Uses of diazepane derivatives

Abstract

The present invention provides compounds of Formula (II) (e.g., compounds of Formula (I)), and pharmaceutically compositions thereof. Compounds of Formula (II) are believed to be binders of bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits using the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain-containing proteins and for treating and/or preventing in a subject diseases associated with bromodomains or bromodomain-containing proteins (e.g., proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning). The compounds, pharmaceutical compositions, and kits are also useful for male contraception. ##STR00001##

Claims

1. A method of treating a leukemia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the formula: ##STR00040## or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the leukemia is biphenotypic B myelomonocytic leukemia, acute monocytic leukemia, erythroleukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or mixed-lineage leukemia (MLL).

3. The method of claim 1, wherein the subject is a human.

4. The method of claim 2, wherein the subject is a human.

5. The method of claim 1, wherein the leukemia is acute lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, precursor T-lymphoblastic leukemia, or chronic neutrophilic leukemia.

6. The method of claim 5, wherein the subject is a human.

7. The method of claim 1, wherein the leukemia is acute myeloid leukemia, acute monocytic leukemia, or erythroleukemia.

8. The method of claim 1, wherein the leukemia is acute myeloid leukemia and the subject is a human.

9. The method of claim 1, wherein the leukemia is acute monocytic leukemia and the subject is a human.

10. The method of claim 1, wherein the leukemia is erythroleukemia and the subject is a human.

11. A method of treating a leukemia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the formula: ##STR00041## or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the subject is a human.

13. The method of claim 11, wherein the leukemia is biphenotypic B myelomonocytic leukemia, acute monocytic leukemia, erythroleukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or mixed-lineage leukemia (MLL).

14. The method of claim 13, wherein the subject is a human.

15. The method of claim 11, wherein the leukemia is acute lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, precursor T-lymphoblastic leukemia, or chronic neutrophilic leukemia.

16. The method of claim 15, wherein the subject is a human.

17. The method of claim 11, wherein the leukemia is acute myeloid leukemia, acute monocytic leukemia, or erythroleukemia.

18. The method of claim 11, wherein the leukemia is acute myeloid leukemia and the subject is a human.

19. The method of claim 11, wherein the leukemia is acute monocytic leukemia and the subject is a human.

20. The method of claim 11, wherein the leukemia is erythroleukemia and the subject is a human.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the results of an exemplary measurement of K.sub.d values of an exemplary compound as measured by Isothermal Titration calorimetery (ITC) at BRD4.1.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

(2) Recently, some compounds have been reported to be bromodomain binding agents, e.g., WO 2012/075383, WO 2011/054553, WO 2011/054841, WO 2011/054844, WO 2011/054845, WO 2011/054846, WO 2011/054848, WO 2011/143669, and WO 2011/161031. Moreover, Japanese patent application publication JP 2008/156311 discloses a benzimidazole derivative which is said to be a BRD2 bromodomain binding agent which has utility with respect to virus infection and/or proliferation. International PCT publication WO 2009/084693 discloses a series of thienotriazolodiazepine derivatives that are said to inhibit the binding between an acetylated histone and a bromodomain-containing protein which are said to be useful as anti-cancer agents. International PCT publication WO 2011/054843 suggests compounds which inhibit the binding of a bromodomain with its cognate acetylated proteins may have utility in the treatment of a range of autoimmune and inflammatory diseases or conditions. However, there remains a need for additional potent and safe bromodomain binders.

(3) The present invention provides compounds of Formula (II) (e.g., compounds of Formula (I)), which are binders of bromodomains and/or bromodomain-containing proteins. The compounds described herein may be able to bind to in a binding pocket of a bromodomain (e.g., a bromodomain of a bromodomain-containing protein). Without wishing to be bound by any particular theory, the compounds described herein may bind to the binding pocket of a bromodomain by mimicking the contact between an acetylated lysine residue of a second protein (e.g., a histone) and the binding pocket. In certain embodiments, the compounds described herein bind to the binding pocket of the bromodomain. The compound described herein may also be inhibitors of bromodomains and/or bromodomain-containing proteins. Also provided in the present invention are pharmaceutical compositions, methods, uses, and kits useful in inhibiting the activity of a bromodomain-containing protein (e.g., a transcription factor). The compounds, pharmaceutical compositions, methods, uses, and kits may be useful in treating and/or preventing diseases associated with a bromodomain, diseases associated with a bromodomain-containing protein, diseases associated with the activity (e.g., aberrant activity) of a bromodomain, and diseases associated with the activity (e.g., aberrant activity) of a bromodomain-containing protein. Exemplary diseases that maybe prevented and/or treated with compounds described herein include proliferative diseases (e.g., cancers, benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases), autoimmune diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning. The compounds, pharmaceutical compositions, methods, uses, and kits may also be useful for male contraception and for inhibiting the replication of or killing a virus.

(4) Compounds

(5) In one aspect, the present invention provides compounds of Formula (II):

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

(7) is a single or double bond;

(8) W is C(O)OR.sup.Z1, C(O)N(R.sup.Z1).sub.2, S(O)OR.sup.Z1, S(O)N(R.sup.Z1).sub.2, S(O).sub.2OR.sup.Z1, S(O).sub.2N(R.sup.Z1).sub.2, or

(9) ##STR00008##

(10) Z is O, N(R.sup.Z) or C(R.sup.Z).sub.2, wherein each instance of R.sup.Z is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.Z1, SR.sup.Z1, N(R.sup.Z1).sub.2, or a nitrogen protecting group when attached to a nitrogen atom, or two instances of R.sup.Z are joined to form a substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring;

(11) each instance of R.sup.Z1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom, or two instances of R.sup.Z1 are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

(12) each instance of R.sup.A is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.A1, N(R.sup.A1).sub.2, SR.sup.A1, CN, SCN, C(NR.sup.A1)R.sup.A1, C(NR.sup.A1)OR.sup.A1, C(NR.sup.A1)N(R.sup.A1).sub.2, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, NO.sub.2, NR.sup.A1C(O)R.sup.A1, NR.sup.A1C(O)OR.sup.A1, NR.sup.A1C(O)N(R.sup.A1).sub.2, OC(O)R.sup.A1, OC(O)OR.sup.A1, or OC(O)N(R.sup.A1).sub.2, wherein each instance of R.sup.A1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R.sup.A1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

(13) n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

(14) X is absent, C(O), or C(R.sup.X).sub.2, wherein each instance of R.sup.X is independently hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl;

(15) each instance of R.sup.B is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.B1, N(R.sup.B1).sub.2, SR.sup.B1, CN, SCN, C(NR.sup.B1)R.sup.B1, C(NR.sup.B1)OR.sup.B1, C(NR.sup.B1)N(R.sup.B1).sub.2, C(O)R.sup.B1, C(O)OR.sup.B1, C(O)N(R.sup.B1).sub.2, NO.sub.2, NR.sup.B1C(O)R.sup.B1, NR.sup.B1C(O)OR.sup.B1, NR.sup.B1C(O)N(R.sup.B1).sub.2, OC(O)R.sup.B1, OC(O)OR.sup.B1, or OC(O)N(R.sup.B1).sub.2, wherein each instance of R.sup.B1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R.sup.B1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

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

(17) R.sup.C is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl;

(18) R.sup.D is hydrogen or substituted or unsubstituted alkyl;

(19) R.sup.E is hydrogen or substituted or unsubstituted alkyl;

(20) R.sup.F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

(21) R.sup.G is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

(22) R.sup.H is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

(23) or R.sup.G and R.sup.H are joined to form a substituted or unsubstituted phenyl ring.

(24) Formula (II) includes moiety W on the phenyl ring. In certain embodiments, W is C(O)OR.sup.Z1, optionally wherein R.sup.Z1 is substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me), substituted or unsubstituted phenyl, or an oxygen protecting group. In certain embodiments, W is C(O)OH. In certain embodiments, W is C(O)OR.sup.Z1, wherein R.sup.Z1 is not H. In certain embodiments, W is C(O)N(R.sup.Z1).sub.2, optionally wherein each instance of R.sup.Z1 is independently substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me), substituted or unsubstituted phenyl, or a nitrogen protecting group, or optionally wherein two instances of R.sup.Z1 are joined to form a substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring. In certain embodiments, W is C(O)NHR.sup.Z1, optionally R.sup.Z1 is substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me), substituted or unsubstituted phenyl, or a nitrogen protecting group. In certain embodiments, W is C(O)NH.sub.2. In certain embodiments, W is S(O)OR.sup.Z1 or S(O)N(R.sup.Z1).sub.2, optionally wherein each instance of R.sup.Z1 is independently substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me), substituted or unsubstituted phenyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom, or optionally wherein two instances of R.sup.Z1 are joined to form a substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring. In certain embodiments, W is S(O)OH. In certain embodiments, W is S(O)NH(R.sup.Z1), optionally wherein R.sup.Z1 is substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me), substituted or unsubstituted phenyl, or a nitrogen protecting group. In certain embodiments, W is S(O)NH.sub.2. In certain embodiments, W is S(O).sub.2OR.sup.Z1, optionally wherein R.sup.Z1 is substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me), substituted or unsubstituted phenyl, or an oxygen protecting group. In certain embodiments, W is S(O).sub.2OH. In certain embodiments, W is S(O).sub.2N(R.sup.Z1).sub.2, optionally wherein each instance of R.sup.Z1 is independently substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me), substituted or unsubstituted phenyl, or a nitrogen protecting group, or optionally wherein two instances of R.sup.Z1 are joined to form a substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring. In certain embodiments, W is S(O).sub.2NH(R.sup.Z1), optionally wherein R.sup.Z1 is substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me), substituted or unsubstituted phenyl, or a nitrogen protecting group. In certain embodiments, W is S(O).sub.2NH.sub.2.

(25) In certain embodiments, W is of the formula:

(26) ##STR00009##
and thus a compound of Formula (II) is of Formula (I):

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

(28) Formula (I) or (II) includes a bond . In certain embodiments, is a single bond. In certain embodiments, is a double bond.

(29) Formula (I) includes a divalent moiety Z. In certain embodiments, Z is O. In certain embodiments, Z is N(R.sup.Z). In certain embodiments, Z is NH. In certain embodiments, Z is N(substituted or unsubstituted, C.sub.1-6 alkyl)-. In certain embodiments, Z is N(substituted or unsubstituted, 4- to 7-membered, monocyclic heterocyclyl)-. In certain embodiments, Z is C(R.sup.Z).sub.2. In certain embodiments, Z is CH(R.sup.Z). In certain embodiments, Z is CH(substituted or unsubstituted, C.sub.1-6 alkyl)-. In certain embodiments, Z is CH(substituted or unsubstituted, 4- to 7-membered, monocyclic heterocyclyl)-.

(30) Formula (I) or (II) may include one or more substituents R.sup.Z on the divalent moiety Z. In certain embodiments, at least one instance of R.sup.Z is H. In certain embodiments, at least one instance of R.sup.Z is substituted acyl. In certain embodiments, at least one instance of R.sup.Z is unsubstituted acyl. In certain embodiments, at least one instance of R.sup.Z is acetyl. In certain embodiments, at least one instance of R.sup.Z is substituted alkyl. In certain embodiments, at least one instance of R.sup.Z is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.Z is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.Z is methyl. In certain embodiments, at least one instance of R.sup.Z is ethyl. In certain embodiments, at least one instance of R.sup.Z is propyl. In certain embodiments, at least one instance of R.sup.Z is butyl. In certain embodiments, at least one instance of R.sup.Z is pentyl. In certain embodiments, at least one instance of R.sup.Z is hexyl. In certain embodiments, at least one instance of R.sup.Z is substituted alkenyl. In certain embodiments, at least one instance of R.sup.Z is unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.Z is substituted alkynyl. In certain embodiments, at least one instance of R.sup.Z is unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.Z is substituted or unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.Z is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.Z is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.Z is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.Z is substituted or unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.Z is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.Z is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.Z is substituted or unsubstituted, 4- to 7-membered, monocyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, at least one instance of R.sup.Z is substituted or unsubstituted, 6-membered, monocyclic heterocyclyl, wherein one or two atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, at least one instance of R.sup.Z is of the formula:

(31) ##STR00011##
In certain embodiments, at least one instance of R.sup.Z is of the formula:

(32) ##STR00012##
In certain embodiments, at least one instance of R.sup.Z is of the formula:

(33) ##STR00013##
In certain embodiments, at least one instance of R.sup.Z is of the formula:

(34) ##STR00014##
In certain embodiments, at least one instance of R.sup.Z is of the formula:

(35) ##STR00015##
In certain embodiments, at least one instance of R.sup.Z is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.Z is 6- to 10-membered aryl. In certain embodiments, at least one instance of R.sup.Z is monocyclic aryl. In certain embodiments, at least one instance of R.sup.Z is substituted phenyl. In certain embodiments, at least one instance of R.sup.Z is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.Z is bicyclic aryl. In certain embodiments, at least one instance of R.sup.Z is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.Z is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.Z is monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.Z is 5- or 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.Z is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, R.sup.Z is OR.sup.Z1. In certain embodiments, R.sup.Z is OH. In certain embodiments, R.sup.Z is OMe. In certain embodiments, R.sup.Z is OEt. In certain embodiments, R.sup.Z is OPr. In certain embodiments, R.sup.Z is OBu. In certain embodiments, R.sup.Z is OBn. In certain embodiments, R.sup.Z is OPh. In certain embodiments, R.sup.Z is SR.sup.Z1. In certain embodiments, R.sup.Z is SH. In certain embodiments, R.sup.Z is SMe. In certain embodiments, R.sup.Z is N(R.sup.Z1).sub.2. In certain embodiments, R.sup.Z is NH.sub.2. In certain embodiments, R.sup.Z is NHMe. In certain embodiments, R.sup.Z is NMe.sub.2. In certain embodiments, at least one instance of R.sup.Z is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one instance of R.sup.Z is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to a nitrogen atom.

(36) In certain embodiments, two instances of R.sup.Z are joined to form a substituted or unsubstituted carbocyclic ring. In certain embodiments, two instances of R.sup.Z are joined to form a saturated or unsaturated carbocyclic ring. In certain embodiments, two instances of R.sup.Z are joined to form a substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclic ring. In certain embodiments, two instances of R.sup.Z are joined to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, two instances of R.sup.Z are joined to form a saturated or unsaturated heterocyclic ring. In certain embodiments, two instances of R.sup.Z are joined to form a heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, two instances of R.sup.Z are joined to form a 3- to 7-membered, monocyclic heterocyclic ring.

(37) In certain embodiments, at least one instance of R.sup.Z1 is H. In certain embodiments, at least one instance of R.sup.Z1 is substituted acyl. In certain embodiments, at least one instance of R.sup.Z1 is unsubstituted acyl. In certain embodiments, at least one instance of R.sup.Z1 is acetyl. In certain embodiments, at least one instance of R.sup.Z1 is substituted alkyl. In certain embodiments, at least one instance of R.sup.Z1 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.Z1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.Z1 is methyl. In certain embodiments, at least one instance of R.sup.Z1 is ethyl. In certain embodiments, at least one instance of R.sup.Z1 is propyl. In certain embodiments, at least one instance of R.sup.Z1 is butyl. In certain embodiments, at least one instance of R.sup.Z1 is pentyl. In certain embodiments, at least one instance of R.sup.Z1 is hexyl. In certain embodiments, R.sup.Z1 is substituted alkenyl. In certain embodiments, R.sup.Z1 is unsubstituted alkenyl. In certain embodiments, R.sup.Z1 is substituted alkynyl. In certain embodiments, R.sup.Z1 is unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.Z1 is substituted or unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.Z1 is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.Z1 is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.Z1 is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.Z1 is substituted or unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.Z1 is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.Z1 is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.Z1 is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.Z1 is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.Z1 is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.Z1 is 6- to 10-membered aryl. In certain embodiments, at least one instance of R.sup.Z1 is monocyclic aryl. In certain embodiments, at least one instance of R.sup.Z1 is substituted phenyl. In certain embodiments, at least one instance of R.sup.Z1 is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.Z1 is bicyclic aryl. In certain embodiments, at least one instance of R.sup.Z1 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.Z1 is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.Z1 is monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.Z1 is 5- or 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.Z1 is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of R.sup.Z1 is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one instance of R.sup.Z1 is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to a nitrogen atom. In certain embodiments, at least one instance of R.sup.Z1 is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, at least one instance of R.sup.Z1 is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, at least one instance of R.sup.Z1 is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, at least one instance of R.sup.Z1 is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two instances of R.sup.Z1 are joined to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, two instances of R.sup.Z1 are joined to form a saturated or unsaturated heterocyclic ring. In certain embodiments, two instances of R.sup.Z1 are joined to form a heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, two instances of R.sup.Z1 are joined to form a 3- to 7-membered, monocyclic heterocyclic ring. In certain embodiments, two instances of R.sup.Z1 are joined to form a substituted or unsubstituted heteroaryl ring. In certain embodiments, two instances of R.sup.Z1 are joined to form a substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.

(38) Formula (I) or (H) may include one or more substituents R.sup.A. In certain embodiments, at least two instances of R.sup.A are different. In certain embodiments, all instances of R.sup.A are the same. In certain embodiments, at least one instance of R.sup.A is H. In certain embodiments, all instances of R.sup.A are H. In certain embodiments, at least one instance of R.sup.A is halogen. In certain embodiments, at least one instance of R.sup.A is F. In certain embodiments, at least one instance of R.sup.A is Cl. In certain embodiments, at least one instance of R.sup.A is Br. In certain embodiments, at least one instance of R.sup.A is I (iodine). In certain embodiments, at least one instance of R.sup.A is substituted alkyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, all instances of R.sup.A are unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.A is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.A is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, at least one instance of R.sup.A is CH.sub.3. In certain embodiments, all instances of R.sup.A are CH.sub.3. In certain embodiments, at least one instance of R.sup.A is substituted methyl. In certain embodiments, at least one instance of R.sup.A is CH.sub.2F. In certain embodiments, at least one instance of R.sup.A is CHF.sub.2. In certain embodiments, at least one instance of R.sup.A is CF.sub.3. In certain embodiments, at least one instance of R.sup.A is ethyl. In certain embodiments, at least one instance of R.sup.A is propyl. In certain embodiments, at least one instance of R.sup.A is butyl. In certain embodiments, at least one instance of R.sup.A is pentyl. In certain embodiments, at least one instance of R.sup.A is hexyl. In certain embodiments, at least one instance of R.sup.A is substituted alkenyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.A is substituted alkynyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.A is substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.A is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.A is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.A is monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.A is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.A is substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.A is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.A is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.A is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.A is monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.A is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.A is substituted aryl. In certain embodiments, at least one instance of R.sup.A is unsubstituted aryl. In certain embodiments, at least one instance of R.sup.A is 6- to 10-membered aryl. In certain embodiments, at least one instance of R.sup.A is substituted phenyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.A is substituted heteroaryl. In certain embodiments, at least one instance of R.sup.A is unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.A is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.A is monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A is 5-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A is 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of R.sup.A is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A is OR.sup.A1. In certain embodiments, at least one instance of R.sup.A is OH. In certain embodiments, at least one instance of R.sup.A is OMe. In certain embodiments, at least one instance of R.sup.A is OEt. In certain embodiments, at least one instance of R.sup.A is OPr. In certain embodiments, at least one instance of R.sup.A is OBu. In certain embodiments, at least one instance of R.sup.A is OBn. In certain embodiments, at least one instance of R.sup.A is OPh. In certain embodiments, at least one instance of R.sup.A is SR.sup.A1. In certain embodiments, at least one instance of R.sup.A is SH. In certain embodiments, at least one instance of R.sup.A is SMe. In certain embodiments, at least one instance of R.sup.A is N(R.sup.A1).sub.2. In certain embodiments, at least one instance of R.sup.A is NH.sub.2. In certain embodiments, at least one instance of R.sup.A is NHMe. In certain embodiments, at least one instance of R.sup.A is NMe.sub.2. In certain embodiments, at least one instance of R.sup.A is CN. In certain embodiments, at least one instance of R.sup.A is SCN. In certain embodiments, at least one instance of R.sup.A is C(NR.sup.A1)R.sup.A1, C(NR.sup.A1)OR.sup.A1, or C(NR.sup.A1)N(R.sup.A1).sub.2. In certain embodiments, at least one instance of R.sup.A is C(O)R.sup.A1 or C(O)OR.sup.A1. In certain embodiments, at least one instance of R.sup.A is C(O)N(R.sup.A1).sub.2. In certain embodiments, at least one instance of R.sup.A is C(O)NMe.sub.2, C(O)NHMe, or C(O)NH.sub.2. In certain embodiments, at least one instance of R.sup.A is NO.sub.2. In certain embodiments, at least one instance of R.sup.A is NR.sup.A1C(O)R.sup.A1, NR.sup.A1C(O)OR.sup.A1, or NR.sup.A1C(O)N(R.sup.A1).sub.2. In certain embodiments, at least one instance of R.sup.A is OC(O)R.sup.A1, OC(O)OR.sup.A1, or OC(O)N(R.sup.A1).sub.2.

(39) In certain embodiments, at least one instance of R.sup.A1 is H. In certain embodiments, at least one instance of R.sup.A1 is substituted acyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted acyl. In certain embodiments, at least one instance of R.sup.A1 is acetyl. In certain embodiments, at least one instance of R.sup.A1 is substituted alkyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.A1 is methyl. In certain embodiments, at least one instance of R.sup.A1 is ethyl. In certain embodiments, at least one instance of R.sup.A1 is propyl. In certain embodiments, at least one instance of R.sup.A1 is butyl. In certain embodiments, at least one instance of R.sup.A1 is pentyl. In certain embodiments, at least one instance of R.sup.A1 is hexyl. In certain embodiments, at least one instance of R.sup.A1 is substituted alkenyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.A1 is substituted alkynyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.A1 is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.A1 is 6- to 10-membered aryl. In certain embodiments, at least one instance of R.sup.A1 is monocyclic aryl. In certain embodiments, at least one instance of R.sup.A1 is substituted phenyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.A1 is bicyclic aryl. In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.A1 is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.A1 is monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A1 is 5- or 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A1 is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of R.sup.A1 is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one instance of R.sup.A1 is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to a nitrogen atom. In certain embodiments, R.sup.A1 is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.A1 is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R.sup.A1 is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.A1 is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two instances of R.sup.A1 are joined to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, two instances of R.sup.A1 are joined to form a saturated or unsaturated heterocyclic ring. In certain embodiments, two instances of R.sup.A1 are joined to form a heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, two instances of R.sup.A1 are joined to form a 3- to 7-membered, monocyclic heterocyclic ring. In certain embodiments, two instances of R.sup.A1 are joined to form a substituted or unsubstituted heteroaryl ring. In certain embodiments, two instances of R.sup.A1 are joined to form a substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.

(40) In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8.

(41) Formula (I) includes a divalent moiety X. In certain embodiments, X is absent. In certain embodiments, X is C(O). In certain embodiments, X is C(R.sup.X).sub.2. In certain embodiments, X is CH(R.sup.X). In certain embodiments, X is CH.sub.2.

(42) In certain embodiments, at least one instance of R.sup.X is H. In certain embodiments, each instance of R.sup.X is H. In certain embodiments, at least one instance of R.sup.X is halogen. In certain embodiments, at least one instance of R.sup.X is F. In certain embodiments, at least one instance of R.sup.X is Cl. In certain embodiments, at least one instance of R.sup.X is Br. In certain embodiments, at least one instance of R.sup.X is I (iodine). In certain embodiments, at least one instance of R.sup.X is unsubstituted C.sub.1-6 alkyl. In certain embodiments, each instance of R.sup.X is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.X is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.X is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, at least one instance of R.sup.X is CH.sub.3. In certain embodiments, each instance of R.sup.X is CH.sub.3. In certain embodiments, at least one instance of R.sup.X is substituted methyl. In certain embodiments, at least one instance of R.sup.X is CH.sub.2F. In certain embodiments, at least one instance of R.sup.X is CHF.sub.2. In certain embodiments, at least one instance of R.sup.X is CF.sub.3. In certain embodiments, at least one instance of R.sup.X is ethyl. In certain embodiments, at least one instance of R.sup.X is propyl. In certain embodiments, at least one instance of R.sup.X is butyl. In certain embodiments, at least one instance of R.sup.X is pentyl. In certain embodiments, at least one instance of R.sup.X is hexyl.

(43) Formula (I) or (II) may include one or more substituents R.sup.B. In certain embodiments, at least two instances of R.sup.B are different. In certain embodiments, all instances of R.sup.B are the same. In certain embodiments, at least one instance of R.sup.B is H. In certain embodiments, all instances of R.sup.B are H. In certain embodiments, at least one instance of R.sup.B is halogen. In certain embodiments, at least one instance of R.sup.B is F. In certain embodiments, at least one instance of R.sup.B is Cl. In certain embodiments, at least one instance of R.sup.B is Br. In certain embodiments, at least one instance of R.sup.B is I (iodine). In certain embodiments, at least one instance of R.sup.B is substituted alkyl. In certain embodiments, at least one instance of R.sup.B is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.B is unsubstituted C.sub.1-6 alkyl. In certain embodiments, all instances of R.sup.B are unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.B is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.B is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, at least one instance of R.sup.B is CH.sub.3. In certain embodiments, all instances of R.sup.B are CH.sub.3. In certain embodiments, at least one instance of R.sup.B is substituted methyl. In certain embodiments, at least one instance of R.sup.B is CH.sub.2F. In certain embodiments, at least one instance of R.sup.B is CHF.sub.2. In certain embodiments, at least one instance of R.sup.B is CF.sub.3. In certain embodiments, at least one instance of R.sup.B is ethyl. In certain embodiments, at least one instance of R.sup.B is propyl. In certain embodiments, at least one instance of R.sup.B is butyl. In certain embodiments, at least one instance of R.sup.B is pentyl. In certain embodiments, at least one instance of R.sup.B is hexyl. In certain embodiments, at least one instance of R.sup.B is substituted alkenyl. In certain embodiments, at least one instance of R.sup.B is unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.B is substituted alkynyl. In certain embodiments, at least one instance of R.sup.B is unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.B is substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.B is unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.B is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.B is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.B is monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.B is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.B is substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.B is unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.B is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.B is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.B is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.B is monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.B is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.B is substituted aryl. In certain embodiments, at least one instance of R.sup.B is unsubstituted aryl. In certain embodiments, at least one instance of R.sup.B is 6- to 10-membered aryl. In certain embodiments, at least one instance of R.sup.B is substituted phenyl. In certain embodiments, at least one instance of R.sup.B is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.B is substituted heteroaryl. In certain embodiments, at least one instance of R.sup.B is unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.B is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.B is monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.B is 5-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.B is 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.B is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of R.sup.B is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.B is OR.sup.B1. In certain embodiments, at least one instance of R.sup.B is OH. In certain embodiments, at least one instance of R.sup.B is OMe. In certain embodiments, at least one instance of R.sup.B is OEt. In certain embodiments, at least one instance of R.sup.B is OPr. In certain embodiments, at least one instance of R.sup.B is OBu. In certain embodiments, at least one instance of R.sup.B is OBn. In certain embodiments, at least one instance of R.sup.B is OPh. In certain embodiments, at least one instance of R.sup.B is SR.sup.B1. In certain embodiments, at least one instance of R.sup.B is SH. In certain embodiments, at least one instance of R.sup.B is SMe. In certain embodiments, at least one instance of R.sup.B is N(R.sup.B1).sub.2. In certain embodiments, at least one instance of R.sup.B is NH.sub.2. In certain embodiments, at least one instance of R.sup.B is NHMe. In certain embodiments, at least one instance of R.sup.B is NMe.sub.2. In certain embodiments, at least one instance of R.sup.B is CN. In certain embodiments, at least one instance of R.sup.B is SCN. In certain embodiments, at least one instance of R.sup.B is C(NR.sup.B1)R.sup.B1, C(NR.sup.B1)OR.sup.B1, or C(NR.sup.B1)N(R.sup.B1).sub.2. In certain embodiments, at least one instance of R.sup.B is C(O)R.sup.B1 or C(O)OR.sup.B1. In certain embodiments, at least one instance of R.sup.B is C(O)N(R.sup.B1).sub.2. In certain embodiments, at least one instance of R.sup.B is C(O)NMe.sub.2, C(O)NHMe, or C(O)NH.sub.2. In certain embodiments, at least one instance of R.sup.B is NO.sub.2. In certain embodiments, at least one instance of R.sup.B is NR.sup.B1C(O)R.sup.B1, NR.sup.B1C(O)OR.sup.B1, or NR.sup.B1C(O)N(R.sup.B1).sub.2. In certain embodiments, at least one instance of R.sup.B is OC(O)R.sup.B1, OC(O)OR.sup.B1, or OC(O)N(R.sup.B1).sub.2.

(44) In certain embodiments, at least one instance of R.sup.B1 is H. In certain embodiments, at least one instance of R.sup.B1 is substituted acyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted acyl. In certain embodiments, at least one instance of R.sup.B1 is acetyl. In certain embodiments, at least one instance of R.sup.B1 is substituted alkyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.B1 is methyl. In certain embodiments, at least one instance of R.sup.B1 is ethyl. In certain embodiments, at least one instance of R.sup.B1 is propyl. In certain embodiments, at least one instance of R.sup.B1 is butyl. In certain embodiments, at least one instance of R.sup.B1 is pentyl. In certain embodiments, at least one instance of R.sup.B1 is hexyl. In certain embodiments, at least one instance of R.sup.B1 is substituted alkenyl. In certain embodiments, at least one instance of RBI is unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.B1 is substituted alkynyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.B1 is substituted or unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.B1 is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.B1 is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.B1 is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.B1 is substituted or unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.B1 is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.B1 is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.B1 is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.B1 is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.B1 is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.B1 is 6- to 10-membered aryl. In certain embodiments, at least one instance of R.sup.B1 is monocyclic aryl. In certain embodiments, at least one instance of R.sup.B1 is substituted phenyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.B1 is bicyclic aryl. In certain embodiments, at least one instance of R.sup.B1 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.B1 is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.B1 is monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.B1 is 5- or 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.B1 is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of R.sup.B1 is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one instance of R.sup.B1 is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to a nitrogen atom. In certain embodiments, R.sup.B1 is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.B1 is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R.sup.B1 is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.B1 is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two instances of R.sup.B1 are joined to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, two instances of R.sup.B1 are joined to form a saturated or unsaturated heterocyclic ring. In certain embodiments, two instances of R.sup.B1 are joined to form a heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, two instances of R.sup.B1 are joined to form a 3- to 7-membered, monocyclic heterocyclic ring. In certain embodiments, two instances of R.sup.B1 are joined to form a substituted or unsubstituted heteroaryl ring. In certain embodiments, two instances of R.sup.B1 are joined to form a substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.

(45) 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.

(46) Formula (I) or (II) includes substituent R.sup.C on a nitrogen atom. In certain embodiments, R.sup.C is H. In certain embodiments, R.sup.C is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.C is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.C is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, R.sup.C is CH.sub.3. In certain embodiments, R.sup.C is substituted methyl. In certain embodiments, R.sup.C is CH.sub.2F. In certain embodiments, R.sup.C is CHF.sub.2. In certain embodiments, R.sup.C is CF.sub.3. In certain embodiments, R.sup.C is ethyl. In certain embodiments, R.sup.C is propyl. In certain embodiments, R.sup.C is butyl. In certain embodiments, R.sup.C is pentyl. In certain embodiments, R.sup.C is hexyl.

(47) Formula (I) or (II) includes substituent R.sup.D on a pyrimidinyl ring. In certain embodiments, R.sup.D is H. In certain embodiments, R.sup.D is unsubstituted alkyl. In certain embodiments, R.sup.D is substituted alkyl. In certain embodiments, R.sup.D is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.D is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.D is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, R.sup.D is CH.sub.3. In certain embodiments, R.sup.D is substituted methyl. In certain embodiments, R.sup.D is CH.sub.2F. In certain embodiments, R.sup.D is CHF.sub.2. In certain embodiments, R.sup.D is CF.sub.3. In certain embodiments, R.sup.D is ethyl. In certain embodiments, R.sup.D is propyl. In certain embodiments, R.sup.D is butyl. In certain embodiments, R.sup.D is pentyl. In certain embodiments, R.sup.D is hexyl.

(48) Formula (I) or (II) includes substituent R.sup.E on a nitrogen atom. In certain embodiments, R.sup.E is H. In certain embodiments, R.sup.E is unsubstituted alkyl. In certain embodiments, R.sup.E is substituted alkyl. In certain embodiments, R.sup.E is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.E is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.E is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, R.sup.E is CH.sub.3. In certain embodiments, R.sup.E is substituted methyl. In certain embodiments, R.sup.E is CH.sub.2F. In certain embodiments, R.sup.E is CHF.sub.2. In certain embodiments, R.sup.E is CF.sub.3. In certain embodiments, R.sup.E is ethyl. In certain embodiments, R.sup.E is propyl. In certain embodiments, R.sup.E is butyl. In certain embodiments, R.sup.E is pentyl. In certain embodiments, R.sup.E is hexyl.

(49) Formula (I) or (II) includes substituent R.sup.F on a nitrogen atom. In certain embodiments, R.sup.F is H. In certain embodiments, R.sup.F is substituted alkyl. In certain embodiments, R.sup.F is unsubstituted alkyl. In certain embodiments, R.sup.F is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.F is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.F is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, R.sup.F is CH.sub.3. In certain embodiments, R.sup.F is substituted methyl. In certain embodiments, R.sup.F is CH.sub.2F. In certain embodiments, R.sup.F is CHF.sub.2. In certain embodiments, R.sup.F is CF.sub.3. In certain embodiments, R.sup.F is ethyl. In certain embodiments, R.sup.F is propyl. In certain embodiments, R.sup.F is butyl. In certain embodiments, R.sup.F is pentyl. In certain embodiments, R.sup.F is hexyl. In certain embodiments, R.sup.F is substituted alkenyl. In certain embodiments, R.sup.F is unsubstituted alkenyl. In certain embodiments, R.sup.F is substituted carbocyclyl. In certain embodiments, R.sup.F is unsubstituted carbocyclyl. In certain embodiments, R.sup.F is saturated carbocyclyl. In certain embodiments, R.sup.F is unsaturated carbocyclyl. In certain embodiments, R.sup.F is monocyclic carbocyclyl. In certain embodiments, R.sup.F is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, R.sup.F is substituted heterocyclyl. In certain embodiments, R.sup.F is unsubstituted heterocyclyl. In certain embodiments, R.sup.F is saturated heterocyclyl. In certain embodiments, R.sup.F is unsaturated heterocyclyl. In certain embodiments, R.sup.F is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.F is monocyclic heterocyclyl. In certain embodiments, R.sup.F is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, R.sup.F is substituted aryl. In certain embodiments, R.sup.F is unsubstituted aryl. In certain embodiments, R.sup.F is 6- to 10-membered aryl. In certain embodiments, R.sup.F is substituted phenyl. In certain embodiments, R.sup.F is unsubstituted phenyl. In certain embodiments, R.sup.F is substituted heteroaryl. In certain embodiments, R.sup.F is unsubstituted heteroaryl. In certain embodiments, R.sup.F is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.F is monocyclic heteroaryl. In certain embodiments, R.sup.F is 5-membered, monocyclic heteroaryl. In certain embodiments, R.sup.F is 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.F is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, R.sup.F is 9- or 10-membered, bicyclic heteroaryl.

(50) Formula (I) or (II) includes substituent R.sup.G. In certain embodiments, R.sup.G is H. In certain embodiments, R.sup.G is substituted alkyl. In certain embodiments, R.sup.G is unsubstituted alkyl. In certain embodiments, R.sup.G is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.G is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.G is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, R.sup.G is CH.sub.3. In certain embodiments, R.sup.G is substituted methyl. In certain embodiments, R.sup.G is CH.sub.2F. In certain embodiments, R.sup.G is CHF.sub.2. In certain embodiments, R.sup.G is CF.sub.3. In certain embodiments, R.sup.G is ethyl. In certain embodiments, R.sup.G is propyl. In certain embodiments, R.sup.G is butyl. In certain embodiments, R.sup.G is pentyl. In certain embodiments, R.sup.G is hexyl. In certain embodiments, R.sup.G is substituted alkenyl. In certain embodiments, R.sup.G is unsubstituted alkenyl. In certain embodiments, R.sup.G is substituted carbocyclyl. In certain embodiments, R.sup.G is unsubstituted carbocyclyl. In certain embodiments, R.sup.G is saturated carbocyclyl. In certain embodiments, R.sup.G is unsaturated carbocyclyl. In certain embodiments, R.sup.G is monocyclic carbocyclyl. In certain embodiments, R.sup.G is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, R.sup.G is substituted heterocyclyl. In certain embodiments, R.sup.G is unsubstituted heterocyclyl. In certain embodiments, R.sup.G is saturated heterocyclyl. In certain embodiments, R.sup.G is unsaturated heterocyclyl. In certain embodiments, R.sup.G is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.G is monocyclic heterocyclyl. In certain embodiments, R.sup.G is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, R.sup.G is substituted aryl. In certain embodiments, R.sup.G is unsubstituted aryl. In certain embodiments, R.sup.G is 6- to 10-membered aryl. In certain embodiments, R.sup.G is substituted phenyl. In certain embodiments, R.sup.G is unsubstituted phenyl. In certain embodiments, R.sup.G is substituted heteroaryl. In certain embodiments, R.sup.G is unsubstituted heteroaryl. In certain embodiments, R.sup.G is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.G is monocyclic heteroaryl. In certain embodiments, R.sup.G is 5-membered, monocyclic heteroaryl. In certain embodiments, R.sup.G is 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.G is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, R.sup.G is 9- or 10-membered, bicyclic heteroaryl.

(51) Formula (I) or (II) includes substituent R.sup.H. In certain embodiments, R.sup.H is H. In certain embodiments, R.sup.H is substituted alkyl. In certain embodiments, R.sup.H is unsubstituted alkyl. In certain embodiments, R.sup.H is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.H is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.H is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, R.sup.H is CH.sub.3. In certain embodiments, R.sup.H is substituted methyl. In certain embodiments, R.sup.H is CH.sub.2F. In certain embodiments, R.sup.H is CHF.sub.2. In certain embodiments, R.sup.H is CF.sub.3. In certain embodiments, R.sup.H is ethyl. In certain embodiments, R.sup.H is propyl. In certain embodiments, R.sup.H is butyl. In certain embodiments, R.sup.H is pentyl. In certain embodiments, R.sup.H is hexyl. In certain embodiments, R.sup.H is substituted alkenyl. In certain embodiments, R.sup.H is unsubstituted alkenyl. In certain embodiments, R.sup.H is substituted carbocyclyl. In certain embodiments, R.sup.H is unsubstituted carbocyclyl. In certain embodiments, R.sup.H is saturated carbocyclyl. In certain embodiments, R.sup.H is unsaturated carbocyclyl. In certain embodiments, R.sup.H is monocyclic carbocyclyl. In certain embodiments, R.sup.H is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, R.sup.H is substituted heterocyclyl. In certain embodiments, R.sup.H is unsubstituted heterocyclyl. In certain embodiments, R.sup.H is saturated heterocyclyl. In certain embodiments, R.sup.H is unsaturated heterocyclyl. In certain embodiments, R.sup.H is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.H is monocyclic heterocyclyl. In certain embodiments, R.sup.H is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, R.sup.H is substituted aryl. In certain embodiments, R.sup.H is unsubstituted aryl. In certain embodiments, R.sup.H is 6- to 10-membered aryl. In certain embodiments, R.sup.H is substituted phenyl. In certain embodiments, R.sup.H is unsubstituted phenyl. In certain embodiments, R.sup.H is substituted heteroaryl. In certain embodiments, R.sup.H is unsubstituted heteroaryl. In certain embodiments, R.sup.H is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.H is monocyclic heteroaryl. In certain embodiments, R.sup.H is 5-membered, monocyclic heteroaryl. In certain embodiments, R.sup.H is 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.H is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, R.sup.H is 9- or 10-membered, bicyclic heteroaryl.

(52) In certain embodiments, each of R.sup.G and R.sup.H is hydrogen.

(53) In certain embodiments, R.sup.G and R.sup.H are joined to form a substituted phenyl ring. In certain embodiments, R.sup.G and R.sup.H are joined to form an unsubstituted phenyl ring. In certain embodiments, a compound described herein is of Formula (II-A):

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

(55) each instance of R.sup.J is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.J1, N(R.sup.J1).sub.2, SR.sup.J1, CN, SCN, C(NR.sup.J1)R.sup.J1, C(NR.sup.J1)OR.sup.J1, C(NR.sup.J1)N(R.sup.J1).sub.2, C(O)R.sup.J1, C(O)OR.sup.J1, C(O)N(R.sup.J1).sub.2, NO.sub.2, NR.sup.J1C(O)R.sup.J1, NR.sup.J1C(O)OR.sup.J1, NR.sup.J1C(O)N(R.sup.J1).sub.2, OC(O)R.sup.J1, OC(O)OR.sup.J1, or OC(O)N(R.sup.J1).sub.2, wherein each instance of R.sup.J1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R.sup.J1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and

(56) k is 0, 1, 2, 3, or 4.

(57) In certain embodiments, a compound described herein is of Formula (I-A):

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

(59) Formula (I-A) or (II-A) may include one or more substituents R.sup.J1. In certain embodiments, at least two instances of R.sup.J are different. In certain embodiments, all instances of R.sup.J are the same. In certain embodiments, at least one instance of R.sup.J is H. In certain embodiments, all instances of R.sup.J are H. In certain embodiments, at least one instance of R.sup.J is halogen. In certain embodiments, at least one instance of R.sup.J is F. In certain embodiments, at least one instance of R.sup.J is Cl. In certain embodiments, at least one instance of Fe is Br. In certain embodiments, at least one instance of R.sup.J is I (iodine). In certain embodiments, at least one instance of R.sup.J is substituted alkyl. In certain embodiments, at least one instance of R.sup.J is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.J is unsubstituted C.sub.1-6 alkyl. In certain embodiments, all instances of R.sup.J are unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.J is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.J is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, at least one instance of R.sup.J is CH.sub.3. In certain embodiments, all instances of R.sup.J1 are CH.sub.3. In certain embodiments, at least one instance of R.sup.J is substituted methyl. In certain embodiments, at least one instance of R.sup.J is CH.sub.2F. In certain embodiments, at least one instance of R.sup.J is CHF.sub.2. In certain embodiments, at least one instance of R.sup.J is CF.sub.3. In certain embodiments, at least one instance of R.sup.J is ethyl. In certain embodiments, at least one instance of R.sup.J is propyl. In certain embodiments, at least one instance of R.sup.J is butyl. In certain embodiments, at least one instance of R.sup.J is pentyl. In certain embodiments, at least one instance of R.sup.J is hexyl. In certain embodiments, at least one instance of R.sup.J is substituted alkenyl. In certain embodiments, at least one instance of R.sup.J is unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.J is substituted alkynyl. In certain embodiments, at least one instance of R.sup.J is unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.J is substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.J is unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.J is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.J is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.J is monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.J is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.J is substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.J is unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.J is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.J is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.J is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.J is monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.J is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.J is substituted aryl. In certain embodiments, at least one instance of R.sup.J is unsubstituted aryl. In certain embodiments, at least one instance of R.sup.J is 6- to 10-membered aryl. In certain embodiments, at least one instance of R.sup.J is substituted phenyl. In certain embodiments, at least one instance of R.sup.J is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.J is substituted heteroaryl. In certain embodiments, at least one instance of R.sup.J is unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.J is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.J is monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.J is 5-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.J is 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.J is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of R.sup.J is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.J is OR.sup.J1. In certain embodiments, at least one instance of R.sup.J is OH. In certain embodiments, at least one instance of R.sup.J is OMe. In certain embodiments, at least one instance of R.sup.J is OEt. In certain embodiments, at least one instance of R.sup.J is OPr. In certain embodiments, at least one instance of R.sup.J is OBu. In certain embodiments, at least one instance of R.sup.J is OBn. In certain embodiments, at least one instance of R.sup.J is OPh. In certain embodiments, at least one instance of R.sup.J is SR.sup.J1. In certain embodiments, at least one instance of R.sup.J is SH. In certain embodiments, at least one instance of R.sup.J is SMe. In certain embodiments, at least one instance of R.sup.J is N(R.sup.J1).sub.2. In certain embodiments, at least one instance of R.sup.J is NH.sub.2. In certain embodiments, at least one instance of R.sup.J is NHMe. In certain embodiments, at least one instance of R.sup.J is NMe.sub.2. In certain embodiments, at least one instance of R.sup.J is CN. In certain embodiments, at least one instance of R.sup.J is SCN. In certain embodiments, at least one instance of R.sup.J is C(NR.sup.J1)R.sup.J1, C(NR.sup.J1)O R.sup.J1, or C(NR.sup.J1)N(R.sup.J1).sub.2. In certain embodiments, at least one instance of R.sup.J is C(O)R.sup.J1 or C(O)O R.sup.J1. In certain embodiments, at least one instance of R.sup.J is C(O)N(R.sup.J1).sub.2. In certain embodiments, at least one instance of R.sup.J is C(O)NMe.sub.2, C(O)NHMe, or C(O)NH.sub.2. In certain embodiments, at least one instance of R.sup.J is NO.sub.2. In certain embodiments, at least one instance of R.sup.J is NR.sup.J1C(O) R.sup.J1, NR.sup.J1C(O)O R.sup.J1, or NR.sup.J1C(O)N(R.sup.J1).sub.2. In certain embodiments, at least one instance of R.sup.J is OC(O)R.sup.J1, OC(O)OR.sup.J1, or OC(O)N(R.sup.J1).sub.2.

(60) In certain embodiments, at least one instance of R.sup.J1 is H. In certain embodiments, at least one instance of R.sup.J1 is substituted acyl. In certain embodiments, at least one instance of R.sup.J1 is unsubstituted acyl. In certain embodiments, at least one instance of R.sup.J1 is acetyl. In certain embodiments, at least one instance of R.sup.J1 is substituted alkyl. In certain embodiments, at least one instance of R.sup.J1 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.J1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.J1 is methyl. In certain embodiments, at least one instance of R.sup.J1 is ethyl. In certain embodiments, at least one instance of R.sup.J1 is propyl. In certain embodiments, at least one instance of R.sup.J1 is butyl. In certain embodiments, at least one instance of R.sup.J1 is pentyl. In certain embodiments, at least one instance of R.sup.J1 is hexyl. In certain embodiments, at least one instance of R.sup.J1 is substituted alkenyl. In certain embodiments, at least one instance of R.sup.J1 is unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.J1 is substituted alkynyl. In certain embodiments, at least one instance of R.sup.J1 is unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.J1 is substituted or unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.J1 is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.J1 is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.J1 is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.J1 is substituted or unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.J1 is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.J1 is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.J1 is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.J1 is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.J1 is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.J1 is 6- to 10-membered aryl. In certain embodiments, at least one instance of R.sup.J1 is monocyclic aryl. In certain embodiments, at least one instance of R.sup.J1 is substituted phenyl. In certain embodiments, at least one instance of R.sup.J1 is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.J1 is bicyclic aryl. In certain embodiments, at least one instance of R.sup.J1 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.J1 is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.J1 is monocyclic heteroaryl. In certain embodiments, at least one instance of is 5- or 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.J1 is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of R.sup.J1 is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one instance of R.sup.J1 is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to a nitrogen atom. In certain embodiments, R.sup.J1 is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.J1 is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R.sup.J1 is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.J1 is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two instances of R.sup.J1 are joined to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, two instances of are joined to form a saturated or unsaturated heterocyclic ring. In certain embodiments, two instances of R.sup.J1 are joined to form a heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, two instances of R.sup.J1 are joined to form a 3- to 7-membered, monocyclic heterocyclic ring. In certain embodiments, two instances of R.sup.J1 are joined to form a substituted or unsubstituted heteroaryl ring. In certain embodiments, two instances of R.sup.J1 are joined to form a substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.

(61) In certain embodiments, k is 0. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4.

(62) In certain embodiments, a compound described herein is of Formula (II-B):

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

(64) In certain embodiments, a compound described herein is of Formula (I-B):

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

(66) In certain embodiments, a compound described herein is of the formula:

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

(68) In certain embodiments, a compound described herein is of the formula:

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

(70) In certain embodiments, a compound described herein is of the formula:

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

(72) In certain embodiments, a compound described herein is of the formula:

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

(74) In certain embodiments, a compound described herein is of the formula:

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

(76) In certain embodiments, a compound described herein is of the formula:

(77) ##STR00025##
or a pharmaceutically acceptable salt (e.g., a trifluoroacetic acid salt (compound 2-075)), solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

(78) In certain embodiments, the compounds described herein are compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. In certain embodiments, the compounds described herein are compounds of Formula (II), and pharmaceutically acceptable salts, solvates, and hydrates thereof. In certain embodiments, the compounds described herein are compounds of Formula (II), and pharmaceutically acceptable salts thereof. In certain embodiments, the compounds described herein are compounds of Formula (II). In certain embodiments, the compounds described herein are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. In certain embodiments, the compounds described herein are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, and hydrates thereof. In certain embodiments, the compounds described herein are compounds of Formula (I), and pharmaceutically acceptable salts thereof. In certain embodiments, the compounds described herein are compounds of Formula (I).

(79) Compounds described herein are binders of bromodomain-containing proteins. In certain embodiments, the compounds described herein bind to a bromodomain-containing protein. Without wishing to be bound by any particular theory, the compounds described herein are thought to bind in a binding pocket of a bromodomain of a bromodomain-containing protein. In certain embodiments, the compounds described herein bind to the binding pocket of the bromodomain by mimicking the contact between an acetyl-lysine residue of a second protein (e.g., a histone) and the binding pocket. In certain embodiments, the compounds described herein bind to the binding pocket of the bromodomain. In certain embodiments, the compounds described herein covalently bind to the bromodomain-containing protein. In certain embodiments, the compounds described herein non-covalently bind to the bromodomain-containing protein. In certain embodiments, the compounds described herein reversibly bind to the bromodomain-containing protein. In certain embodiments, the compounds described herein non-reversibly bind to the bromodomain-containing protein. In certain embodiments, the compounds described herein inhibit the activity of a bromodomain-containing protein. In certain embodiments, the compounds described herein inhibit the activity of a bromodomain-containing protein because of the binding of the compound to the bromodomain-containing protein. In certain embodiments, the compounds described herein inhibit the activity of a bromodomain-containing protein because of the binding of the compounds to a bromodomain of the bromodomain-containing protein. In certain embodiments, the compounds described herein inhibit the activity of a bromodomain. In certain embodiments, the activity of a bromodomain is the activity of bromodomain in binding an acetylated lysine residue (e.g., an acetylated lysine residue on the N-terminal tails of histones). In certain embodiments, the compounds described herein specifically bind to a bromodomain-containing protein. In certain embodiments, the compounds described herein specifically bind to a bromodomain of a bromodomain-containing protein. In certain embodiments, the compounds described herein that specifically bind to a bromodomain-containing protein show a greater binding affinity to the bromodomain-containing protein than to one or more other proteins or one or more other bromodomain-containing proteins. In certain embodiments, the compounds described herein non-specifically bind to a bromodomain-containing protein. In certain embodiments, the compounds described herein non-specifically bind to a bromodomain of a bromodomain-containing protein. In certain embodiments, the compounds described herein reduce transcriptional elongation. In certain embodiments, the compounds described herein disrupt the subcellular localization of a bromodomain-containing protein. In certain embodiments, the compounds described herein reduce chromatin binding. In certain embodiments, the compounds described herein inhibit the binding of Histone H4 Kac peptide to a bromodomain of a bromodomain-containing protein. In certain embodiments, the compounds described herein form one or more hydrogen bonds with an evolutionarily conserved asparagine in a bromodomain of a bromodomain-containing protein. In certain embodiments, the asparagine is Asn140 in BRD4(1) and Asn429 in BRD2(2). In certain embodiments, the bromodomain-containing protein is BRD4 or BRD2; and the asparagine is Asn140 in BRD4(1) and Asn429 in BRD2(2). In certain embodiments, the compounds described herein bind competitively with chromatin in a cellular environment. It is thus expected that the compounds described herein may be useful in the treatment of a disease associated with the activity a bromodomain-containing protein (e.g., a proliferative disease).

(80) The bromodomain-containing proteins that may be bound, and/or whose activity may be inhibited, by the compounds described herein include, but are not limited to, the bromodomain-containing proteins described herein. In certain embodiments, the bromodomain-containing protein is a bromo and extra terminal (BET) protein. In certain embodiments, the bromodomain-containing protein is BRD2. In certain embodiments, the bromodomain-containing protein is BRD2(1). In certain embodiments, the bromodomain-containing protein is BRD2(2). In certain embodiments, the bromodomain-containing protein is BRD3. In certain embodiments, the bromodomain-containing protein is BRD3(1). In certain embodiments, the bromodomain-containing protein is BRD3(2). In certain embodiments, the bromodomain-containing protein is BRD4. In certain embodiments, the bromodomain-containing protein is BRD4(1). In certain embodiments, the bromodomain-containing protein is BRD4(2). In certain embodiments, the bromodomain-containing protein is BRDT. In certain embodiments, the bromodomain-containing protein is BRDT(1). In certain embodiments, the bromodomain-containing protein is BRDT(2). In certain embodiments, the bromodomain-containing protein is a TBP (TATA box binding protein)-associated factor protein (TAF). In certain embodiments, the bromodomain-containing protein is TAF1. In certain embodiments, the bromodomain-containing protein is TAF1L. In certain embodiments, the bromodomain-containing protein is CREB-binding protein (CBP). In certain embodiments, the bromodomain-containing protein is E1A binding protein p300 (EP300).

(81) The binding affinity of a compound described herein to a bromodomain-containing protein may be measured by the dissociation constant (K.sub.d) value of an adduct of the compound described herein and the bromodomain-containing protein using methods known in the art (e.g., isothermal titration calorimetry (ITC)). In certain embodiments, the adduct comprises the compound described herein and the bromodomain-containing protein, which are bound (e.g., covalently or non-covalently) to each other. In certain embodiments, the K.sub.d value of the adduct is at most about 100 M, at most about 30 M, at most about 10 M, at most about 3 M, at most about 1 M, at most about 300 nM, at most about 100 nM, at most about 30 nM, at most about 10 nM, at most about 3 nM, or at most about 1 nM. In certain embodiments, the K.sub.d value of the adduct is at least about 1 nM, at least about 10 nM, at least about 100 nM, at least about 1 M, at least about 10 M, or at least about 100 M. Combinations of the above-referenced ranges (e.g., at most about 10 M and at least about 1 nM) are also within the scope of the invention. Other ranges are also possible. In certain embodiments, the K.sub.d value of the adduct is at most about 10 M. In certain embodiments, the K.sub.d value of the adduct is at most about 300 nM. In certain embodiments, the K.sub.d value of the adduct is at most about 100 nM.

(82) In certain embodiments, the activity of the bromodomain-containing proteins described herein is inhibited by the compounds described herein. The inhibition of the activity of a bromodomain-containing protein by a compound described herein may be measured by the half maximal inhibitory concentration (IC.sub.50) value of a compound described herein when the compound described herein, or a pharmaceutical composition thereof, is contacted, directly or indirectly, with the bromodomain-containing protein. The IC.sub.50 values may be obtained using methods known in the art. In certain embodiments, IC.sub.50 values are obtained by a competition binding assay. In certain embodiments, IC.sub.50 values are obtained by a method described herein. In certain embodiments, the IC.sub.5O value of a compound described herein is at most about 1 mM, at most about 300 M, at most about 100 M, at most about 30 M, at most about 10 M, at most about 3 M, at most about 1 M, at most about 300 nM, at most about 100 nM, at most about 30 nM, at most about 10 nM, at most about 3 nM, or at most about 1 nM. In certain embodiments, the IC.sub.50 value of a compound described herein is at least about 1 nM, at least about 3 nM, at least about 10 nM, at least about 30 nM, at least about 100 nM, at least about 300 nM, at least about 1 M, at least about 3 M, at least about 10 M, at least about 30 M, at least about 100 M, at least about 300 M, or at least 1 mM. Combinations of the above-referenced ranges (e.g., at most about 300 M and at least about 1 M) are also within the scope of the invention. Other ranges are also possible. In certain embodiments, the IC.sub.50 value of a compound described herein is at most about 300 M. In certain embodiments, the IC.sub.50 value of a compound described herein is at most about 30 M. In certain embodiments, the IC.sub.50 value of a compound described herein is at most about 10 M.

(83) The compounds described herein may selectively inhibit the activity of a bromodomain-containing protein. It is understood that, when a compound, pharmaceutical composition, method, use, or kit is referred to as selectively inhibiting the activity of a first protein, the compound, pharmaceutical composition, method, use, or kit inhibits the activity of the first protein to a greater extent than of at least a second protein that is different from the first protein. In certain embodiments, the compounds described herein selectively inhibit the activity of a bromodomain-containing protein, compared to a different bromodomain-containing protein. In certain embodiments, the compounds described herein selectively inhibit the activity of a bromodomain-containing protein, compared to a protein that is not a bromodomain-containing protein. In certain embodiments, the compounds described herein selectively inhibit the activity of a bromodomain-containing protein, compared to a kinase (e.g., a kinase described herein). In certain embodiments, the compounds described herein selectively inhibit the activity of a bromodomain-containing protein, compared to MPS1 (TTK), ERK5 (BMK1, MAPK7), a polo kinase (e.g., polo kinase 1, polo kinase 2, polo kinase 3, polo kinase 4), Ack1, Ack2, AbI, DCAMKL1, ABL1, an AbI mutant, DCAMKL2, ARKS, BRK, MKNK2, FGFR4, TNK1, PLK1, ULK2, PLK4, PRKD1, PRKD2, PRKD3, ROS 1, RPS6KA6, TAOK1, TAOK3, TNK2, Bcr-Abl, GAK, cSrc, TPR-Met, Tie2, MET, FGFR3, Aurora, AxI, Bmx, BTK, c-kit, CHK2, Flt3, MST2, p70S6K, PDGFR, PKB, PKC, Raf, ROCK-H, Rsk1, SGK, TrkA, TrkB, and/or TrkC. In certain embodiments, the compounds described herein selectively inhibit the activity of a bromodomain-containing protein, compared to a MAP kinase. In certain embodiments, the compounds described herein selectively inhibit the activity of a bromodomain-containing protein, compared to a mitotic spindle kinase. In certain embodiments, the compounds described herein selectively inhibit the activity of a bromodomain-containing protein, compared to a polo kinase. In certain embodiments, the compounds described herein selectively inhibit a BET protein. In certain embodiments, the compounds described herein selectively inhibit BRD2. In certain embodiments, the compounds described herein selectively inhibit BRD3. In certain embodiments, the compounds described herein selectively inhibit BRD4. In certain embodiments, the compounds described herein selectively inhibit BRDT. In certain embodiments, the compounds described herein selectively inhibit a TAF protein (e.g., TAF1 or TAF1L), CBP, and/or EP300. In certain embodiments, a compound described herein is a non-selective inhibitor of two or more bromodomain-containing proteins. In certain embodiments, a compound described herein is a non-selective inhibitor of a bromodomain-containing protein and a protein that is not a bromodomain-containing protein.

(84) The compounds described herein may also selectively bind to a bromodomain of a bromodomain-containing protein. It is understood that, when a compound is referred to as selectively binding to a bromodomain of a bromodomain-containing protein, the compound binds to the bromodomain of the bromodomain-containing protein with a great affinity than to a non-bromodomain of the bromodomain-containing protein.

(85) The selectivity of a compound described herein in inhibiting the activity of a bromodomain-containing protein over a second protein (e.g., a kinase) that is different from the bromodomain-containing protein may be measured by the quotient of the IC.sub.50 value of the compound described herein in inhibiting the activity of the second protein over the IC.sub.50 value of the compound described herein in inhibiting the activity of the bromodomain-containing protein. The selectivity of a compound described herein for a bromodomain-containing protein over second protein may also be measured by the quotient of the K.sub.d value of an adduct of the compound described herein and the second protein over the K.sub.d value of an adduct of the compound described herein and the bromodomain-containing protein. In certain embodiments, the selectivity is at least about 1-fold, at least about 3-fold, at least about 5-fold, at least about 10-fold, at least about 30-fold, at least about 100-fold, at least about 300-fold, at least about 1,000-fold, at least about 3,000-fold, at least about 10,000-fold, at least about 30,000-fold, or at least about 100,000-fold. In certain embodiments, the selectivity is at most about 100,000-fold, at most about 10,000-fold, at most about 1,000-fold, at most about 100-fold, at most about 10-fold, or at most about 1-fold. Combinations of the above-referenced ranges (e.g., and at least about 2-fold and at most about 10,000-fold) are also within the scope of the invention. Other ranges are also possible. In certain embodiments, the selectivity is at least about 3-fold. In certain embodiments, the selectivity is at least about 10-fold. In certain embodiments, the selectivity is at least about 100-fold.

(86) It is known in the art that a bromodomain-containing protein is implicated in a wide range of diseases. For example, BRD3 and BRD4 are related to BRD3 NUT midline carcinoma and BRD4 NUT midline carcinoma, respectively, BRDT is related to sperm formation, and CBP is related to mixed-lineage leukemia (MLL). Therefore, the compounds described herein are expected to be useful in treating and/or preventing diseases associated with bromodomain-containing proteins or as a male contraceptive.

(87) Pharmaceutical Compositions, Kits, and Administration

(88) The present invention provides pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula (II) (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof), and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

(89) In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating and/or preventing a disease (e.g., a disease described herein) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for contraception in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for inhibiting the replication of a virus. In certain embodiments, the effective amount is an amount effective for kill a virus. In certain embodiments, the effective amount is an amount effective for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a bromodomain-containing protein in a subject or cell. In certain embodiments, the effective amount is an amount effective for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a bromodomain in a subject or cell. In certain embodiments, the effective amount is an amount effective for inhibiting the binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., a histone) in a subject or cell. In certain embodiments, the effective amount is an amount effective for modulating (e.g., inhibiting) transcriptional elongation in a subject or cell. In certain embodiments, the effective amount is an amount effective for modulating (e.g., down-regulating or inhibiting) the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein in a subject or cell. In certain embodiments, the effective amount is an amount effective for modulating (e.g., reducing) the level of a bromodomain-containing protein in a subject or cell.

(90) An effective amount of a compound may vary from about 0.001 mg/kg to about 1000 mg/kg in one or more dose administrations for one or several days (depending on the mode of administration). In certain embodiments, the effective amount per dose varies from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg.

(91) In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a bromodomain-containing protein, the activity of a bromodomain, the binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., a histone), the transcriptional elongation, and/or the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a bromodomain-containing protein, the binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., a histone), and/or the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein by at most about 90%, at most about 80%, at most about 70%, at most about 60%, at most about 50%, at most about 40%, at most about 30%, at most about 20%, or at most about 10%. Combinations of the ranges described herein (e.g., at least about 20% and at most about 50%) are also within the scope of the invention. In certain embodiments, the activity of a bromodomain-containing protein, the binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., a histone), and/or the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein are inhibited by a percentage or a range of percentage described herein by an effective amount of a compound described herein.

(92) In certain embodiments, the gene regulated by a bromodomain-containing protein is a gene regulated by a bromo and extra terminal protein (BET). In certain embodiments, the gene regulated by a bromodomain-containing protein is BRD2. In certain embodiments, the gene regulated by a bromodomain-containing protein is BRD2(1). In certain embodiments, the gene regulated by a bromodomain-containing protein is BRD2(2). In certain embodiments, the gene regulated by a bromodomain-containing protein is BRD3. In certain embodiments, the gene regulated by a bromodomain-containing protein is BRD3(1). In certain embodiments, the gene regulated by a bromodomain-containing protein is BRD3(2). In certain embodiments, the gene regulated by a bromodomain-containing protein is BRD4. In certain embodiments, the gene regulated by a bromodomain-containing protein is BRD4(1). In certain embodiments, the gene regulated by a bromodomain-containing protein is BRD4(2). In certain embodiments, the gene regulated by a bromodomain-containing protein is BRDT. In certain embodiments, the gene regulated by a bromodomain-containing protein is BRDT(1). In certain embodiments, the gene regulated by a bromodomain-containing protein is BRDT(2). In certain embodiments, the gene regulated by a bromodomain-containing protein is a gene regulated by a TBP (TATA box binding protein)-associated factor protein (TAF). In certain embodiments, the gene regulated by a bromodomain-containing protein is TAF1. In certain embodiments, the gene regulated by a bromodomain-containing protein is TAF1L. In certain embodiments, the gene regulated by a bromodomain-containing protein is a gene regulated by a CREB-binding protein (CBP). In certain embodiments, the gene regulated by a bromodomain-containing protein is a gene regulated by an E1A binding protein p300 (EP300).

(93) 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 described herein (i.e., the active ingredient) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.

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

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

(96) 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.

(97) 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.

(98) 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.

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

(100) 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.

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

(102) Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, and sodium sulfite.

(103) 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.

(104) 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.

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

(106) 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.

(107) 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 bisulfate, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, German 115, Germaben II, Neolone, Kathon, and Euxyl.

(108) 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.

(109) 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.

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

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

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

(113) 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.

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

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

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

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

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

(119) Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present 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.

(120) 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. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. 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 the compound in powder form through the outer layers of the skin to the dermis are suitable.

(121) 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.

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

(123) 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).

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

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

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

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

(128) 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.

(129) Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by 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 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.

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

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

(132) 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.

(133) In certain embodiments, the compounds described herein 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 and/or prophylactic effect.

(134) 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.

(135) It will be also appreciated that a compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to have a disease in a subject in need thereof, in inhibiting the replication of a virus, in killing a virus, in inhibiting the activity of a bromodomain-containing protein in a subject or cell, in inhibiting the activity of a bromodomain in a subject or cell, in inhibiting the binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., a histone) in a subject or cell, in modulating (e.g., inhibiting) the transcription elongation, in modulating (e.g., inhibiting) the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein in a subject or cell), in modulating (e.g., reducing) the level of a bromodomain-containing protein in a subject or cell, bioavailability, and/or safety, reduce drug resistance, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body of a subject. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.

(136) The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease described herein. Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) 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.

(137) The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, and pain-relieving agents. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-leukemia agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ADE, Adriamycin RDF (doxorubicin hydrochloride), Ambochlorin (chlorambucil), ARRANON (nelarabine), ARZERRA (ofatumumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicin hydrochloride), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine), CLOLAR (clofarabine), CVP, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), ERWINAZE (Asparaginase Erwinia Chrysanthemi), FLUDARA (fludarabine phosphate), FOLEX (methotrexate), FOLEX PFS (methotrexate), GAZYVA (obinutuzumab), GLEEVEC (imatinib mesylate), Hyper-CVAD, ICLUSIG (ponatinib hydrochloride), IMBRUVICA (ibrutinib), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), MARQIBO (vincristine sulfate liposome), METHOTREXATE LPF (methorexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), mitoxantrone hydrochloride, MUSTARGEN (mechlorethamine hydrochloride), MYLERAN (busulfan), NEOSAR (cyclophosphamide), ONCASPAR (Pegaspargase), PURINETHOL (mercaptopurine), PURIXAN (mercaptopurine), Rubidomycin (daunorubicin hydrochloride), SPRYCEL (dasatinib), SYNRIBO (omacetaxine mepesuccinate), TARABINE PFS (cytarabine), TASIGNA (nilotinib), TREANDA (bendamustine hydrochloride), TRISENOX (arsenic trioxide), VINCASAR PFS (vincristine sulfate), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-lymphoma agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC, ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), AMBOCHLORIN (chlorambucil), AMBOCLORIN (chlorambucil), ARRANON (nelarabine), BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR (tositumomab and iodine I 131 tositumomab), BICNU (carmustine), BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide), COPP, COPP-ABV, CVP, CYTOXAN (cyclophosphamide), DEPOCYT (liposomal cytarabine), DTIC-DOME (dacarbazine), EPOCH, FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLOTYN (pralatrexate), HYPER-CVAD, ICE, IMBRUVICA (ibrutinib), INTRON A (recombinant interferon alfa-2b), ISTODAX (romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), Lomustine, MATULANE (procarbazine hydrochloride), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MOPP, MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (denileukin diftitox), OPPA, R-CHOP, REVLIMID (lenalidomide), RITUXAN (rituximab), STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VINCASAR PFS (vincristine sulfate), ZEVALIN (ibritumomab tiuxetan), ZOLINZA (vorinostat), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is REVLIMID (lenalidomide), DACOGEN (decitabine), VIDAZA (azacitidine), CYTOSAR-U (cytarabine), IDAMYCIN (idarubicin), CERUBIDINE (daunorubicin), LEUKERAN (chlorambucil), NEOSAR (cyclophosphamide), FLUDARA (fludarabine), LEUSTATIN (cladribine), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABRAXANE (paclitaxel albumin-stabilized nanoparticle formulation), AC, AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITOR DISPERZ (everolimus), ALDARA (imiquimod), ALIMTA (pemetrexed disodium), AREDIA (pamidronate disodium), ARIMIDEX (anastrozole), AROMASIN (exemestane), AVASTIN (bevacizumab), BECENUM (carmustine), BEP, BICNU (carmustine), BLENOXANE (bleomycin), CAF, CAMPTOSAR (irinotecan hydrochloride), CAPDX, CAPRELSA (vandetanib), CARBOPLATIN-TAXOL, CARMUBRIS (carmustine), CASODEX (bicalutamide), CEENU (lomustine), CERUBIDINE (daunorubicin hydrochloride), CERVARIX (recombinant HPV bivalent vaccine), CLAFEN (cyclophosphamide), CMF, COMETRIQ (cabozantinib-s-malate), COSMEGEN (dactinomycin), CYFOS (ifosfamide), CYRAMZA (ramucirumab), CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), DACOGEN (decitabine), DEGARELIX, DOXIL (doxorubicin hydrochloride liposome), DOXORUBICIN HYDROCHLORIDE, DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME (dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicin hydrochloride), ELOXATIN (oxaliplatin), ERBITUX (cetuximab), ERIVEDGE (vismodegib), ETOPOPHOS (etoposide phosphate), EVACET (doxorubicin hydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant), FEC, FEMARA (letrozole), FLUOROPLEX (fluorouracil), FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, GARDASIL (recombinant human papillomavirus (HPV) quadrivalent vaccine), GEMCITABINE-CISPLATIN, GEMCITABINE-OXALIPLATIN, GEMZAR (gemcitabine hydrochloride), GILOTRIF (afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustine implant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab), HYCAMTIN (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (axitinib), INTRON A (recombinant interferon alfa-2b), IRESSA (gefitinib), IXEMPRA (ixabepilone), JAKAFI (ruxolitinib phosphate), JEVTANA (cabazitaxel), KADCYLA (ado-trastuzumab emtansine), KEYTRUDA (pembrolizumab), KYPROLIS (carfilzomib), LIPODOX (doxorubicin hydrochloride liposome), LUPRON (leuprolide acetate), LUPRON DEPOT (leuprolide acetate), LUPRON DEPOT-3 MONTH (leuprolide acetate), LUPRON DEPOT-4 MONTH (leuprolide acetate), LUPRON DEPOT-PED (leuprolide acetate), MEGACE (megestrol acetate), MEKINIST (trametinib), METHAZOLASTONE (temozolomide), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MITOXANTRONE HYDROCHLORIDE, MITOZYTREX (mitomycin c), MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR (azacitidine), NAVELBINE (vinorelbine tartrate), NEOSAR (cyclophosphamide), NEXAVAR (sorafenib tosylate), NOLVADEX (tamoxifen citrate), NOVALDEX (tamoxifen citrate), OFF, PAD, PARAPLAT (carboplatin), PARAPLATIN (carboplatin), PEG-INTRON (peginterferon alfa-2b), PEMETREXED DISODIUM, PERJETA (pertuzumab), PLATINOL (cisplatin), PLATINOL-AQ (cisplatin), POMALYST (pomalidomide), prednisone, PROLEUKIN (aldesleukin), PROLIA (denosumab), PROVENGE (sipuleucel-t), REVLIMID (lenalidomide), RUBIDOMYCIN (daunorubicin hydrochloride), SPRYCEL (dasatinib), STIVARGA (regorafenib), SUTENT (sunitinib malate), SYLATRON (peginterferon alfa-2b), SYLVANT (siltuximab), SYNOVIR (thalidomide), TAC, TAFINLAR (dabrafenib), TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA (nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), TEMODAR (temozolomide), THALOMID (thalidomide), TOPOSAR (etoposide), TORISEL (temsirolimus), TPF, TRISENOX (arsenic trioxide), TYKERB (lapatinib ditosylate), VECTIBIX (panitumumab), VEIP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VEPESID (etoposide), VIADUR (leuprolide acetate), VIDAZA (azacitidine), VINCASAR PFS (vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVORIN (leucovorin calcium), XALKORI (crizotinib), XELODA (capecitabine), XELOX, XGEVA (denosumab), XOFIGO (radium 223 dichloride), XTANDI (enzalutamide), YERVOY (ipilimumab), ZALTRAP (ziv-aflibercept), ZELBORAF (vemurafenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid), ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is a binder of a bromodomain-containing protein. In certain embodiments, the additional pharmaceutical agent is a binder of a bromodomain. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a bromodomain-containing protein. In certain embodiments, the additional pharmaceutical agent is an binder or inhibitor of a bromodomain. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy), and chemotherapy.

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

(139) Thus, in one aspect, provided are kits including a first container comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the kits are useful for treating and/or preventing a disease described herein in a subject in need thereof. In certain embodiments, the kits are useful for treating a disease described herein in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease described herein in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease described herein in a subject in need thereof. In certain embodiments, the kits are useful for contraception (e.g., male contraception). In certain embodiments, the kits are useful for in inhibiting the replication of a virus. In certain embodiments, the kits are useful for killing a virus. In certain embodiments, the kits are useful for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a bromodomain-containing protein in a subject or cell. In certain embodiments, the kits are useful for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a bromodomain in a subject or cell. In certain embodiments, the kits are useful for inhibiting the binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., a histone) in a subject or cell. In certain embodiments, the kits are useful for modulating (e.g., inhibiting) the transcriptional elongation in a subject or cell. In certain embodiments, the kits are useful for modulating (e.g., down-regulating or inhibiting) the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein in a subject or cell. In certain embodiments, the kits are useful for modulating (e.g., reducing) the level of a bromodomain-containing protein in a subject or cell.

(140) In certain embodiments, the kits are useful for screening a library of compounds to identify a compound that is useful in a method of the invention.

(141) In certain embodiments, a kit described herein further includes instructions for using the kit, such as instructions for using the kit in a method of the invention (e.g., instructions for administering a compound or pharmaceutical composition described herein to a subject). A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating and/or preventing a disease described herein in a subject in need thereof. In certain embodiments, the kits and instructions provide for treating a disease described herein in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease described herein in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease described herein in a subject in need thereof. In certain embodiments, the kits and instructions provide for contraception (e.g., male contraception). In certain embodiments, the kits and instructions provide for inhibiting the replication of a virus. In certain embodiments, the kits and instructions provide for killing a virus. In certain embodiments, the kits and instructions provide for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a bromodomain-containing protein in a subject or cell. In certain embodiments, the kits and instructions provide for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a bromodomain in a subject or cell. In certain embodiments, the kits and instructions provide for inhibiting the binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., a histone) in a subject or cell. In certain embodiments, the kits and instructions provide for modulating (e.g., inhibiting) the transcriptional elongation. In certain embodiments, the kits and instructions provide for modulating (e.g., down-regulating or inhibiting) the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein in a subject or cell. In certain embodiments, the kits and instructions provide for modulating (e.g., reducing) the level of a bromodomain-containing protein in a subject or cell. In certain embodiments, the kits and instructions provide for screening a library of compounds to identify a compound that is useful in a method of the invention. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

(142) Methods of Treatment and Uses

(143) The present invention provides methods for the treatment of a wide range of diseases, such as diseases associated with bromodomains, diseases associated with the activity (e.g., aberrant activity) of bromodomains, diseases associated with bromodomain-containing proteins, and disease associated with the activity (e.g., aberrant activity) of bromodomain-containing proteins. Exemplary diseases include, but are not limited to, proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning. Also provided by the present invention are methods for contraception (e.g., male contraception). The present invention further provides methods of inhibiting the activity (e.g., aberrant activity, such as increased activity) of a bromodomain or bromodomain-containing protein, methods of inhibiting the binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., a histone), methods of modulating (e.g., inhibiting) the transcriptional elongation, and methods of modulating (e.g., down-regulating or inhibiting) the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein.

(144) Gene regulation is fundamentally governed by reversible, non-covalent assembly of macromolecules. Signal transduction to RNA polymerase requires higher-ordered protein complexes, spatially regulated by assembly factors capable of interpreting the post-translational modification states of chromatin. Epigenetic readers are structurally diverse proteins, and each of the epigenetic readers possesses one or more evolutionarily conserved effector modules, which recognize covalent modifications of proteins (e.g., histones) or DNA. The E-N-acetylation of lysine residues (Kac) on histone tails is associated with an open chromatin architecture and transcriptional activation. Context-specific molecular recognition of acetyl-lysine is principally mediated by bromodomains.

(145) Bromodomain-containing proteins are of substantial biological interest, as components of transcription factor complexes (e.g., TBP (TATA box binding protein)-associated factor 1 (TAF1), CREB-binding protein (CBP or CREBBP), P300/CBP-associated factor (PCAF), and Gcn5) and determinants of epigenetic memory. There are 41 human proteins containing a total of 57 diverse bromodomains. Despite large sequence variations, all bromodomains share a conserved fold comprising a left-handed bundle of four alpha helices (.sub.z, .sub.A, .sub.B, and .sub.C), linked by diverse loop regions (ZA and BC loops) that determine substrate specificity. Co-crystal structures with peptidic substrates showed that the acetyl-lysine is recognized by a central hydrophobic cavity and is anchored by a hydrogen bond with an asparagine residue present in most bromodomains. The bromo and extra-terminal (BET) family (e.g., BRD2, BRD3, BRD4 and BRDT) shares a common domain architecture comprising two N-terminal bromodomains that exhibit high level of sequence conservation, and a more divergent C-terminal recruitment domain.

(146) Recent research has established a compelling rationale for targeting BRD4 in cancer. BRD4 functions to facilitate cell cycle progression and knock-down in cultured cancer cell lines prompts G1 arrest. BRD4 is an important mediator of transcriptional elongation, functioning to recruit the positive transcription elongation factor complex (P-TEFb). Cyclin dependent kinase-9, a core component of P-TEFb, is a validated target in chronic lymphocytic leukemia, and has recently been linked to c-Myc dependent transcription. Bromodomains present in BRD4 recruit P-TEFb to mitotic chromosomes resulting in increased expression of growth promoting genes. BRD4 remains bound to transcriptional start sites of genes expressed during M/G1 but has not been found present at start sites that are expressed later in the cell cycle. Knockdown of BRD4 in proliferating cells has been shown to lead to G1 arrest and apoptosis by decreasing expression levels of genes important for mitotic progression and survival.

(147) Importantly, BRD4 has recently been identified as a component of a recurrent t(15;19) chromosomal translocation in an aggressive form of human squamous cell carcinoma. Such translocations express the tandem N-terminal bromodomains of BRD4 as an in-frame chimera with the nuclear protein in testis (NUT) protein, genetically defining the NUT midline carcinoma (NMC). Functional studies in patient-derived NMC cell lines have validated the essential role of the BRD4-NUT oncoprotein in maintaining the characteristic proliferation advantage and differentiation block of this malignancy. Notably, RNA silencing of BRD4-NUT gene expression arrests proliferation and prompts squamous differentiation with a marked increase in cytokeratin expression. A bromodomain may also down-regulates Myc and other transcripitional factors, such as interleukin 7 receptor (IL7R). These observations underscore the utility and therapeutic potential of an binder or inhibitor of bromodomain-containing proteins.

(148) In another aspect, the present invention provides methods of inhibiting the activity of a bromodomain-containing protein in a subject or cell. In certain embodiments, the bromodomain-containing protein is a bromodomain-containing protein described herein (e.g., a BET protein, such as BRD2, BRD3, BRD4, or BRDT). In certain embodiments, the activity of a bromodomain-containing protein in a subject or cell is inhibited by the inventive methods. In certain embodiments, the activity of a bromodomain-containing protein in a subject or cell is inhibited by the inventive methods by at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In certain embodiments, the activity of a bromodomain-containing protein in a subject or cell is inhibited by the inventive methods by at most about 90%, at most about 80%, at most about 70%, at most about 60%, at most about 50%, at most about 40%, at most about 30%, at most about 20%, at most about 10%, at most about 3%, or at most about 1%. Combinations of the above-referenced ranges (e.g., at least about 10% and at most about 50%) are also within the scope of the invention. Other ranges are also possible. In some embodiments, the activity of a bromodomain-containing protein in a subject or cell is selectively inhibited by the inventive methods. In some embodiments, the activity of a bromodomain-containing protein in a subject or cell is selectively inhibited by the inventive methods, compared to the activity of a kinase (e.g., a MAP kinase, a mitotic spindle kinase, a polo kinase). In other embodiments, the activity of a bromodomain-containing protein in a subject or cell is non-selectively inhibited by the inventive methods. In certain embodiments, the cytokine level and/or histamine release are reduced by the inventive methods.

(149) In certain embodiments, the activity of a bromodomain-containing protein is an aberrant activity of the bromodomain-containing protein. In certain embodiments, the activity of a bromodomain-containing protein is an increased activity of the bromodomain-containing protein. In certain embodiments, the activity of a bromodomain-containing protein is reduced by a method of the invention.

(150) In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject is a male. In certain embodiments, the subject is a female. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject described herein is a human male. In certain embodiments, the subject described herein is a human female. In certain embodiments, the subject is a human diagnosed as having a disease described herein. In certain embodiments, the subject is a human diagnosed as being at a higher-than-normal risk to have a disease described herein. In certain embodiments, the subject is a human suspected of having a disease described herein. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a fish. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a human or non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs).

(151) In certain embodiments, the cell described herein is present in vitro. In certain embodiments, the cell is present ex vivo. In certain embodiments, the cell is present in vivo.

(152) In another aspect, the present invention provides methods of inhibiting the activity of a bromodomain in a subject or cell. In certain embodiments, the activity of a bromodomain is an aberrant activity of the bromodomain. In certain embodiments, the activity of a bromodomain is an increased activity of the bromodomain. In certain embodiments, the activity of a bromodomain is reduced by a method of the invention.

(153) Another aspect of the present invention relates to methods of inhibiting the binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., a histone) in a subject or cell. In certain embodiments, the second protein is a protein including at least one acetyl-lysine residue. In certain embodiments, the second protein is not a bromodomain-containing protein. In certain embodiments, the second protein is a histone. In certain embodiments, the histone is selected from the group consisting of H1, H2A, H2B, H3, H4, and H5. In certain embodiments, the binding of a bromodomain of the bromodomain-containing protein to an acetyl-lysine residue of the second protein (e.g., a histone) is inhibited by the inventive methods.

(154) In another aspect, the present invention provides methods of modulating (e.g., inhibiting) the transcription elongation. In certain embodiments, the transcription elongation is modulated (e.g., inhibited) by the inventive methods.

(155) In another aspect, the present invention provides methods of modulating the expression (e.g., transcription) of a gene (e.g., a gene described herein) that is regulated by a bromodomain-containing protein in a subject or cell. In certain embodiments, the present invention provides methods of down-regulating or inhibiting the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein in a subject or cell. Without wishing to be bound by any particular theory, the compounds and pharmaceutical compositions described herein may be able to interfere with the binding of a bromodomain-containing protein to a transcriptional start site of the gene. In certain embodiments, the compounds and pharmaceutical compositions described herein interfere with the acetyl-lysine recognition during the expression (e.g., transcription) of the gene. In certain embodiments, the compounds and pharmaceutical compositions described herein interfere with the acetyl-lysine anchoring during the expression (e.g., transcription) of the gene. In certain embodiments, the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein in a subject or cell is modulated by the inventive methods. In certain embodiments, the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein in a subject or cell is down-regulated or inhibited by the inventive methods. In certain embodiments, the gene that is regulated by a bromodomain-containing protein is an oncogene.

(156) Another aspect of the present invention relates to methods of treating a disease in a subject in need thereof. In certain embodiments, the disease is treated by the inventive methods.

(157) In certain embodiments, the disease is a disease associated with a bromodomain-containing protein. In certain embodiments, the disease is a disease associated with the activity of a bromodomain-containing protein. In certain embodiments, the disease is a disease associated with the aberrant activity (e.g., increased activity) of a bromodomain-containing protein.

(158) In certain embodiments, the disease is a disease associated with a bromodomain (e.g., a bromodomain of a bromodomain-containing protein). In certain embodiments, the disease is a disease associated with the activity of a bromodomain. In certain embodiments, the disease is a disease associated with the aberrant activity (e.g., increased activity) of a bromodomain. In certain embodiments, the disease is a disease associated with the function (e.g., dysfunction) of a bromodomain.

(159) In certain embodiments, the disease described herein is driven by a transcriptional activator. In certain embodiments, the transcriptional activator is Myc. In certain embodiments, the disease is associated with a NUT rearrangement. In certain embodiments, the disease is a disease associated with aberrant Myc function. In certain embodiments, the disease is a disease associated with interleukin 7 receptor (IL7R).

(160) In certain embodiments, the disease is a proliferative disease (e.g., a proliferative disease described herein). In certain embodiments, the disease is cancer (e.g., a cancer described herein). In certain embodiments, the disease is lung cancer. In certain embodiments, the disease is multiple myeloma. In certain embodiments, the disease is neuroblastoma. In certain embodiments, the disease is colon cancer. In certain embodiments, the disease is testicular cancer. In certain embodiments, the disease is ovarian cancer. In certain embodiments, the disease is lung cancer (e.g., small-cell lung cancer or non-small-cell lung cancer). In certain embodiments, the disease is NUT midline carcinoma (e.g., BRD3 NUT midline carcinoma or BRD4 NUT midline carcinoma). In certain embodiments, the disease is leukemia. In certain embodiments, the disease is mixed-lineage leukemia (MLL). In certain embodiments, the disease is acute myelocytic leukemia (AML), biphenotypic B myelomonocytic leukemia, or erythroleukemia. In certain embodiments, the disease is selected from the group consisting of Burkitt's lymphoma, breast cancer, colon cancer, neuroblastoma, glial blastoma multiforme, chronic lymphocytic leukemia, and squamous cell carcinoma.

(161) In certain embodiments, the disease is a benign neoplasm (e.g., a benign neoplasm described herein).

(162) In certain embodiments, the disease is an inflammatory disease (e.g., an inflammatory disease described herein). In certain embodiments, the disease is a disease that involves an inflammatory response to an infection with a bacterium, virus, fungus, parasite, and/or protozoon. In certain embodiments, the disease is selected from the group consisting of osteoarthritis, acute gout, multiple sclerosis, an inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), neuroinflammation, asthma, a chronic obstructive airways disease, pneumonitis, myositis, eczema, dermatitis, acne, cellulitis, an occlusive disease, thrombosis, alopecia, nephritis, vasculitis, retinitis, uveitis, scleritis, sclerosing cholangitis, hypophysitis, thyroiditis, septic shock, systemic inflammatory response syndrome (SIRS), toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, burns, pancreatitis (e.g., acute pancreatitis), post-surgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis, and malaria. In certain embodiments, the disease is acute or chronic pancreatitis. In certain embodiments, the disease is burns. In certain embodiments, the disease is an inflammatory bowel disease. In certain embodiments, the disease is neuroinflammation. In certain embodiments, the disease is sepsis or sepsis syndrome. In certain embodiments, the disease is graft-versus-host disease (GVHD).

(163) In certain embodiments, the disease is an autoimmune disease (e.g., an autoimmune disease described herein). In certain embodiments, the disease is rheumatoid arthritis. In certain embodiments, the disease is psoriasis, systemic lupus erythematosus, vitiligo, a bullous skin disease.

(164) In certain embodiments, the disease is a cardiovascular disease. In certain embodiments, the disease is atherogenesis or atherosclerosis. In certain embodiments, the disease is arterial stent occlusion, heart failure (e.g., congestive heart failure), a coronary arterial disease, myocarditis, pericarditis, a cardiac valvular disease, stenosis, restenosis, in-stent-stenosis, angina pectoris, myocardial infarction, acute coronary syndromes, coronary artery bypass grafting, a cardio-pulmonary bypass procedure, endotoxemia, ischemia-reperfusion injury, cerebrovascular ischemia (stroke), renal reperfusion injury, embolism (e.g., pulmonary, renal, hepatic, gastro-intestinal, or peripheral limb embolism), or myocardial ischemia.

(165) In certain embodiments, the disease is a viral infection. In certain embodiments, the disease is a DNA virus infection. In certain embodiments, the disease is a dsDNA virus infection. In certain embodiments, the disease is an ssDNA virus infection. In certain embodiments, the disease is an RNA virus infection. In certain embodiments, the disease is a dsRNA virus infection. In certain embodiments, the disease is a (+)ssRNA virus infection. In certain embodiments, the disease is a ()ssRNA virus infection. In certain embodiments, the disease is a reverse transcribing (RT) virus infection. In certain embodiments, the disease is an ssRNA-RT virus infection. In certain embodiments, the disease is a dsDNA-RT virus infection. In certain embodiments, the disease is human immunodeficiency virus (HIV) infection. In certain embodiments, the disease is acquired immunodeficiency syndrome (AIDS). In certain embodiments, the disease is human papillomavirus (HPV) infection. In certain embodiments, the disease is hepatitis C virus (HCV) infection. In certain embodiments, the disease is a herpes virus infection (e.g., herpes simplex virus (HSV) infection). In certain embodiments, the disease is Ebola virus infection. In certain embodiments, the disease is severe acute respiratory syndrome (SARS). In certain embodiments, the disease is influenza virus infection. In certain embodiments, the disease is an influenza virus infection. In certain embodiments, the disease is an influenza A virus infection. In certain embodiments, the disease is human flu (e.g., H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, or H10N7 virus infection). In certain embodiments, the disease is bird flu (e.g., H5N1 or H7N9 virus infection). In certain embodiments, the disease is swine influenza (e.g., H1N1, H1N2, H2N1, H3N1, H3N2, or H2N3 virus infection, or influenza C virus infection). In certain embodiments, the disease is equine influenza (e.g., H7N7 or H3N8 virus infection). In certain embodiments, the disease is canine influenza (e.g., H3N8 virus infection). In certain embodiments, the disease is an influenza B virus infection. In certain embodiments, the disease is an influenza C virus infection. In certain embodiments, the disease is Dengue fever, Dengue hemorrhagic fever (DHF), Dengue shock syndrome (DSS), hepatitis A, hepatitis B, hepatitis D, hepatitis E, hepatitis F, Coxsackie A virus infection, Coxsackie B virus infection, fulminant viral hepatitis, viral myocarditis, parainfluenza virus infection, an RS virus (RSV) infection (e.g., RSV bronchiolitis, RSV pneumonia, especially an infant and childhood RSV infection and RSV pneumonia in the patients with cardiopulmonary disorders), measles virus infection, vesicular stomatitis virus infection, rabies virus infection, Japanese encephalitis, Junin virus infection, human cytomegalovirus infection, varicellovirus infection, cytomegalovirus infection, muromegalovirus infection, proboscivirus infection, roseolovirus infection, lymphocryptovirus infection, macavirus infection, percavirus infection, rhadinovirus infection), poliovirus infection, Marburg virus infection, Lassa fever virus infection, Venezuelan equine encephalitis, Rift Valley Fever virus infection, Korean hemorrhagic fever virus infection, Crimean-Congo hemorrhagic fever virus infection, encephalitis, Saint Louise encephalitis, Kyasanur Forest disease, Murray Valley encephalitis, tick-borne encephalitis, West Nile encephalitis, yellow fever, adenovirus infection, poxvirus infection, or a viral infection in subjects with immune disorders.

(166) In certain embodiments, the disease is a fibrotic condition. In certain embodiments, the disease is selected from the group consisting of renal fibrosis, post-operative stricture, keloid formation, hepatic cirrhosis, biliary cirrhosis, and cardiac fibrosis. In certain embodiments, the disease is scleroderma. In certain embodiments, the disease is idiopathic pulmonary fibrosis.

(167) In certain embodiments, the disease is an endocrine disease. In certain embodiments, the disease is Addison's disease.

(168) In certain embodiments, the disease is a metabolic disease. In certain embodiments, the disease is diabetes. In certain embodiments, the disease is type 1 diabetes. In certain embodiments, the disease is type 2 diabetes or gestational diabetes. In certain embodiments, the disease is obesity. In certain embodiments, the disease is fatty liver (NASH or otherwise), cachexia, hypercholesterolemia, or a disorder of lipid metabolism via the regulation of apolipoprotein A1 (APOA1).

(169) In certain embodiments, the disease is radiation poisoning. In certain embodiments, the disease is radiation injury.

(170) In certain embodiments, the disease is acute rejection of transplanted organs or multi-organ dysfunction syndrome.

(171) In certain embodiments, the disease is Alzheimer's disease.

(172) In still another aspect, the present invention provides methods of preventing a disease described herein in a subject in need thereof. In certain embodiments, the disease is prevented by the inventive methods.

(173) In yet another aspect, the present invention provides methods of reducing the risk to have a disease described herein in a subject in need thereof. In certain embodiments, the risk to have the disease is reduced by the inventive methods.

(174) In yet another aspect, the present invention provides methods for contraception in a subject in need thereof. In certain embodiments, the present invention provides methods of male contraception in a male subject in need thereof. In certain embodiments, the present invention provides methods of female contraception in a female subject in need thereof.

(175) In yet another aspect, the present invention provides methods of inhibiting sperm formation in a subject in need thereof.

(176) Another aspect of the present invention relates to methods of inhibiting the replication of a virus. In certain embodiments, the replication of the virus is inhibited by the inventive methods.

(177) In certain embodiments, the virus is a virus described herein. In certain embodiments, the virus is the virus causing a viral infection described herein. In certain embodiments, the virus is human immunodeficiency virus (HIV), human papillomavirus (HPV), hepatitis C virus (HCV), herpes simplex virus (HSV), Ebola virus, or influenza virus.

(178) In certain embodiments, the virus described herein is present in vitro. In certain embodiments, the virus is present ex vivo. In certain embodiments, the virus is present in vivo.

(179) Another aspect of the present invention relates to methods of killing a virus. In certain embodiments, the virus is killed by the inventive methods.

(180) Another aspect of the invention relates to methods of inhibiting the interaction between a bromodomain-containing protein and an immunoglobulin (Ig) regulatory element in a subject or cell.

(181) In certain embodiments, the methods of the invention include administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition described herein. In certain embodiments, the methods of the invention include administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition described herein. In certain embodiments, the methods of the invention include administering to a subject in need thereof a prophylactically effective amount of a compound or pharmaceutical composition described herein. In certain embodiments, the methods of the invention include contacting a cell with an effective amount of a compound or pharmaceutical composition described herein. In certain embodiments, the methods of the invention include contacting a virus with an effective amount of a compound or pharmaceutical composition described herein.

(182) Another aspect of the invention relates to methods of modulating gene that is regulated by a bromodomain-containing protein expressing in a subject or cell.

(183) Another aspect of the invention relates to methods of modulating the level of a bromodomain-containing protein in a subject or cell.

(184) Another aspect of the invention relates to methods of screening a library of compounds, and pharmaceutical acceptable salts thereof, to identify a compound, or a pharmaceutical acceptable salt thereof, that is useful in the methods of the invention. In certain embodiments, the methods of screening a library include obtaining at least two different compounds described herein; and performing at least one assay using the different compounds described herein. In certain embodiments, at least one assay is useful in identifying a compound that is useful in the inventive methods.

(185) Typically, the methods of screening a library of compounds involve at least one assay. In certain embodiments, the assay is performed to detect one or more characteristics associated with the treatment and/or prevention of a disease described herein, with the inhibition of the activity of a bromodomain-containing protein, with the inhibition of the activity of a bromodomain, with the inhibition of the binding of a bromodomain to an acetyl-lysine residue of a second protein (e.g., a histone), with the modulation (e.g., inhibition) of the transcriptional elongation, and/or with the modulation (e.g., inhibition) of the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein. The characteristics may be desired characteristics (e.g., a disease having been treated, a disease having been prevented, the risk to have a disease having been reduced, the replication of a virus having been inhibited, a virus having been killed, the activity of a bromodomain-containing protein having been inhibited, the activity of a bromodomain, the binding of a bromodomain to an acetyl-lysine residue of a second protein (e.g., a histone)having been inhibited, the transcriptional elongation having been modulated (e.g., having been inhibited), the level of a bromodomain-containing protein in a subject or cell having been modulated (e.g., reduced), or the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein having been modulated (e.g., having been inhibited)). The characteristics may be undesired characteristics (e.g., a disease having not been treated, a disease having not been prevented, the risk to have a disease having not been reduced, the replication of a virus having not been inhibited, a virus not having been killed, the activity of a bromodomain-containing protein having not been inhibited, the activity of a bromodomain having not been inhibited, the binding of a bromodomain to an acetyl-lysine residue of a second protein (e.g., a histone)having not been inhibited, the transcriptional elongation having not been modulated (e.g., having not been inhibited), the level of a bromodomain-containing protein in a subject or cell having not been modulated (e.g., having not been reduced), or the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein having not been modulated (e.g., having not been inhibited)). The assay may be an immunoassay, such as a sandwich-type assay, competitive binding assay, one-step direct test, two-step test, or blot assay. The step of performing at least one assay may be performed robotically or manually. In certain embodiments, the assay comprises (a) contacting a library of compounds with a bromodomain-containing protein; and (b) detecting the binding of the library of compounds to the bromodomain-containing protein. In certain embodiments, the assay comprises detecting the specific binding of the library of compounds to the bromodomain-containing protein. In certain embodiments, the assay comprises detecting the specific binding of the library of compounds to a bromodomain of the bromodomain-containing protein. In certain embodiments, the detected binding of the library of compounds to the bromodomain-containing protein is useful in identifying the compound that is useful in the methods of the invention. In certain embodiments, the step of detecting the binding comprises using differential scanning fluorimetry (DSF), isothermal titration calorimetry (ITC), and/or an amplified luminescence proximity homogeneous assay (ALPHA). The step of performing at least one assay may be performed in a cell (e.g., a cancer cell) in vitro, ex vivo, or in vivo. In certain embodiments, the step of performing at least one assay is performed in a cell (e.g., a cancer cell) in vitro. In certain embodiments, the assay comprises (a) contacting a library of compounds with a cell; and (b) detecting a decrease in cell proliferation, an increase in cell death, and/or an increase in cell differentiation. In certain embodiments, the cell death is apoptotic cell death. In certain embodiments, the cell differentiation is identified by detecting an increase in cytokeratin expression. In certain embodiments, the step of performing at least one assay further comprises detecting a reduction in transcriptional elongation.

(186) In another aspect, the present invention provides the compounds described herein for use in a method of the invention.

(187) In still another aspect, the present invention provides the pharmaceutical compositions described herein for use in a method of the invention.

(188) In still another aspect, the present invention provides uses of the compounds described herein in a method of the invention.

(189) In further another aspect, the present invention provides uses of the pharmaceutical compositions described herein in a method of the invention.

EXAMPLES

(190) In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

(191) Preparation of Compounds

(192) The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures or methods known in the art (e.g., methods reported in U.S. Patent Application Publication, US 2012/040961; Elkins et al., Journal of Medicinal Chemistry (2013), 56(11), 4413-4421; Kavanagh et al., Bioorganic & Medicinal Chemistry Letters (2013), 23(13), 3690-3696; Deng et al., European Journal of Medicinal Chemistry (2013), 70, 758-767; Delbroek et al., Journal of Pharmaceutical and Biomedical Analysis (2013), 76, 49-58; Choi et al., ACS Medicinal Chemistry Letters (2012), 3(8), 658-662; Deng et al., Nature Chemical Biology (2011), 7(4), 203-205; and Deng et al., ACS Medicinal Chemistry Letters (2011), 2(3), 195-200). It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures.

(193) Various established synthetic methods may be used to arrive at the inventive compounds described herein. In one embodiment, the inventive compounds can be prepared using the sequence provided in Scheme 1. Amine addition of S-1 into nitropyrimidines S-2 wherein X.sup.2 and X.sup.3 are each independently halide (e.g. fluoro, chloro, bromo, or iodo) provide intermediates S-3 wherein R.sup.E1 is hydrogen or substituted or unsubstituted alkyl. In some embodiments, both X.sup.2 and X.sup.3 are chloro. Reduction of the nitro functionality in S-3 produces compounds S-4. In certain embodiments, the reduction conditions comprise a metal catalyst; e.g. palladium on carbon or Raney nickel. In certain embodiments, the reduction conditions comprise a metal at the (0) oxidation state; e.g. iron(0), tin(0), zinc(0). In certain embodiments, the reduction conditions comprise addition of an acid; e.g. acetic or hydrochloric acid. Cyclization of the free amino group leads to compounds S-5. In certain embodiments, the reduction and cyclization steps occur in one-pot. In certain embodiments, the cyclization conditions comprise an amide coupling agent; e.g. HATU or EDC. Various leaving group conjugates of R.sup.E (i.e. LG-R.sup.E, wherein LG is a leaving group as defined herein) can be contacted with compounds S-5 under appropriate conditions to afford intermediates S-6. In certain embodiments, the conditions comprise a base. In some embodiments, the conditions comprise an inorganic base; e.g. sodium hydride. In certain embodiments, the leaving group conjugate of R.sup.3 is a halide; e.g. bromo or iodo. Subsequent linkage to the sidechain S-7 can be accomplished under aromatic substitution or coupling conditions to product compounds of Formula (I). In certain embodiments, the conditions comprise a base. In some embodiments, the conditions comprise an inorganic base; e.g. potassium or sodium carbonate. In certain embodiments, the conditions comprise a transition metal catalyst; e.g. a palladium or nickel catalyst. In certain embodiments, the conditions comprise a ligand; e.g. a phosphine ligand such as X-phos. In certain embodiments, compounds of S-6 can be alternatively modified by leaving group conjugates of R.sup.F (i.e. LG-R.sup.F, wherein LG is a leaving group as defined herein) following cyclization. In certain embodiments, precursors to compounds of Formula (I) can be modified by leaving group conjugates of R.sup.C (i.e. LG-R.sup.C, wherein LG is a leaving group as defined herein) as an alternative to introduction of R.sup.C through intermediate S-7. Alternative orders of assembly for the various synthetic intermediates into compounds of Formula (I) are contemplated.

(194) ##STR00026##

(195) When linker of X.sup.1 are alkyl, alternate methods of constructing the linkage to compounds S-6 are utilized (see Scheme 2). An organometal species S-8 wherein M.sup.x is a metal or metalloid (e.g. magnesium, lithium, zinc, boron, tin, or silicon) can be utilized to displace the halide X.sup.3 of compounds S-6 to generate compounds of Formula (I). In certain embodiments, the reaction conditions may comprise a transition metal catalyst; e.g. palladium, nickel. In certain embodiments, the reaction conditions may comprise a ligand; e.g. a phosphine ligand such as X-phos. Alternatively, the metal species S-9 can be used to couple to or displace halides of S-10 (see Scheme 3). Alternative orders of assembly for the various synthetic intermediates into compounds of Formula (I) are contemplated.

(196) ##STR00027##

(197) ##STR00028##

(198) Compounds of Formula (II) can be prepared using methods analogous to the methods described in Schemes 1 to 3, except that compound S-7, S-8, and S-10 are replaced with compounds S-11, S-12, and S-13, respectively:

(199) ##STR00029##

(200) Non-limiting examples of the preparation of exemplary compounds described herein are illustrated in Examples 1 to 3.

Example 1. Preparation of 2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl)phenyl)(methyl)amino)-5,11-dimethyl-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6(11H)-one

(201) ##STR00030##

(202) 4-((5,11-Dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)(methyl)amino)-3-methoxybenzoic acid (27.8 mg, 0.0663 mmol, 1 eq) was dissolved in DMF (1.4 mL). HATU (28.7 mg, 0.0754 mmol, 1.1 eq) and DIPEA (23.9 microliters, 0.137 mmol, 2 eq) were added, followed by 1-methyl-4-(piperidin-4-yl)piperazine (15.1 mg, 0.0823 mmol, 1.2 eq). After 15 hours, the mixture was diluted with aqueous sodium bicarbonate and extracted with DCM and EtOAc. The combined organic layer was dried over sodium sulfate, filtered and condensed. Purification by column chromatography (ISCO, 4 g silica column, 0-15% MeOH/DCM, 15 minute gradient) gave the product as a white solid (30.06 mg, 0.0514 mmol, 78%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.07 (s, 1H), 7.71 (dd, J=7.9, 1.7 Hz, 1H), 7.51-7.43 (m, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.17-7.10 (m, 3H), 7.03 (dd, J=7.9, 1.7 Hz, 1H), 4.65 (s, 1H), 3.92 (s, 1H), 3.78 (s, 3H), 3.43 (s, 3H), 3.40 (s, 3H), 3.22 (d, J=19.9 Hz, 4H), 2.90 (s, 2H), 2.79-2.56 (m, 8H), 2.42 (s, 3H), 2.01 (s, 1H), 1.90 (s, 1H), 1.52 (s, 2H). .sup.13C NMR (100 MHz, cd.sub.3od) 170.36, 169.05, 163.86, 158.32, 155.62, 151.12, 149.75, 135.46, 134.96, 132.45, 131.33, 129.03, 126.10, 123.27, 119.61, 118.94, 117.26, 110.65, 72.42, 63.00, 61.16, 54.93, 54.90, 54.30, 43.95, 37.12, 37.09, 36.93, 36.91, 34.36, 28.49, 27.63. LCMS 585.60 (M+H).

Example 2. Preparation of 2-(ethyl(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl)phenyl)amino)-5,11-dimethyl-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6(11H)-one

(203) ##STR00031##

(204) 4-((5,11-Dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)(ethyl)amino)-3-methoxybenzoic acid (12.4 mg, 0.0286 mmol, 1 equivalent) was dissolved in DMF (0.57 mL). HATU (11.9 mg, 0.0314 mmol, 1.1 eq) and DIPEA (10 microliters, 0.0571 mmol, 2 eq) were added, followed by 1-methyl-4-(piperidin-4-yl)piperazine (6.3 mg, 0.0343 mmol, 1.2 eq). After 18 hours, the mixture was diluted with aqueous sodium bicarbonate and extracted with DCM and EtOAc. The combined organic layer was dried over sodium sulfate, filtered and condensed. Purification by preparative HPLC, followed by free basing gave the product as a white solid (9.77 mg, 0.0163 mmol, 57%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.06 (s, 1H), 7.72 (dd, J=8.0, 1.7 Hz, 1H), 7.54-7.45 (m, 1H), 7.28 (d, J=7.9 Hz, 1H), 7.15 (t, J=7.2 Hz, 2H), 7.12 (d, J=1.7 Hz, 1H), 7.04 (dd, J=7.9, 1.7 Hz, 1H), 4.66 (s, 1H), 3.94 (s, 3H), 3.77 (s, 3H), 3.44 (s, 3H), 3.28-3.10 (m, 4H), 2.92 (d, J=25.6 Hz, 2H), 2.77-2.46 (m, 8H), 2.31 (s, 3H), 1.91 (s, 1H), 1.51 (s, 2H), 1.23-1.18 (m, 3H). .sup.13C NMR (100 MHz, cd.sub.3od) 171.81, 170.52, 165.37, 159.32, 157.47, 152.61, 151.24, 137.02, 134.86, 133.84, 132.75, 131.29, 127.57, 124.70, 120.92, 120.29, 118.61, 112.03, 64.44, 62.74, 56.29, 55.93, 46.26, 45.87, 38.47, 35.76, 14.46, 13.42. LCMS 599.56 (M+H).

Example 3. Preparation of 3-(cyclopentyloxy)-4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoic Acid

(205) ##STR00032##

(206) Methyl 3-(cyclopentyloxy)-4-((5,11-dimethyl-6-oxo-6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)amino)benzoate (9.35 mg, 0.0197 mmol, 1 eq) and LiOH (1.4 mg) was dissolved in THF (0.2 mL) and water (0.1 mL). After 16 hours, the mixture was diluted with MeOH and purified by preparative HPLC to give an off-white solid (3.35 mg). .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.51 (d, J=8.5 Hz, 1H), 8.19 (s, 1H), 7.75 (dd, J=7.9, 1.7 Hz, 1H), 7.70 (dd, J=8.5, 1.8 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.48-7.42 (m, 1H), 7.14 (dd, J=7.7, 5.6 Hz, 2H), 4.94 (tt, J=5.1, 2.3 Hz, 1H), 3.48 (s, 3H), 3.46 (s, 3H), 2.05-1.89 (m, 4H), 1.88-1.78 (m, 2H), 1.72-1.62 (m, 2H). LCMS 460.36 (M+H).

Example 4. Biochemical and Cellular Assays of the Compounds

(207) Acetyl-Histone Binding Assay

(208) Assays were performed with minor modifications from the manufacturer's protocol (PerkinElmer, USA). All reagents were diluted in 50 mM HEPES, 150 mM NaCl, 0.1% w/v BSA, and 0.01% w/v Tween.sup. 20 at pH 7.5 and allowed to equilibrate to room temperature prior to addition to plates. After addition of Alpha beads to master solutions, all subsequent steps were performed in low light conditions. A 2 solution of components with final concentrations of BRD4.1 at 80 nM, Ni-coated Acceptor Bead at 25 g/ml, and 80 nM biotinylated H4-tetra acetyl was added in 10 L to 384-well plates (AlphaPlate384, PerkinElmer, USA). Biotinylated peptide for BRD4.1 was synthesized in-house on a CEM Liberty 9008005 microwave peptide synthesizer: H4-tetra acetyl, biotin-PEG2-SGRGKacGGKacGLGKacGGAKacRHRK-COOH. Addition to wells was performed with either a multichannel pipet (for optimization experiments) or a Biotek EL406 liquid handler. After a 1000-rpm spin-down for 1 minute, 100 nL of the solutions of the compounds of the invention from stock plates were added by pin transfer using a Janus Workstation (PerkinElmer, USA). The streptavidin-coated donor beads (25 g/ml final) were added as with previous solution in a 2x, 10 L volume. Following this addition, the plates were sealed with foil to block light exposure and to prevent evaporation. The plates were spun down again at 1000 rpm for 1 minute. Next, the plates were incubated in the room with the plate reader (for temperature equilibration) for 1.5 hour prior to reading the assay. AlphaScreen.sup. measurements were performed on an Envision 2104 (PerkinElmer, USA) utilizing the manufacturer's protocol.

(209) Cellular Assay

(210) The compounds of the invention are also evaluated in the BRD4 dependant cell line for the cellular activity to generate cellular IC.sub.50 values.

(211) Cells (e.g., BRD4 dependant cells) were counted and adjusted to 60,000 cells/mL. Using a Biotek EL406, 50 L, of the cells in media were distributed into 384 well white plates from Thermo. Immediately after plating, compounds of the invention in DMSO were distributed to plates. For large plate sets, cells were returned to a 37 C. incubator while not in use. The compounds were added to plates using a 100 nL 384 well pin transfer manifold on a Janus workstation. Stocks were arrayed in 10 point quadruplicate dose response in DMSO stock in 384-well Greiner compound plates. After addition of the compounds, plates were incubated for three days in a 37 C. incubator. Cell viability was read out using ATPlite from Perkin Elmer. Plates were removed from the incubator and brought to room temperature prior to use. Lyophilized powder was resuspended in lysis buffer and diluted 1:2 with DI water. 25 L of this solution was added to each well using the Biotek liquid handler. Plates were sealed with adherent aluminum seals prior to vortexing and spinning down at 1000 g for 1 minute. Plates were incubated for 15 minutes at room temperature before signal was read on an Envision Plate Reader.

(212) Isothermal Titration Calorimetery

(213) ITC was performed using a ITC200 microcalorimeter from GE(Northampton, Mass.). All experiments were carried out at 25 C. while stirring at 1000 rpm, in ITC buffer (50 mM HEPES pH 7.4 at 25 C., 150 mM NaCl). The microsyringe was loaded with a solution of the protein sample (225 M, in ITC buffer). The compound solution (22.5 M, in ITC buffer) was titrated into the protein solution via syringe. All titrations were conducted using an initial injection of 0.2 l, followed by 19 identical injections of 2 l with a duration of 5 sec (per injection) and a spacing of 90 sec between injections. The heat of dilution was determined by independent titrations (protein into buffer) and was subtracted from the experimental data. The collected data were implicated in the MicroCal Origin software supplied with the instrument to yield enthalpies of binding (H) and binding constants (K.sub.a). The collected data were implicated in the MicroCal Origin software supplied with the instrument to yield enthalpies of binding (H) and binding constants (K.sub.B) as previously described by Wiseman and coworkers. Thermodynamic parameters were calculated (G=HTS=RTlnK.sub.B, where G, H and S are the changes in free energy, enthalpy and entropy of binding respectively). A single binding site model was employed.

(214) Cell Cycle Analysis by Flow Cytometry

(215) 797, MOLM-13, and HL60 cells were plated in T-75 flasks and grown in DMEM (797) or RPMI (MOLM-13 and HL60) containing 10% fetal bovine serum and 1% penicillin/streptomycin. Cells were treated with compound at 1 uM (797) or 500 nM (MOLM-13 and HL60), or the equivalent volume of DMSO for 24 hours. 2106 cells were spun at 500g for minutes at 4 C. and washed with PBS. Pellets were resuspended in 1 mL of cold PBS and added dropwise while gently vortexing to 9 mL 70% ethanol in a 15 mL polypropylene centrifuge tube. Fixed cells were then frozen at 20 C. overnight. The next day, cells were centrifuged at 500g for 10 minutes at 4 C. and washed with 3 mL of cold PBS. Cells were resuspended in 500 L. of propidium iodide staining solution (0.2 mg/mL RNAse A, 0.2 mg/mL propidium iodide, 01.% Triton-X in PBS) and incubated for 20 min at 37 C. Samples were then transferred to ice and analyzed on a BD FACS Canto H. Histograms were generated and cell cycle analysis was performed using ModFit flow cytometry analysis software.

(216) Results

(217) Shown in Table 1 are exemplary in vitro percent inhibition values of BRD4.1 at 2.5 M compound concentration for exemplary compounds, where uM refers to micromolar, and % INHIB refers to % inhibition.

(218) TABLE-US-00001 TABLE 1 % INHIB Structure (at 2.5 uM) 20.5 45.8 36.1 29.5 50.8

(219) Shown in Table 2 are exemplary IC.sub.50 values of select compounds described herein and compounds JQ1 and GSK461364 against select bromodomain-containing proteins, kinases, and cell lines. uM: M.

(220) TABLE-US-00002 TABLE 2 Compound IC.sub.50 1-226 BRD4 IC.sub.50 = 303 nM BRDT IC.sub.50 = 2,110 nM BRD4 IC.sub.50 = 488 nM LRRK2 IC.sub.50 = 7 nM MV411 IC.sub.50 = 549 nM NOMO1 IC.sub.50 = 2 uM Kasumi-1 IC.sub.50 = 393 uM TF-1 IC.sub.50 = 3.36 uM MOLM-13 IC.sub.50 = 1.27 uM 797 IC.sub.50 = 1,304 nM 1-284 BRD4 IC.sub.50 = 1,987 nM BRDT IC.sub.50 = 5,546 nM BRD4 IC.sub.50 = 2.6 uM LRRK2 IC.sub.50 = 4.0 uM MV411 IC.sub.50 = 2,437 nM NOMO1 IC.sub.50 = 8.6 uM Kasumi-1 IC.sub.50 = 1.86 uM TF-1 IC.sub.50 = 6.16 uM MOLM-13 IC.sub.50 = 4.63 uM 797 IC.sub.50 = 7,417 nM 2-041 BRD4 IC.sub.50 = 2.060 nM BRDT IC.sub.50 = 9,608 nM BRD4 IC.sub.50 = 5.7 uM LRRK2 IC.sub.50 = 3.0 uM MV411 IC.sub.50 = 3,476 nM NOMO1 IC.sub.50 = 8.3 uM Kasumi-1 IC.sub.50 = 2.36 uM TF-1 IC.sub.50 = 7.21 uM MOLM-13 IC.sub.50 = 5.74 uM 797 IC.sub.50 = 7,100 nM 2-043 BRD4 IC.sub.50 = 732 nM BRDT IC.sub.50 = 2,728 nM BRD4 IC.sub.50 = 1.51 uM MV411 IC.sub.50 >10 uM NOMOI IC.sub.50 = 6.8 uM Kasumi-1 IC.sub.50 = 4.78 uM TF-1 IC.sub.50 = 7.1 uM MOLM-13 IC.sub.50 = 6,61 uM 797 IC.sub.50 = 1,788 nM 2-075 BRD4 IC.sub.50 = 970 nm BRDT IC.sub.50 = 2,879 nM BRD4 IC.sub.50 = 1.80 uM CREBBP IC.sub.50 = 431 nM BRD4 K.sub.D = 180 nM (DiscoveRx) CREBBP K.sub.D = 23 nM (DiscoveRx) MV411 IC.sub.50 = 252 nM NOMO1 IC.sub.50 = 2.5 uM Kasumi-1 IC.sub.50 = 96 nM TF-1 IC.sub.50 = 2.14 uM MOLM-13 IC.sub.50 = 433 nM 797 IC.sub.50 = 34 nM BRD4 IC.sub.50 = 44 nM BRDT IC.sub.50 = 147 nM MV411 IC.sub.50 = 65.6 nM NOMO1 IC.sub.50 = 172 nM Kasumi-1 IC.sub.50 = 48.8 nM TF-1 IC.sub.50 = 109 uM MOLM-13 IC.sub.50 = 89.2 nM 797 IC.sub.50 = 92 nM JQ1 BRD4 IC.sub.50 >50 uM BRDT IC.sub.50 >50 uM MV411 IC.sub.50 = 7.1 nM NOMO1 IC.sub.50 = 5.91 nM Kasumi-1 IC.sub.50 = 7.8 nM TF-1 IC.sub.50 = poor convergence MOLM-13 IC.sub.50 = 6.93 nM 797 IC.sub.50 = 8 nM GSK461364