sup.B1b).sub.2, —SC(═NR.sup.B1b)R.sup.B1a, —SC(═NR.sup.B1b)OR.sup.B1a, —SC(═NR.sup.B1b)SR.sup.B1aSC(═NR.sup.B1b)N(R.sup.B1b).sub.2, —C(═S)R.sup.B1a, —C(═S)OR.sup.B1a, —C(═S)SR.sup.B1a, —C(═S)N(R.sup.B1b).sub.2, —OC(═S)R.sup.B1a, —OC(═S)OR.sup.B1a, —OC(═S)SR.sup.B1a, —OC(═S)N(R.sup.B1b).sub.2, —NR.sup.B1bC(═S)R.sup.B1b, —NR.sup.B1bC(═S)OR.sup.B1a, —NR.sup.B1bC(═S)SR.sup.B1a, —NR.sup.B1bC(═S)N(R.sup.B1b).sub.2, —SC(═S)R.sup.B1a, —SC(═S)OR.sup.B1a, —SC(═S)SR.sup.B1a, —SC(═S)N(R.sup.B1b).sub.2, —S(═O)R.sup.B1a, —SO.sub.2R.sup.B1a, —NR.sup.B1bSO.sub.2R.sup.B1a, —SO.sub.2N(R.sup.B1b).sub.2, —CN, —SCN, and —NO.sub.2, wherein each occurrence of R.sup.B1a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R.sup.B1b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.B1b groups are joined to form an optionally substituted heterocyclic ring:

(66) each instance of R.sup.B2, R.sup.B3, R.sup.B4, and R.sup.B5 is independently hydrogen, halogen, or C.sub.1-6 alkyl;

(67) R.sup.B6 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.B6a, —N(R.sup.B4b).sub.2, or —SR.sup.B6a, wherein each occurrence of R.sup.B6a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R.sup.B6b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.B6b groups are joined to form an optionally substituted heterocyclic ring:

(68) p is 0, 1, 2, 3, or 4.

(69) In certain embodiments, X.sup.B1 is oxygen. In certain embodiments, X.sup.B1 is sulfur. In certain embodiments, X.sup.B1 is NR.sup.B4, wherein NR.sup.B4a is as defined herein. In certain embodiments, X.sup.B1 is NH. In certain embodiments, X.sup.B1 is C(R.sup.B4b).sub.2, wherein R.sup.B4b is defined herein.

(70) In certain embodiments, X.sup.B2 is nitrogen. In certain embodiments, X.sup.B2 is CR.sup.B2a, wherein R.sup.B2a is as defined herein.

(71) In certain embodiments, X.sup.B3 is oxygen. In certain embodiments, X.sup.B3 is sulfur. In certain embodiments, X.sup.B3 is NR.sup.B48, wherein NR.sup.B4a is as defined herein. In certain embodiments, X.sup.B3 is NH. In certain embodiments, X.sup.B3 is C(R.sup.B4b).sub.2, wherein R.sup.B4b is defined herein.

(72) In certain embodiments. X.sup.B4 is oxygen. In certain embodiments, X.sup.B4 is sulfur. In certain embodiments, X.sup.B4 is NR.sup.B4a, wherein NR.sup.B4a is as defined herein. In certain embodiments, X.sup.B4 is NH. In certain embodiments, X.sup.B4 is C(R.sup.B4b).sub.2, wherein R.sup.B4b is defined herein.

(73) In certain embodiments, X.sup.B1 is NH, and X.sup.B2 is nitrogen.

(74) In certain embodiments, one or more R.sup.B1 is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl. In certain embodiments, one or more R.sup.B1 is independently halogen. In certain embodiments, one or more R.sup.B1 is independently C.sub.1-6 alkyl.

(75) In certain embodiments, R.sup.B2 is hydrogen. In certain embodiments, R.sup.B2 is halogen. In certain embodiments, R.sup.B2 is fluorine. In certain embodiments, R.sup.B2 is chlorine. In certain embodiments, R.sup.B2 is bromine. In certain embodiments, R.sup.B2 is iodine. In certain embodiments, R.sup.B2 is C.sub.1-6 alkyl. In certain embodiments. R.sup.B2 is methyl. In certain embodiments, R.sup.B2 is ethyl. In certain embodiments, R.sup.B2 is propyl. In certain embodiments, R.sup.B2 is butyl.

(76) In certain embodiments, R.sup.B3 is hydrogen. In certain embodiments, R.sup.B3 is halogen. In certain embodiments, R.sup.B3 is fluorine. In certain embodiments, R.sup.B3 is chlorine. In certain embodiments, R.sup.B3 is bromine. In certain embodiments, R.sup.B3 is iodine. In certain embodiments, R.sup.B3 is C.sub.1-6 alkyl. In certain embodiments, R.sup.B3 is methyl. In certain embodiments, R.sup.B3 is ethyl. In certain embodiments, R.sup.B3 is propyl. In certain embodiments, R.sup.B3 is butyl.

(77) In certain embodiments, R.sup.B4 is hydrogen. In certain embodiments, R.sup.B4 is halogen. In certain embodiments, R.sup.B4 is fluorine. In certain embodiments, R.sup.B4 is chlorine. In certain embodiments, R.sup.B4 is bromine. In certain embodiments, R.sup.B4 is iodine. In certain embodiments, R.sup.B4 is C.sub.1-6 alkyl. In certain embodiments, R.sup.B4 is methyl. In certain embodiments, R.sup.B4 is ethyl. In certain embodiments, R.sup.B4 is propyl. In certain embodiments, R.sup.B4 is butyl.

(78) In certain embodiments, R.sup.B5 is hydrogen. In certain embodiments, R.sup.B5 is halogen. In certain embodiments, R.sup.B5 is fluorine. In certain embodiments, R.sup.B5 is chlorine. In certain embodiments, R.sup.Bs is bromine. In certain embodiments, R.sup.B5 is iodine. In certain embodiments, R.sup.B5 is C.sub.1-6 alkyl. In certain embodiments, R.sup.B5 is methyl. In certain embodiments, R.sup.B5 is ethyl. In certain embodiments, R.sup.B5 is propyl. In certain embodiments, R.sup.B5 is butyl.

(79) In certain embodiments, R.sup.B6 is hydrogen. In certain embodiments. R.sup.B6 is optionally substituted alkyl. In certain embodiments, R.sup.B6 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.B6 is methyl. In certain embodiments, R.sup.B6 is ethyl. In certain embodiments, R.sup.B6 is propyl. In certain embodiments, R.sup.B6 is butyl. In certain embodiments, R.sup.B6 is pentyl. In certain embodiments, R.sup.B6 is hexyl.

(80) In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4.

(81) In certain embodiments of Formula (B), wherein p is 1, provided is a compound of any one of the formulae:

(82) ##STR00020##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein X.sup.B1, X.sup.B2, X.sup.B3. X.sup.B4, R.sup.B1, R.sup.B2, R.sup.B3, R.sup.B4, R.sup.B5, and R.sup.B6 are as defined herein.

(83) In certain embodiments, provided is a compound of Formula (B-II):

(84) ##STR00021##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein X.sup.B3, X.sup.B4, R.sup.B2, R.sup.B3, R.sup.B4, R.sup.B5, and R.sup.B6 are as defined herein.

(85) In certain embodiments, provided is a compound of Formula (B-III):

(86) ##STR00022##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein X.sup.B4, R.sup.B2, R.sup.B3, R.sup.B4, R.sup.B5, and R.sup.B6 are as defined herein.

(87) In certain embodiments, provided is a compound of Formula (B-IV):

(88) ##STR00023##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein X.sup.B3, R.sup.B2, R.sup.B3, R.sup.B4, R.sup.B5, and R.sup.B6 are as defined herein.

(89) In certain embodiments, provided is a compound of Formula (B-V):

(90) ##STR00024##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.B2, R.sup.B3, R.sup.B4, R.sup.B5, and R.sup.B6 are as defined herein.

(91) In certain embodiments, provided is a compound of Formula (B-VI):

(92) ##STR00025##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.B4, R.sup.B5, and R.sup.B6 are as defined herein.

(93) In certain embodiments, provided is a compound of Formula (B-VII):

(94) ##STR00026##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.B6 is as defined herein.

(95) In certain embodiments, provided is a compound of Formula (B-VIII):

(96) ##STR00027##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein X.sup.B3, X.sup.B4, R.sup.B2, R.sup.B3, R.sup.B4, and R.sup.B5 are as defined herein.

(97) In certain embodiments, provided is a compound of Formula (B-IX):

(98) ##STR00028##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein X.sup.B1, X.sup.B2, X.sup.B3, R.sup.B1, R.sup.B4, and R.sup.B5 are as defined herein.

(99) In a certain embodiment, the compound of Formula (B) is not of the formula:

(100) ##STR00029##
or a pharmaceutically acceptable salt thereof.

(101) Another hit from the library was identified with a structural framework as shown in Formula (C):

(102) ##STR00030##
Therefore, in certain embodiments, provided is a compound of Formula (C), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein

(103) X.sup.C1 is oxygen, sulfur, or NR.sup.C1a, wherein R.sup.C1a is hydrogen, a nitrogen protecting group, or C.sub.1-6 alkyl;

(104) each instance of X.sup.C2, X.sup.C3, and X.sup.C4 is independently nitrogen or CR.sup.C4a, wherein R.sup.C4a is hydrogen, halogen, or C.sub.1-6 alkyl;

(105) L is a bond; cyclic or acyclic, substituted or unsubstituted alkylene; cyclic or acyclic, substituted or unsubstituted alkenylene; cyclic or acyclic, substituted or unsubstituted alkynylene; cyclic or acyclic, substituted or unsubstituted heteroalkylene; cyclic or acyclic, substituted or unsubstituted heteroalkenylene; cyclic or acyclic, substituted or unsubstituted heteroalkynylene; substituted or unsubstituted arylene; or substituted or unsubstituted heteroarylenelene;

(106) each instance of R.sup.C1 and R.sup.C2 is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.C2a, —N(R.sup.C2b).sub.2, —SR.sup.C2a, —C(═O)R.sup.C2a, —C(═O)OR.sup.C2a, —C(═O)SR.sup.C2a, —C(═O)N(R.sup.C2b).sub.2, —OC(═O)R.sup.C2a, —OC(═O)OR.sup.C2a, —OC(═O)SR.sup.C2a, —OC(═O)N(R.sup.C2b).sub.2, —NR.sup.C2bC(═O)R.sup.C2b, —NR.sup.C2bC(═O)OR.sup.C2a, —NR.sup.C2bC(═O)SR.sup.C2a, NR.sup.C2bC(O)N(R.sup.C2b).sub.2, —SC(═O)R.sup.C2a, —SC(═O)OR.sup.C2a, —SC(═O)SR.sup.C2a, —SC(═O)N(R.sup.C2b).sub.2, —C(═NR.sup.C2b)R.sup.C2a, —C(═NR.sup.C2b)OR.sup.C2a, —C(═NR.sup.C2b)SR.sup.C2a, —C(═NR.sup.C2b)N(R.sup.C2b).sub.2, —OC(═NR.sup.C2b)R.sup.C2a, —OC(═NR.sup.C2b)OR.sup.C2a, —OC(═NR.sup.C2b)SR.sup.C2a, —OC(═NR.sup.C2b)N(R.sup.C2b).sub.2, —NR.sup.C2bC(═NR.sup.C2b)R.sup.C2b, —NR.sup.C2bC(═NR.sup.C2b)OR.sup.C2a, —NR.sup.C2bC(═NR.sup.C2b)SR.sup.C2a, —NR.sup.C2bC(═NR.sup.C2b)N(R.sup.C2b).sub.2, —SC(═NR.sup.C2b)R.sup.C2b, —SC(═NR.sup.C2b)OR.sup.C2a, —SC(═NR.sup.C2b)SR.sup.C2a, —SC(═NR.sup.C2b)N(R.sup.C2b).sub.2, —C(═S)R.sup.C2a, —C(═S)OR.sup.C2a, —C(═S)SR.sup.C2a, —C(═S)N(R.sup.C2b).sub.2, OC(═S)R.sup.C2a, —OC(═S)OR.sup.C2a, —OC(═S)SR.sup.C2a, —OC(═S)N(R.sup.C2b).sub.2, —NR.sup.C2bC(═S)R.sup.C2b, —NR.sup.C2bC(═S)OR.sup.C2a, —NR.sup.C2bC(═S)SR.sup.C2a, —NR.sup.C2bC(═S)N(R.sup.C2b).sub.2, —SC(═S)R.sup.C2a, —SC(═S)OR.sup.C2a, —SC(═S)SR.sup.C2a, —SC(═S)N(R.sup.C2b).sub.2, —S(═O)R.sup.C2a, —SO.sub.2R.sup.C2a, —NR.sup.C2bSO.sub.2R.sup.C2a, —SO.sub.2N(R.sup.C2b).sub.2, —CN, —SCN, and —NO.sub.2, wherein each occurrence of R.sup.C2a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R.sup.C2b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.C2b groups are joined to form an optionally substituted heterocyclic ring;

(107) q is 0, 1, 2, 3, or 4:

(108) r is 0, 1, 2, 3, 4, or 5, and

(109) In certain embodiments. X.sup.C1 is NR.sup.C1a, wherein R.sup.C1a is hydrogen, a nitrogen protecting group, or C.sub.1-6 alkyl. In certain embodiments, X.sup.C1 is NH. In certain embodiments, X.sup.C1 is oxygen. In certain embodiments, X.sup.C1 is sulfur.

(110) In certain embodiments, X.sup.C2 is nitrogen. In certain embodiments, X.sup.C2 is CR.sup.C4a. In certain embodiments, X.sup.C3 is nitrogen. In certain embodiments, X.sup.C3 is CR.sup.C4a. In certain embodiments, X.sup.C4 is nitrogen. In certain embodiments, X.sup.C4 is CR.sup.C4a. In any of the above described embodiments, each instance of R.sup.C4a is independently nitrogen or CR.sup.C4a, wherein R.sup.C4a is hydrogen, halogen, or C.sub.1-6 alkyl.

(111) In certain embodiments, L is a bond. In certain embodiments, L is cyclic or acyclic, substituted or unsubstituted alkylene. In certain embodiments, L is cyclic or acyclic, substituted or unsubstituted alkenylene. In certain embodiments, L is cyclic or acyclic, substituted or unsubstituted alkynylene. In certain embodiments, L is cyclic or acyclic, substituted or unsubstituted heteroalkylene. In certain embodiments, L is cyclic or acyclic, substituted or unsubstituted heteroalkenylene. In certain embodiments, L is cyclic or acyclic, substituted or unsubstituted heteroalkynylene. In certain embodiments, L is substituted or unsubstituted arylene. In certain embodiments, L is substituted or unsubstituted heteroarylene.

(112) In certain embodiments, wherein L is substituted or unsubstituted heteroalkenylene, L comprises at least 5 atoms which are not hydrogen. In certain embodiments, wherein L is substituted or unsubstituted heteroalkenylene, L comprises at least 4 atoms which are not hydrogen. In certain embodiments, wherein L is substituted or unsubstituted heteroalkenylene, L comprises at least 3 atoms which are not hydrogen. In certain embodiments, wherein L is substituted or unsubstituted heteroalkenylene, L comprises at least 2 atoms which are not hydrogen.

(113) In certain embodiments, each instance of R.sup.C1 is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. In certain embodiments, at least one R.sup.C1 is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.C1 is methyl. In certain embodiments, at least one R.sup.C1 is ethyl. In certain embodiments, at least one R.sup.C1 is propyl. In certain embodiments, at least one R.sup.C1 is butyl.

(114) In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4.

(115) In certain embodiments, r is 0. In certain embodiments, r is 1. In certain embodiments, r is 2. In certain embodiments, r is 3. In certain embodiments, r is 4. In certain embodiments, r is 5.

(116) In certain embodiments, X.sup.C1, X.sup.C2, X.sup.C3, and X.sup.C4 are nitrogen.

(117) In certain embodiments, provided is a compound of Formula (C-I):

(118) ##STR00031##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein

(119) X.sup.C1, X.sup.C2, X.sup.C3, X.sup.C4, R.sup.C1, R.sup.C2, q, and r are as defined herein;

(120) X.sup.C5 is oxygen, sulfur, NR.sup.C5a, or C(R.sup.C5b).sub.2, wherein R.sup.C5a is hydrogen or C.sub.1-6 alkyl, and each occurrence of R.sup.C5b is hydrogen, halogen, or C.sub.1-6 alkyl, or two R.sup.C5b groups are joined to form an optionally substituted carbocyclic or heterocyclic ring; and

(121) each instance of X.sup.C6 and X.sup.C7 is independently nitrogen or CR.sup.C7a, wherein R.sup.C7a is hydrogen, halogen, or C.sub.1-6 alkyl.

(122) In certain embodiments of Formula (C-I), or a pharmaceutically acceptable salt thereof. X.sup.C5 is NH. In certain embodiments of Formula (C-I), or a pharmaceutically acceptable salt thereof, X.sup.C5 is NR.sup.C5a, wherein R.sup.C5a is as defined herein.

(123) In certain embodiments of Formula (C-I), or a pharmaceutically acceptable salt thereof, X.sup.C6 is nitrogen.

(124) In certain embodiments of Formula (C-I), or a pharmaceutically acceptable salt thereof, X.sup.C7 is CH. In certain embodiments of Formula (C-I), or a pharmaceutically acceptable salt thereof, X.sup.C7 is C(R.sup.C5b).sub.2, wherein R.sup.C5b is as defined herein.

(125) In certain embodiments of Formula (C-I), provided is a compound of Formula (C-II):

(126) ##STR00032##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein X.sup.C1, X.sup.C2, X.sup.C3, X.sup.C4, R.sup.C1, R.sup.C2, q, and r are as defined herein.

(127) In certain embodiments, provided is a compound of Formula (C-III):

(128) ##STR00033##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.C1, R.sup.C2, q, and r are as defined herein.

(129) In certain embodiments of Formula (C-III), wherein q is 1, provided is a compound of any of the formulae:

(130) ##STR00034##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.C1, R.sup.C2, and r are as defined herein.

(131) In certain embodiments of the formulae (C-III-a), (C-III-b), (C-III-c), and (C-III-d), or a pharmaceutically acceptable salt thereof, wherein R.sup.C2 and r are as defined herein, R.sup.C1 is C.sub.1-6 alkyl. In certain embodiments of the formulae (C-III-a), (C-III-b), (C-III-c), and (C-III-d), or a pharmaceutically acceptable salt thereof, wherein R.sup.C2 and r are as defined herein, R.sup.C1 is methyl. In certain embodiments of the formulae (C-III-a), (C-III-b), (C-III-c), and (C-III-d), or a pharmaceutically acceptable salt thereof, wherein R.sup.C2 and r are as defined herein, R.sup.C1 is ethyl. In certain embodiments of the formulae (C-III-a), (C-III-b), (C-III-c), and (C-III-d), or a pharmaceutically acceptable salt thereof, wherein R.sup.C2 and r are as defined herein, R.sup.C1 propyl. In certain embodiments of the formulae (C-II-a), (C-II-b), (C-II-c), and (C-III-d), or a pharmaceutically acceptable salt thereof, wherein R.sup.C2 and r are as defined herein, R.sup.C1 is butyl.

(132) In certain embodiments, provided is a compound of Formula (C-IV):

(133) ##STR00035##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.C2 and r are as defined herein.

(134) In certain embodiments, provided is a compound of Formula (C-V):

(135) ##STR00036##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein

(136) each instance of R.sup.C3 and R.sup.C4 is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.C4a, —N(R.sup.C4b).sub.2, —SR.sup.C4a, —C(═O)R.sup.C4a, —C(═O)OR.sup.C4a, —C(═O)SR.sup.C4a, —C(═O)N(R.sup.C4b).sub.2, —OC(═O)R.sup.C4a, —OC(═O)OR.sup.C4a, —OC(═O)SR.sup.C4a, —OC(═O)N(R.sup.C4b).sub.2, —NR.sup.C4bC(═O)R.sup.C4a, —NR.sup.C4bC(═O)OR.sup.C4a, —NR.sup.C4a, —OC(═O)SR.sup.C4a, —NR.sup.C4bC(═O)N(R.sup.C4b).sub.2, —SC(═O)R.sup.C4a, —SC(═O)OR.sup.C4a, —SC(═O)SR.sup.C4a, —SC(═O)N(R.sup.C4b).sub.2, —C(═NR.sup.C4b)R.sup.C4a, —C(═NR.sup.C4b)OR.sup.C4a, —C(═NR.sup.C4b)SR.sup.C4a, —C(═NR.sup.C4b)N(R.sup.C4b).sub.2, —OC(═NR.sup.C4b)R.sup.C4a, —OC(═NR.sup.C4b)OR.sup.C4a, —OC(═NR.sup.C4a)SR.sup.C4a, —OC(═NR.sup.C4b)N(R.sup.C4b).sub.2, —NR.sup.C4bC(═NR.sup.C4b)R.sup.C4b, —NR.sup.C4bC(═NR.sup.C4b)OR.sup.C4a, —NR.sup.C4bC(═NR.sup.C4b)SR.sup.C4a, —NR.sup.C4bC(═NR.sup.C4b)N(R.sup.C4b).sub.2, —SC(═NR.sup.C4b)R.sup.C4a, —SC(═NR.sup.C4b)OR.sup.C4a, —SC(═NR.sup.C4a)SR.sup.C4a, —SC(═NR.sup.C4b)N(R.sup.C4b).sub.2, —C(═S)R.sup.C4a, —C(═S)OR.sup.C4a, —C(═S)SR.sup.C4a, —C(═S)N(R.sup.C4b).sub.2, —OC(═S)R.sup.C4a, —OC(═S)OR.sup.C4a, —OC(═S)SR.sup.C4a, —OC(═S)N(R.sup.C4b).sub.2, —NR.sup.C4bC(═S)R.sup.C4b, —NR.sup.C4bC(═S)OR.sup.C4a, —NR.sup.C4bC(═S)SR.sup.C4a, —NR.sup.C4bC(═S)N(R.sup.C4b).sub.2, —SC(═S)R.sup.C4a, —SC(═S)OR.sup.C4a, —SC(═S)SR.sup.C4a, —SC(═S)N(R.sup.C4b).sub.2, —S(═O)R.sup.C4a, —SO.sub.2R.sup.C4b, —NR.sup.C4bSO.sub.2R.sup.C4a, —SO.sub.2N(R.sup.C4b).sub.2, —CN, —SCN, and —NO.sub.2, wherein each occurrence of R.sup.C4a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R.sup.C4b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.C4b groups are joined to form an optionally substituted heterocyclic ring; and

(137) v is 0, 1, 2, or 3.

(138) In certain embodiments, v is 0. In certain embodiments, v is 1. In certain embodiments, v is 2. In certain embodiments, v is 3.

(139) In certain embodiments of Formula (C-V), wherein v is 1, provided is a compound of any of the formulae:

(140) ##STR00037##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.C1, R.sup.C2, R.sup.C3, R.sup.C4, and q are as defined herein.

(141) In certain embodiments of the formulae (C-V-a), (C-V-b), and (C-V-c), or a pharmaceutically acceptable salt thereof, R.sup.C2, R.sup.C3, or R.sup.C4 is hydroxyl, —OR.sup.C2a, —N(R.sup.C2b).sub.2, or —SR.sup.C2a, wherein R.sup.C1, q, R.sup.C2a, and R.sup.C2b are as defined herein. In certain embodiments of the formulae (C-V-a), (C-V-b), and (C-V-c), or a pharmaceutically acceptable salt thereof, R.sup.C2 and R.sup.C3 are independently hydroxyl, —OR.sup.C2a, —N(R.sup.C2b).sub.2, or —SR.sup.C2a, wherein R.sup.C1, R.sup.C4, q, R.sup.C2a, and R.sup.C2b are as defined herein. In certain embodiments of the formulae (C-V-a), (C-V-b), and (C-V-c), or a pharmaceutically acceptable salt thereof, R.sup.C2 and R.sup.C4 are independently hydroxyl, —OR.sup.C2a, —N(R.sup.C2b).sub.2, or —SR.sup.C2a, wherein R.sup.C1, R.sup.C3, q, R.sup.C1, and R.sup.C2b are as defined herein. In certain embodiments of the formulae (C-V-a), (C-V-b), and (C-V-c), or a pharmaceutically acceptable salt thereof, R.sup.C3 and R.sup.C4 are independently hydroxyl, —OR.sup.C2a, —N(R.sup.C2b).sub.2, or —SR.sup.C2a, wherein R.sup.C1, R.sup.C2, q, R.sup.C2a, and R.sup.C2b are as defined herein. In certain embodiments of the formulae (C-V-a), (C-V-b), and (C-V-c), or a pharmaceutically acceptable salt thereof. R.sup.C2, R.sup.C3, and R.sup.C4 are independently hydroxyl, —OR.sup.C2a, —N(R.sup.C2b).sub.2, or —SR.sup.C2a, wherein R.sup.C1, q, R.sup.C2a, and R.sup.C2b are as defined herein.

(142) In certain embodiments of Formula (C-V), provided is a compound of Formula (C-VI):

(143) ##STR00038##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.C1, R.sup.C3, R.sup.C4, and q are as defined herein.

(144) In certain embodiments of Formula (C-VI), or a pharmaceutically acceptable salt thereof, R.sup.C3 is hydroxyl, —OR.sup.C4a, —N(R.sup.C4b).sub.2, or —SR.sup.C4a, wherein R.sup.C1, R.sup.C4, q, R.sup.C4a, and R.sup.C4b are as defined herein. In certain embodiments of Formula (C-VI), or a pharmaceutically acceptable salt thereof. R.sup.C4 is hydroxyl, —OR.sup.C4a, —N(R.sup.C4b).sub.2, or —SR.sup.C4a, wherein R.sup.C1, R.sup.C3, q, R.sup.C4a, and R.sup.C4b are as defined herein. In certain embodiments of Formula (C-VI), or a pharmaceutically acceptable salt thereof, R.sup.C3 and R.sup.C4 are independently hydroxyl, —OR.sup.C4a, —N(R.sup.C4b).sub.2, or —SR.sup.C4a, wherein R.sup.C1, q, R.sup.C4a, and R.sup.C4b are as defined herein. In certain embodiments of Formula (C-VI), R.sup.C3 and R.sup.C4 are both hydroxyl, —OR.sup.C4a, —N(R.sup.C4b).sub.2, or —SR.sup.C4a, wherein R.sup.C1, q, R.sup.C4a, and R.sup.C4b are as defined herein.

(145) In certain embodiments of Formula (C-V), provided is a compound of Formula (C-VII):

(146) ##STR00039##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.C1, R.sup.C2, q, and v are as defined herein.

(147) In certain embodiments of Formula (C-V), provided is a compound of Formula (C-VIII):

(148) ##STR00040##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.C1 and q are as defined herein.

(149) In certain embodiments of Formula (C-VIII), or a pharmaceutically acceptable salt thereof, each instance of R.sup.C1 is C.sub.1-6 alkyl. In certain embodiments of Formula (C-VIII), or a pharmaceutically acceptable salt thereof, each instance of R.sup.C1 is methyl. In certain embodiments of Formula (C-VIII), or a pharmaceutically acceptable salt thereof, each instance of R.sup.C1 is ethyl. In certain embodiments of Formula (C-VIII), or a pharmaceutically acceptable salt thereof, each instance of R.sup.C1 is propyl. In certain embodiments of Formula (C-VIII), or a pharmaceutically acceptable salt thereof, each instance of R.sup.C1 is butyl.

(150) In certain embodiments of Formula (C-VIII), wherein q is 1, provided is a compound of any of the formulae:

(151) ##STR00041##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.C1 is as defined herein.

(152) In certain embodiments, the compound of Formula (C) is not of the formula:

(153) ##STR00042##
or a pharmaceutically acceptable salt thereof.

(154) Another hit from the library was identified with a structural framework as shown in Formula (D):

(155) ##STR00043##

(156) Therefore, in certain embodiments, provided is a compound of Formula (D), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein

(157) each instance of X.sup.D1 is independently oxygen, sulfur. NR.sup.D1a, or C(R.sup.D1b).sub.2, wherein R.sup.D1a is hydrogen or C.sub.1-6 alkyl, and each occurrence of R.sup.D1b is hydrogen, halogen, or C.sub.1-6 alkyl, or two R.sup.D1b groups are joined to form an optionally substituted carbocyclic or heterocyclic ring;

(158) s is 0, 1, 2, 3, 4, 5, or 6:

(159) each instance of R.sup.D1 and R.sup.D2 is independently hydrogen, an oxygen protecting group, C.sub.1-6 alkyl, —C(═O)R.sup.D2a, —C(═O)OR.sup.D2a, —C(═O)SR.sup.D2a, —C(═O)N(R.sup.D2b).sub.2, —S(═O)R.sup.D2a, or —S(═O).sub.2R.sup.D2a, wherein each occurrence of R.sup.D2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R.sup.D2b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.D2b groups are joined to form an optionally substituted heterocyclic ring;

(160) each instance of R.sup.D3 and R.sup.D1 is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.D4a, —N(R.sup.D4b).sub.2, —SR.sup.D4a, —C(═O)R.sup.D4a, —C(═O)OR.sup.D4a, —C(═O)SR.sup.D4a, —C(═O)N(R.sup.D4b).sub.2, —OC(═O)R.sup.D4a, —OC(═O)OR.sup.D4a, —OC(═O)SR.sup.D4a, —OC(═O)N(R.sup.D4b).sub.2, —NR.sup.D4bC(═O)R.sup.D4b, —NR.sup.D4bC(═O)OR.sup.D4a, —NR.sup.D4bC(═O)SR.sup.D4a, —NR.sup.C4b(═O)N(R.sup.D4b).sub.2, —SC(═O)R.sup.D4a, —SC(═O)OR.sup.D4a, —SC(═O)SR.sup.D4a, —SC(═O)N(R.sup.D4b).sub.2, —C(═NR.sup.D4b)R.sup.D4a, —C(═NR.sup.D4b)OR.sup.D4a, —C(═NR.sup.D4b)SR.sup.D4a, —C(═NR.sup.D4b)N(R.sup.D4b).sub.2, —OC(═NR.sup.D4b)R.sup.D4a, —OC(═NR.sup.D4b)OR.sup.D4a, —OC(═NR.sup.D4b)SR.sup.D4a, —OC(═NR.sup.D4b)N(R.sup.D4b).sub.2, —NR.sup.D4bC(═NR.sup.D4b)R.sup.D4b, —NR.sup.D4bC(═NR.sup.D4b)OR.sup.D4a, —NR.sup.D4bC(═NR.sup.D4b)SR.sup.D4a, NR.sup.D4bC(═NR.sup.D4b)N(R.sup.D4b).sub.2, —SC(═NR.sup.D4b)R.sup.D4a, —SC(═NR.sup.D4b)OR.sup.D4a, —SC(═NR.sup.D4b)SR.sup.D4a, —SC(═NR.sup.D4b)N(R.sup.D4b).sub.2, —C(═S)R.sup.D4a, —C(═S)OR.sup.D4a, —C(═S)SR.sup.D4a, —C(═S)N(R.sup.D4b).sub.2, —OC(═S)R.sup.D4a, —OC(═S)OR.sup.D4a, —OC(═S)SR.sup.D4a, —OC(═S)N(R.sup.D4b).sub.2, —NR.sup.D4bC(═S)R.sup.D4b, —NR.sup.D4bC(═S)OR.sup.D4a, —NR.sup.D4bC(═S)SR.sup.D4a, —NR.sup.D4bC(═S)N(R.sup.D4b).sub.2, —SC(═S)R.sup.D4a, —SC(═S)OR.sup.D4a, —SC(═S)SR.sup.D4a, —SC(═S)N(R.sup.D4b).sub.2, —S(═O)R.sup.D4a, —SO.sub.2R.sup.D4a, —NR.sup.D4bSO.sub.2R.sup.D4a, —SO.sub.2N(R.sup.D4b).sub.2, —CN, —SCN, and —NO.sub.2, wherein each occurrence of R.sup.D4a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R.sup.D4b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.D4b groups are joined to form an optionally substituted heterocyclic ring;

(161) t is 0, 1, 2, or 3; and

(162) u is 0, 1, 2, 3, 4 or 5.

(163) In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6.

(164) In certain embodiments of Formula (D), wherein s is 2, provided is a compound of Formula (D-I):

(165) ##STR00044##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.D1, R.sup.D2, R.sup.D3, R.sup.D4, R.sup.D1a, t, and u are as defined herein.

(166) In certain embodiments of Formula (D-I), provided is a compound of Formula (D-II):

(167) ##STR00045##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.D1, R.sup.D2, R.sup.D3, R.sup.D4, t, and u are as defined herein.

(168) In certain embodiments of Formula (D-II), or a pharmaceutically acceptable salt thereof. R.sup.D1, R.sup.D2, or both is C.sub.1-6 alkyl. In certain embodiments of Formula (D-II), or a pharmaceutically acceptable salt thereof. R.sup.D1, R.sup.D2, or both is methyl. In certain embodiments of Formula (D-II), or a pharmaceutically acceptable salt thereof, R.sup.D1, R.sup.D2, or both is ethyl. In certain embodiments of Formula (D-II), or a pharmaceutically acceptable salt thereof, R.sup.D1, R.sup.D2, or both is propyl. In certain embodiments of Formula (D-II), or a pharmaceutically acceptable salt thereof. R.sup.D1, R.sup.D2, or both is butyl.

(169) In certain embodiments of Formula (D-II), wherein t is 1, provided is a compound of any of the formulae:

(170) ##STR00046##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.D1, R.sup.D2, R.sup.D3, R.sup.D4, and u are as defined herein.

(171) In certain embodiments of Formula (D-II), provided is a compound of Formula (D-III):

(172) ##STR00047##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.D3, R.sup.D4, t, and u are as defined herein.

(173) In certain embodiments of Formula (D-III), wherein t is 1, provided is a compound of any of the formulae:

(174) ##STR00048##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.D3, R.sup.D4, and u are as defined herein.

(175) In certain embodiments of Formula (D), provided is a compound of Formula (D-III):

(176) ##STR00049##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein

(177) R.sup.D1, R.sup.D2, R.sup.D3, R.sup.D4, and t are as defined herein:

(178) each instance of R.sup.D5 and R.sup.D6 is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.D6a, —N(R.sup.D6b).sub.2, —SR.sup.D6a, —C(═O)R.sup.D6a, —C(═O)OR.sup.D6a, —C(═O)SR.sup.D6a, —C(═O)N(R.sup.D6b).sub.2, —OC(═O)R.sup.D6a, —OC(═O)OR.sup.D6a, —OC(═O)SR.sup.D6a, —OC(═O)N(R.sup.D6b).sub.2, —NR.sup.D6bC(═O)R.sup.D6b, —NR.sup.D6bC(═O)OR.sup.D6a, —NR.sup.D6bC(═O)SR.sup.D6a, —NR.sup.D6bC(═O)N(R.sup.D6b).sub.2, —SC(═O)R.sup.D6a, —SC(═O)OR.sup.D6a, —SC(═O)SR.sup.D6a, —SC(═O)N(R.sup.D6b).sub.2, —C(═NR.sup.D6b)R.sup.D6a, —C(═NR.sup.D6b)OR.sup.D6a, C(═NR.sup.D6b)SR.sup.D6a, —C(═NR.sup.D6b)N(R.sup.D6b).sub.2, —OC(═NR.sup.D6b)R.sup.D6a, —OC(═NR.sup.D6b)OR.sup.D6a, —OC(═NR.sup.D6b)SR.sup.D6a, —OC(═NR.sup.D6b)N(R.sup.D6b).sub.2, —NR.sup.D6bC(═NR.sup.D6b)R.sup.D6b, —NR.sup.D6bC(═NR.sup.D6b)OR.sup.D6a, —NR.sup.D6bC(═NR.sup.D6b)SR.sup.D6a, —NR.sup.D6bC(═NR.sup.D6b)N(R.sup.D6b).sub.2, —SC(═NR.sup.D6b)R.sup.D6a, —SC(═NR.sup.D6b)OR.sup.D6a, —SC(═NR.sup.D6b)SR.sup.D6a, —SC(═NR.sup.D6b)N(R.sup.D6b).sub.2, —C(═S)R.sup.D6a, —C(═S)OR.sup.D6a, —C(═S)SR.sup.D6a, —C(═S)N(R.sup.D6b).sub.2, —OC(═S)R.sup.D6a, —OC(═S)OR.sup.D6a, —OC(═S)SR.sup.D6a, —OC(═S)N(R.sup.D6b).sub.2, —NR.sup.D6aC(═S)R.sup.D6a, —NR.sup.D6bC(═S)OR.sup.D6a, —NR.sup.D6bC(═S)SR.sup.D6a, —NR.sup.D6bC(═S)N(R.sup.D6b).sub.2, —SC(═S)R.sup.D6a, —SC(═S)OR.sup.D6a, —SC(═S)SR.sup.D6a, —SC(═S)N(R.sup.D6b).sub.2, —S(═O)R.sup.D6a, —SO.sub.2R.sup.D6a, —NR.sup.D6bSO.sub.2R.sup.D6a, —SO.sub.2N(R.sup.D6b).sub.2, —CN, —SCN, and —NO.sub.2, wherein each occurrence of R.sup.D6a is independently hydrogen optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each occurrence of R.sup.D6b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.D6b groups are joined to form an optionally substituted heterocyclic ring; and

(179) w is 0, 1, 2, or 3.

(180) In certain embodiments of Formula (D-IV), wherein w is 1, provided is a compound of any of the formulae:

(181) ##STR00050##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.D1, R.sup.D2, R.sup.D3, R.sup.D4, R.sup.D5, R.sup.D6, and t are as defined herein.

(182) In certain embodiments of Formula (D-IV), or a pharmaceutically acceptable salt thereof, R.sup.D5, R.sup.D6, or both are C.sub.1-6 alkyl. In certain embodiments of Formula (D-IV), or a pharmaceutically acceptable salt thereof, R.sup.D5, R.sup.D6, or both are methyl. In certain embodiments of Formula (D-IV), or a pharmaceutically acceptable salt thereof, R.sup.D5, R.sup.D6, or both are ethyl. In certain embodiments of Formula (D-IV), or a pharmaceutically acceptable salt thereof, R.sup.D5, R.sup.D6, or both are propyl. In certain embodiments of Formula (D-IV), or a pharmaceutically acceptable salt thereof, R.sup.D5, R.sup.D6, or both are butyl.

(183) In certain embodiments, provided is a compound of Formula (D-V):

(184) ##STR00051##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.D1, R.sup.D2, R.sup.D3, R.sup.D4, t and w are as defined herein.

(185) In certain embodiments of Formula (D-V), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein w is 1, provided is a compound of any of the formulae:

(186) ##STR00052##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.D1, R.sup.D2, R.sup.D3, R.sup.D4, and t are as defined herein.

(187) In certain embodiments, provided is a compound of Formula (D-VI):

(188) ##STR00053##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein R.sup.D3, R.sup.D4, t, and w are as defined herein.

(189) In certain embodiments, the compound of Formula (D) is not of the formula:

(190) ##STR00054##
or a pharmaceutically acceptable salt thereof.
Pharmaceutical Compositions, Kits, and Administration

(191) The present invention provides pharmaceutical compositions comprising a compound of the present invention, e.g., a compound of any one of the Formulae (A), (B), (C), and (D), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, as described herein, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof 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.

(192) Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound of the present invention (the “active ingredient”) into association with a carrier 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.

(193) 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. As used herein, 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, for example, one-half or one-third of such a dosage.

(194) Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention 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. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.

(195) 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.

(196) 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.

(197) 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.

(198) 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 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

(199) 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.

(200) Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.

(201) 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.

(202) 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.

(203) 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.

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

(205) 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.

(206) 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. In certain embodiments, the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent.

(207) 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.

(208) 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.

(209) Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthom, 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.

(210) 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 of the invention are mixed with solubilizing agents such as Cremophor™, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

(211) 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 diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

(212) 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.

(213) 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 is accomplished by dissolving or suspending the drug in an oil vehicle.

(214) Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention 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.

(215) 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 comprise buffering agents.

(216) 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 pharmaceutical formulating art. 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 embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

(217) The active ingredient can be in 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 embedding compositions which can be used include polymeric substances and waxes.

(218) Dosage forms for topical and/or transdermal administration of a compound of this invention 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 and/or any needed preservatives and/or buffers as can be required. Additionally, the present invention 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.

(219) Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices such as those described in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin, such as those described in PCT publication WO 99/34850 and functional equivalents thereof. Jet injection devices which deliver liquid vaccines 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. Jet injection devices are described, for example, in U.S. Pat. Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballistic powder/particle delivery devices which use compressed gas to accelerate vaccine in powder form through the outer layers of the skin to the dermis are suitable. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration.

(220) 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.

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

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

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

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

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

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

(227) 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.

(228) 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 of the present invention will be decided by the attending 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, disorder, or condition 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.

(229) 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).

(230) 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(s), mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

(231) In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

(232) In certain embodiments, the compounds of the invention may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

(233) It will be appreciated that 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.

(234) It will be also appreciated that a compound or composition, as described herein, can be administered in combination with one or more additional therapeutically active agents. The compounds or compositions can be administered in combination with additional therapeutically active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body. 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.

(235) The compound or composition can 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. In 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.

(236) Exemplary additional therapeutically active agents include, but are not limited to, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and a pain-relieving agent. Therapeutically active agents include small organic molecules such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

(237) Also encompassed by the invention are kits (e.g., pharmaceutical packs). The kits provided may comprise an inventive pharmaceutical composition or compound 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 an inventive pharmaceutical composition or compound. In some embodiments, the inventive pharmaceutical composition or compound provided in the container and the second container are combined to form one unit dosage form.

(238) Thus, in one aspect, provided is a pharmaceutical composition comprising a compound of any one of the Formulae (A), (B), (C), and (D), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and a pharmaceutically acceptable excipient. In certain embodiments, provided is a composition described herein, wherein the compound or pharmaceutically acceptable salt thereof is provided in an effective amount.

(239) In another aspect, provided is a kit for treating or preventing a neurological disorder comprising:

(240) a first container comprising an HDAC (histone deacetylase) activator; and

(241) instructions for administering the HDAC activator to a subject to treat a neurological disorder. In certain embodiments, the HDAC activator is a class I HDAC activator. In certain embodiments, the class I HDAC activator is an HDAC1 (histone deacetylase 1) activator.

(242) In certain embodiments, provided is a kit for treating a neurological disorder comprising:

(243) a first container comprising the compound of Formula (DAC-001):

(244) ##STR00055##
and

(245) instructions for administering the compound of Formula (DAC-001) to a subject to treat a neurological disorder.

(246) In certain embodiments, provided is a kit for treating a neurological disorder comprising:

(247) a first container comprising the compound of Formula (DAC-002):

(248) ##STR00056##
and

(249) instructions for administering the compound of Formula (DAC-002) to a subject to treat a neurological disorder.

(250) In certain embodiments, provided is a kit for treating a neurological disorder comprising:

(251) a first container comprising the compound of Formula (DAC-009):

(252) ##STR00057##
or a pharmaceutically acceptable salt thereof; and

(253) instructions for administering the compound of Formula (DAC-009) to a subject to treat a neurological disorder.

(254) In certain embodiments, provided is a kit for treating a neurological disorder comprising:

(255) a first container comprising the compound of Formula (DAC-003):

(256) ##STR00058##
or a pharmaceutically acceptable salt thereof; and

(257) instructions for administering the compound of Formula (DAC-003) to a subject to treat a neurological disorder.

(258) In certain embodiments, provided is a kit for treating a neurological disorder comprising:

(259) a first container comprising the compound of Formula (DAC-012):

(260) ##STR00059##
or a pharmaceutically acceptable salt thereof; and

(261) instructions for administering the compound of Formula (DAC-012) to a subject to treat a neurological disorder.

(262) In certain embodiments, provided is a kit for treating a neurological disorder comprising:

(263) a first container comprising a compound selected from the group of compounds consisting of the compounds of the Formulae (A), (B), (C), and (D), or a pharmaceutically acceptable salt thereof; and

(264) instructions for administering the compound selected in the previous step to a subject to treat a neurological disorder.

(265) Methods of Treatment

(266) In one aspect, the invention provides methods and compositions for the treatment or prevention of neurological disorders. In some embodiments, neurological disorders are treated by decreasing the amount of DNA damage within the neuronal cell. In some embodiments, neurological disorders are treated by increasing HDAC activity within the neuronal cell. In some embodiments, neurological disorders are treated by decreasing histone acetyl transferase activity within the neuronal cell. In some embodiments, neurological disorders are treated by increasing the activity of class I histone deacetylases. In some embodiments, neurological disorders are treated by increasing the activity of class I HDAC. In some embodiments, neurological disorders are treated by increasing the activity of HDAC1. In some embodiments, neurological disorders are treated by increasing the activity of HDAC2. In some embodiments, neurological disorders are treated by increasing the activity of HDAC3. In some embodiments, neurological disorders are treated by increasing the activity of HDAC8.

(267) Regulating histone acetylation is an integral aspect of chromatin modulation and gene regulation that plays a critical role in many biological processes including cell proliferation and differentiation (Roth et al., Annu. Rev. Biochem. (2001) 70:81-120). Recent reports have detailed the importance of histone acetylation in CNS functions such as neuronal differentiation, memory formation, drug addiction and depression (Citrome, Psychopharmacol. Bull. (2003) 37 Suppl, 2:74-88: Johannessen et al., CNS Drug Rev. (2003) 9:199-216; Tsankova et al., Nature Neuroscience (2006) 9:519-525). Histone deacetylases remove acetyl groups from histones, resulting in increased chromatin compaction and decreased accessibility to DNA for interacting molecules such as transcription factors (Cema et al., Curr. Top. Dev. Biol. (2006) 73:173-204).

(268) Of the HDACs, HDAC1 was the first protein identified to have histone-directed deacetylase activity (Taunton et al., Science (1996) 272:408-411; Vidal et al., Mol. Cell Biol. (1991) 11:6317-6327). HDAC1 plays important roles in regulating the cell cycle and is required in the transcriptional repression of cell cycle genes such as p21/WAF, E2F-1, and cyclins A and E (Brehm et al., Nature (1998) 391:597-601: Iavarone et al., Mol. Cell Biol. (1999) 19:916-922; Lagger et al., Embo. J. (2002) 21:2672-2681; Rayman et al., Genes Dev. (2002) 16:933-947; Stadler et al., Dev. Dyn. (2005) 233:883-889; Stiegler et al., Cancer Res. (1998) 58:5049-5052). The association of HDAC1 with promotor regions of specific genes is linked to their transcriptional repression (Brehm et al., Nature (1998) 391:597-601: Gui et al., Proc. Natl. Acad. Sci. USA (2004) 101:1241-1246; Iavarone et al., Mol. Cell Biol. (1999) 19:916-922; Rayman et al., Genes Dev. (2002) 16:933-947).

(269) It has been found that agents that increase HDAC1 activity are neuroprotective (PCT Patent Application Publication No. WO 2010/011318). Those agents may serve for the treatment of neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), ischemic brain damage, traumatic brain injury, stroke, frontal temporal dementia, Pick's disease, corticobasal degeneration, supra cerebral palsy, prion diseases (e.g., Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia, and Kuru), Nieman Pick type C, spinal cerebellar ataxia, spinal muscular dystrophy, ataxia telangiectasia, hippocampal sclerosis, Cockayne syndrome, Werner syndrome, xeroderma pigmentosaum, and Bloom syndrome.

(270) Nucleosomes, the primary scaffold of chromatin folding, are dynamic macromolecular structures, influencing chromatin solution conformations. The nucleosome core is made up of histone proteins, H2A, H2B. H3, and H4. Histone acetylation causes nucleosomes and nucleosomal arrangements to behave with altered biophysical properties. The balance between activities of histone acetyl transferases (HAT) and histone deacetylases determines the level of histone acetylation. Acetylated histones cause relaxation of chromatin and activation of gene transcription, whereas deacetylated chromatin generally is transcriptionally inactive.

(271) In some embodiments, neurological disorders are treated by decreasing histone acetylation by the administration of histone acetylase activators. In some embodiments, neurological disorders are treated by decreasing histone acetylation by methods other than increasing HDAC activity. Methods for decreasing histone acetylation, by a method other than a classic HDAC activator include, but are not limited to, the administration of nucleic acid molecule inhibitors such as antisense and RNAi molecules which reduce the expression of histone acetyl transferases and the administration of histone acetyl transferase inhibitors. Histone acetyl transferase inhibitors are known in the art (Eliseeva et al., Mol. Cancer Ther. (2007) 6:2391-98). The invention embraces methods that regulate the function of any protein involved with histone modification, function and regulation.

(272) In some embodiments, neurological disorders are treated by protecting cells from DNA damage by increasing the histone deacetylation activity within the cell. Protection from DNA damage includes both a decrease in the current level of DNA damage accumulated within the cell, or a decrease in the rate of DNA damage acquired by the cell, including DNA damage acquired during exposure of the cell to DNA damaging events, such as exposure to DNA damaging agents, including radiation, and events that lead to increased oxidative stress. Increased deacetylase activity can protect against any form of DNA damage, including base modifications, DNA single strand breaks, and DNA double strand breaks. DNA double strand breaks are potentially the most damaging to the cell, and other forms of DNA damage can be turned into DNA double strand breaks by the action of DNA repair enzymes and other cellular processes. DNA damage, including DNA double strand breaks, can accumulate in both actively dividing and non-dividing cells. In actively dividing cells, DNA double strand breaks may inhibit the replication machinery, while in both actively dividing and non-dividing cells the transcription machinery may be inhibited by DNA double strand breaks. In addition, DNA double strand breaks may initiate potentially damaging recombination events. Thus, increased deacetylase activity may be protective in any cell type, including dividing and non-dividing cells. In some embodiments, increased deacetylase activity is protective in neuronal cells. In some embodiments, increased deacetylase activity is induced in cells that are susceptible to acquiring DNA damage, or cells that will be subjected to a DNA damage inducing event. For instance, histone deacetylase activity may be increased in cells or tissue in a subject that need to be protected when a DNA damaging agent is administered throughout the body (for instance, during chemotherapy). In some embodiments, neuroprotection is provided by increasing the histone deacetylation activity within a neuronal cell. In some embodiments, neuroprotection is provided by decreasing the histone acetyl transferase activity within a neuronal cell.

(273) The invention embraces any method of increasing deacetylase activity. In some embodiments, deacetylase activity is increased by increasing the activity of class I HDAC. In some embodiments, deacetylase activity is increased by increasing the activity of HDAC1. In some embodiments, deacetylase activity is increased by increasing the activity of HDAC2. In some embodiments, deacetylase activity is increased by increasing the activity of HDAC3. In some embodiments, deacetylase activity is increased by increasing the activity of HDAC8. In some embodiments, deacetylase activity is increased by adding an HDAC activator to the cell. In some embodiments, the HDAC activator is a class I HDAC activator. In some embodiments, the HDAC activator is an HDAC1 activator. In some embodiments, the HDAC activator is an HDAC2 activator. In some embodiments, the HDAC activator is an HDAC3 activator. In some embodiments, the HDAC activator is an HDAC8 activator. In some embodiments, HDAC activity is increased by increasing the expression level of one or more HDACs. In some embodiments, HDAC activity is increased by selectively increasing the expression level of one or more HDACs relative to one or more HDACs. In some embodiments. HDAC activity is increased by selectively increasing the expression level of one or more HDACs by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%/0, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100% relative to one or more HDACs. In some embodiments. HDAC activity is increased by selectively increasing the expression level of one or more HDACs by 100% to 200%, 200% to 300%, 300% to 500%, 500% to 1000%, 1000% to 10000%, or 10000% to 10000% relative to one or more other HDACs. In some embodiments, the expression level is increased by increasing the level and/or activity of transcription factors that act on a specific gene encoding a histone deacetylase. In some embodiments, the activity is increased by decreasing the activity of repressor elements. In some embodiments, deacetylase activity within a cell or subject is increased by administering histone deacetylase protein to the cell or subject. In some embodiments, the activity is increased by inactivating or sequestering an agent that acts as an inhibitor on a HDAC suppressor pathway.

(274) An “HDAC activator” as defined herein is any compound that results in an increase in the level of HDAC activity. Any increase in enzymatic function of an HDAC is embraced by the invention. In some embodiments, the activity increase of HDAC is an increase in HDAC deacetylase activity. In some embodiments, the activity increase of HDAC is an increase in HDAC esterase activity. HDAC activity corresponds to the level of histone deacetylase activity of the HDAC. One of ordinary skill in the art can select suitable compounds on the basis of the known structures of histone deacetylases. Examples of such compounds are peptides, nucleic acids expressing such peptides, small molecules, etc., each of which can be naturally occurring molecules, synthetic molecules, and/or FDA approved molecules, that specifically react with the histone deacetylase and increase its activity.

(275) In certain embodiments, the HDAC activator is a naturally occurring compound or a compound that has been synthesized, or a pharmaceutically acceptable salt thereof, such as a compound of the Formula (DAC-001), (DAC-002). (DAC-003), (DAC-009), or (DAC-012), or pharmaceutically acceptable salt thereof.

(276) In certain embodiments, the HDAC activator is a compound of Formula (A), (B), (C), or (D), or pharmaceutically acceptable salt thereof.

(277) In certain embodiments, provided is a method for treating or preventing a neurological disorder in a subject, the method comprising administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of the compound of Formula (DAC-001), or a pharmaceutically acceptable salt thereof.

(278) In certain embodiments, provided is a method for treating or preventing a neurological disorder in a subject, the method comprising administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of the compound of Formula (DAC-002), or a pharmaceutically acceptable salt thereof.

(279) In certain embodiments, provided is a method for treating or preventing a neurological disorder in a subject, the method comprising administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of the compound of Formula (DAC-009), or a pharmaceutically acceptable salt thereof.

(280) In certain embodiments, provided is a method for treating or preventing a neurological disorder in a subject, the method comprising administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of the compound of Formula (DAC-003), or a pharmaceutically acceptable salt thereof.

(281) In certain embodiments, provided is a method for treating or preventing a neurological disorder in a subject, the method comprising administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of the compound of Formula (DAC-012), or a pharmaceutically acceptable salt thereof.

(282) In certain embodiments, provided is a method for treating or preventing a neurological disorder in a subject, the method comprising administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof.

(283) In certain embodiments, provided is a method for treating or preventing a neurological disorder in a subject, the method comprising administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of a compound of Formula (B), or a pharmaceutically acceptable salt thereof.

(284) In certain embodiments, provided is a method for treating or preventing a neurological disorder in a subject, the method comprising administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of a compound of Formula (C), or a pharmaceutically acceptable salt thereof.

(285) In certain embodiments, provided is a method for treating or preventing a neurological disorder in a subject, the method comprising administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of a compound of Formula (D), or a pharmaceutically acceptable salt thereof.

(286) In certain embodiments, the neurological disorder being treated or prevented is Alzheimer's disease.

(287) In certain embodiments, the neurological disorder being treated or prevented is Parkinson's disease.

(288) In certain embodiments, the neurological disorder being treated or prevented is Huntington's disease.

(289) In certain embodiments, the neurological disorder being treated or prevented is ALS (amyotrophic lateral sclerosis).

(290) In certain embodiments, the neurological disorder being treated or prevented is traumatic brain injury.

(291) In certain embodiments, the neurological disorder being treated or prevented is ischemic brain injury.

(292) In certain embodiments, the neurological disorder being treated or prevented is stroke.

(293) In certain embodiments, the neurological disorder being treated or prevented is frontal temporal dementia.

(294) In certain embodiments, the neurological disorder being treated or prevented is Pick's disease.

(295) In certain embodiments, the neurological disorder being treated or prevented is corticobasal degeneration.

(296) In certain embodiments, the neurological disorder being treated or prevented is supra cerebral palsy.

(297) In certain embodiments, the neurological disorder being treated or prevented is prion diseases (e.g., Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia, and Kuru).

(298) In certain embodiments, the neurological disorder being treated or prevented is Nieman Pick type C.

(299) In certain embodiments, the neurological disorder being treated or prevented is spinal cerebellar ataxia.

(300) In certain embodiments, the neurological disorder being treated or prevented is spinal muscular dystrophy.

(301) In certain embodiments, the neurological disorder being treated or prevented is ataxia telangiectasia.

(302) In certain embodiments, the neurological disorder being treated or prevented is hippocampal sclerosis.

(303) In certain embodiments, the neurological disorder being treated or prevented is Cockayne syndrome.

(304) In certain embodiments, the neurological disorder being treated or prevented is Werner syndrome.

(305) In certain embodiments, the neurological disorder being treated or prevented is xeroderma pigmentosaum.

(306) In certain embodiments, the neurological disorder being treated or prevented is Bloom syndrome.

EXAMPLES

(307) In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

Example 1. Recombinant HDAC1 Expression. Purification, and Proteomic Analysis

(308) Recombinant, full-length human HDAC1 (GenBank Accession No. NM_004964) with a C-terminal FLAG tag was produced by BPS Biosciences (San Diego, Calif.) using large-scale insect cell protein expression and purification in order to support a large-scale high-throughput screen (HTS).

(309) To determine the quality of the protein preparation, and to confirm the existence of only HDAC1 as the only deacetylase in the preparation, NanoLC-MSIMS peptide sequencing technology was carried out by ProtTech, Inc (Norristown, Pa.). In brief, each protein gel band was destained, cleaned, and digested in-gel with sequencing grade modified trypsin obtained from Promega (Madison, Wis.). All other chemicals used in proteolytic digestion and HPLC were obtained from Sigma (St. Louis, Mo.). The resulting peptide mixture was analyzed using a LC-MS/MS system Thermo (Palo Alto, Calif.), in which a high pressure liquid chromatography (HPLC) with a 75 micrometer inner diameter reverse phase C.sub.1-8 column was on-line coupled with a Quadrupole ion trap mass spectrometer. The mass spectrometric data acquired were used to search the most recent non-redundant protein database (downloaded from NCBI) with ProtTech's proprietary software suite.

(310) For the two principle bands in the preparation isolated after SDS-PAGE, the first was identified as histone deacetylase 1 (HDAC1) with multiple peptides with a minor fraction of peptides from chaperonin TCP-1β4 that contains t-complex polypeptide 1 (TCP-1) beta subunit 4 (β4) from the Sf9 cells. The second predominant band was identified as heat shock cognate protein 70 (HSC70) from the Sf9 cells with a minor fraction of HDAC1. Interestingly, HSC70 has been reported to have ATPase function, which is common to many chromatin-remodeling complexes, and HSC70 has been shown to interact with Tau protein, a protein implicated in the pathology of Alzheimer's disease and other neurodegenerative disorders. An “ATPase” is an enzyme that uses ATP, i.e., adenosine triphosphate, as an energy source. In the case of TCP-β4, these findings are of potential interest because, for HDAC3, a similar class I HDAC, the assembly of the SMRT-HDAC3 co-repressor complex requires the TCP-1 ring complex (Guenther et al., Genes Dev. (2002) 16:3130-35). It is thus possible that the regulation of HDAC1 conformation by TCP-1 ring complex is important for its deacetylase activity, which will be taken into consideration when the mechanisms of action of hits identified in the HTS are analyzed.

Example 2. Primary HDAC1 High-Throughput Screen

(311) Using the microfluidics-based HDAC1 assay developed by Nanosyn (Durham, N.C.) at total of 47,144 compounds from a diverse, drug-like library were tested for their ability to enhance the deacetylase activity of recombinant HDAC1. Compounds were tested with a reaction time of 6 h with compounds tested at a single concentration (10 μM) in duplicate. As a positive control, the biflavonoid gingketin was chosen.

(312) High-Throughput Screen Information

(313) 47,144 compounds were tested for their effect on the enzymatic activity of HDAC1. Compounds were tested in duplicate at 10 μM nominal final concentration in 384-well plate format. The reference activator compound, ginkgetin (50 μM), was included in duplicates in each HTS plate as a positive control condition, 24 negative control samples (DMSO only) were included in each plate to provide for the 0% activation baseline.

(314) Screening Results

(315) Within each HTS plate, the effect of individual compounds on the enzymatic activity of HDAC1 was calculated as % change in the conversion of the peptide substrate relative to the average substrate conversion value calculated across the 24 negative control samples.

(316) A compounds was considered active if its effect (calculated as average of two duplicates) on the enzymatic activity of HDAC1 is above the 6a standard deviations value of the assay, which is the commonly accepted statistical significance threshold for active compounds in HTS.

(317) HDAC1 microfluidics assay control data of 7,080 negative control samples (DMSO) and 580 ginkgetin positive control samples (50 μM) are shown in FIG. 2A and FIG. 2B, respectively.

(318) FIGS. 3A to 3B include HDAC1 HTS data. FIG. 3A depicts a primary microfluidic fluorescence reader trace for ginkgetin (positive control) showing increased conversion of the peptidic substrate FAM-TSRHKacKL to the deacetylated product FAM-TSRHKKL (illustrated with arrows). FIG. 3B depicts a primary microfluidic fluorescence reader trace for DAC-001, showing increased conversion of the peptidic substrate FAM-TSRHKacKL to the deacetylated product FAM-TSRHKKL (illustrated with arrows).

(319) HTS results are summarized in Table 1. A total of 21 hits, including DAC-001, DAC-002, DAC-003, DAC-009, and DAC-012, were identified by the HTS, the structures of which were determined using HPLC/UV/MS/ELSD analysis. Analysis of the structures of the hit compounds revealed multiple common structural frameworks suggesting the existence of a defined structure-activity-relationship for HDAC1 activation. All confirmed hits were re-ordered from commercial sources for further testing. Percent activation data are included in Table 2 for ginkgetin, DAC-001, DAC-002. DAC-003, DAC-009, and DAC-012.

(320) TABLE-US-00001 TABLE 1 Summary of data obtained from high-thoughput screening Total number of compounds screened 47,144 6σ value of the assay 15.5% activation Positive Name ginkgetin control Total number of measurements 580 Average effect 26% activation (standard deviation: 4%) Measurements above 6σ 571 (98.5% of total number of measurements) Measurements below 6σ 9 (1.5% of total number of measurements) Estimated probability that a potentially <0.00023 active compound has not been detected in at least one of the two replica samples Total number of active compounds 21 (0.044% of total number of compounds screened)

(321) TABLE-US-00002 TABLE 2 Activation of HDAC1 by certain compounds in high-thoughput screening Percent activation (%) Compound ID Replicate 1 Replicate 2 Average ginkgetin 25.6 ± 4.7 DAC-001 122.6 138.4 130.5 DAC-002 52.7 56.6 54.7 DAC-003 24.2 24.9 24.6 DAC-009 15.1 22.2 18.7 DAC-012 17.5 17.9 17.7

Example 3. Secondary HDAC1 High-Throughput Screen

(322) Based upon the results of the HDAC1 activator screen performed, a total of 21 compounds (for structures, see FIGS. 6A to 6C) were initially selected as hits due to their ability to enhance the deacetylase activity of recombinant HDAC1. Those hits, designated as “DACs” (deacetylase activating compounds), were measured using a microfluidics-based assay with an acetylated peptidic substrate (FAM-TSRHKacKL) over a reaction time of 6 h. The 21 HTS hits plus two controls: ginkgetin (an activator) and TSA (trichostatin A, an inhibitor; for its structure, see FIG. 6A) were retested in an 8-point dose response ranging from 50 μM to 0.02 μM. The positive control (ginkgetin) again demonstrated dose-dependent activation of HDAC1 (maximal effect of 20% and plateau at 10 μM), HDAC2 (AC.sub.50=28 μM, maximal effect 165%) and HDAC3 (maximal effect 20% at 100 μM). TSA demonstrated dose dependent inhibition of all HDAC isoforms as expected. Compounds were considered as confirmed hits if their AC.sub.50 curve showed dose-dependent activation of the HDAC1 activity in microfluidics-based assay. The two most active HTS hits, compounds DAC-001 and DAC-002 demonstrated activation of up to 287% and 221% with AC.sub.50 values of 4.05 μM and 8.31 μM, respectively. These data, included in Table 3, demonstrate the successful discovery of compounds that activate the deacetylase activity of HDAC1 in vitro.

(323) TABLE-US-00003 TABLE 3 Activation of HDAC1 by certain comopunds in a microfluidics-based assay with an acetylated peptidic substrate (FAM-TSRHKacKL) Maximum activation Average activation % during dose % during HTS response (50 μM Compound ID (10 μM) maximum) Ginkgetin 25.6 23 Trichostatin A 0 0 DAC-001 130.5 287 DAC-002 54.7 221 DAC-003 24.6 34 DAC-009 18.7 12 DAC-012 17.7 26

(324) Microfluidics-based deacetylase assays were also performed using recombinant HDAC2, HDAC3, and HDAC8 to determine the selectivity of the compounds. Many of the confirmed compounds also activated HDAC2 isoform to a similar or even greater extent. Some compounds activated HDAC3 and inhibited the HDAC8 isoform.

Example 4. Characterization of HDAC1 Activators in Cellular Models of Neurodegeneration

(325) Next, what was tested was whether a treatment of HDAC1 activators can increase HDAC1 enzymatic activity in cultured cells. Human HEK293T cells were treated with compounds at different concentrations (10 μM or 50 μM) for 20 h. Histone proteins were extracted, and Western blotting was used to analyze the acetylation of certain histone lysine residues known to be HDAC1 targets. Treatment with some compounds, such as DAC-001, DAC-002, DAC-003, and DAC-009, reduced the levels of Ac-H3K56, Ac-H3K14, Ac-H4K12 and Ac-H2B, indicating those compounds' ability to activate HDAC1 in cultured cells (FIG. 4).

(326) HT-22 cells, a hippocampal neuron derived cell line, were used to model neurodegeneration. Two types of insults were used. Glutamate treatment induced oxidative stress by depleting glutathione. Etoposide, a topoisomerase II inhibitor, stressed cells through DNA damage. These two types of stresses have been documented in neurodegenerative diseases.

(327) HT-22 cells were treated with compounds for 3 h prior to the addition of 2.5 mM glutamate. Cell viability was measured by CellTiter-Glo assays (Promega) (FIG. 5A). DAC-003 can significantly protect cells from oxidative stress (p<0.05, student's t-test). DAC-012 also showed a trend of protection.

(328) Similarly, HT-22 cells were pre-incubated with compounds (5 μM for DAC-001 and DAC-003; 10 μM for others) for 3 h. Then, 2 μM etoposide was added to the culture medium. Cell viability was measured 72 h later (FIG. 5B). Of the DAC compounds tested, DAC-001, DAC-002, DAC-003, DAC-009, and DAC-012 showed significant protection (p<0.001, student's t-test) against DNA damage stress. This result is consistent with previous findings that HDAC1 is directly involved in DNA damage repair, and that over-expression of HDAC1 is able to protect neurons from DNA damage.

(329) Additionally, the safety of these compounds was tested in HT-22 cells (FIG. 5C). Cell survival was measured 72 h after compound treatment. Most compounds showed minimum effects (less than 10%) upon cell survival. This data also indicate that DAC compounds are less likely to affect cell proliferation.

(330) The neuroprotection potential of the candidate compounds were also tested using a neuronal excitoxicity model. DIV 14 cortical neurons were treated with the compounds for 20 h, 50 μM glutamate was added to the culture 1 h before processing the samples for immunocytochemistry. MAP2 staining for the neuronal dendrites demonstrated that treatment with some of the compounds was able to protect neurons from excitotoxicity, as evidenced by their retention of dendrites. Ginkgetin was used as a positive control. Of the DAC compounds tested, DAC-002 and DAC-003 showed a trend of protection, while DAC-001 showed significant protection (p<0.01, student's t-test).