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Cyano thienotriazolodiazepines and uses thereof

11306105 · 2022-04-19

Assignee

Inventors

Cpc classification

International classification

Abstract

The present invention provides compounds and pharmaceutically compositions thereof. The compounds and compositions are 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.

Claims

1. A compound of Formula (I): ##STR00129## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R.sup.A1 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; R.sup.A2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; X.sup.1 is N or CR.sup.5, wherein R.sup.5 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; R.sup.B is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; Ring C is of formula: ##STR00130## each occurrence of R.sup.C is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; c is 0, 1, 2, 3, or 4; R.sup.1 is ##STR00131## ##STR00132## ##STR00133## R.sup.2 is hydrogen, halogen, or optionally substituted alkyl; R.sup.3 is, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl, or an oxygen protecting group; and each occurrence of R.sup.f is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, an oxygen protecting group, a sulfur protecting group, or a nitrogen protecting group, or two R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; provided the compound is not: ##STR00134## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: each oxygen protecting group is independently —R.sup.aa, —N(R.sup.bb).sub.2, —C(═O)SR.sup.aa, —C(═O)R.sup.aa, —CO.sub.2R.sup.aa, —C(═O)N(R.sup.bb).sub.2, —C(═NR.sup.bb)R.sup.aa, —C(═NR.sup.bb)OR.sup.aa, —C(═NR.sup.bb)N(R.sup.bb).sub.2, —S(═O)R.sup.aa, —SO.sub.2R.sup.aa, —Si(R.sup.aa).sub.3, —P(R.sup.cc).sub.2, —P(R.sup.cc).sub.3.sup.+X.sup.−, —P(OR.sup.cc).sub.2, —P(OR.sup.cc).sub.3.sup.+X.sup.−, —P(═O)(R.sup.aa).sub.2, —P(═O)(OR.sup.cc).sub.2, or —P(═O)(N(R.sup.bb).sub.2).sub.2; each sulfur protecting group is independently —R.sup.aa, —N(R.sup.bb).sub.2, —C(═O)SR.sup.aa, —C(═O)R.sup.aa, —CO.sub.2R.sup.aa, —C(═O)N(R.sup.bb).sub.2, —C(═NR.sup.bb)R.sup.aa, —C(═NR.sup.bb)OR.sup.aa, —C(═NR.sup.bb)N(R.sup.bb).sub.2, —S(═O)R.sup.aa, —SO.sub.2R.sup.aa, —Si(R.sup.aa).sub.3, —P(R.sup.cc).sub.2, —P(R.sup.cc).sub.3.sup.+X.sup.−, —P(OR.sup.cc).sub.2, —P(OR.sup.cc).sub.3.sup.+X.sup.−, —P(═O)(R.sup.aa).sub.2, —P(═O)(OR.sup.cc).sub.2, or —P(═O)(N(R.sup.bb).sub.2).sub.2; each nitrogen protecting group is independently —OH, —OR.sup.aa, —N(R.sup.cc).sub.2, —C(═O)R.sup.aa, —C(═O)N(R.sup.cc).sub.2, —CO.sub.2R.sup.aa, —SO.sub.2R.sup.aa, —C(═NR.sup.cc)R.sup.aa, —C(═NR.sup.cc)OR.sup.aa, —C(═NR.sup.cc)N(R.sup.cc).sub.2, —SO.sub.2N(R.sup.cc).sub.2, —SO.sub.2R.sup.cc, —SO.sub.2OR.sup.cc, —SOR.sup.aa, —C(═S)N(R.sup.cc).sub.2, —C(═O)SR.sup.cc, —C(═S)SR.sup.cc, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl, heteroC.sub.2-10 alkenyl, heteroC.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, or 5-14 membered heteroaryl; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; each instance of R.sup.aa is, independently, selected from the group consisting of C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl, heteroC.sub.2-10alkenyl, heteroC.sub.2-10alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two R.sup.aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; each instance of R.sup.bb is, independently, selected from the group consisting of hydrogen, —OH, —OR.sup.aa, —N(R.sup.cc).sub.2, —CN, —C(═O)R.sup.aa, —C(═O)N(R.sup.cc).sub.2, —CO.sub.2R.sup.aa, —SO.sub.2R.sup.aa, —C(═NR.sup.cc)OR.sup.aa, —C(═NR.sup.cc)N(R.sup.cc).sub.2, —SO.sub.2N(R.sup.cc).sub.2, —SO.sub.2R.sup.cc, —SO.sub.2OR.sup.cc, —SOR.sup.aa, —C(═S)N(R.sup.cc).sub.2, —C(═O)SR.sup.cc, —C(═S)SR.sup.cc, —P(═O)(R.sup.aa).sub.2, —P(═O)(OR.sup.cc).sub.2, —P(═O)(N(R.sup.cc).sub.2).sub.2, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroC.sub.1-10alkyl, heteroC.sub.2-10alkenyl, heteroC.sub.2-10alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two R.sup.bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; each instance of R.sup.cc is, independently, selected from the group consisting of hydrogen, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl, heteroC.sub.2-10 alkenyl, heteroC.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two R.sup.cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; each instance of R.sup.dd is, independently, selected from the group consisting of halogen, —CN, —NO.sub.2, —N.sub.3, —SO.sub.2H, —SO.sub.3H, —OH, —OR.sup.ee, —ON(R.sup.ff).sub.2, —N(R.sup.ff).sub.2, —N(R.sup.ff).sub.3.sup.+X.sup.−, —N(OR.sup.ee)R.sup.ff, —SH, —SR.sup.ee, —SSR.sup.ee, —C(═O)R.sup.ee, —CO.sub.2H, —CO.sub.2R.sup.ee, —OC(═O)R.sup.ee, —OCO.sub.2R.sup.ee, —C(═O)N(R.sup.ff).sub.2, —OC(═O)N(R.sup.ff).sub.2, —NR.sup.ffC(═O)R.sup.ee, —NR.sup.ffCO.sub.2R.sup.ee, —NR.sup.ffC(═O)N(R.sup.ff).sub.2, —C(═NR.sup.ff)OR.sup.ee, —OC(═NR.sup.ff)R.sup.ee, —OC(═NR.sup.ff)OR.sup.ee, —C(═NR.sup.ff)N(R.sup.ff).sub.2, —OC(═NR.sup.ff)N(R.sup.ff).sub.2, —NR.sup.ffC(═NR.sup.ff)N(R.sup.ff).sub.2, —NR.sup.ffSO.sub.2R.sup.ee, —SO.sub.2N(R.sup.ff).sub.2, —SO.sub.2R.sup.ee, —SO.sub.2OR.sup.ee, —OSO.sub.2R.sup.ee, —S(═O)R.sup.ee, —Si(R.sup.ee).sub.3, —OSi(R.sup.ee).sub.3, —C(═S)N(R.sup.ff).sub.2, —C(═O)SR.sup.ee, —C(═S)SR.sup.ee, —SC(═S)SR.sup.ee, —P(═O)(OR.sup.ee).sub.2, —P(═O)(R.sup.ee).sub.2, —OP(═O)(R.sup.ee).sub.2, —OP(═O)(OR.sup.ee).sub.2, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, heteroC.sub.1-6alkyl, heteroC.sub.2-6alkenyl, heteroC.sub.2-6alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered heterocyclyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups, or two geminal R.sup.dd substituents are joined to form ═O or ═S; each instance of R.sup.ee is, independently, selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, heteroC.sub.1-6 alkyl, heteroC.sub.2-6alkenyl, heteroC.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups; each instance of R.sup.ff is, independently, selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, heteroC.sub.1-6 alkyl, heteroC.sub.2-6alkenyl, heteroC.sub.2-6alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered heterocyclyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl, or two R.sup.ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups; and each instance of R.sup.gg is, independently, selected from the group consisting of halogen, —CN, —NO.sub.2, —N.sub.3, —SO.sub.2H, —SO.sub.3H, —OH, —OC.sub.1-6 alkyl, —ON(C.sub.1-6 alkyl), —N(C.sub.1-6 alkyl).sub.2, —N(C.sub.1-6 alkyl).sub.3.sup.+X.sup.−, —NH(C.sub.1-6 alkyl).sup.+X.sup.−, —NH.sub.2(C.sub.1-6 alkyl).sup.+X.sup.−, —NH.sub.3.sup.+X.sup.−, —N(OC.sub.1-6 alkyl)(C.sub.1-6 alkyl), —N(OH)(C.sub.1-6 alkyl), —NH(OH), —SH, —SC.sub.1-6 alkyl, —SS(C.sub.1-6 alkyl), —C(═O)(C.sub.1-6 alkyl), —CO.sub.2H, —CO.sub.2(C.sub.1-6 alkyl), —OC(═O)(C.sub.1-6 alkyl), —OCO.sub.2(C.sub.1-6 alkyl), —C(═O)NH.sub.2, —C(═O)N(C.sub.1-6 alkyl).sub.2, —OC(═O)NH(C.sub.1-6 alkyl), —NHC(═O)(C.sub.1-6 alkyl), —N(C.sub.1-6 alkyl)C(═O)(C.sub.1-6 alkyl), —NHCO.sub.2(C.sub.1-6 alkyl), —NHC(═O)N(C.sub.1-6 alkyl), —NHC(═O)NH(C.sub.1-6 alkyl), —NHC(═O)NH.sub.2, —C(═NH)O(C.sub.1-6 alkyl), —OC(═NH)(C.sub.1-6 alkyl), —OC(═NH)OC.sub.1-6 alkyl, —C(═NH)N(C.sub.1-6 alkyl).sub.2, —C(═NH)NH(C.sub.1-6 alkyl), —C(═NH)NH.sub.2, —OC(═NH)N(C.sub.1-6 alkyl).sub.2, —OC(NH)NH(C.sub.1-6 alkyl), —OC(NH)NH.sub.2, —NHC(NH)N(C.sub.1-6 alkyl).sub.2, —NHC(═NH)NH.sub.2, —NHSO.sub.2(C.sub.1-6 alkyl), —SO.sub.2N(C.sub.1-6 alkyl).sub.2, —SO.sub.2NH(C.sub.1-6 alkyl), —SO.sub.2NH.sub.2, —SO.sub.2C.sub.1-6 alkyl, —SO.sub.2OC.sub.1-6 alkyl, —OSO.sub.2C.sub.1-6 alkyl, —SOC.sub.1-6 alkyl, —Si(C.sub.1-6 alkyl).sub.3, —OSi(C.sub.1-6 alkyl).sub.3 —C(═S)N(C.sub.1-6 alkyl).sub.2, C(═S)NH(C.sub.1-6 alkyl), C(═S)NH.sub.2, —C(═O)S(C.sub.1-6 alkyl), —C(═S)SC.sub.1-6 alkyl, —SC(═S)SC.sub.1-6 alkyl, —P(═O)(OC.sub.1-6 alkyl).sub.2, —P(═O)(C.sub.1-6 alkyl).sub.2, —OP(═O)(C.sub.1-6 alkyl).sub.2, —OP(═O)(OC.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, heteroC.sub.1-6alkyl, heteroC.sub.2-6alkenyl, heteroC.sub.2-6alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl; or two geminal R.sup.gg substituents are joined to form ═O or ═S; wherein X.sup.− is a counterion.

2. The compound of claim 1, wherein the compound is of Formula (I-A-1), (I-A-2), (I-B-1), or (I-C-1): ##STR00135## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

3. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Ring C is of formula: ##STR00136##

4. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein both R.sup.A1 and R.sup.A2 are hydrogen or optionally substituted C.sub.1-6 alkyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R.sup.1 is: ##STR00137##

6. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R.sup.1 is: ##STR00138##

7. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R.sup.2 is hydrogen.

8. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein X.sup.1 is N.

9. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R.sup.B is hydrogen or optionally substituted C.sub.1-6 alkyl.

10. The compound of claim 1, wherein the compound is of formula: ##STR00139## ##STR00140## ##STR00141## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

11. A compound of Formula (II): ##STR00142## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R.sup.M is —CN; R.sup.A2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; X.sup.1 is N or CR.sup.5, wherein R.sup.5 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; R.sup.B is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; Ring C is phenyl; each occurrence of R.sup.C is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; c is 0, 1, 2, 3, or 4; R.sup.1 is hydrogen, halogen, optionally substituted alkyl, or —(CH.sub.2).sub.nL, wherein n is 0, 1, 2, 3, or 4, and L is —C(═O)R.sup.3, —C(═O)OR.sup.3, or —C(═O)NR.sup.3R.sup.4; R.sup.2 is hydrogen, halogen, or optionally substituted alkyl; each R.sup.3 and R.sup.4 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or R.sup.3 and R.sup.4 are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; and each occurrence of R.sup.f is independently, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, an oxygen protecting group, a sulfur protecting group, or a nitrogen protecting group, or two R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; wherein: each oxygen protecting group is independently —R.sup.aa, —N(R.sup.bb).sub.2, —C(═O)SR.sup.aa, —C(═O)R.sup.aa, —CO.sub.2R.sup.aa, —C(═O)N(R.sup.bb).sub.2, —C(═NR.sup.bb)R.sup.aa, —C(═NR.sup.bb)OR.sup.aa, —C(═NR.sup.bb)N(R.sup.bb).sub.2, —S(═O)R.sup.aa, —SO.sub.2R.sup.aa, —Si(R.sup.aa).sub.3, —P(R.sup.cc).sub.2, —P(R.sup.cc).sub.3.sup.+X.sup.−, —P(OR.sup.cc).sub.2, —P(OR.sup.cc).sub.3.sup.+X.sup.−, —P(═O)(R.sup.aa).sub.2, —P(═O)(OR.sup.cc).sub.2, or —P(═O)(N(R.sup.bb).sub.2).sub.2; each sulfur protecting group is independently —R.sup.aa, —N(R.sup.bb).sub.2, —C(═O)SR.sup.aa, —C(═O)R.sup.aa, —CO.sub.2R.sup.aa, —C(═O)N(R.sup.bb).sub.2, —C(═NR.sup.bb)R.sup.aa, —C(═NR.sup.bb)OR.sup.aa, —C(═NR.sup.bb)N(R.sup.bb).sub.2, —S(═O)R.sup.aa, —SO.sub.2R.sup.aa, —Si(R.sup.aa).sub.3, —P(R.sup.cc).sub.2, —P(R.sup.cc).sub.3.sup.+X.sup.−, —P(OR.sup.cc).sub.2, —P(OR.sup.cc).sub.3.sup.+X.sup.−, —P(═O)(R.sup.aa).sub.2, —P(═O)(OR.sup.cc).sub.2, or —P(═O)(N(R.sup.bb).sub.2).sub.2; each nitrogen protecting group is independently —OH, —OR.sup.aa, —N(R.sup.cc).sub.2, —C(═O)R.sup.aa, —C(═O)N(R.sup.cc).sub.2, —CO.sub.2R.sup.aa, —SO.sub.2R.sup.aa, —C(═NR.sup.cc)R.sup.aa, —C(═NR.sup.cc)OR.sup.aa, —C(═NR.sup.cc)N(R.sup.cc).sub.2, —SO.sub.2N(R.sup.cc).sub.2, —SO.sub.2R.sup.cc, —SO.sub.2OR.sup.cc, —SOR.sup.aa, —C(═S)N(R.sup.cc).sub.2, —C(═O)SR.sup.cc, —C(═S)SR.sup.cc, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl, heteroC.sub.2-10 alkenyl, heteroC.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, or 5-14 membered heteroaryl; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; each instance of R.sup.aa is, independently, selected from the group consisting of C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl, heteroC.sub.2-10alkenyl, heteroC.sub.2-10alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two R.sup.aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; each instance of R.sup.bb is, independently, selected from the group consisting of hydrogen, —OH, —OR.sup.aa, —N(R.sup.cc).sub.2, —CN, —C(═O)R.sup.aa, —C(═O)N(R.sup.cc).sub.2, —CO.sub.2R.sup.aa, —SO.sub.2R.sup.aa, —C(═NR.sup.cc)OR.sup.aa, —C(═NR.sup.cc)N(R.sup.cc).sub.2, —SO.sub.2N(R.sup.cc).sub.2, —SO.sub.2R.sup.cc, —SO.sub.2OR.sup.cc, —SOR.sup.aa, —C(═S)N(R.sup.cc).sub.2, —C(═O)SR.sup.cc, —C(═S)SR.sup.cc, —P(═O)(R.sup.aa).sub.2, —P(═O)(OR.sup.cc).sub.2, —P(═O)(N(R.sup.cc).sub.2).sub.2, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroC.sub.1-10alkyl, heteroC.sub.2-10alkenyl, heteroC.sub.2-10alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two R.sup.bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; each instance of R.sup.cc is, independently, selected from the group consisting of hydrogen, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl, heteroC.sub.2-10 alkenyl, heteroC.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two R.sup.cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; each instance of R.sup.dd is, independently, selected from the group consisting of halogen, —CN, —NO.sub.2, —N.sub.3, —SO.sub.2H, —SO.sub.3H, —OH, —OR.sup.ee, —ON(R.sup.ff).sub.2, —N(R.sup.ff).sub.2, —N(R.sup.ff).sub.3.sup.+X.sup.−, —N(OR.sup.ee)R.sup.ff, —SH, —SR.sup.ee, —SSR.sup.ee, —C(═O)R.sup.ee, —CO.sub.2H, —CO.sub.2R.sup.ee, —OC(═O)R.sup.ee, —OCO.sub.2R.sup.ee, —C(═O)N(R.sup.ff).sub.2, —OC(═O)N(R.sup.ff).sub.2, —NR.sup.ffC(═O)R.sup.ee, —NR.sup.ffCO.sub.2R.sup.ee, —NR.sup.ffC(═O)N(R.sup.ff).sub.2, —C(═NR.sup.ff)OR.sup.ee, —OC(═NR.sup.ff)R.sup.ee, —OC(═NR.sup.ff)OR.sup.ee, —C(═NR.sup.ff)N(R.sup.ff).sub.2, —OC(═NR.sup.ff)N(R.sup.ff).sub.2, —NR.sup.ffC(═NR.sup.ff)N(R.sup.ff).sub.2, —NR.sup.ffSO.sub.2R.sup.ee, —SO.sub.2N(R.sup.ff).sub.2, —SO.sub.2R.sup.ee, —SO.sub.2OR.sup.ee, —OSO.sub.2R.sup.ee, —S(═O)R.sup.ee, —Si(R.sup.ee).sub.3, —OSi(R.sup.ee).sub.3, —C(═S)N(R.sup.ff).sub.2, —C(═O)SR.sup.ee, —C(═S)SR.sup.ee, —SC(═S)SR.sup.ee, —P(═O)(OR.sup.ee).sub.2, —P(═O)(R.sup.ee).sub.2, —OP(═O)(R.sup.ee).sub.2, —OP(═O)(OR.sup.ee).sub.2, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, heteroC.sub.1-6alkyl, heteroC.sub.2-6alkenyl, heteroC.sub.2-6alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered heterocyclyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups, or two geminal R.sup.dd substituents are joined to form ═O or ═S; each instance of R.sup.ee is, independently, selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, heteroC.sub.1-6 alkyl, heteroC.sub.2-6alkenyl, heteroC.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups; each instance of R.sup.ff is, independently, selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, heteroC.sub.1-6alkyl, heteroC.sub.2-6alkenyl, heteroC.sub.2-6alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered heterocyclyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl, or two e groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups; and each instance of R.sup.gg is, independently, selected from the group consisting of halogen, —CN, —NO.sub.2, —N.sub.3, —SO.sub.2H, —SO.sub.3H, —OH, —OC.sub.1-6 alkyl, —ON(C.sub.1-6 alkyl).sub.2, —N(C.sub.1-6 alkyl).sub.2, —N(C.sub.1-6 alkyl).sub.3.sup.+X.sup.−, —NH(C.sub.1-6 alkyl).sub.2.sup.+X.sup.−, —NH.sub.2(C.sub.1-6 alkyl).sup.+X.sup.−, —NH.sub.3.sup.+X.sup.−, —N(OC.sub.1-6 alkyl)(C.sub.1-6 alkyl), —N(OH)(C.sub.1-6 alkyl), —NH(OH), —SH, —SC.sub.1-6 alkyl, —SS(C.sub.1-6 alkyl), —C(═O)(C.sub.1-6 alkyl), —CO.sub.2H, —CO.sub.2(C.sub.1-6 alkyl), —OC(═O)(C.sub.1-6 alkyl), —OCO.sub.2(C.sub.1-6 alkyl), —C(═O)NH.sub.2, —C(═O)N(C.sub.1-6 alkyl).sub.2, —OC(═O)NH(C.sub.1-6 alkyl), —NHC(═O)(C.sub.1-6 alkyl), —N(C.sub.1-6 alkyl)C(═O)(C.sub.1-6 alkyl), —NHCO.sub.2(C.sub.1-6 alkyl), —NHC(═O)N(C.sub.1-6 alkyl).sub.2, —NHC(═O)NH(C.sub.1-6 alkyl), —NHC(═O)NH.sub.2, —C(═NH)O(C.sub.1-6 alkyl), —OC(═NH)(C.sub.1-6 alkyl), —OC(═NH)OC.sub.1-6 alkyl, —C(═NH)N(C.sub.1-6 alkyl).sub.2, —C(═NH)NH(C.sub.1-6 alkyl), —C(═NH)NH.sub.2, —OC(═NH)N(C.sub.1-6 alkyl).sub.2, —OC(NH)NH(C.sub.1-6 alkyl), —OC(NH)NH.sub.2, —NHC(NH)N(C.sub.1-6 alkyl).sub.2, —NHC(═NH)NH.sub.2, —NHSO.sub.2(C.sub.1-6 alkyl), —SO.sub.2N(C.sub.1-6 alkyl).sub.2, —SO.sub.2NH(C.sub.1-6 alkyl), —SO.sub.2NH.sub.2, —SO.sub.2C.sub.1-6 alkyl, —SO.sub.2OC.sub.1-6 alkyl, —OSO.sub.2C.sub.1-6 alkyl, —SOC.sub.1-6 alkyl, —Si(C.sub.1-6 alkyl).sub.3, —OSi(C.sub.1-6 alkyl).sub.3 —C(═S)N(C.sub.1-6 alkyl).sub.2, C(═S)NH(C.sub.1-6 alkyl), C(═S)NH.sub.2, —C(═O)S(C.sub.1-6 alkyl), —C(═S)SC.sub.1-6 alkyl, —SC(═S)SC.sub.1-6 alkyl, —P(═O)(OC.sub.1-6 alkyl).sub.2, —P(═O)(C.sub.1-6 alkyl).sub.2, —OP(═O)(C.sub.1-6 alkyl).sub.2, —OP(═O)(OC.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, heteroC.sub.1-6alkyl, heteroC.sub.2-6alkenyl, heteroC.sub.2-6alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl; or two geminal R.sup.gg substituents are joined to form ═O or ═S; wherein X.sup.− is a counterion.

12. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient.

13. A method of treating a disease associated with a bromodomain or bromodomain-containing protein in a subject in need thereof, wherein the disease is selected from the group consisting of testicular cancer, ovarian cancer, NUT midline carcinoma, chronic lymphocytic leukemia, mixed-lineage leukemia, epithelial neoplasia, and squamous cell carcinoma, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

14. A method for male contraception, the method comprising administering to a male subject in need thereof an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

15. The compound of claim 11, the compound is of Formula (II-A-1), (II-A-2), (II-C-1), (II-D-1), (II-E-1), or (II-G-1): ##STR00143## ##STR00144## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

16. The compound of claim 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R.sup.A2 is hydrogen or optionally substituted C.sub.1-6 alkyl.

17. The compound of claim 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Ring C is of formula: ##STR00145##

18. The compound of claim 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R.sup.1 is —(CH.sub.2).sub.nC(═O)OR.sup.3 or —(CH.sub.2).sub.nC(═O)NR.sup.3R.sup.4.

19. The compound of claim 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R.sup.1 is —(CH.sub.2).sub.nC(═O)NR.sup.3R.sup.4, and R.sup.3 and R.sup.4 are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.

20. The compound of claim 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R.sup.3 is hydrogen, and R.sup.4 is optionally substituted C.sub.1-6 alkyl or optionally substituted aryl.

21. The compound of claim 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R.sup.1 is: ##STR00146## ##STR00147## ##STR00148##

22. The compound of claim 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R.sup.2 is hydrogen.

23. The compound of claim 11, wherein the compound is of formula: ##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

24. The compound of claim 1, wherein the compound is of Formula (I): ##STR00156## or a pharmaceutically acceptable salt thereof.

25. The compound of claim 11, wherein the compound is of Formula (II): ##STR00157## or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound of claim 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient.

27. A method of treating a disease associated with a bromodomain or bromodomain-containing protein in a subject in need thereof, wherein the disease is selected from the group consisting of testicular cancer, ovarian cancer, NUT midline carcinoma, chronic lymphocytic leukemia, mixed-lineage leukemia, epithelial neoplasia, and squamous cell carcinoma, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

28. A method for male contraception, the method comprising administering to a male subject in need thereof an effective amount of a compound of claim 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

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

(2) FIG. 1. Mean whole blood concentration-time profiles for compounds 200 (A), 107 (B), and 109 (C) after intravenous dose at 5 mg/kg or oral dose at 10 mg/kg (N=3) in male CD1 mice.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

(3) The present disclosure provides compounds of Formulae (I) and (II), which bind bromodomains and/or bromodomain-containing proteins. The compounds described herein may be able to bind in a pocket of a bromodomain (e.g., a bromodomain of a bromodomain-containing protein). In certain embodiments, the compounds described herein may bind in the pocket of a bromodomain and disrupt the interaction between the bromodomain binding pocket and an acetylated lysine residue of a second protein (e.g., a histone). In certain embodiments, the compounds described herein bind in the pocket of the bromodomain. The compound described herein may also modulate (e.g., inhibit) the activity of a bromodomain and/or bromodomain-containing protein. Also provided in the present disclosure are pharmaceutical compositions, methods, uses, and kits useful in modulating (e.g., 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, pathological angiogenesis, inflammatory diseases, and autoimmune diseases), autoimmune diseases, cardiovascular diseases, viral infections, fibrotic diseases, neurological 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 preventing and/or treating a viral infection (e.g., by inhibiting the replication of a virus, by killing a virus).

(4) Compounds described herein (e.g., compounds of Formulae (I) and (II)) have been found to bind 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 pocket of a bromodomain of a bromodomain-containing protein. In certain embodiments, the compounds described herein bind in 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 hind in 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 (e.g., aberrant activity, increased activity) of a bromodomain-containing protein. In certain embodiments, the compounds described herein inhibit the activity (e.g., aberrant activity, increased activity) of a bromodomain. In certain embodiments, the activity of a bromodomain is the ability of the bromodomain to bind an acetylated lysine residue (e.g., an acetylated lysine residue on the NT-terminal tails of histones), which may be part of another protein or peptide. In certain embodiments, the compounds described herein specifically bind to a bromodomain-containing protein (e.g., bind to a bromodomain-containing protein with a higher binding affinity than to a different bromodomain-containing protein and/or to a protein that is not a bromodomain-containing protein). In certain embodiments, the compounds described herein specifically bind to a bromodomain of a bromodomain-containing protein (e.g., hind to a bromodomain of a bromodomain-containing protein with a higher binding affinity than to a non-bromodomain of the bromodomain-containing protein). In certain embodiments, the compounds described herein non-specifically bind to a bromodomain-containing protein (e.g., bind to a bromodomain of the 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 formation of a chromatin by reducing the binding of a protein (e.g., histone) to a DNA. 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).

(5) The compounds described herein may bind bromodomain-containing proteins and may inhibit the activity of the bromodomain-containing proteins. 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).

(6) 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 at most about 30 μM, at most about 10 μM, at most about 3 μM, at most about 1 μM, 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 μM, at least about 10 μM, or at least about 100 μM. Combinations of the above-referenced ranges (e.g., at most about 10 μM and at least about 1 nM) are also within the scope of the disclosure. Other ranges are also possible. In certain embodiments, the K.sub.d value of the adduct is at most about 10 μM. 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.

(7) 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 with the bromodomain-containing protein. 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.50 value of a compound described herein is at most about 1 mM, at most about 300 μM, at most about 100 μM, at most about 30 μM, at most about 10 μM, at most about 3 μM, at most about 1 μM, 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 μM, at least about 3 μM, at least about 10 μM, at least about 30 μM, at least about 100 μM, at least about 300 μM, or at least 1 mM. Combinations of the above-referenced ranges (e.g., at most about 300 μM and at least about 1 μM) are also within the scope of the disclosure. Other ranges are also possible. In certain embodiments, the IC.sub.50 value of a compound described herein is at most about 300 μM. In certain embodiments, the IC.sub.50 value of a compound described herein is at most about 30 μM. In certain embodiments, the IC.sub.50 value of a compound described herein is at most about 10 μM.

(8) The compounds described herein may selectively inhibit the activity of a bromodomain-containing 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, ARK5, 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.

(9) 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 a 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., at least about 2-fold and at most about 10,000-fold) are also within the scope of the disclosure. 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 50-fold. In certain embodiments, the selectivity is at least about 100-fold. In certain embodiments, the selectivity is at least about 1,000-fold.

(10) 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.

(11) Compounds of Formula (I) and (II)

(12) In one aspect, the present invention provides compounds of Formula (I):

(13) ##STR00005##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, wherein: R.sup.A1 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; R.sup.A2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; X.sup.1 is N or CR.sup.5, wherein R.sup.5 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; R.sup.B is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; Ring C is aryl or heteroaryl; each occurrence of R.sup.C is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; c is 0, 1, 2, 3, or 4; R.sup.1 is hydrogen, halogen, optionally substituted alkyl, or —(CH.sub.2).sub.nL, wherein n is 0, 1, 2, 3 or 4, and L is —C(═O)R.sup.3, —C(═O)OR.sup.3, —C(═O)NR.sup.3R.sup.4, —S(═O).sub.2R.sup.3, —S(═O).sub.2OR.sup.3, —S(═O).sub.2NR.sup.3R.sup.4, —OR.sup.3, —NR.sup.3R.sup.4, —N(R.sup.4)C(═O)R.sup.3, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R.sup.2 is hydrogen, halogen, or optionally substituted alkyl; each of R.sup.3 and R.sup.4 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or R.sup.3 and R.sup.4 are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; and each occurrence of R.sup.f is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.

(14) In certain embodiments, the compound of Formula (I) is not of formula:

(15) ##STR00006##

(16) In certain embodiments, the compound of Formula (I) is not of formula:

(17) ##STR00007##

(18) In certain embodiments, R.sup.A1 is not substituted alkyl. In certain embodiments, R.sup.A1 is not substituted C.sub.1 alkyl. In certain embodiments, R.sup.A1 is not sulfonyl substituted alkyl. In certain embodiments, R.sup.A1 is hydrogen, halogen, methyl, optionally substituted C.sub.2-6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally Substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN.

(19) In certain embodiments, R.sup.1 is not —CH.sub.2C(═O)OR.sup.3. In certain embodiments, R.sup.1 is hydrogen, halogen, or —(CH.sub.2).sub.nL, wherein n is 0, 1, 2, 3 or 4, and L is —C(═O)R.sup.3, —C(═O)NR.sup.3R.sup.4, —S(═O).sub.2R.sup.3, —S(═O).sub.2OR.sup.3, —S(═O).sub.2NR.sup.3R.sup.4, —OR.sup.3, —NR.sup.3R.sup.4, —N(R.sup.4)C(═O)R.sup.3, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and R.sup.2 is hydrogen or halogen.

(20) In certain embodiments, Ring C is not of formula:

(21) ##STR00008##

(22) In certain embodiments, Ring C is not of formula:

(23) ##STR00009##

(24) In certain embodiments, compounds of Formula (I) do not include compounds disclosed in any of U.S. Pat. Nos. 5,712,274, 8,044,042, 8,476,260, 8,981,083, WIPO Application No. PCT/US2014/023386, filed Mar. 11, 2014, WIPO Application No. PCT/US2011/036647, filed May 16, 2011, WIPO Application No. PCT/US2011/036667, filed May 16, 2011, WIPO Application No. PCT/US2011/036672, filed May 16, 2011, WIPO Application No. PCT/US2011/036701, filed May 16, 2011, WIPO Application No. PCT/JP2008/073864, filed Dec. 26, 2008, WIPO Application No. PCT/JP1992/001198, Sep. 18, 1992, WIPO Application No. PCT/JP1993/001329, filed Sep. 16, 1993, and WIPO Application No. PCT/JP2006/310709, filed May 30, 2006.

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

(26) ##STR00010##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, wherein: R.sup.M is —CN, —N(R.sup.f).sub.2, or —CH.sub.2N(R.sup.f).sub.2; R.sup.A2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; X.sup.1 is N or CR.sup.5, wherein R.sup.5 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; R.sup.B is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; Ring C is aryl or heteroaryl; each occurrence of R.sup.C is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN; c is 0, 1, 2, 3, or 4; R.sup.1 is hydrogen, halogen, optionally substituted alkyl, or —(CH.sub.2).sub.nL, wherein n is 0, 1, 2, 3, or 4, and L is —C(═O)R.sup.3, —C(═O)OR.sup.3, —C(═O)NR.sup.3R.sup.4, —S(═O).sub.2R.sup.3, —S(═O).sub.2OR.sup.3, —S(═O).sub.2NR.sup.3R.sup.4, —OR.sup.3, —NR.sup.3R.sup.4, —N(R.sup.4)C(═O)R.sup.3, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R.sup.2 is hydrogen, halogen, or optionally substituted alkyl; each R.sup.3 and R.sup.4 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or R.sup.3 and R.sup.4 are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; and each occurrence of R.sup.f is independently, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.

(27) In certain embodiments, the compound of Formula (I) is not of formula:

(28) ##STR00011##

(29) In certain embodiments, the compound of Formula (I) is not of formula:

(30) ##STR00012##

(31) In certain embodiments, R.sup.1 is not —CH.sub.2C(═O)OR.sup.3. In certain embodiments, R.sup.1 is hydrogen, halogen, or —(CH.sub.2).sub.nL, wherein n is 0, 1, 2, 3 or 4, and L is —C(═O)R.sup.3, —C(═O)NR.sup.3R.sup.4, —S(═O).sub.2R.sup.3, —S(═O).sub.2OR.sup.3, —S(═O).sub.2NR.sup.3R.sup.4, —OR.sup.3, —NR.sup.3R.sup.4, —N(R.sup.4)C(═O)R.sup.3, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and R.sup.2 is hydrogen or halogen.

(32) In certain embodiments, compounds of Formula (II) do not include compounds disclosed in any of U.S. Pat. Nos. 5,712,274, 8,044,042, 8,476,260, 8,981,083, WIPO Application No. PCT/US2014/023386, filed Mar. 11, 2014, WIPO Application No. PCT/US2011/036647, filed May 16, 2011, WIPO Application No. PCT/US2011/036667, filed May 16, 2011, WIPO Application No. PCT/US2011/036672, filed May 16, 2011, WIPO Application No. PCT/US2011/036701, filed May 16, 2011, WIPO Application No. PCT/JP2008/073864, filed Dec. 26, 2008, WIPO Application No. PCT/JP1992/001198, Sep. 18, 1992, WIPO Application No. PCT/JP1993/001329, filed Sep. 16, 1993, and WIPO Application No. PCT/JP2006/310709, filed May 30, 2006.

(33) R.sup.1 and R.sup.2

(34) Compounds of Formulae (I) and (II) comprise R.sup.1 and R.sup.2. In some embodiments, the carbon to which R.sup.1 and R.sup.2 is attached is in the (R)-configuration. In some embodiments, the carbon to which R.sup.1 and R.sup.2 is attached is in the (S)-configuration. In some embodiments, R.sup.2 is hydrogen, and the carbon to which R.sup.1 is attached is in the (R)-configuration. In some embodiments, R.sup.2 is hydrogen, and the carbon to which R.sup.1 is attached is in the (S)-configuration. In some embodiments, R.sup.1 and R.sup.2 are the same. In some embodiments, R.sup.1 and R.sup.2 are different.

(35) As generally defined herein, R.sup.1 is hydrogen, halogen, optionally substituted alkyl, or —(CH.sub.2).sub.nL, wherein n is 0, 1, 2, 3 or 4, and L is —C(═O)R.sup.3, —C(═O)OR.sup.3, —C(═O)NR.sup.3R.sup.4, —S(═O).sub.2R.sup.3, —S(═O).sub.2OR.sup.3, —S(═O).sub.2NR.sup.3R.sup.4, —OR.sup.3, —NR.sup.3R.sup.4, —N(R.sup.4)C(═O)R.sup.3, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

(36) In certain embodiments, R.sup.1 is hydrogen. In certain embodiments, R.sup.1 is a non-hydrogen group. In certain embodiments, R.sup.1 is halogen. In certain embodiments, R.sup.1 is —F. In certain embodiments, R.sup.1 is —Cl, —Br, or —I.

(37) In certain embodiments, R.sup.1 is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-.sup.1 alkyl, optionally substituted C.sup.1.sub.-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.1 is unsubstituted alkyl e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-.sup.1 alkyl, unsubstituted C.sup.1.sub.-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.1 is methyl. In certain embodiments, R.sup.1 is ethyl, propyl, or butyl. In certain embodiments, R.sup.1 is haloalkyl, e.g., —CHF.sup.1, —CHCl.sup.1, —CH.sup.1CHF.sup.1, —CH.sup.1CHCl.sup.1. In certain embodiments, R.sup.1 is perhaloalkyl, e.g., —CF.sub.3, —CF.sup.1CF.sub.3, —CCl.sub.3. In certain embodiments, R.sup.1 is hydroxyalkyl, e.g., —CH.sup.1OH, —CH.sup.1CH.sup.1OH, —CH.sup.1OR.sup.f, —CH.sup.1CH.sup.1OR.sup.f. In certain embodiments, R.sup.1 is aminoalkyl, e.g., —CH.sup.1NH.sup.1, —CH.sup.1CH.sup.1NH.sup.1, —CH.sup.1NMe.sup.1, —CH.sup.1CH.sup.1NMe.sup.1, —CH.sup.1N(R.sup.f).sup.1, —CH.sup.1CH.sup.1N(R.sup.f).sup.1.

(38) In certain embodiments, R.sup.1 is —(CH.sub.2).sub.nL, wherein n is 0, 1, 2, 3 or 4, and L is —C(═O)R.sup.3, —C(═O)OR.sup.3, —C(═O)NR.sup.3R.sup.4, —S(═O).sub.2R.sup.3, —S(═O).sub.2OR.sup.3, —S(═O).sub.2NR.sup.3R.sup.4, —OR.sup.3, —NR.sup.3R.sup.4, —N(R.sup.4)C(═O)R.sup.3, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. 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 0, 1, 2, or 3. In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 0 or 1. In certain embodiments, n is 1, 2, 3, or 4. In certain embodiments, n is 2, 3, or 4. In certain embodiments, n is 3 or 4. When n is 0, R.sup.1 is -L, such that R.sup.1 is —C(═O)R.sup.3, —C(═O)OR.sup.3, —C(═O)NR.sup.3R.sup.4, —S(═O).sub.2R.sup.3, —S(═O).sub.2OR.sup.3, —S(═O).sub.2NR.sup.3R.sup.4, —OR.sup.3, —NR.sup.3R.sup.4, —N(R.sup.4)C(═O)R.sup.3, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

(39) In certain embodiments, L is —C(═O)R.sup.3. In certain embodiments, L is —C(═O)OR.sup.3. In certain embodiments, L is —C(═O)NR.sup.3R.sup.4. In certain embodiments, L is —C(═O)NHR.sup.3. In certain embodiments, L is —S(═O).sub.2R.sup.3. In certain embodiments, L is —S(═O).sub.2OR.sup.3. In certain embodiments, L is —S(═O).sub.2NR.sup.3R.sup.4. In certain embodiments, L is —S(═O).sub.2OR.sup.3. In certain embodiments, L is —S(═O).sub.2NHR.sup.3. In certain embodiments, L is —OR.sup.3. In certain embodiments, L is —NR.sup.3R.sup.4. In certain embodiments, L is —NHR.sup.3. In certain embodiments, L is —N(R.sup.4)C(═O)R.sup.3. In certain embodiments, L is —NHC(═O)R.sup.3.

(40) As generally defined herein, each of R.sup.3 and R.sup.4 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or R.sup.3 and R.sup.4 are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.

(41) In certain embodiments, R.sup.3 is hydrogen. In certain embodiments, R.sup.3 is a non-hydrogen group. In certain embodiments. R.sup.3 is halogen. In certain embodiments, R.sup.3 is —F. In certain embodiments, R.sup.3 is —Cl, —Br, or —I. In certain embodiments, R.sup.3 is —NO.sub.2. In certain embodiments, R.sup.3 is —CN.

(42) In certain embodiments, R.sup.3 is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.3 is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.3 is methyl. In certain embodiments, R.sup.3 is ethyl, propyl, or butyl. In certain embodiments, R.sup.3 is haloalkyl, e.g., —CHF.sub.2, —CHCl.sub.2, —CH.sub.2CHF.sub.2, —CH.sub.2CHCl.sub.2. In certain embodiments, R.sup.3 is perhaloalkyl, e.g., —CF.sub.3, —CF.sub.2CF.sub.3, —CCl.sub.3. In certain embodiments, R.sup.3 is hydroxyalkyl, e.g., —CH.sub.2CH.sub.2OH, —CH.sub.2OR.sup.f, —CH.sub.2CH.sub.2OR.sup.f. In certain embodiments, R.sup.3 is aminoalkyl, e.g., —CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2NMe.sub.2, —CH.sub.2CH.sub.2NMe.sub.2, —CH.sub.2N(R.sup.f).sub.2, —CH2CH2N(R.sup.f).sub.2.

(43) In certain embodiments, R.sup.3 is optionally substituted alkenyl, e.g., optionally substituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.3 is unsubstituted alkenyl, e.g., unsubstituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.3 is vinyl, allyl, or prenyl. In certain embodiments, R.sup.3 is optionally substituted alkynyl, e.g., optionally substituted C.sub.2-6 alkynyl. In certain embodiments, R.sup.3 is unsubstituted alkynyl, e.g., unsubstituted C.sub.2L.sub.6 alkynyl.

(44) In certain embodiments, R.sup.3 is optionally substituted carbocyclyl, e.g., optionally substituted C.sub.3-6 carbocyclyl, optionally substituted C.sub.3-4 carbocyclyl, optionally substituted C.sub.4-5 carbocyclyl, or optionally substituted C.sub.5-6 carbocyclyl. In certain embodiments, R.sup.3 is unsubstituted carbocyclyl, e.g., unsubstituted C.sub.3-6 carbocyclyl. In some embodiments, R.sup.3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R.sup.3 is optionally substituted heterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted 4-5 membered heterocyclyl, or optionally substituted 5-6 membered heterocyclyl. In certain embodiments, R.sup.3 is unsubstituted heterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

(45) In certain embodiments, R.sup.3 is optionally substituted aryl, e.g., optionally substituted phenyl. In certain embodiments, R.sup.3 is unsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments, R.sup.3 is optionally substituted heteroaryl, e.g., optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.3 is unsubstituted heteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, or unsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.3 is optionally substituted aralkyl, e.g., optionally substituted benzyl. In certain embodiments, R.sup.3 is optionally substituted heteroaralkyl, e.g., methyl substituted with an optionally substituted 5-6 membered heteroaryl ring. In certain embodiments, R.sup.3 is unsubstituted aralkyl, e.g., unsubstituted benzyl. In certain embodiments, R.sup.3 is unsubstituted heteroaralkyl, e.g., methyl substituted with an unsubstituted 5-6 membered heteroaryl ring.

(46) In certain embodiments, R.sup.3 is optionally substituted acyl, e.g., —CHO, —CO.sub.2H, or —C(═O)NH.sub.2. In certain embodiments, R.sup.3 is —C(═O)R.sup.f, —C(═O)OR.sup.f, —C(═O)NH(R.sup.f), or —C(═O)N(R.sup.f).sub.2. In certain embodiments, R.sup.3 is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., —C(═O)Me. In certain embodiments, R.sup.3 is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.3 is —C(═O)R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.3 is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.3 is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.3 is —C(═O)OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.3 is —C(═O)N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.3 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.3 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.3 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.3 is a nitrogen protecting group. In some embodiments, R.sup.3 is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

(47) In certain embodiments, R.sup.4 is hydrogen. In certain embodiments, R.sup.4 is a non-hydrogen group. In certain embodiments, R.sup.4 is halogen. In certain embodiments, R.sup.4 is —F. In certain embodiments, R.sup.4 is —Cl, —Br, or —I. In certain embodiments, R.sup.4 is —NO.sub.2. In certain embodiments, R.sup.4 is —CN.

(48) In certain embodiments, R.sup.4 is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.4 is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.4 is methyl. In certain embodiments, R.sup.4 is ethyl, propyl, or butyl. In certain embodiments, R.sup.4 is haloalkyl, e.g., —CHF.sub.2, —CHCl.sub.2, —CH.sub.2CHF.sub.2, —CH.sub.2CHCl.sub.2. In certain embodiments, R.sup.4 is perhaloalkyl, e.g., —CF.sub.3, —CF.sub.2CF.sub.3, —CCl.sub.3. In certain embodiments, R.sup.4 is hydroxyalkyl, e.g., —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CH.sub.2OR.sup.f, —CH.sub.2CH.sub.2OR.sup.f. In certain embodiments, R.sup.4 is aminoalkyl, e.g., —CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2NMe.sub.2, —CH.sub.2CH.sub.2NMe.sub.2, —CH.sub.2N(R.sup.f).sub.2, —CH2CH2N(R.sup.f).sub.2.

(49) In certain embodiments, R.sup.4 is optionally substituted alkenyl, e.g., optionally substituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.4 is unsubstituted alkenyl, e.g., unsubstituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.4 is vinyl, allyl, or prenyl. In certain embodiments, R.sup.4 is optionally substituted alkynyl, e.g., optionally substituted C.sub.2-6 alkynyl. In certain embodiments, R.sup.4 is unsubstituted alkynyl, e.g., unsubstituted C.sub.2-6 alkynyl.

(50) In certain embodiments, R.sup.4 is optionally substituted carbocyclyl, e.g., optionally substituted C.sub.3-6 carbocyclyl, optionally substituted C.sub.3-4 carbocyclyl, optionally substituted C.sub.4-5 carbocyclyl, or optionally substituted C.sub.5-6 carbocyclyl. In certain embodiments, R.sup.4 is unsubstituted carbocyclyl, e.g., unsubstituted C.sub.3-6 carbocyclyl. In some embodiments, R.sup.4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R.sup.4 is optionally substituted heterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted 4-5 membered heterocyclyl, or optionally substituted 5-6 membered heterocyclyl. In certain embodiments, R.sup.4 is unsubstituted heterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

(51) In certain embodiments, R.sup.4 is optionally substituted aryl, e.g., optionally substituted phenyl. In certain embodiments, R.sup.4 is unsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments, R.sup.4 is optionally substituted heteroaryl, e.g., optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.4 is unsubstituted heteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, or unsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.4 is optionally substituted aralkyl, e.g., optionally substituted benzyl. In certain embodiments, R.sup.4 is optionally substituted heteroaralkyl, e.g., methyl substituted with an optionally substituted 5-6 membered heteroaryl ring. In certain embodiments, R.sup.4 is unsubstituted aralkyl, e.g., unsubstituted benzyl. In certain embodiments, R.sup.4 is unsubstituted heteroaralkyl, e.g., methyl substituted with an unsubstituted 5-6 membered heteroaryl ring.

(52) In certain embodiments, R.sup.4 is optionally substituted acyl, e.g., —CHO, —CO.sub.2H, or —C(═O)NH.sub.2. In certain embodiments, R.sup.4 is —C(═O)R.sup.f, —C(═O)OR.sup.f, —C(═O)NH(R.sup.f), or —C(═O)N(R.sup.f).sub.2. In certain embodiments, R.sup.4 is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., —C(═O)Me. In certain embodiments, R.sup.4 is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.4 is —C(═O)R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.4 is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.4 is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.4 is —C(═O)OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.4 is —C(═O)N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.4 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.4 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.4 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.4 is a nitrogen protecting group. In some embodiments, R.sup.4 is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

(53) In certain embodiments, R.sup.3 and R.sup.4 are the same. In certain embodiments, R.sup.3 and R.sup.4 are different. In certain embodiments, R.sup.3 and R.sup.4 are both hydrogen. In certain embodiments, R.sup.3 and R.sup.4 are both optionally substituted alkyl. In certain embodiments, R.sup.3 and R.sup.4 are both optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.3 and R.sup.4 are both unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.3 and R.sup.4 are both methyl. In certain embodiments, R.sup.3 and R.sup.4 are both ethyl, propyl, or butyl.

(54) In certain embodiments, R.sup.3 and R.sup.4 are joined to form an optionally substituted heterocyclic ring. In certain embodiments, R.sup.3 and R.sup.4 are joined to form an unsubstituted heterocyclic ring. In some embodiments, R.sup.3 and R.sup.4 are joined to form a substituted or unsubstituted piperidinyl, dihydropyridinyl, piperazinyl, or morpholinyl ring. In certain embodiments, R.sup.3 and R.sup.4 are joined to form a substituted or unsubstituted piperidinyl ring. In certain embodiments, R.sup.3 and R.sup.4 are joined to form a substituted or unsubstituted dihydropyridinyl ring. In certain embodiments, R.sup.3 and R.sup.4 are joined to form a substituted or unsubstituted piperazinyl ring. In certain embodiments, R.sup.3 and R.sup.4 are joined to form a substituted or unsubstituted morpholinyl ring. In certain embodiments, R.sup.3 and R.sup.4 are joined to form an optionally substituted heteroaryl ring. In certain embodiments, R.sup.3 and R.sup.4 are joined to form an unsubstituted heteroaryl ring. In some embodiments, R.sup.3 and R.sup.4 are joined to form a substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl ring. In certain embodiments, R.sup.3 and R.sup.4 are joined to form a substituted or unsubstituted pyrrolyl ring. In certain embodiments, R.sup.3 and R.sup.4 are joined to form a substituted or unsubstituted imidazolyl ring. In certain embodiments, R.sup.3 and R.sup.4 are joined to form a substituted or unsubstituted pyrazolyl ring. In certain embodiments, R.sup.3 and R.sup.4 are joined to form a substituted or unsubstituted triazolyl ring. In certain embodiments, R.sup.3 and R.sup.4 are joined to form a substituted or unsubstituted tetrazolyl ring.

(55) In certain embodiments, R.sup.L is optionally substituted carbocyclyl, e.g., optionally substituted C.sub.3-6 carbocyclyl, optionally substituted C.sub.3-4 carbocyclyl, optionally substituted C.sub.4-5 carbocyclyl, or optionally substituted C.sub.5-6 carbocyclyl. In certain embodiments, R.sup.L is unsubstituted carbocyclyl, e.g., unsubstituted C.sub.3-6 carbocyclyl. In some embodiments, R.sup.L is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R.sup.L is optionally substituted heterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted 4-5 membered heterocyclyl, or optionally substituted 5-6 membered heterocyclyl. In certain embodiments, R.sup.L is unsubstituted heterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

(56) In certain embodiments, R.sup.L is optionally substituted aryl, e.g., optionally substituted phenyl. In certain embodiments, R.sup.L is unsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments, R.sup.L is optionally substituted heteroaryl, e.g., optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.L is unsubstituted heteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, or unsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.L is optionally substituted aralkyl, e.g., optionally substituted benzyl. In certain embodiments, R.sup.L is optionally substituted heteroaralkyl, e.g., methyl substituted with an optionally substituted 5-6 membered heteroaryl ring. In certain embodiments, R.sup.L is unsubstituted aralkyl, e.g., unsubstituted benzyl. In certain embodiments, R.sup.L is unsubstituted heteroaralkyl, e.g., methyl substituted with an unsubstituted 5-6 membered heteroaryl ring.

(57) In certain embodiments, L is —OR.sup.3, e.g., —OH. In certain embodiments, L is —OR.sup.3, and R.sup.3 is optionally substituted alkyl. In certain embodiments, L is —OR.sup.3, and R.sup.3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, L is —OR.sup.3, and R.sup.3 is optionally substituted alkenyl. In certain embodiments, L is —OR.sup.3, and R.sup.3 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl optionally substituted heteroaryl. In certain embodiments, L is —OR.sup.3, and R.sup.3 is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl. In certain embodiments, L is —OR.sup.3, and R.sup.3 is optionally substituted acyl, e.g., L is —OC(═O)R.sup.f, —OC(═O)OR.sup.f, or —OC(═O)N(R.sup.f).sub.2. In certain embodiments, L is —OR.sup.3, and R.sup.3 is an oxygen protecting group.

(58) In certain embodiments, L is —NR.sup.3R.sup.4, e.g., —NH.sub.2, —NHR.sup.3. In certain embodiments, L is —NHR.sup.3, and R.sup.3 is optionally substituted alkyl. In certain embodiments, L is —NR.sup.3R.sup.4, and at least one of R.sup.3 and R.sup.4 is optionally substituted alkyl. In certain embodiments, L is —NHR.sup.3, and R.sup.3 is unsubstituted alkyl. In certain embodiments, L is —NR.sup.3R.sup.4, and at least one of R.sup.3 and R.sup.4 is unsubstituted alkyl. In certain embodiments, R.sup.1 is —(CH.sub.2)NH (optionally substituted C.sub.1-6 alkyl). In certain embodiments, L is —NHR.sup.3, and R.sup.3 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, L is —NHR.sup.3, and R.sup.3 is optionally substituted phenyl. In certain embodiments, R.sup.1 is of the formula:

(59) ##STR00013##
wherein R.sup.3a is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.g).sub.2, or —NO.sub.2; R.sup.g is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or nitrogen protecting group; n is 0, 1, 2, 3 or 4; and A is 0, 1, 2, 3, 4, or 5. In certain embodiments, R.sup.3a is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one R.sup.A1 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.3a is substituted or unsubstituted methyl. In certain embodiments, R.sup.3a is substituted or unsubstituted ethyl. In certain embodiments, R.sup.3a is substituted or unsubstituted propyl. In certain embodiments, R.sup.3a is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.3a is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.3a is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.3a is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, Ria is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.3a is benzyl. In certain embodiments, R.sup.3a is substituted or unsubstituted phenyl. In certain embodiments, R.sup.3a is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.3a is —OR.sup.f (e.g., —OH or —OMe). In certain embodiments, R.sup.3a is optionally substituted acyl (e.g., —C(═O)R.sup.f) (e.g., —C(═O)Me). In certain embodiments, R.sup.3a is —SR.sup.f, —N(R.sup.g).sub.2, or —NO.sub.2, In certain embodiments, R.sup.g is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or nitrogen protecting group. 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, A is 0. In certain embodiments, A is 1. In certain embodiments, A is 2. In certain embodiments, A is 3. In certain embodiments, A is 4. In certain embodiments, A is 5. In certain embodiments, R.sup.f is hydrogen. In certain embodiments, R.sup.f is optionally substituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.f is substituted or unsubstituted methyl. In certain embodiments, R.sup.f is substituted or unsubstituted ethyl. In certain embodiments, R R.sup.f3a is substituted or unsubstituted propyl. In certain embodiments, R.sup.f is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.f is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.f is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.f is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocycle or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.f is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.f is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocycle heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, two R.sup.f are joined to form an optionally substituted heterocyclic ring (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur), or optionally substituted heteroaryl ring (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.f is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In certain embodiments, R.sup.f is optionally substituted acyl or optionally substituted sulfonyl. In certain embodiments. L is —NHR.sup.3, and R.sup.3 is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In certain embodiments, L is —NHR.sup.3, and R.sup.3 is optionally substituted acyl, e.g., L is —NHC(═O)R.sup.f, —NHC(═O)OR.sup.f, or —NHC(═O)NHR.sup.f. In certain embodiments, L is —NR.sup.3R.sup.4, and at least one of R.sup.3 and R.sup.4 is a nitrogen protecting group. In certain embodiments, L is —NR.sup.3R.sup.4, and R.sup.3 and R.sup.4 are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In certain embodiments, L is —NR.sup.3R.sup.4, and R.sup.3 and R.sup.4 are joined to form an unsubstituted heterocyclic or unsubstituted heteroaryl ring.

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

(61) ##STR00014##

(62) In certain embodiments. R.sup.1 is of formula:

(63) ##STR00015##

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

(65) ##STR00016##

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

(67) ##STR00017##

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

(69) ##STR00018##

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

(71) ##STR00019## ##STR00020##

(72) As generally defined herein, R.sup.2 is hydrogen, halogen, or optionally substituted alkyl. In certain embodiments, R.sup.2 is hydrogen. In certain embodiments, R.sup.2 is a non-hydrogen group. In certain embodiments, R.sup.2 is halogen. In certain embodiments, R.sup.2 is —F. In certain embodiments, R.sup.2 is —Cl, —Br, or —I.

(73) In certain embodiments, R.sup.2 is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.2 is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.2 is methyl. In certain embodiments, R.sup.2 is ethyl, propyl, or butyl. In certain embodiments, R.sup.2 is haloalkyl, e.g., —CHF.sub.2, —CHCl.sub.2, —CH.sub.2CHF.sub.2, —CH.sub.2CHCl.sub.2. In certain embodiments, R.sup.2 is perhaloalkyl, e.g., —CF.sub.3, —CF.sub.2CF.sub.3, —CCl.sub.3. In certain embodiments, R.sup.2 is hydroxyalkyl, e.g., —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CH.sub.2OR.sup.f, —.sub.2CH.sub.2OR.sup.f. In certain embodiments, R.sup.2 is aminoalkyl, e.g., —CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2NMe.sub.2, —CH.sub.2CH.sub.2NMe.sub.2, —CH.sub.2N(R.sup.f).sub.2, —CH2CH2N(R.sup.f).sub.2.

(74) R.sup.A1 and R.sup.A2

(75) Compounds of Formula (I) comprise groups R.sup.A1 and R.sup.A2. Compounds of Formula (II) comprise group R.sup.A2 and —CH.sub.2R.sup.M at the position to which R.sup.A1 is attached in compounds of Formula (I).

(76) As generally defined herein, R.sup.A1 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN. In certain embodiments, R.sup.A1 is —CH.sub.2R.sup.M, wherein R.sup.M is —CN, —N(R.sup.f).sub.2, or —CH.sub.2N(R.sup.f).sub.2. In certain embodiments, R.sup.A2 is —CH.sub.2R.sup.M, wherein R.sup.M is —CN, —N(R.sup.f).sub.2, or —CH.sub.2N(R.sup.f).sub.2.

(77) In certain embodiments, R.sup.A1 is hydrogen. In certain embodiments, R.sup.A1 is a non-hydrogen group. In certain embodiments, R.sup.A1 is halogen. In certain embodiments, R.sup.A1 is —F. In certain embodiments, R.sup.A1 is —Cl, —Br, or —I. In certain embodiments, R.sup.A1 is —NO.sub.2. In certain embodiments, R.sup.A1 is —CN.

(78) In certain embodiments, R.sup.A1 is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.A1 is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.A1 is methyl. In certain embodiments, R.sup.A1 is ethyl, propyl, or butyl. In certain embodiments, R.sup.A1 is haloalkyl, e.g., —CHF.sub.2, —CHCl.sub.2, —CH.sub.2CHF.sub.2, —CH.sub.2CHCl.sub.2. In certain embodiments, R.sup.A1 is perhaloalkyl, e.g., —CF.sub.3, —CF.sub.2CF.sub.3, —CCl.sub.3. In certain embodiments, R.sup.A1 is hydroxyalkyl, e.g., —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CH.sub.2OR.sup.f, —CH.sub.2CH.sub.2OR.sup.f. In certain embodiments, R.sup.A1 is aminoalkyl, e.g., —CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2NMe.sub.2, —CH.sub.2CH.sub.2NMe.sub.2, —CH.sub.2N(R.sup.f).sub.2, —CH2CH2N(R.sup.f).sub.2.

(79) In certain embodiments, R.sup.A1 is optionally substituted alkenyl, e.g., optionally substituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.A1 is unsubstituted alkenyl, e.g., unsubstituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.A1 is vinyl, allyl, or prenyl. In certain embodiments, R.sup.A1 is optionally substituted alkynyl, e.g., optionally substituted C.sub.2-6 alkynyl. In certain embodiments, R.sup.A1 is unsubstituted alkynyl, e.g., unsubstituted C.sub.2-6 alkynyl.

(80) In certain embodiments, R.sup.A1 is optionally substituted carbocyclyl, e.g., optionally substituted C.sub.3-6 carbocyclyl, optionally substituted C.sub.3-4 carbocyclyl, optionally substituted C.sub.4-5 or optionally substituted C.sub.5-6 carbocyclyl. In certain embodiments, R.sup.A1 is unsubstituted carbocyclyl, e.g., unsubstituted C.sub.3-6 carbocyclyl. In some embodiments, R.sup.A1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R.sup.A1 is optionally substituted heterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted 4-5 membered heterocyclyl, or optionally substituted 5-6 membered heterocyclyl. In certain embodiments, R.sup.A1 is unsubstituted heterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

(81) In certain embodiments, R.sup.A1 is optionally substituted aryl, e.g., optionally substituted phenyl. In certain embodiments, R.sup.A1 is unsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments, R.sup.A1 is optionally substituted heteroaryl, e.g., optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.A1 is unsubstituted heteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, or unsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.A1 is optionally substituted aralkyl, e.g., optionally substituted benzyl. In certain embodiments, R.sup.A1 is optionally substituted heteroaralkyl, e.g., methyl substituted with an optionally substituted 5-6 membered heteroaryl ring. In certain embodiments, R.sup.A1 is unsubstituted aralkyl, e.g., unsubstituted benzyl. In certain embodiments, R.sup.A1 is unsubstituted heteroaralkyl, e.g., methyl substituted with an unsubstituted 5-6 membered heteroaryl ring.

(82) In certain embodiments, R.sup.A1 is optionally substituted acyl, e.g., —CHO, —CO.sub.2H, or —C(═O)NH.sub.2. In certain embodiments, R.sup.A1 is —C(═O)R.sup.f, —C(═O)OR.sup.f, —C(═O)NH(R.sup.f), or —C(═O)N(R.sup.f).sub.2. In certain embodiments, R.sup.A1 is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., —C(═O)Me. In certain embodiments, R.sup.A1 is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.A1 is —C(═O)R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.A1 is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.A1 is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.A1 is —C(═O)OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.A1 is —C(═O)N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.A1 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.A1 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.A1 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

(83) In certain embodiments, R.sup.A1 is —OR.sup.f, e.g., —OH. In certain embodiments, R.sup.A1 is —OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.A1 is —OR.sup.f, and R.sup.f is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A1 is —OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.A1 is —OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl optionally substituted heteroaryl. In certain embodiments, R.sup.A1 is —OR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl. In certain embodiments, R.sup.A1 is —OR.sup.f, and R.sup.f is optionally substituted acyl, e.g., R.sup.A1 is —OC(═O)R.sup.f, —OC(═O) OR.sup.f, or —OC(═O)N(R.sup.f).sub.2. In certain embodiments, R.sup.A1 is —OR.sup.f, and R.sup.f is an oxygen protecting group.

(84) In certain embodiments, R.sup.A1 is —SR.sup.f, e.g., —SH. In certain embodiments, R.sup.A1 is —SR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.A1 is —SR.sup.f, and R.sup.f is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A1 is —SR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl optionally substituted heteroaryl. In certain embodiments, R.sup.A1 is —SR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl. In certain embodiments, R.sup.A1 is —SR.sup.f, and R.sup.f is a sulfur protecting group.

(85) In certain embodiments, R.sup.A1 is —N(R.sup.f).sub.2, e.g., —NH.sub.2, —NHR.sup.f. In certain embodiments, R.sup.A1 is —NH(R.sup.f), and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.A1 is —N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.A1 is —NH(R.sup.f), and R.sup.f is unsubstituted alkyl. In certain embodiments, R.sup.A1 is —N(R.sup.f).sub.2, and at least one R.sup.f is unsubstituted alkyl. In certain embodiments, R.sup.A1 is —NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, R.sup.A1 is —NHR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In certain embodiments, R.sup.A1 is —NHR.sup.f, and R.sup.f is optionally substituted acyl. e.g., R.sup.A1 is —NHC(═O)R.sup.f. —NHC(═O)OR.sup.f, or —NHC(═O)NHR.sup.f. In certain embodiments, R.sup.A1 is —N(R.sup.f).sub.2, and at least one R.sup.f is a nitrogen protecting group. In certain embodiments, R.sup.A1 is —N(R.sup.f).sub.2, and both R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In certain embodiments, R.sup.A1 is —N(R.sup.f).sub.2, and both R.sup.f are joined to form an unsubstituted heterocyclic or unsubstituted heteroaryl ring.

(86) As generally defined herein, R.sup.A2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN.

(87) In certain embodiments, R.sup.A2 is hydrogen. In certain embodiments, R.sup.A2 is a non-hydrogen group. In certain embodiments, R.sup.A2 is halogen. In certain embodiments, R.sup.A2 is —F. In certain embodiments, R.sup.A2 is —Cl, —Br, or —I. In certain embodiments, R.sup.A2 is —NO.sub.2. In certain embodiments, R.sup.A2 is —CN.

(88) In certain embodiments, R.sup.A2 is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.A2 is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.A2 is methyl. In certain embodiments, R.sup.A2 is ethyl, propyl, or butyl. In certain embodiments, R.sup.A2 is haloalkyl, e.g., —CHF.sub.2, —CHCl.sub.2, —CH.sub.2CHF.sub.2, —CH.sub.2CHCl.sub.2. In certain embodiments, R.sup.A2 is perhaloalkyl, e.g., —CF.sub.3, —CF.sub.2CF.sub.3, —CCl.sub.3. In certain embodiments, R.sup.A2 is hydroxyalkyl, e.g., —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CH.sub.2OR.sup.f, —CH.sub.2CH.sub.2OR.sup.f. In certain embodiments, R.sup.A2 is aminoalkyl, e.g., —CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2NMe.sub.2, —CH.sub.2CH.sub.2NMe.sub.2, —CH.sub.2N(R.sup.f).sub.2, —CH2CH2N(R.sup.f).sub.2.

(89) In certain embodiments. R.sup.A2 is optionally substituted alkenyl, e.g., optionally substituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.A2 is unsubstituted alkenyl, e.g., unsubstituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.A2 is vinyl, allyl, or prenyl. In certain embodiments, R.sup.A2 is optionally substituted alkynyl, e.g., optionally substituted C.sub.1-6 alkynyl. In certain embodiments, R.sup.A2 is unsubstituted alkynyl, e.g., unsubstituted C.sub.2-6 alkynyl.

(90) In certain embodiments, R.sup.A2 is optionally substituted carbocyclyl, e.g., optionally substituted C.sub.3-6 carbocyclyl, optionally substituted C.sub.3-4 carbocyclyl, optionally substituted C.sub.4-5 carbocyclyl, or optionally substituted C.sub.5-6 carbocyclyl. In certain embodiments, R.sup.A2 is unsubstituted carbocyclyl, e.g., unsubstituted C.sub.3-6 carbocyclyl. In some embodiments, R.sup.A2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R.sup.A2 is optionally substituted heterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted 4-5 membered heterocyclyl, or optionally substituted 5-6 membered heterocyclyl. In certain embodiments, R.sup.A2 is unsubstituted heterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

(91) In certain embodiments, R.sup.A2 is optionally substituted aryl, e.g., optionally substituted phenyl. In certain embodiments, R.sup.A2 is unsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments, R.sup.A2 is optionally substituted heteroaryl, e.g., optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.A2 is unsubstituted heteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, or unsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.A2 is optionally substituted aralkyl, e.g., optionally substituted benzyl. In certain embodiments, R.sup.A2 is optionally substituted heteroaralkyl, e.g., methyl substituted with an optionally substituted 5-6 membered heteroaryl ring. In certain embodiments, R.sup.A2 is unsubstituted aralkyl, e.g., unsubstituted benzyl. In certain embodiments, R.sup.A2 is unsubstituted heteroaralkyl, e.g., methyl substituted with an unsubstituted 5-6 membered heteroaryl ring.

(92) In certain embodiments, R.sup.A2 is optionally substituted acyl, e.g., —CHO, —CO.sub.2H, or —C(═O)NH.sub.2. In certain embodiments, R.sup.A2 is —C(═O)R.sup.f, —C(═O)OR.sup.f, —C(═O)NH(R.sup.f), or —C(═O)N(R.sup.f).sub.2. In certain embodiments, R.sup.A2 is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., —C(═O)Me. In certain embodiments, R.sup.A2 is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.A2 is —C(═O)R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.A2 is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.A2 is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.A2 is —C(═O)OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.A2 is —C(═O)N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.A2 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.A2 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.A2 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

(93) In certain embodiments, R.sup.A2 is —OR.sup.f, e.g., —OH. In certain embodiments, R.sup.A2 is —OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.A2 is —OR.sup.f, and R.sup.f is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A2 is —OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.A2 is —OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl optionally substituted heteroaryl. In certain embodiments, R.sup.A2 is —OR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl. In certain embodiments, R.sup.A2 is —OR.sup.f, and R.sup.f is optionally substituted acyl, e.g., R.sup.A2 is —OC(═O)R.sup.f, —OC(═O)OR.sup.f, or —OC(═O)N(R.sup.f).sub.2. In certain embodiments, R.sup.A2 is —OR.sup.f, and R.sup.f is a sulfur protecting group.

(94) In certain embodiments, R.sup.A2 is —SR.sup.f, e.g., —SH. In certain embodiments, R.sup.A2 is —SR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.A2 is —SR.sup.f, and R.sup.f is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A2 is —SR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl optionally substituted heteroaryl. In certain embodiments, R.sup.A2 is —SR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl. In certain embodiments, R.sup.A2 is —SR.sup.f, and R.sup.f is an oxygen protecting group.

(95) In certain embodiments, R.sup.A2 is —N(R.sup.f).sub.2, e.g., —NH.sub.2, —NHR.sup.f. In certain embodiments, R.sup.A2 is —NH(R.sup.f), and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.A2 is —N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.A2 is —NH(R.sup.f), and R.sup.f is unsubstituted alkyl. In certain embodiments, R.sup.A2 is —N(R.sup.f).sub.2, and at least one R.sup.f is unsubstituted alkyl. In certain embodiments, R.sup.A2 is —NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, R.sup.A2 is —NHR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In certain embodiments, R.sup.A2 is —NHR.sup.f, and R.sup.f is optionally substituted acyl, e.g., R.sup.A2 is —NHC(═O)R.sup.f, —NHC(═O)OR.sup.f, or —NHC(═O)NHR.sup.f. In certain embodiments, R.sup.A2 is —N(R.sup.f).sub.2, and at least one R.sup.f is a nitrogen protecting group. In certain embodiments, R.sup.A2 is —N(R.sup.f).sub.2, and both R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In certain embodiments, R.sup.A2 is —N(R.sup.f).sub.2, and both R.sup.f are joined to form an unsubstituted heterocyclic or unsubstituted heteroaryl ring.

(96) In some embodiments, R.sup.A1 and R.sup.A2 are the same. In some embodiments, R.sup.A1 and R.sup.A2 are different. In certain embodiments, both R.sup.A1 and R.sup.A2 are hydrogen. In certain embodiments, both R.sup.A1 and R.sup.A2 are optionally substituted halogen. In certain embodiments, both R.sup.A1 and R.sup.A2 are optionally substituted alkyl. In certain embodiments, both R.sup.A1 and R.sup.A2 are optionally substituted C.sub.1-6 alkyl. In certain embodiments, both R.sup.A1 and R.sup.A2 are unsubstituted C.sub.1-6 alkyl. In certain embodiments, both R.sup.A1 and R.sup.A2 are methyl.

(97) R.sup.M

(98) As generally defined herein, R.sup.M is —CN, —N(R.sup.f).sub.2, or —CH.sub.2N(R.sup.f).sub.2. In certain embodiments, R.sup.M is —CN. In certain embodiments, R.sup.M is —N(R.sup.f).sub.2. In some embodiments, R.sup.M is —NHR.sup.f. In some embodiments, R.sup.M is NH.sub.2. In certain embodiments, R.sup.M is —CH.sub.2N(R.sup.f).sub.2. In certain embodiments, R.sup.M is —CH.sub.2NHR.sup.f. In certain embodiments, R.sup.M is —CH.sub.2NH.sub.2.

(99) In certain embodiments, R.sup.M is —NH(R.sup.f), and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.M is —N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.M is —NH(R.sup.f), and R.sup.f is unsubstituted alkyl. In certain embodiments, R.sup.M is —N(R.sup.f).sub.2, and at least one R.sup.f is unsubstituted alkyl. In certain embodiments, R.sup.M is —NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, R.sup.M is —NHR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In certain embodiments, R.sup.M is —NHR.sup.f, and R.sup.f is optionally substituted acyl, e.g., R.sup.M is —NHC(═O)R.sup.f, —NHC(═O)OR.sup.f, or —NHC(═O)NHR.sup.f. In certain embodiments, R.sup.M is —N(R.sup.f).sub.2, and at least one R.sup.f is a nitrogen protecting group. In certain embodiments, R.sup.M is —N(R.sup.f).sub.2, and both R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In certain embodiments, R.sup.M is —N(R.sup.f).sub.2, and both R.sup.f are joined to form an unsubstituted heterocyclic or unsubstituted heteroaryl ring.

(100) In certain embodiments, R.sup.M is —CH.sub.2NH(R.sup.f), and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.M is —CH.sub.2N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.M is —CH.sub.2NH(R.sup.f), and R.sup.f is unsubstituted alkyl. In certain embodiments, R.sup.M is —CH.sub.2N(R.sup.f).sub.2, and at least one R.sup.f is unsubstituted alkyl. In certain embodiments, R.sup.M is —CH.sub.2NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, R.sup.M is —CH.sub.2NHR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In certain embodiments, R.sup.M is —CH.sub.2NHR.sup.f, and R.sup.f is optionally substituted acyl, e.g., R.sup.M is —CH.sub.2NHC(═O)R.sup.f, —CH.sub.2NHC(═O)OR.sup.f, or —CH.sub.2NHC(═O)NHR.sup.f. In certain embodiments, R.sup.M is —CH.sub.2N(R.sup.f).sub.2, and at least one R.sup.f is a nitrogen protecting group. In certain embodiments, R.sup.M is —CH.sub.2N(R.sup.f).sub.2, and both R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In certain embodiments, R.sup.M is —CH.sub.2N(R.sup.f).sub.2, and both R.sup.f are joined to form an unsubstituted heterocyclic or unsubstituted heteroaryl ring.

(101) R.sup.B and X.sup.1

(102) As generally defined herein, R.sup.B is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN. In certain embodiments, R.sup.B is —CH.sub.2R.sup.M, wherein R.sup.M is —CN, —N(R.sup.f).sub.2, or —CH.sub.2N(R.sup.f).sub.2.

(103) In certain embodiments, R.sup.B is hydrogen. In certain embodiments, R.sup.B is a non hydrogen group. In certain embodiments, R.sup.B is halogen. In certain embodiments, R.sup.B is —F. In certain embodiments, R.sup.B is —Cl, —Br, or —I. In certain embodiments, R.sup.B is —NO.sub.2. In certain embodiments, R.sup.B is —CN.

(104) In certain embodiments, R.sup.B is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.B is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.B is methyl. In certain embodiments, R.sup.B is ethyl, propyl, or butyl. In certain embodiments, R.sup.B is haloalkyl, e.g., —CHF.sub.2, —CHCl.sub.2, —CH.sub.2CHF.sub.2, —CH.sub.2CHCl.sub.2. In certain embodiments, R.sup.B is perhaloalkyl, e.g., —CF.sub.3, —CF.sub.2CF.sub.3, —CCl.sub.3. In certain embodiments, R.sup.B is hydroxyalkyl, e.g., —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CH.sub.2OR.sup.f, —CH.sub.2CH.sub.2OR.sup.f. In certain embodiments, R.sup.B is aminoalkyl, e.g., —CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2NMe.sub.2, —CH.sub.2CH.sub.2NMe.sub.2, —CH.sub.2N(R.sup.f).sub.2, —CH2CH2N(R.sup.f).sub.2.

(105) In certain embodiments, R.sup.B is optionally substituted alkenyl, e.g., optionally substituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.B is unsubstituted alkenyl, e.g., unsubstituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.B is vinyl, allyl, or prenyl. In certain embodiments, R.sup.B is optionally substituted alkynyl, e.g., optionally substituted C.sub.2-6 alkynyl. In certain embodiments, R.sup.B is unsubstituted alkynyl, e.g., unsubstituted C.sub.2-6 alkynyl.

(106) In certain embodiments, R.sup.B is optionally substituted carbocyclyl, e.g., optionally substituted C.sub.3-6 carbocyclyl, optionally substituted C.sub.3-4 carbocyclyl, optionally substituted C.sub.4-5 carbocyclyl, or optionally substituted C.sub.5-6 carbocyclyl. In certain embodiments, R.sup.B is unsubstituted carbocyclyl, e.g., unsubstituted C.sub.3-6 carbocyclyl. In some embodiments, R.sup.B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R.sup.B is optionally substituted heterocyclyl. e.g., optionally substituted 3-6 membered heterocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted 4-5 membered heterocyclyl, or optionally substituted 5-6 membered heterocyclyl. In certain embodiments, R.sup.B is unsubstituted heterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

(107) In certain embodiments. R.sup.B is optionally substituted aryl, e.g., optionally substituted phenyl. In certain embodiments, R.sup.B is unsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments, R.sup.B is optionally substituted heteroaryl, e.g., optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.B is unsubstituted heteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, or unsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.B is optionally substituted aralkyl, e.g., optionally substituted benzyl. In certain embodiments, R.sup.B is optionally substituted heteroaralkyl, e.g., methyl substituted with an optionally substituted 5-6 membered heteroaryl ring. In certain embodiments, R.sup.B is unsubstituted aralkyl, e.g., unsubstituted benzyl. In certain embodiments, R.sup.B is unsubstituted heteroaralkyl, e.g., methyl substituted with an unsubstituted 5-6 membered heteroaryl ring.

(108) In certain embodiments, R.sup.B is optionally substituted acyl, e.g., —CHO, —CO.sub.2H, or —C(═O)NH.sub.2. In certain embodiments, R.sup.B is —C(═O)R.sup.f, —C(═O)OR.sup.f, —C(═O)NH(R.sup.f), or —C(═O)N(R.sup.f).sub.2. In certain embodiments, R.sup.B is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., —C(═O)Me. In certain embodiments; R.sup.B is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.B is —C(═O)R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.B is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.B is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.B is —C(═O)OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.B is —C(═O)N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.B is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.B is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.B is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

(109) In certain embodiments, R.sup.B is —OR.sup.f, e.g., —OH. In certain embodiments, R.sup.B is —OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.B is —OR.sup.f, and R.sup.f is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.B is —OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.B is —OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl optionally substituted heteroaryl. In certain embodiments, R.sup.B is —OR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl. In certain embodiments, R.sup.B is —OR.sup.f, and R.sup.f is optionally substituted acyl, e.g., R.sup.B is —OC(═O)R.sup.f, —OC(═O)OR.sup.f, or —OC(═O)N(R.sup.f).sub.2. In certain embodiments, R.sup.B is —OR.sup.f, and R.sup.f is an oxygen protecting group.

(110) In certain embodiments, R.sup.B is —SR.sup.f, e.g., —SH. In certain embodiments, R.sup.B is —SR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.B is —SR.sup.f, and R.sup.f is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.B is —SR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl optionally substituted heteroaryl. In certain embodiments, R.sup.B is —SR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl. In certain embodiments, R.sup.B is —SR.sup.f, and R.sup.f is a sulfur protecting group.

(111) In certain embodiments, R.sup.B is —N(R.sup.f).sub.2, e.g., —NH.sub.2, —NHR.sup.f. In certain embodiments, R.sup.B is —NH(R.sup.f), and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.B is —N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.B is —NH(R.sup.f), and R.sup.f is unsubstituted alkyl. In certain embodiments, R.sup.B is —N(R.sup.f).sub.2, and at least one R.sup.f is unsubstituted alkyl. In certain embodiments, R.sup.B is —NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, R.sup.B is —NHR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In certain embodiments, R.sup.B is —NHR.sup.f, and R.sup.f is optionally substituted acyl, e.g., R.sup.B is —NHC(═O)R.sup.f, —NHC(═O)OR.sup.f, or —NHC(═O)NHR.sup.f. In certain embodiments, R.sup.B is —N(R.sup.f).sub.2, and at least one R.sup.f is a nitrogen protecting group. In certain embodiments, R.sup.B is —N(R.sup.f).sub.2, and both R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In certain embodiments, R.sup.B is —N(R.sup.f).sub.2, and both R.sup.f are joined to form an unsubstituted heterocyclic or unsubstituted heteroaryl ring.

(112) As generally defined herein, X.sup.1 is N or CR.sup.5, wherein R.sup.5 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN.

(113) In certain embodiments, X.sup.1 is N. In certain embodiments, X.sup.1 is CR.sup.5. In some embodiments, X.sup.1 is CMe.

(114) As generally defined herein, R.sup.5 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN. In certain embodiments, R.sup.5 is —CH.sub.2R.sup.M, wherein R.sup.M is —CN, —N(R.sup.f).sub.2, or —CH.sub.2N(R.sup.f).sub.2.

(115) In certain embodiments, R.sup.5 is hydrogen. In certain embodiments, R.sup.5 is a non-hydrogen group. In certain embodiments, R.sup.5 is halogen. In certain embodiments, R.sup.5 is —F. In certain embodiments, R.sup.5 is —Cl, —.sup.5r, or —I. In certain embodiments, R.sup.5 is —NO.sub.2. In certain embodiments, R.sup.5 is —CN.

(116) In certain embodiments, R.sup.5 is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.5 is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.5 is methyl. In certain embodiments, R.sup.5 is ethyl, propyl, or butyl. In certain embodiments, R.sup.5 is haloalkyl, e.g., —CHF.sub.2, —CHCl.sub.2, —CH.sub.2CHF.sub.2, —CH.sub.2CHCl.sub.2. In certain embodiments, R.sup.5 is perhaloalkyl, e.g., —CF.sub.2CF.sub.3, —CCl.sub.3. In certain embodiments, R.sup.5 is hydroxyalkyl, e.g., —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CH.sub.2OR.sup.f, —CH.sub.2CH.sub.2OR.sup.f. In certain embodiments, R.sup.5 is aminoalkyl, e.g., —CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2NMe.sub.2, —CH.sub.2CH.sub.2NMe.sub.2, —CH.sub.2N(R.sup.f).sub.2, —CH2CH2N(R.sup.f).sub.2.

(117) In certain embodiments, R.sup.5 is optionally substituted alkenyl, e.g., optionally substituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.5 is unsubstituted alkenyl, e.g., unsubstituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.5 is vinyl, allyl, or prenyl. In certain embodiments, R.sup.5 is optionally substituted alkynyl, e.g., optionally substituted C.sub.2-6 alkynyl. In certain embodiments, R.sup.5 is unsubstituted alkynyl, e.g., unsubstituted C.sub.2-6 alkynyl.

(118) In certain embodiments, R.sup.5 is optionally substituted carbocyclyl, e.g., optionally substituted C.sub.3-6, carbocyclyl, optionally substituted C.sub.3-4 carbocyclyl, optionally substituted C.sub.4-5 carbocyclyl, or optionally substituted C.sub.5-6 carbocyclyl. In certain embodiments, R.sup.5 is unsubstituted carbocyclyl, e.g., unsubstituted C.sub.3-6 carbocyclyl. In some embodiments, R.sup.5 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R.sup.5 is optionally substituted heterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted 4-5 membered heterocyclyl, or optionally substituted 5-6 membered heterocyclyl. In certain embodiments, R.sup.5 is unsubstituted heterocyclyl. e.g., unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

(119) In certain embodiments, R.sup.5 is optionally substituted aryl, e.g., optionally substituted phenyl. In certain embodiments, R.sup.5 is unsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments, R.sup.5 is optionally substituted heteroaryl, e.g., optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.5 is unsubstituted heteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, or unsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.5 is optionally substituted aralkyl, e.g., optionally substituted benzyl. In certain embodiments, R.sup.5 is optionally substituted heteroaralkyl, e.g., methyl substituted with an optionally substituted 5-6 membered heteroaryl ring. In certain embodiments, R.sup.5 is unsubstituted aralkyl, e.g., unsubstituted benzyl. In certain embodiments, R.sup.5 is unsubstituted heteroaralkyl, e.g., methyl substituted with an unsubstituted 5-6 membered heteroaryl ring.

(120) In certain embodiments, R.sup.5 is optionally substituted acyl, e.g., —CHO, —CO.sub.2H, or —C(═O)NH.sub.2. In certain embodiments, R.sup.5 is —C(═O)R.sup.f, —C(═O)OR.sup.f, —C(═O)NH(R.sup.f), or —C(═O)N(R.sup.f).sub.2. In certain embodiments, R.sup.5 is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., —C(═O)Me. In certain embodiments, R.sup.5 is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.5 is —C(═O)R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.5 is —C(—O)OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.3 is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.5 is —C(═O)OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.5 is —C(═O)N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.5 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.5 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.5 is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

(121) In certain embodiments, R.sup.5 is —OR.sup.f, e.g., —OH. In certain embodiments, R.sup.5 is —OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.5 is —OR.sup.f, and R.sup.f is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.5 is —OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.5 is —OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl optionally substituted heteroaryl. In certain embodiments, R.sup.5 is —OR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl. In certain embodiments, R.sup.5 is —OR.sup.f, and R.sup.f is optionally substituted acyl, e.g., R.sup.5 is —OC(═O)R.sup.f, —OC(═O)OR.sup.f, or —OC(═O)N(R.sup.f).sub.1. In certain embodiments, R.sup.5 is —OR.sup.f, and R.sup.f is an oxygen protecting group.

(122) In certain embodiments, R.sup.5 is —SR.sup.f, e.g., —SH. In certain embodiments, R.sup.5 is —SR.sup.f, and R.sup.f is optionally substituted alkyl. In certain, embodiments, R.sup.5 is —SR.sup.f, and R.sup.f is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.5 is —SR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl optionally substituted heteroaryl. In certain embodiments, R.sup.5 is —SR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl. In certain embodiments, R.sup.5 is —SR.sup.f, and R.sup.f is a sulfur protecting group.

(123) In certain embodiments, R.sup.5 is —N(R.sup.f).sub.2, e.g., —NHR.sup.f. In certain embodiments, R.sup.5 is —NH(R.sup.f), and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.5 is —N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.5 is —NH(R.sup.f), and R.sup.f is unsubstituted alkyl. In certain embodiments, R.sup.5 is —N(R.sup.f).sub.1, and at least one R.sup.f is unsubstituted alkyl. In certain embodiments, R.sup.5 is —NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, R.sup.5 is —NHR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In certain embodiments, R.sup.5 is —NHR.sup.f, and R.sup.f is optionally substituted acyl, e.g., R.sup.5 is —NHC(═O)R.sup.f, —NHC(═O)OR.sup.f, or —NHC(O)NHR.sup.f. In certain embodiments, R.sup.5 is —N(R.sup.f).sub.2, and at least one R.sup.f is a nitrogen protecting group. In certain embodiments, R.sup.5 is —N(R.sup.f).sub.2, and both R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In certain embodiments, R.sup.5 is —N(R.sup.f).sub.1, and both R.sup.f are joined to form an unsubstituted heterocyclic or unsubstituted heteroaryl ring.

(124) In some embodiments, X.sup.1 is CR.sup.5, and R.sup.B and R.sup.5 are the same. In some embodiments, X.sup.1 is CR.sup.5, and R.sup.B and R.sup.5 are different. In certain embodiments, X.sup.1 is CR.sup.5, and both R.sup.B and R.sup.5 are hydrogen. In certain embodiments, X.sup.1 is CR.sup.5, and both R.sup.B and R.sup.5 are optionally substituted halogen. In certain embodiments, X.sup.1 is CR.sup.5, and both R.sup.B and R.sup.5 are optionally substituted alkyl. In certain embodiments, X.sup.1 is CR.sup.5, and both R.sup.B and R.sup.5 are optionally substituted C.sub.1-6 alkyl. In certain embodiments, X.sup.1 is CR.sup.5, and both R.sup.B and R.sup.5 are unsubstituted C.sub.1-6 alkyl. In certain embodiments, X.sup.1 is CR.sup.5, and both R.sup.B and R.sup.5 are methyl.

(125) Ring C and R.sup.C

(126) As generally defined herein, Ring C is aryl or heteroaryl. For compounds of Formula (I), Ring C is substituted with at least one —CN group, and may be further substituted by 1, 2, 3, or 4 R.sup.C. For compounds of Formula (II), Ring C may be substituted by 1, 2, 3, or 4 R.sup.C. As generally defined herein, c is 0, 1, 2, 3, or 4. In certain embodiments, c is 0. In certain embodiments, c is 1. In certain embodiments, c is 2. In certain embodiments, c is 3. In certain embodiments, c is 4. In certain embodiments, c is 0, 1, 2, or 3. In certain embodiments, c is 0, 1, or 2. In certain embodiments, c is 0 or 1. In certain embodiments, c is 1, 2, 3, or 4. In certain embodiments, c is 2, 3, or 4. In certain embodiments, c is 3 or 4.

(127) In certain embodiments, Ring C is aryl. In certain embodiments, Ring C is monocyclic aryl. In certain embodiments, Ring C is phenyl. In certain embodiments, Ring C is bicyclic aryl. In certain embodiments, Ring C is naphthyl.

(128) In certain embodiments, Ring C is heteroaryl. In certain embodiments, Ring C is monocyclic heteroaryl. In certain embodiments, Ring C is 5-membered heteroaryl. In some embodiments, Ring C is pyrrolyl, furanyl, or thiophenyl. In some embodiments, Ring C is imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. In some embodiments, Ring C is triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. In certain embodiments, Ring C is 6-membered heteroaryl. In some embodiments, Ring C is pyridinyl. In some embodiments, Ring C is pyridazinyl, pyrimidinyl, and pyrazinyl. In certain embodiments, Ring C is bicyclic heteroaryl. In certain embodiments, Ring C is 9- to 10-membered bicyclic heteroaryl. In some embodiments, Ring C is indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, or purinyl. In some embodiments, Ring C is naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, or quinazolinyl.

(129) In certain embodiments, Ring C is of formula:

(130) ##STR00021##

(131) In certain embodiments, Ring C is of formula:

(132) ##STR00022##

(133) In certain embodiments, Ring C is of formula:

(134) ##STR00023##

(135) In certain embodiments, Ring C is of formula:

(136) ##STR00024##

(137) In certain embodiments, Ring C is of formula:

(138) ##STR00025##

(139) In certain embodiments, Ring C is of formula:

(140) ##STR00026##

(141) In certain embodiments, Ring C is of formula:

(142) ##STR00027##

(143) In certain embodiments, Ring C is of formula:

(144) ##STR00028##

(145) In certain embodiments, Ring C is of formula:

(146) ##STR00029##

(147) In certain embodiments, Ring C is of formula:

(148) ##STR00030##

(149) As generally defined herein, R.sup.C is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, —OR.sup.f, —SR.sup.f, —N(R.sup.f).sub.2, —NO.sub.2, or —CN.

(150) In certain embodiments, R.sup.C is halogen. In certain embodiments. R.sup.C is —F. In certain embodiments, R.sup.C is —Cl, —.sup.Cr, or —I. In certain embodiments, R.sup.C is —NO.sub.2. In certain embodiments, R.sup.C is —CN.

(151) In certain embodiments, R.sup.C is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.C is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.C is methyl. In certain embodiments, R.sup.C is ethyl, propyl, or butyl. In certain embodiments, R.sup.C is haloalkyl, e.g., —CHF.sub.2, —CHCl.sub.2, —CH.sub.2CHF.sub.2, —CH.sub.2CHCl.sub.2. In certain embodiments, R.sup.C is perhaloalkyl, e.g., —CF.sub.3, —CF.sub.2CF.sub.3, —CCl.sub.3. In certain embodiments, R.sup.C is hydroxyalkyl, e.g., —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CH.sub.2OR.sup.f, —CH.sub.2CH.sub.2OR.sup.f. In certain embodiments, R.sup.C is aminoalkyl, e.g., —CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2NMe.sub.2, —CH.sub.2CH.sub.2NMe.sub.2, —CH.sub.2N(R.sup.f).sub.2, —CH2CH2N(R.sup.f).sub.2.

(152) In certain embodiments, R.sup.C is optionally substituted alkenyl, e.g., optionally substituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.C is unsubstituted alkenyl, e.g., unsubstituted C.sub.2-6 alkenyl. In certain embodiments, R.sup.C is vinyl, allyl, or prenyl. In certain embodiments, R.sup.C is optionally substituted alkynyl, e.g., optionally substituted C.sub.2-6 alkynyl. In certain embodiments, R.sup.C is unsubstituted alkynyl, e.g., unsubstituted C.sub.2-6 alkynyl.

(153) In certain embodiments, R.sup.C is optionally substituted carbocyclyl, e.g., optionally substituted C.sub.3-6 carbocyclyl, optionally substituted C.sub.3-4 carbocyclyl, optionally substituted C.sub.4-5 carbocyclyl, or optionally substituted C.sub.5-6 carbocyclyl. In certain embodiments, R.sup.C is unsubstituted carbocyclyl, e.g., unsubstituted C.sub.3-6 carbocyclyl. In some embodiments, R.sup.C is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R.sup.C is optionally substituted heterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted 4-5 membered heterocyclyl, or optionally substituted 5-6 membered heterocyclyl. In certain embodiments, R.sup.C is unsubstituted heterocyclyl. e.g., unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

(154) In certain embodiments, R.sup.C is optionally substituted aryl, e.g., optionally substituted phenyl. In certain embodiments, R.sup.C is unsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments, R.sup.C is optionally substituted heteroaryl, e.g., optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.C is unsubstituted heteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, or unsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.C is optionally substituted aralkyl, e.g., optionally substituted benzyl. In certain embodiments, R.sup.C is optionally substituted heteroaralkyl, e.g., methyl substituted with an optionally substituted 5-6 Membered heteroaryl ring. In certain embodiments, R.sup.C is unsubstituted aralkyl, e.g., unsubstituted benzyl. In certain embodiments, R.sup.C is unsubstituted heteroaralkyl, e.g., methyl substituted with an unsubstituted 5-6 membered heteroaryl ring.

(155) In certain embodiments, R.sup.C is optionally substituted acyl, e.g., —CHO, —CO.sub.2H, or —C(═O)NH.sub.2. In certain embodiments, R.sup.C is —C(═O)R.sup.f, —C(═O)OR.sup.f, —C(═O)NH(R.sup.f), or —C(═O)N(R.sup.f).sub.2. In certain embodiments, R.sup.C is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., —C(═O)Me. In certain embodiments, R.sup.C is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.C is —C(═O)R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.C is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.C is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.C is —C(═O)OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.C is —C(═O)N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.C is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.C is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.C is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

(156) In certain embodiments, R.sup.C is optionally substituted sulfonyl, e.g., —S(═O).sub.2OH. In certain embodiments, R.sup.C is —S(═O).sub.2R.sup.f, —S(═O).sub.2OR.sup.f, —S(═O).sub.2NH(R.sup.f), or —S(═O).sub.2N(R.sup.f).sub.2. In certain embodiments, R.sup.C is —S(═O).sub.2R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., —S(═O).sub.2Me. In certain embodiments, R.sup.C is —S(═O).sub.2R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.C is —S(═O).sub.2OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.C is —S(═O).sub.2OR.sup.f, and R.sup.f is optionally substituted aryl. In certain embodiments, R.sup.C is —S(═O).sub.2N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.C is —S(═O).sub.2NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

(157) In certain embodiments, R.sup.C is —OR.sup.f, e.g., —OH. In certain embodiments, R.sup.C is —OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.C is —OR.sup.f, and R.sup.f is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.C is —OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.C is —OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl optionally substituted heteroaryl. In certain embodiments, R.sup.C is —OR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl. In certain embodiments, R.sup.C is —OR.sup.f, and R.sup.f is optionally substituted acyl, e.g., R.sup.C is —OC(═O)R.sup.f, —OC(═O)OR.sup.f, or —OC(═O)N(R.sup.f).sub.2. In certain embodiments, R.sup.C is —OR.sup.f, and R.sup.f is an oxygen protecting group.

(158) In certain embodiments, R.sup.C is —SR.sup.f, e.g., —SH. In certain embodiments, R.sup.C is —SR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.C is —SR.sup.f, and R.sup.f is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.C is —SR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl optionally substituted heteroaryl. In certain embodiments, R.sup.C is —SR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl. In certain embodiments, R.sup.C is —SR.sup.f, and R.sup.f is a sulfur protecting group.

(159) In certain embodiments, R.sup.C is —N(R.sup.f).sub.2, e.g., —NH.sub.2, —NHR.sup.f. In certain embodiments, R.sup.C is —NH(R.sup.f), and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.C is —N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.C is —NH(R.sup.f), and R.sup.f is unsubstituted alkyl. In certain embodiments, R.sup.C is —N(R.sup.f).sub.2, and at least one R.sup.f is unsubstituted alkyl. In certain embodiments, R.sup.C is —NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, R.sup.C is —NHR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In certain embodiments, R.sup.C is —NHR.sup.f, and R.sup.f is optionally substituted acyl, e.g., R.sup.C is —NHC(═O)R.sup.f, —NHC(═O)OR.sup.f, or —NHC(═O)NHR.sup.f. In certain embodiments, R.sup.C is —N(R.sup.f).sub.2, and at least one R.sup.f is a nitrogen protecting group. In certain embodiments, R.sup.C is —N(R.sup.f).sub.2, and both R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In certain embodiments, R.sup.C is —N(R.sup.f).sub.2, and both R.sup.f are joined to form an unsubstituted heterocyclic or unsubstituted heteroaryl ring.

(160) In certain embodiments, an R.sup.C attached para to the diazepine is halogen. In certain embodiments, an R.sup.C attached para to the diazepine is —F. In certain embodiments, an R.sup.C attached para to the diazepine is —Cl, —Br, or —I. In certain embodiments, an R.sup.C attached para to the diazepine is —NO.sub.2. In certain embodiments, an R.sup.C attached para to the diazepine is —CN.

(161) In certain embodiments, an R.sup.C attached para to the diazepine is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is methyl. In certain embodiments, an R.sup.C attached para to the diazepine is ethyl, propyl, or butyl. In certain embodiments, an R.sup.C attached para to the diazepine is haloalkyl, e.g., —CHF.sub.2, —CHCl.sub.2, —CH.sub.2CHF.sub.2, —CH.sub.2CHCl.sub.2. In certain embodiments, an R.sup.C attached para to the diazepine is perhaloalkyl, e.g., —CF.sub.3, —CF.sub.2CF.sub.3, —CCl.sub.3. In certain embodiments, an R.sup.C attached para to the diazepine is hydroxyalkyl, e.g., —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CH.sub.2OR.sup.f, —CH.sub.2CH.sub.2OR.sup.f. In certain embodiments, an R.sup.C attached para to the diazepine is aminoalkyl, e.g., —CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2NMe.sub.2, —CH.sub.2CH.sub.2NMe.sub.2, —CH.sub.2N(R.sup.f).sub.2, —CH2CH2N(R.sup.f).sub.2.

(162) In certain embodiments, an R.sup.C attached para to the diazepine is optionally substituted alkenyl, e.g., optionally substituted C.sub.2-6 alkenyl. In certain embodiments, an R.sup.C attached para to the diazepine is unsubstituted alkenyl, e.g., unsubstituted C.sub.2-6 alkenyl. In certain embodiments, an R.sup.C attached para to the diazepine is vinyl, allyl, or prenyl. In certain embodiments, an R.sup.C attached para to the diazepine is optionally substituted alkynyl, e.g., optionally substituted C.sub.2-6 alkynyl. In certain embodiments, an R.sup.C attached para to the diazepine is unsubstituted alkynyl, e.g., unsubstituted C.sub.2-6 alkynyl.

(163) In certain embodiments, an R.sup.C attached para to the diazepine is optionally substituted carbocyclyl, e.g., optionally substituted C.sub.3-6 carbocyclyl, optionally substituted C.sub.3-4 carbocyclyl, optionally substituted C.sub.4-5 carbocyclyl, or optionally substituted C.sub.5-6 carbocyclyl. In certain embodiments, an R.sup.C attached para to the diazepine is unsubstituted carbocyclyl, e.g., unsubstituted C.sub.3-6 carbocyclyl. In some embodiments, an R.sup.C attached para to the diazepine is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, an R.sup.C attached para to the diazepine is optionally substituted heterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted 4-5 membered heterocyclyl, or optionally substituted 5-6 membered heterocyclyl. In certain embodiments, an R.sup.C attached para to the diazepine is unsubstituted heterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

(164) In certain embodiments, an R.sup.C attached para to the diazepine is optionally substituted aryl, e.g., optionally substituted phenyl. In certain embodiments, an R.sup.C attached para to the diazepine is unsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments, an R.sup.C attached para to the diazepine is optionally substituted heteroaryl, e.g., optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered bicyclic heteroaryl. In certain embodiments, an R.sup.C attached para to the diazepine is unsubstituted heteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, or unsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments, an R.sup.C attached para to the diazepine is optionally substituted aralkyl, e.g., optionally substituted benzyl. In certain embodiments, an R.sup.C attached para to the diazepine is optionally substituted heteroaralkyl, e.g., methyl substituted with an optionally substituted 5-6 membered heteroaryl ring. In certain embodiments, an R.sup.C attached para to the diazepine is unsubstituted aralkyl, e.g., unsubstituted benzyl. In certain embodiments, an R.sup.C attached para to the diazepine is unsubstituted heteroaralkyl, e.g., methyl substituted with an unsubstituted 5-6 membered heteroaryl ring.

(165) In certain embodiments, an R.sup.C attached para to the diazepine is optionally substituted acyl, e.g., —CHO, —CO.sub.2H, or —C(═O)NH.sub.2. In certain embodiments, an R.sup.C attached para to the diazepine is —C(═O)R.sup.1, —C(═O)OR.sup.f, —C(═O)NH(R.sup.f), or —C(═O)N(R.sup.f).sub.2. In certain embodiments, an R.sup.C attached para to the diazepine is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., —C(═O)Me. In certain embodiments, an R.sup.C attached para to the diazepine is —C(═O)R.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, an R.sup.C attached para to the diazepine is —C(═O)R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, an R.sup.C attached para to the diazepine is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is —C(═O)OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, an R.sup.C attached para to the diazepine is —C(═O)OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, an R.sup.C attached para to the diazepine is —C(═O)N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, an R.sup.C attached para to the diazepine is —C(═O)NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

(166) In certain embodiments, an R.sup.C attached para to the diazepine is —OR.sup.f, e.g., —OH. In certain embodiments, an R.sup.C attached para to the diazepine is —OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is —OR.sup.f, and R.sup.f is unsubstituted C.sub.1-6 alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is —OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, an R.sup.C attached para to the diazepine is —OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl optionally substituted heteroaryl. In certain embodiments, an R.sup.C attached para to the diazepine is —OR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl. In certain embodiments, an R.sup.C attached para to the diazepine is —OR.sup.f, and R.sup.f is optionally substituted acyl, e.g., an R.sup.C attached para to the diazepine is —OC(═O)R.sup.f, —OC(═O)OR.sup.f, or —OC(═O)N(R.sup.f).sub.2. In certain embodiments, an R.sup.C attached para to the diazepine is —OR.sup.f, and R.sup.f is an oxygen protecting group.

(167) In certain embodiments, an R.sup.C attached para to the diazepine is optionally substituted sulfonyl, e.g., —S(═O).sub.2OH. In certain embodiments, an R.sup.C attached para to the diazepine is —S(═O).sub.2R.sup.f, —S(═O).sub.2OR.sup.f, —S(═O).sub.2NH(R.sup.f), or —S(═O).sub.2N(R.sup.f).sub.2. In certain embodiments, an R.sup.C attached para to the diazepine is —S(═O).sub.2R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., —S(═O).sub.2Me. In certain embodiments, an R.sup.C attached para to the diazepine is —S(═O).sub.2R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, an R.sup.C attached para to the diazepine is —S(═O).sub.2OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is —S(═O).sub.2OR.sup.f, and R.sup.f is optionally substituted aryl. In certain embodiments, an R.sup.C attached para to the diazepine is —S(═O).sub.2N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is —S(═O).sub.2NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

(168) In certain embodiments, an R.sup.C attached para to the diazepine is —SR.sup.f, e.g., —SH. In certain embodiments, an R.sup.C attached para to the diazepine is —SR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is —SR.sup.f, and R.sup.f is unsubstituted C.sub.1-6 alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is —SR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl optionally substituted heteroaryl. In certain embodiments, an R.sup.C attached para to the diazepine is —SR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl. In certain embodiments, an R.sup.C attached para to the diazepine is —SR.sup.f, and R.sup.f is a sulfur protecting group.

(169) In certain embodiments, an R.sup.C attached para to the diazepine is —N(R.sup.f).sub.2, e.g., —NH.sub.2, —NHR.sup.f. In certain embodiments, an R.sup.C attached, para to the diazepine is —NH(R.sup.f), and R.sup.f is optionally substituted alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is —N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is —NH(R.sup.f), and R.sup.f is unsubstituted alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is —N(R.sup.f).sub.2, and at least one R.sup.f is unsubstituted alkyl. In certain embodiments, an R.sup.C attached para to the diazepine is —NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, an R.sup.C attached para to the diazepine is —NHR.sup.f, and R.sup.f is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In certain embodiments, an R.sup.C attached para to the diazepine is —NHR.sup.f, and R.sup.f is optionally substituted acyl, e.g., an R.sup.C attached para to the diazepine is —NHC(═O)R.sup.f, —NHC(═O)OR.sup.f, or —NHC(═O)NHR.sup.f. In certain embodiments, an R.sup.C attached para to the diazepine is —N(R.sup.f).sub.2, and at least one R.sup.f is a nitrogen protecting group. In certain embodiments, an R.sup.C attached para to the diazepine is —N(R.sup.f).sub.2, and both R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In certain embodiments, an R.sup.C attached para to the diazepine is —N(R.sup.f).sub.2, and both R.sup.f are joined to form an unsubstituted heterocyclic or unsubstituted heteroaryl ring.

(170) In certain embodiments, the compound of Formula (I) is a compound listed in Table 1.

(171) TABLE-US-00001 TABLE 1 Exemplary compounds of Formula (I) embedded image 101 embedded image 102 embedded image 103 embedded image 104 embedded image 105 embedded image 106 embedded image 107 embedded image 108 embedded image 109 0embedded image 110 embedded image 111 embedded image 100 embedded image

(172) In certain embodiments, the compound of Formula (II) is a compound listed in Table 2.

(173) TABLE-US-00002 TABLE 2 Exemplary compounds of Formula (II) embedded image 201 embedded image 202 embedded image 203 embedded image 204 embedded image 205 embedded image 206 0embedded image 207 embedded image 208 embedded image 209 embedded image 210 embedded image 200 embedded image 300 embedded image embedded image embedded image embedded image 0embedded image embedded image embedded image embedded image embedded image embedded image embedded image embedded image embedded image embedded image 0embedded image

(174) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-A-1):

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

(176) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-A-2):

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

(178) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-B-1):

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

(180) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-B-2):

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

(182) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-B-3):

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

(184) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-B-4):

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

(186) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-B-5):

(187) ##STR00077##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(188) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-B-6):

(189) ##STR00078##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph; co-crystal, or prodrug thereof.

(190) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-C-1):

(191) ##STR00079##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(192) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-C-2):

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

(194) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-C-3):

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

(196) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-C-3):

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

(198) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-C-5):

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

(200) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-C-6):

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

(202) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-D-1):

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

(204) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-D-2):

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

(206) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-D-3):

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

(208) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-D-4):

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

(210) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-D-5):

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

(212) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-D-6):

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

(214) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-E-1):

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

(216) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-E-2):

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

(218) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-E-3):

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

(220) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-E-4):

(221) ##STR00094##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(222) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-E-5):

(223) ##STR00095##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(224) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-E-6):

(225) ##STR00096##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(226) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-F-1):

(227) ##STR00097##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(228) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-F-2):

(229) ##STR00098##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(230) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-F-3):

(231) ##STR00099##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(232) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-F-3):

(233) ##STR00100##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(234) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-F-5):

(235) ##STR00101##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(236) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-F-6):

(237) ##STR00102##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(238) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-G-1):

(239) ##STR00103##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(240) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-G-2):

(241) ##STR00104##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(242) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-G-3):

(243) ##STR00105##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(244) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-G-4):

(245) ##STR00106##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(246) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-G-5):

(247) ##STR00107##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(248) In certain embodiments, the compound of Formula (I) is a compound of Formula (I-G-6):

(249) ##STR00108##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(250) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-A-1):

(251) ##STR00109##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(252) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-A-2):

(253) ##STR00110##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(254) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-B-1):

(255) ##STR00111##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(256) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-B-2):

(257) ##STR00112##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(258) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-C-1):

(259) ##STR00113##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(260) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-C-2):

(261) ##STR00114##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(262) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-D-1):

(263) ##STR00115##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(264) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-D-2):

(265) ##STR00116##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(266) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-E-1):

(267) ##STR00117##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(268) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-E-2):

(269) ##STR00118##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(270) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-F-1):

(271) ##STR00119##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(272) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-F-2):

(273) ##STR00120##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(274) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-G-1):

(275) ##STR00121##
or a pharmaceutically acceptable-salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(276) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-G-2):

(277) ##STR00122##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(278) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-H-1):

(279) ##STR00123##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(280) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-H-2):

(281) ##STR00124##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(282) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-J-1):

(283) ##STR00125##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(284) In certain embodiments, the compound of Formula (II) is a compound of Formula (II-J-2):

(285) ##STR00126##
or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

(286) In certain embodiments, a compound of Formula (I) or (II) has improved metabolic stability relative to a known bromodomain inhibitor (e.g., JQ1). In certain embodiments, a compound of Formula (I) or (II) has decreased lipophilicity relative to a known bromodomain inhibitor (e.g., JQ1). In certain embodiments, a compound of Formula (1) or (II) has improved pharmacokinetic parameters relative to a known bromodomain inhibitor (e.g., JQ1). In some embodiments, the compound has a higher clearance. In some embodiments, the compound has a lower clearance. In some embodiments, the compound has a higher volume distribution (e.g., steady-state volume distribution). In some embodiments, the compound has a lower volume distribution (e.g., steady-state volume distribution). In some embodiments, the compound has a longer half-life (e.g., terminal t.sub.1/2). In some embodiments, the compound has a lower half-life (e.g., terminal t.sub.1/2). In some embodiments, the compound has a higher integral area under the concentration-time curve (e.g., AUC.sub.last, AUC.sub.0-∞). In some embodiments, the compound has a lower integral area under the concentration-time curve (e.g., AUC.sub.last, AUC.sub.0-∞). In some embodiments, the compound has a higher time to maximum concentration. In some embodiments, the compound has a lower time to maximum concentration. In some embodiments, the compound has a higher maximum concentration (e.g., maximum plasma concentration). In some embodiments, the compound has a lower maximum concentration (e.g., maximum plasma concentration). In some embodiments, the compound has a higher bioavailability. In some embodiments, the compound has a lower bioavailability.

(287) Pharmaceutical-Compositions and Administration

(288) The present disclosure provides pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula (I) or (II)), 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 (I) or (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 (I) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

(289) 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 male contraception (e.g., effective for inhibiting sperm formation) 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 killing 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 inducing apoptosis of a cell. In certain embodiments, the effective amount is an amount effective for inducing apoptosis in a subject. In certain embodiments, the effective amount is an amount effective for inducing G1 arrest in a subject or cell. 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.

(290) 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, for inducing or increasing apoptosis, or for inducing or increasing G1 arrest 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%, at least about 90%, at least about 95%, or at least about 98%. 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 disclosure. 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.

(291) 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).

(292) 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.

(293) 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.

(294) 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.

(295) 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.

(296) 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.

(297) 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.

(298) 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.

(299) 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.

(300) 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.

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

(302) 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.

(303) 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.

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

(305) 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.

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

(307) 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.

(308) Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, tale, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

(309) Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, 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, macadamia 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.

(310) 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.

(311) 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.

(312) 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.

(313) 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.

(314) 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.

(315) 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.

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

(317) 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.

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

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

(320) 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.

(321) 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.

(322) 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).

(323) 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.

(324) 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.

(325) 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.

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

(327) 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.

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

(329) 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, intradermal, 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.

(330) 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 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

(331) 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.

(332) 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.

(333) 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.

(334) 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 of developing 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 inducing apoptosis of a cell, in inducing apoptosis in a subject, or in inducing G1 arrest 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.

(335) 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.

(336) 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), CAPOX, 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), 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, and chemotherapy.

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

(338) 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 male contraception. In certain embodiments, the kits are useful for inhibiting sperm formation. 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 inducing apoptosis of a cell. In certain embodiments, the kits are useful for inducing apoptosis in a subject. In certain embodiments, the kits, are useful for inducing G1 arrest in a subject or cell.

(339) 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 disclosure.

(340) 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 disclosure (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 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 inducing apoptosis of an in vitro cell. In certain embodiments, the kits and instructions provide for inducing apoptosis of a cell in a subject. In certain embodiments, the kits and instructions provide for inducing G1 arrest 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 disclosure. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

(341) Methods of Treatment and Uses

(342) The present disclosure 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, neurological diseases, metabolic diseases, endocrine diseases, and radiation poisoning. Also provided by the present disclosure are methods for male contraception. The present disclosure also provides methods of inhibiting sperm formation. The present disclosure 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, 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, methods of inducing apoptosis, and methods of inducing G1 arrest.

(343) 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 ε-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.

(344) 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 Gen5) 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 (α.sub.Z, α.sub.A, α.sub.B, and α.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 a high degree of sequence conservation, and a more divergent C-terminal recruitment domain.

(345) 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.

(346) 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 transcriptional factors, such as interleukin 7 receptor (IL7R). These observations underscore the utility and therapeutic potential of a binder or inhibitor of bromodomain-containing proteins.

(347) In another aspect, the present disclosure provides methods of inhibiting the activity of a bromodomain-containing protein in a subject.

(348) In another aspect, the present disclosure provides methods of inhibiting the activity of a bromodomain-containing protein in a biological sample (e.g., a cell).

(349) 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 a biological sample (e.g., a cell) is inhibited by the described methods. In certain embodiments, the activity of a bromodomain-containing protein in a subject or a biological sample (e.g., a cell) is inhibited by the described 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%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, the activity of a bromodomain-containing protein in a subject or a biological sample (e.g., a cell) is inhibited by the described 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 disclosure. Other ranges are also possible. In some embodiments, the activity of a bromodomain-containing protein in a subject or a biological sample (e.g., a cell) is selectively inhibited by the described methods. In some embodiments, the activity of a bromodomain-containing protein in a subject or a biological sample (e.g., a cell) is selectively inhibited by the described 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 a biological sample (e.g., a cell) is non-selectively inhibited by the described methods. In certain embodiments, the cytokine level and/or histamine release are reduced by the described methods.

(350) 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 disclosure.

(351) 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 of developing 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).

(352) In certain embodiments, a cell described herein is in vitro. In certain embodiments, a cell is ex vivo. In certain embodiments, a cell is in vivo.

(353) In another aspect, the present disclosure provides methods of inhibiting the activity of a bromodomain in a subject.

(354) In another aspect, the present disclosure provides methods of inhibiting the activity of a bromodomain in a biological sample (e.g., a cell).

(355) 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 disclosure.

(356) Another aspect of the present disclosure 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.

(357) Another aspect of the present disclosure 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 biological sample (e.g., a cell).

(358) In certain embodiments, the second protein is a protein with an 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 described methods.

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

(360) In another aspect, the present disclosure provides methods of modulating the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein in a subject.

(361) In another aspect, the present disclosure provides methods of modulating the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein in a biological sample (e.g., a cell).

(362) In certain embodiments, the present disclosure 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 biological sample (e.g., a 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 recognition of acetyl-lysine by a bromodomain or bromodomain-containing protein during the expression (e.g., transcription) of the gene. In certain embodiments, the compounds and pharmaceutical compositions described herein interfere with the anchoring of a bromodomain-containing protein to an acetylated chromatin (e.g., a bromodomain of the bromodomain-containing protein being anchored to an acetyl-lysine of the acetylated chromatin) 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 biological sample (e.g., a cell) is modulated by the described methods. In certain embodiments, the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein in a subject or biological sample (e.g., a cell) is down-regulated or inhibited by the described methods. In certain embodiments, the gene that is regulated by a bromodomain-containing protein is an oncogene.

(363) Another aspect of the present disclosure relates to methods of treating a disease in a subject in need thereof.

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

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

(366) 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 associated with aberrant Myc function. In certain embodiments, the disease is associated with the interleukin 7 receptor (IL7R).

(367) 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.

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

(369) 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).

(370) 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.

(371) 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.

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

(373) 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.

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

(375) In certain embodiments, the disease is a neurological disease (e.g., Alzheimer's disease).

(376) 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 II 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).

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

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

(379) In still another aspect, the present disclosure provides methods of preventing a disease described herein in a subject in need thereof.

(380) disclosure provides methods of reducing the risk of developing a disease described herein in a subject in need thereof.

(381) disclosure provides methods for male contraception in a male subject in need thereof.

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

(383) Another aspect of the present disclosure relates to methods of inhibiting the replication of a virus. In certain embodiments, the replication of the virus is inhibited by the described methods.

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

(385) Another aspect of the present disclosure relates to methods of killing a virus. In certain embodiments, the virus is killed by the described methods.

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

(387) Another aspect of the disclosure relates to methods of inhibiting the interaction between a bromodomain-containing protein and an immunoglobulin (Ig) regulatory element in a biological sample (e.g., a cell).

(388) Another aspect of the disclosure relates to methods of inducing apoptosis (e.g., apoptosis of a cancer cell) in a cell of a subject.

(389) Another aspect of the disclosure relates to methods of inducing apoptosis in a cell of a biological sample (e.g., an in vitro cell, a cancer cell).

(390) Another aspect of the disclosure relates to methods of method for inducing G1 arrest in a cell of a subject.

(391) Another aspect of the disclosure relates to methods of method for inducing G1 arrest in a cell of a biological sample.

(392) In certain embodiments, the methods of the disclosure 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 disclosure 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 disclosure 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 disclosure include contacting a biological sample (e.g., a cell) with an effective amount of a compound or pharmaceutical composition described herein. In certain embodiments, the methods of the disclosure include contacting a virus with an effective amount of a compound or pharmaceutical composition described herein.

(393) In another aspect, the present disclosure provides the compounds described herein for use in a method of the disclosure, or use in the manufacture of a medicament for use in a method or treatment described herein.

(394) In still another aspect, the present disclosure provides the pharmaceutical compositions described herein for use in a method of the disclosure, or use in the manufacture of a medicament for use in a method or treatment described herein.

(395) Methods of Screening a Library of Compounds

(396) Another aspect of the disclosure 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 disclosure. 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 described methods.

(397) 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, with the modulation (e.g., inhibition) of the expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein, with the induction of apoptosis, and/or with the induction of G1 arrest. The characteristics may be desired characteristics (e.g., a disease having been treated, a disease having been prevented, the risk of developing 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 expression (e.g., transcription) of a gene that is regulated by a bromodomain-containing protein having been modulated (e.g., having been inhibited), the apoptosis having been induced, or the G1 arrest having been induced). The characteristics may be undesired characteristics (e.g., a disease having not been treated, a disease having not been prevented, the risk of developing 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 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 apoptosis having not been induced, or the G1 arrest having not been induced). 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 disclosure. 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.

EXAMPLES

(398) In order that the invention described herein may be more fully understood, the following examples are set forth. The 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.

Example I. Preparation of the Compounds

(399) Exemplary Preparation of Compounds of Formula (I)

(400) ##STR00127##
Intermediate A1

(401) Pd.sub.2(dba).sub.3 (16.3 mg, 0.04 eq), dppf (19.3 mg, 0.08 eq), Zn(CN).sub.2 (61.6 mg, 1.2 eq), and Zn (7 mg, 0.24 eq) was added to the solution of JQ1 (200 mg) in 4 mL DMA. The mixture was purged with argon and stirred at 140° C. overnight. After cooling to rt, the mixture was diluted with EtOAc, washed with 2N NH.sub.3.H.sub.2O and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give Intermediate A1 (80 mg, 41%).

(402) Intermediate A2

(403) Intermediate A1 (80 mg) was dissolved in 1:1 CH.sub.2Cl.sub.2/TFA. The mixture was stirred at room temperature for 1 hour. The volatile was removed under reduced pressure. The residue was purified by RP-HPLC to give Intermediate A2 (40 mg, 57%).

(404) CP_011-020 (Compound 110)

(405) HATU (95 mg, 5 eq) was added to the solution of compound 2 (19 mg) in DMF (0.5 mL). The mixture was stirred for 10 mins before NHR.sub.1R.sub.2 (5 eq) and iPr.sub.2Net (61 μL, 5 eq) was added. The mixture was stirred for 2 hours before quenched with H.sub.2O. The mixture was diluted with EtOAc, washed with H.sub.2O and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified RP-HPLC to give CP_011-020 (Compound 110) (55-75%). .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.79 (d, J=8.0 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 4.80 (t, J=6.8 Hz, 1H), 3.82-3.64 (m, 10H), 2.77 (s, 3H), 2.48 (s, 3H), 1.71 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 169.3, 163.6, 142.0, 132.6, 132.1, 132.0, 130.5, 130.4, 129.3, 117.8, 113.9, 66.3, 54.1, 45.9, 42.0, 34.4, 13.0, 11.6, 10.2. LC-MS for C.sub.24H.sub.24N.sub.6O.sub.2S [M+H].sup.+: 461.1 m/z.

(406) Exemplary Preparation of Compounds of Formula (II)

(407) ##STR00128##
Intermediate B1

(408) Concentrated H.sub.2SO.sub.4 (5 drops, cat.) was added slowly to the solution of JQ1 (1 g) in MeOH (10 mL). The mixture was refluxed overnight. After cooling to room temperature, the volatile was removed under reduced pressure. The residue was purified by flash chromatography to give Intermediate B1 (817 mg, 90%).

(409) Intermediate B2

(410) SO.sub.2Cl.sub.2 (74 μL, 3 eq) was added to the solution of Intermediate B1 (124 mg) in CH.sub.2Cl.sub.2 (3 mL) at 0° C. The mixture was stirred at room temperature for 4 hours. The reaction was quenched with H.sub.2O. The aqueous layer was extracted with CH.sub.2Cl.sub.2 twice. The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give Intermediate B2 (45 mg, 34%).

(411) Intermediate B3

(412) KCN (40 mg, 2 eq) was added to the solution of Intermediate B2 (135 mg) in DMF (3 mL). The mixture was stirred at 90° C. for 4 hours. After cooling to room temperature, the mixture was diluted with EtOAc, washed with H.sub.2O and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give Intermediate B3 (92 mg, 67%).

(413) Intermediate B4

(414) 3M LiOH solution (1 mL) was added to the solution of Intermediate B3 (208 mg) in THF (4 mL). The mixture was stirred at rt for 2 hours. The mixture was acidified with 1N HCl, and extracted with EtOAc three times. The combined organic layers was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC to give Intermediate B4 (151 mg, 80%).

(415) CP_001-010 (Compound 210)

(416) HATU (95 mg, 5 eq) was added to the solution of Intermediate B4 (20 mg) in DMF (0.5 mL). The mixture was stirred for 10 mins before NHR.sub.1R.sub.2 (5 eq) and iPr.sub.2NEt (61 μL, 5 eq) was added. The mixture was stirred for 2 hours before quenched with H.sub.2O. The mixture was diluted with EtOAc, washed with H.sub.2O and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified RP-HPLC to give CP-001-010 (55-75%). .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.53 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 4.74 (t, J=6.8 Hz, 1H), 3.82-3.63 (m, 10H), 3.45-3.28 (m, 2H), 2.75 (s, 3H), 2.62 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 169.4, 163.5, 137.1, 136.3, 136.1, 133.4, 130.1, 129.4, 128.9, 123.7, 116.0, 66.3, 54.0, 45.9, 42.0, 34.5, 15.7, 11.8, 10.2. LC-MS for C.sub.24H.sub.23ClN.sub.6O.sub.2S [M+H].sup.+: 495.1 m/z.

(417) Characterization of Selected Compounds

(418) Compound 201

(419) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.51 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 4.75 (dd, J=8.4, 5.6 Hz, 1H), 3.62 (dd, J=15.2, 8.8 Hz 1H), 3.51 (dd, J=15.2, 8.8 Hz 1H), 3.35 (m, 2H), 2.76 (s, 3H), 2.62 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 169.2, 163.7, 154.1, 137.1, 136.4, 136.1, 133.3, 130.2, 130.1, 129.4, 128.8, 123.7, 121.9, 116.0, 114.8, 53.8, 37.8, 15.8, 11.8, 10.2. LC-MS for C.sub.26H.sub.21ClN.sub.6O.sub.2S [M+H].sup.+: 517.1 m/z.

(420) Compound 202

(421) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.53 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 4.70 (dd, J=8.4, 5.6 Hz, 1H), 3.46-3.25 (m, 6H), 2.76 (s, 3H), 2.62 (s, 3H), 1.20 (t, J=7.6 Hz, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 170.9, 163.7, 154.1, 137.2, 136.5, 136.0, 133.2, 130.1, 129.5, 128.9, 123.7, 116.0, 53.8, 37.2, 34.0, 15.8, 13.5, 11.8, 10.2. LC-MS for C.sub.22H.sub.21ClN.sub.6OS [M+H].sup.+: 453.0 m/z.

(422) Compound 203

(423) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.54 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 4.70 (t, J=7.2 Hz, 1H), 3.55-3.41 (m, 12H), 3.22-3.18 (m, 4H), 2.96 (s, 3H), 2.75 (s, 3H), 2.60 (s, 3H), 2.01-1.94 (m, 2H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 172.2, 163.7, 154.1, 137.2, 136.1, 136.0, 133.5, 130.1, 130.0, 129.1, 128.9, 123.5, 116.1, 54.1, 53.9, 50.7, 42.1, 37.3, 35.8, 24.5, 24.4, 15.8, 11.7, 10.2. LC-MS for C.sub.28H.sub.33ClN.sub.8OS [M+H].sup.+: 565.2 m/z.

(424) Compound 204

(425) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.42 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H), 4.58 (t, J=7.2 Hz, 1H), 3.95 (br, 2H), 3.75-3.0 (m, 14H), 2.62 (s, 3H), 2.48 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 183.0, 172.8, 163.9, 137.2, 136.1, 135.9, 133.6, 130.1, 129.1, 128.9, 123.5, 116.1, 63.7, 58.0, 53.8, 52.0, 37.7, 33.6, 15.8, 11.7, 10.3. LC-MS for C.sub.26H.sub.28ClN.sub.7O.sub.2S [M+H].sup.+: 538.1 m/z.

(426) Compound 205

(427) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.54 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 4.66 (dd, J=8.4, 5.6 Hz, 1H), 3.47-3.30 (m, 6H), 2.74 (s, 3H), 2.62 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 170.9, 163.5, 154.1, 137.2, 136.5, 136.0, 133.2, 130.1, 129.5, 128.9, 123.7, 116.0, 53.7, 36.7, 15.8, 11.8, 10.2. LC-MS for C.sub.20H.sub.17ClN.sub.6OS [M+H].sup.+: 425.0 m/z.

(428) Compound 206

(429) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.42 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.56 (dd, J=8.8, 5.6 Hz, 1H), 3.55 (t, J=6 Hz, 1H), 3.39-3.22 (m, 6H), 2.62 (s, 3H), 2.49 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 171.6, 163.6, 155.5, 137.1, 136.2, 136.1, 133.4, 130.1, 129.3, 128.8, 123.6, 116.0, 60.2, 53.9, 41.7, 37.3, 15.8, 11.8, 10.2. LC-MS for C.sub.22H.sub.21ClN.sub.6O.sub.2S [M+H].sup.+: 469.1 m/z.

(430) Compound 207

(431) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.42 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.57 (dd, J=8.8, 5.6 Hz, 1H), 3.78 (m, 1H), 3.40-3.05 (m, 6H), 2.63 (s, 3H), 2.49 (s, 3H), 1.09 (d, J=6.4 Hz, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 171.5, 163.7, 137.1, 136.3, 136.0, 133.3, 130.2, 129.4, 128.9, 123.6, 116.0, 66.0, 53.9, 46.5, 37.2, 19.6, 15.8, 11.8, 10.2. LC-MS for C.sub.23H.sub.23ClN.sub.6O.sub.2S [M+H].sup.+: 483.1 m/z.

(432) Compound 208

(433) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.53 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 4.68 (dd, J=8.8, 5.6 Hz, 1H), 3.90 (m, 1H), 3.51-3.19 (m, 6H), 2.74 (s, 3H), 2.61 (s, 3H), 1.20 (d, J=6.4 Hz, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 171.5, 163.7, 137.1, 136.2, 136.1, 133.4, 130.1, 129.3, 128.8, 123.6, 116.0, 65.9, 53.9, 46.5, 37.3, 19.6, 15.8, 11.8, 10.2. LC-MS for C.sub.23H.sub.23ClN.sub.6O.sub.2S [M+H].sup.+: 483.0 m/z.

(434) Compound 209

(435) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.53 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 5.96 (tt, J=56, 4.0 Hz, 1H), 4.68 (dd, J=8.8, 5.6 Hz, 1H), 3.55 (t, J=6 Hz, 1H), 3.77-3.27 (m, 6H), 2.75 (s, 3H), 2.62 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 172.0, 163.6, 155.5, 137.1, 136.3, 136.0, 133.3, 130.1, 129.4, 128.8, 123.6, 116.0, 114.1 (t, J=239 Hz), 53.8, 41.4 (t, J=27.4 Hz), 37.1, 15.8, 11.8, 10.2. LC-MS for C.sub.22H.sub.19ClF.sub.2N.sub.6OS [M+H].sup.+: 489.0 m/z.

(436) Compound 210

(437) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.53 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 4.74 (t, J=6.8 Hz, 1H), 3.82-3.63 (m, 10H), 3.45-3.28 (m, 2H), 2.75 (s, 3H), 2.62 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 169.4, 163.5, 137.1, 136.3, 136.1, 133.4, 130.1, 129.4, 128.9, 123.7, 116.0, 66.3, 54.0, 45.9, 42.0, 34.5, 15.7, 11.8, 10.2. LC-MS for C.sub.24H.sub.23ClN.sub.6O.sub.2S [M+H].sup.+: 495.1 m/z.

(438) Compound 101

(439) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.77 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 4.75 (dd, J=8.8, 5.6 Hz, 1H), 3.64 (dd, J=15.2, 8.8 Hz 1H), 3.51 (dd, J=15.2, 8.8 Hz 1H), 2.79 (s, 3H), 2.48 (s, 3H), 1.70 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 169.1, 164.8, 154.1, 141.9, 132.8, 132.1, 131.8, 130.6, 130.2, 129.3, 121.8, 117.8, 114.9, 113.9, 53.8, 37.8, 13.0, 11.6, 10.1. LC-MS for C.sub.26H.sub.22N.sub.6O.sub.2S [M+H].sup.+: 483.1 m/z.

(440) Compound 102

(441) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.81 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 4.87 (m, 1H), 3.48-3.28 (m, 4H), 2.94 (s, 3H), 2.52 (s, 3H), 1.73 (s, 3H), 1.21 (t, J=7.2 Hz, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 165.3, 141.2, 137.2, 134.9, 132.1, 131.8, 131.1, 129.5, 128.9, 117.7, 114.3, 53.2, 34.0, 13.4, 12.8, 11.7, 9.8. LC-MS for C.sub.22H.sub.22N.sub.6OS [M+H].sup.+: 419.1 m/z.

(442) Compound 103

(443) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.80 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H), 4.74 (m, 1H), 3.56-3.41 (m, 10H), 3.39-3.19 (m, 4H), 2.93 (s, 3H), 2.75 (s, 3H), 2.48 (s, 3H), 2.03-1.92 (m, 2H), 1.70 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 172.2, 164.9, 154.1, 142.0, 132.4, 132.1, 130.4, 130.1, 129.3, 128.9, 123.5, 117.8, 113.9, 54.2, 53.9, 50.8, 48.9, 42.1, 37.2, 35.6, 30.7, 24.4, 13.0, 11.5, 10.2. LC-MS for C.sub.28H.sub.34N.sub.8OS [M+H].sup.+: 531.2 m/z.

(444) Compound 104

(445) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.81 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H), 4.73 (t, J=7.2 Hz, 1H), 4.09 (br, 2H), 3.90-3.15 (m, 12H), 2.74 (s, 3H), 2.48 (s, 3H), 1.70 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 172.8, 164.9, 142.0, 132.4, 132.1, 130.4, 130.1, 129.2, 117.8, 113.9, 63.7, 57.0, 53.7, 52.4, 51.9, 37.0, 33.5, 13.0, 11.5, 10.2. LC-MS for C.sub.26H.sub.29N.sub.7O.sub.2S [M+H].sup.+: 504.2 m/z.

(446) Compound 105

(447) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.80 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 4.83 (m, 1H), 3.54 (dd, J=15.6, 8.4 Hz, 1H), 3.40 (dd, J=15.6, 5.2 Hz, 1H), 2.91 (s, 3H), 2.51 (s, 3H), 1.72 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 165.2, 141.4, 134.4, 132.1, 131.6, 131.0, 129.5, 117.7, 114.2, 53.2, 36.1, 13.0, 11.7, 9.9. LC-MS for C.sub.20H.sub.18N.sub.6OS [M+H].sup.+: 391.1 m/z.

(448) Compound 106

(449) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.79 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 4.75 (dd, J=8.8, 5.6 Hz, 1H), 3.69 (t, J=5.6 Hz, 1H), 3.53-3.32 (m, 4H), 2.78 (s, 3H), 2.48 (s, 3H), 1.70 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 171.4, 164.8, 141.9, 132.8, 132.1, 131.8, 130.5, 129.3, 117.8, 113.9, 60.2, 53.9, 41.7, 37.1, 13.0, 11.6, 10.1. LC-MS for C.sub.22H.sub.22N.sub.6O.sub.2S [M+H].sup.+: 435.1 m/z.

(450) Compound 107

(451) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.79 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 4.78 (dd, J=8.8, 5.6 Hz, 1H), 3.91 (m, 1H), 3.51 (dd, J=15.2, 8.8 Hz, 1H), 3.40-3.31 (m, 2H), 3.24 (dd, J=15.2, 7.2 Hz, 1H), 2.82 (s, 3H), 2.49 (s, 3H), 1.70 (s, 3H), 1.21 (d, J=6.4 Hz, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 171.2, 164.9, 141.7, 133.3, 132.1, 131.3, 130.9, 130.7, 129.4, 117.8, 114.0, 66.0, 53.7, 46.5, 37.0, 19.6, 13.0, 11.6, 10.1. LC-MS for C.sub.23H.sub.24N.sub.6O.sub.2S [M+H].sup.+: 449.1 m/z.

(452) Compound 108

(453) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.79 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 4.80 (m, 1H), 3.91 (m, 1H), 3.57-3.26 (m, 4H), 2.85 (s, 3H), 2.50 (s, 3H), 1.70 (s, 3H), 1.22 (d, J=6.4 Hz, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 171.1, 165.0, 141.6, 133.7, 132.0, 131.1, 130.9, 130.8, 129.4, 117.8, 114.0, 66.0, 53.6, 46.5, 36.9, 19.6, 13.0, 11.6, 10.0. LC-MS for C.sub.23H.sub.24N.sub.6O.sub.2S [M+H].sup.+: 449.2 m/z.

(454) Compound 109

(455) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.79 (d, J=8.0 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 5.98 (tt, J=56, 3.6 Hz, 1H), 4.74 (dd, J=8.8, 4.8 Hz, 1H), 3.77-3.30 (m, 4H), 2.76 (s, 3H), 2.48 (s, 3H), 1.70 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 172.0, 164.6, 155.5, 142.0, 132.6, 132.1, 132.0, 130.5, 130.4, 129.2, 117.8, 116.4, 114.0 (t, J=239 Hz), 113.9, 53.8, 41.1 (t, J=26.5 Hz), 37.0, 13.0, 11.5, 10.1. LC-MS for C.sub.22H.sub.20F.sub.2N.sub.6OS [M+H].sup.+: 455.1 m/z.

(456) Compound 110

(457) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.79 (d, J=8.0 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 4.80 (t, J=6.8 Hz, 1H), 3.82-3.64 (m, 10H), 2.77 (s, 3H), 2.48 (s, 3H), 1.71 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 169.3, 163.6, 142.0, 132.6, 132.1, 132.0, 130.5, 130.4, 129.3, 117.8, 113.9, 66.3, 54.1, 45.9, 42.0, 34.4, 13.0, 11.6, 10.2. LC-MS for C.sub.24H.sub.24N.sub.6O.sub.2S [M+H].sup.+: 461.1 m/z.

(458) Compound 111

(459) .sup.1H NMR (400 MHz, CD.sub.3OD, 25° C.) δ 7.78 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 4.74 (dd, J=8.8, 4.8 Hz, 1H), 4.11-3.92 (m, 2H), 3.56 (dd, J=15.2, 9.2 Hz, 1H), 3.41 (dd, J=15.2, 4.8 Hz, 1H), 2.76 (s, 3H), 2.48 (s, 3H), 1.70 (s, 3H). .sup.13C NMR (100 MHz, CD.sub.3OD, 25° C.) δ 171.8, 164.6, 142.0, 132.6, 132.1, 132.0, 130.5, 130.4, 129.2, 125.9, 117.8, 113.9, 53.8, 40.1, 39.8, 37.0, 13.0, 11.5, 10.1. LC-MS for C.sub.22H.sub.19F.sub.3N.sub.6OS [M+H].sup.+: 473.1 m/z.

(460) Compound 100

(461) .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.) δ 7.67 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 4.61 (t, J=6.8 Hz, 1H), 3.55 (m, 2H), 3.35 (m, 2H), 2.71 (s, 3H), 2.43 (s, 3H), 1.67 (s, 3H), 1.50 (s, 9H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.) δ 170.6, 163.3, 155.1, 142.1, 132.4, 132.3, 131.4, 130.5, 130.0, 129.1, 118.8, 114.1, 81.2, 54.1, 37.9, 28.2, 14.5, 13.2, 11.8, 0.0. LC-MS for C.sub.20H.sub.17N.sub.5O.sub.2S [M+H].sup.+: 392.1 m/z.

Example II. Selected Compounds and Biological Activity

(462) The IC.sub.50 of the compounds were determined by ALPHASCREENING assays for BRD4 and BRDT proteins. NMC797 cell line is a BRD4 dependent NUT midline carcinoma line. NMC797 showed high dependency on BRD4 inhibition, and the IC.sub.50 was determined by ATPLITE assay.

(463) Acetyl-Histone Binding Assay. Assays were performed as described previously with minor modifications from the manufacturer's protocol (PerkinElmer, USA). All reagents were diluted in 50 mM HEPES, 100 mM NaCl, 0.1% BSA, pH 7.4 supplemented with 0.05% CHAPS and allowed to equilibrate to room temperature prior to addition to plates. A 24-point 1:2 serial dilution of the ligands was prepared over the range of 150-0 μM and 4 μl transferred to low-volume 384-well plates (ProxiPlate™-384 Plus, PerkinElmer, USA), followed by 4 μl of HIS-tagged protein (BRD4/1, 250 nM, BRD4/2 and CREBBP, 2000 nM). Plates were scaled and incubated at room temperature for 30 minutes, before the addition of 4 μl of biotinylated peptide at equimolar concentration to the protein [peptide for BRD4(1) & BRD4(2), and BRDT: H4K5acK8acK12acK16ac, H-SGRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRK(Biotin)-OH; peptide for CREBBP: H3K36ac, Biotin-KSAPATGGVK(Ac)KPHRYRPGT-OH (Cambridge Research Biochemicals, UK)]. Plates were sealed and incubated for a further 30 minutes, before the addition of 4 μl of streptavidin-coated donor beads (25 μg/ml) and 4 μl nickel chelate acceptor beads (25 μg/ml) under low light conditions. Plates were foil-sealed to protect from light, incubated at room temperature for 60 minutes and read on a PHERAstar FS plate reader (BMG Labtech, Germany) using an AlphaScreen 680 excitation/570 emission filter set. IC.sub.50 values were calculated in Prism 5 (GraphPad Software, USA) after normalization against corresponding DMSO controls and are given as the final concentration of compound in the 20 μl reaction volume.

(464) Cell Proliferation Assay. Cells were seeded into white, 384-well microtiter plates (Nunc) at 500 cells per well in a total volume of 50 μL media. The 797, TT, and TE10 cells were grown in DMEM containing 1% penicillin/streptomycin and 10% FBS. The Per403 cells were grown in DMEM containing 1% penicillin/streptomycin and 20% FBS. Compounds were delivered to microtiter assay plates by robotic pin transfer (PerkinElmer JANUS equipped with a V&P Scientific 100 nL pin tool). Following a 48 h incubation at 37° C., cells were lysed and wells were assessed for total ATP content using a commercial proliferation assay (Cell TITERGLO; Promega). Replicate measurements were analyzed with respect to dose and estimates of IC.sub.50 were calculated by logistic regression (GRAPHPAD PRISM).

(465) TABLE-US-00003 TABLE E1 IC.sub.50 of exemplary compounds for BRDT(1), BRD4(1), and NMC797. IC.sub.50 BRDT(1) IC.sub.50 BRD4(1) IC.sub.50 NMC797 Compound (nM) (nM) (nM) JQ1  77 29 21 100 — 97 185 101 120 79 133 102 458 120 275 103 120 50 333 104 216 53 183 105 565 174 366 106 105 33 328 107 187 61 107 108 133 52 258 109 142 37 70 110 197 89 116 111 — 117 125 200 132 48 52 201 — 175 1895 202 — 310 1134 203 — 134 6788 204 — 300 3464 205 612 206 903 206 642 197 9631 207 — 623 4249 208 1,197   415 6103 209 — 386 912 210 1,416   466 118 300  60 16 61

(466) Pharmacokinetic parameters were determined by administration of a candidate bromodomain inhibitor to male CD1 mice. Intravenous doses were delivered at 5 mg/kg, and oral doses at 10 mg/kg (N=3). The results are listed in Table E2 and Table E3 for certain compounds described herein and for the known inhibitor JQ1. The compound half-life in mice as revealed by pharmacokinetic analyses of mean whole blood concentration with time after iIV injection at 5 mg/kg in malc CD1 mice (n=3) for IV injection, and 10 mg/kg oral. The compound concentration in mouse blood was monitored over 24 hour time period to check the compound concentration in blood at 5 min, 30 mm, 1 h, 2 h, 6 h, 12, 24 h via a series bleeding.

(467) TABLE-US-00004 TABLE E2 Average pharmacokinetic parameters for exemplary compounds (IV administration). CL Terminal AUC.sub.last AUC.sub.INF (L/hr/ V.sub.SS t.sub.1/2 (hr .Math. (hr .Math. MRT.sub.INF Compound kg) (L/kg) (hr) ng/mL) ng/mL) (hr) JQ1 2.35 2.02 0.897 2130 2130 0.861 107 1.76 0.583 0.411 2916 2921 0.336 109 1.42 1.18 1.11 3505 3514 0.829 200 1.25 1.57 1.38 4001 4050 1.28

(468) TABLE-US-00005 TABLE E3 Average pharmacokinetic parameters of exemplary compounds (oral administration). Terminal AUC.sub.last AUC.sub.INF T.sub.max C.sub.max t.sub.1/2 (hr .Math. (hr .Math. F Compound (hr) (ng/mL) (hr) ng/mL) ng/mL) (%) JQ1 0.250 1180 1.39 2040 2090 49.1 107 0.500 319 1.62 512 532 9.10 109 0.667 1208 1.69 3634 3781 53.8 200 0.500 1504 1.97 5522 6037 72.4

EQUIVALENTS AND SCOPE

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

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

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

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