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KDM INHIBITORS AND USES THEREOF

20220348563 · 2022-11-03

Assignee

Inventors

Cpc classification

International classification

Abstract

Provided herein are compounds that inhibit histone lysine demethylase (KDM) and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, pharmaceutical compositions thereof, and methods of treating or preventing diseases (e.g., proliferative diseases, e.g., cancer). In certain embodiments, the compounds described herein are represented by formulas (I) and (II).

##STR00001##

Claims

1. A compound of Formula (I): ##STR00237## or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: each instance of R.sup.1 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(10).sub.2, or —SR.sup.S; n is an integer from 0-4, inclusive; Y.sup.1 is —C(R.sup.C).sub.2—, —O—, —NR.sup.N—, or —S—; each instance of R.sup.3 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; m is 0, or an integer from 1 to 5, inclusive; each instance of r is independently 0 or 1; L.sup.1 is optionally substituted C.sub.1-6 alkylene, optionally substituted C.sub.2-6 alkenylene, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylene, or optionally substituted heteroarylene; each instance of Y.sup.2 is independently a bond, —O—, or —NR.sup.N—; L.sup.2 is a bond, optionally substituted C.sub.1-6 alkylene, optionally substituted C.sub.1-6 heteroalkylene, optionally substituted C.sub.2-6 alkenylene, optionally substituted C.sub.2-6 alkynylene, optionally substituted C.sub.1-6 acylene, or a combination thereof; R.sup.2 is —N(R.sup.N).sub.2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.C is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; or two R.sup.C bonded to the same carbon are taken together with the intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, or ═O; each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a sulfur protecting group, or R.sup.S, taken together with the sulfur atom to which it is attached forms a disulfide group substituted with hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl, provided that the compound is not: ##STR00238##

2. The compound of claim 1, wherein the compound is of Formula (I-i), (I-ii), or (I-iii): ##STR00239## or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

3.-4. (canceled)

5. The compound of claim 1, wherein the compound is of Formula (I-a), (I-b), or (I-c): ##STR00240## or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: each instance of R4 is independently hydrogen, halogen, —CN, —N3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S, p is an integer from 1 to 6, inclusive; and w is 0, or an integer from 1 to 4, inclusive.

6. The compound of claim 5, wherein the compound is of Formula (I-a) and represented by Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), or (I-a-5): ##STR00241## wherein: s is an integer from 1 to 6, inclusive, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

7.-9. (canceled)

10. The compound of claim 5, wherein the compound is of Formula (I-b) and represented by Formula (I-b-1), (I-b-2)), (I-b-3), (I-b-4), (I-b-5), or (I-b-6): ##STR00242## wherein: s is an integer from 1 to 6, inclusive, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

11.-13. (canceled)

14. The compound of claim 5, wherein the compound is of Formula (I-c) and represented by Formula (I-c-1), (I-c-2), (I-c-3), (I-c-4), (I-c-5), (I-c-6), (I-c-7), or (I-c-8): ##STR00243## ##STR00244## wherein: s is an integer from 1 to 6, inclusive, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

15.-21. (canceled)

22. The compound of claim 1, wherein: L.sup.1 is optionally substituted C.sub.1-6 alkylene, optionally substituted C.sub.2-6 alkenylene, optionally substituted arylene, or optionally substituted heteroarylene; or L.sup.1 is optionally substituted carbocyclyl or optionally substituted heterocyclyl.

23. (canceled)

24. The compound of claim 22, wherein L.sup.1 is optionally substituted C.sub.2-3 alkylene.

25.-30. (canceled)

31. The compound of claim 1, wherein L.sup.1 is of the structure: ##STR00245## wherein p is an integer from 1 to 6, inclusive.

32. The compound of claim 31, wherein p is 2 or 3.

33.-35. (canceled)

36. The compound of claim 1, wherein L.sup.1 is of structure: ##STR00246## wherein, each instance of R.sup.4 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; and w is 0, or an integer from 1 to 4, inclusive.

37. The compound of claim 36, wherein L.sup.1 is any one of structures: ##STR00247##

38.-40. (canceled)

41. The compound of claim 36, wherein L.sup.1 is of structure: ##STR00248##

42.-44. (canceled)

45. The compound of claim 22, wherein L.sup.1 is of structure: ##STR00249## wherein, each instance of R.sup.4 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; and t is 0, or an integer from 1 to 2, inclusive.

46. The compound of claim 45, wherein L.sup.1 is of structure: ##STR00250##

47. (canceled)

48. The compound of claim 45, wherein at least one instance of R.sup.4 is hydrogen, halogen, or optionally substituted acyl.

49. (canceled)

50. The compound of claim 45, wherein at least one instance of R.sup.4 is —F, or —CO.sub.2alkyl.

51. (canceled)

52. The compound of claim 45, wherein at least one instance of R.sup.4 is —CO.sub.2Et.

53. The compound of claim 1, wherein: w is 0 or 1; or t is 0; or Y.sup.1 is —O—, —NR.sup.N—, —NH—, or —CH.sub.2—; or at least one instance of Y.sup.2 is —NH— or —N(R.sup.N)—; or wherein one instance of Y.sub.2 is —NH— or —N(R.sup.N)—, and the other instance is a bond; L.sup.2 is optionally substituted C.sub.1-6 alkylene; or R.sup.2 is optionally substituted aryl or ##STR00251## or R.sup.1 is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heterocyclyl.

54.-68. (canceled)

69. The compound of claim 53, wherein L.sup.2 is optionally substituted C.sub.2-3 alkylene.

70.-76. (canceled)

77. The compound of claim 53, wherein R.sup.2 is of structure: ##STR00252## wherein, each instance of R.sup.7 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; and v is 0, or an integer from 1 to 5, inclusive.

78. The compound of claim 77, wherein R.sup.2 is of structure: ##STR00253##

79. The compound of claim 77, wherein R.sup.2 is of structure: ##STR00254##

80.-83. (canceled)

84. The compound of claim 53, wherein: R.sup.1 is haloalkyl; or R.sup.1 is heterocyclyl; or R.sup.1 is morpholinyl; or R.sup.1 is piperidinyl.

85.-89. (canceled)

90. The compound of claim 53, wherein R.sup.1 is of structure: ##STR00255## wherein: each instance of R.sup.7 is independently Br, optionally substituted alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, or —N(R.sup.N).sub.2.

91. (canceled)

92. The compound of claim 90, wherein R.sup.1 is of structure: ##STR00256##

93. The compound of claim 92, wherein R.sup.1 is of structure: ##STR00257##

94. The compound of claim 90, wherein at least one instance of R.sup.7 is: —N(CH.sub.3).sub.2; or methyl; or haloalkyl; or alkyl-heterocyclyl; or alkyl-morpholinyl or alkyl-piperidinyl; or —NHC(O)-alkyl, —NHC(O)-alkyl-C(O)OH, or —NHC(O)-alkyl-C(O)O-alkyl.

95.-105. (canceled)

106. The compound of claim 1, wherein at least one instance of R.sup.3 is hydrogen or wherein each instance of R.sub.3 is hydrogen.

107. (canceled)

108. The compound of claim 1, wherein: provided that when L.sup.1 is optionally substituted C.sub.1-2 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—; and R.sup.2 is optionally substituted aryl or optionally substituted heteroaryl; or provided that when L.sup.1 is optionally substituted C.sub.1-2 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—, and R.sup.2 is not optionally substituted carbocyclyl; or provided that when L.sup.1 is optionally substituted C.sub.1-2 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—, and R.sup.2 is not cyclopentyl; or provided that when L.sup.1 is optionally substituted C.sub.1-4 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—; or provided that when L.sup.1 is optionally substituted C.sub.1 alkylene or unsubstituted C.sub.4 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—; or provided that when L.sup.1 is optionally substituted C.sub.2 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—, and R.sup.2 is optionally substituted aryl or optionally substituted heteroaryl; or provided that when L.sup.1 is optionally substituted C.sub.2 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—, and R.sup.2 is not optionally substituted carbocyclyl; or provided that when L.sup.1 is optionally substituted C.sub.2 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—, and R.sup.2 is not cyclopentyl; or provided that when R.sup.1 is optionally substituted C.sub.1 alkyl, then at least one instance of Y.sup.2 is —NR.sup.N—; or provided that when R.sup.1 is optionally substituted alkyl, L.sup.1 is optionally substituted C.sub.2 alkyl, each instance of Y2 is a bond, and L2 is a bond, then R.sup.2 is not optionally substituted aryl; or provided that where R.sup.1 is halo, L.sup.1 is optionally substituted C.sub.2 alkyl, one of Y.sup.2 is —NR.sup.N— and the other is a bond, and L.sup.2 is a bond, then R.sup.2 is not optionally substituted carbocyclyl; or provided that where R.sup.1 is halo, L.sup.1 is optionally substituted C.sub.2 alkyl, one of Y.sup.2 is —NR.sup.N— and the other is a bond, and L.sup.2 is a bond, then R.sup.2 is not cyclopentyl; or provided that when R.sup.1 is optionally substituted C.sub.1 alkyl, then at least one instance of Y.sup.2 is —NR.sup.N—; or provided that when R.sup.1 is optionally substituted alkyl, L.sup.1 is optionally substituted C.sub.2 alkyl, each instance of Y2 is a bond, and L2 is a bond, then R.sup.2 is not optionally substituted aryl; or provided that where R.sup.1 is halo, L.sup.1 is optionally substituted C.sub.2 alkyl, one of Y.sup.2 is —N.sub.10— and the other is a bond, and L.sup.2 is a bond, then R.sup.2 is not optionally substituted carbocyclyl; or provided that where R.sup.1 is halo, L.sup.1 is optionally substituted C.sub.2 alkyl, one of Y.sup.2 is —NR.sup.N— and the other is a bond, and L.sup.2 is a bond, then R.sup.2 is not cyclopentyl; or R.sup.1 is not oxazolidinone.

109.-122. (canceled)

123. The compound of claim 1, wherein ##STR00258## is any one of structures: ##STR00259##

124.-129. (canceled)

130. The compound of claim 1, wherein the compound is any one of structures: ##STR00260## ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265## ##STR00266## ##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271## ##STR00272## ##STR00273## ##STR00274## ##STR00275## and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

131. A compound of Formula (II): ##STR00276## or a pharmaceutically acceptable, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: each instance of R.sup.A is independently optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or —N(R.sup.N).sub.2; each instance of R.sup.8 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; x is an integer from 0-3, inclusive; Y.sup.4 is —C(R.sup.C).sub.2—, —O—, —NR.sup.N—, or —S—; each instance of R.sup.9 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; y is 0, or an integer from 1 to 9, inclusive; each instance of r is independently 0 or 1; R.sup.5 is hydrogen, —OH, —NO.sub.2, —N(R.sup.N1).sub.2, or —C(═O)N(R.sup.N1).sub.2, —C(═O)OR.sup.O1, or —C(═O)R.sup.C1; each instance of R.sup.N1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, or a nitrogen protecting group; or two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.6 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; q is 0, or an integer from 1 to 4, inclusive; each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.C is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; or two R.sup.C bonded to the same carbon are taken together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and each instance of R.sup.O1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; each instance of R.sup.C1 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; or two R.sup.C bonded to the same carbon are taken together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a sulfur protecting group, or R.sup.S, taken together with the sulfur atom to which it is attached forms a disulfide group substituted with hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl, provided that the compound is not: ##STR00277##

132. The compound of claim 131, wherein: provided that when Y.sup.4 is —NH—, each instance of r is 1, and R.sup.5 is —N(Me).sub.2, then R.sup.A is not optionally substituted heteroaryl; or provided that when Y.sup.4 is —NH—, each instance of r is 1, and R.sup.5 is —N(Me).sub.2, then R.sup.A is not optionally substituted pyridyl; or provided that when Y.sup.4 is —NR.sup.N—, each instance of r is 1, and R.sup.5 is —N(R.sup.N1).sub.2, then R.sup.A is not optionally substituted pyridyl; or provided that when Y.sup.4 is —NH—, each instance of r is 1, and R.sup.5 is —N(Me).sub.2, then R.sup.A is optionally substituted aryl; or provided that when Y.sup.4 is —NR.sup.N—, each instance of r is 1, and R.sup.5 is —N(R.sup.N1).sub.2, then R.sup.A is optionally substituted aryl; or provided that when Y.sup.4 is —NH—, each instance of r is 1, and R.sup.5 is —N(Me).sub.2, then R.sup.A is optionally substituted phenyl; or provided that when Y.sup.4 is —NR.sup.N—, each instance of r is 1, and R.sup.5 is —N(R.sup.N1).sub.2, then R.sup.A is optionally substituted phenyl.

133.-139. (canceled)

140. The compound of claim 131, wherein the compound is of Formula (II-i), (II-ii), or (II-iii): ##STR00278## or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

141.-142. (canceled)

143. The compound of claim 131, wherein the compound is of Formula (II-a): ##STR00279## or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein each instance of R.sup.7 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; and v is 0, or an integer from 1 to 5, inclusive.

144. The compound of claim 131, wherein the compound is of Formula (II-a-1), (II-a-3), (II-a-4), (II-a-5), or (II-a-6): ##STR00280## or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

145.-146. (canceled)

147. The compound of claim 131, wherein: each instance of r is 1, or one instance of r is 1, and the other instance is 0; or each instance of r is 0; or Y.sup.4 is —NR.sup.N—; or Y.sup.4 is —O—, —NH—, or —CH.sub.2—; or at least one instance of R.sup.9 is hydrogen; or each instance of R.sup.9 is hydrogen; or m is 0; or at least one instance of R.sup.8 is optionally substituted aryl; or at least one instance of R.sup.8 is optionally substituted phenyl; or R.sup.A is optionally substituted aryl; or R.sup.A is optionally substituted phenyl; or R.sup.5 is —N(R.sup.N1).sub.2; or R.sup.5 is —NO.sub.2, —NH.sub.2, —C(═O)NH.sub.2, —C(═O)OH, R.sup.5 is —C(═O)OEt, or R.sup.5 is NHC(═O)CH.sub.3; or each instance of R.sup.N1 is hydrogen; or at least one instance of R.sup.6 is optionally substituted acyl, —N(R.sup.N).sub.2, or halogen; or at least one instance of R.sup.6 is —CO.sub.2alkyl, —CO.sub.2H, —NHC(O)Me, or —C.sub.1; or q is 0 or 1; or at least one instance of R.sup.6 is ortho, meta, or para relative to R.sup.5; or q is 1 and R.sup.6 is ortho, meta, or para relative to R.sup.5; or at least one instance of R.sup.7 is —N(R.sup.N).sub.2; or at least one instance of R.sup.7 is —N(Me).sub.2; or v is 1; at least one instance of R.sup.N is hydrogen, acetyl, or optionally substituted C.sub.1-6 alkyl; or at least one instance of R.sup.N is unsubstituted C.sub.1-3 alkyl; or at least one instance of R.sup.N is methyl; or at least one instance of R.sup.O is hydrogen, optionally substituted methyl, or optionally substituted acetyl; or at least one instance of R.sup.S is hydrogen.

148-158. (canceled)

159. The compound of claim 131, wherein at least one instance of R.sup.8 is of structure: ##STR00281## wherein: each instance of R.sup.7 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; and v is 0, or an integer from 1 to 5, inclusive.

160. The compound of claim 159, wherein: at least one instance of R.sup.8 is of structure: ##STR00282## or at least one instance of R.sup.8 is of structure: ##STR00283## or at least one instance of R.sup.8 is hydrogen; or each instance of R.sup.8 is hydrogen; or n is 0 or 1.

161.-167. (canceled)

168. The compound of claim 131, wherein R.sup.A is of structure: ##STR00284## wherein: each instance of R.sup.7 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; and v is 0, or an integer from 1 to 5, inclusive.

169. The compound of claim 168, wherein R.sup.A is of structure: ##STR00285##

170. The compound of claim 169, wherein R.sup.A is of structure: ##STR00286##

171.-205. (canceled)

206. The compound of claim 131, wherein the compound is any one of structures: ##STR00287## ##STR00288## ##STR00289## ##STR00290## and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

207. A compound, which is represented by any one of structures: ##STR00291## ##STR00292## ##STR00293## ##STR00294## ##STR00295## ##STR00296## ##STR00297## or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, and prodrug thereof.

208. A pharmaceutical composition, comprising the compound or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof of any one of claims 131, and 207, and a pharmaceutically acceptable carrier or excipient.

209. A method of treating a proliferative disease in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof any one of claims 1, 131, and 207, wherein the proliferative disease is cancer.

210. (canceled)

211. The method of claim 209, wherein the cancer is multiple myeloma, leukemia, lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, ovarian cancer, or colon cancer.

212.-215. (canceled)

216. A method of inhibiting a histone lysine demethylase (KDM) in vivo or in vitro comprising contacting the KDM with the compound or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, of any one of claims 1, 131, and 207, wherein the KDM is a KDM1, KDM2, KDM3, KDM4, KDM5, or KDM6.

217.-218. (canceled)

219. The method of claim 216, wherein the KDM3 is KDM3A, KDM3B, or Jumonji domain containing 1C (JMJD1C).

220.-231. (canceled)

232. The method of claim 211, wherein the leukemia is acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0102] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the present disclosure and together with the description, serve to explain the principles of the present disclosure.

[0103] FIG. 1 shows a Western Blot, produced from testing histone methylation activity of JADA94 (a mixture of JADA94-1 and JADA94-2) in RPMI8226 cell line after 24 hours, demonstrating selectivity of JADA94 for KDM3.

[0104] FIG. 2A shows MTT cell growth inhibition assay results of JADA94 at 72 hours in H929, RPMI8226, MM.1S, and OPM2 cells. FIG. 2B shows MTT cell growth inhibition assay results of JADA94 at 6 days in H929, RPMI8226, and MM.1S cells.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0105] Provided herein compounds of Formulas (I), (II), compounds 1-22 and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof. The inventive compounds provided herein are histone lysine demethylase (KDM) inhibitors (e.g., KDM3 inhibitors), and are therefore useful for the treatment and/or prevention of diseases (e.g., proliferative diseases, e.g., cancer). In certain embodiments, the compounds described herein are selective inhibitors of a KDM (e.g., KDM3). Therefore, also provided herein are methods and uses related to treating diseases or conditions (e.g., proliferative diseases (e.g., cancer), cardiovascular diseases) in a subject, inhibiting the activity of a KDM (e.g., KDM3) in a subject or biological sample; inducing apoptosis in the cell of a subject or biological sample, and/or modulating the expression of a gene.

Compounds of Formula (I)

[0106] Provided herein are compounds of Formula (I):

##STR00011##

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

[0107] each instance of R.sup.1 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S;

[0108] n is 0, or an integer from 1 to 4, inclusive;

[0109] Y.sup.1 is —C(R.sup.C).sub.2—, —O—, —NR.sup.N—, or —S—;

[0110] each instance of R.sup.3 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S;

[0111] m is 0, or an integer from 1 to 5, inclusive;

[0112] each instance of r is independently 0 or 1;

[0113] L.sup.1 is optionally substituted C.sub.1-6 alkylene, optionally substituted C.sub.2-6 alkenylene, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylene, or optionally substituted heteroarylene;

[0114] each instance of Y.sup.2 is independently a bond, —O—, or —NR.sup.N—;

[0115] L.sup.2 is a bond, optionally substituted C.sub.1-6 alkylene, optionally substituted C.sub.1-6 heteroalkylene, optionally substituted C.sub.2-6 alkenylene, optionally substituted C.sub.2-6 alkynylene, optionally substituted C.sub.1-6 acylene, or a combination thereof;

[0116] R.sup.2 is —N(R.sup.N).sub.2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;

[0117] each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;

[0118] each instance of R.sup.C is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; or two R.sup.C bonded to the same carbon are taken together with the intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, or ═O;

[0119] each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and

[0120] each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a sulfur protecting group, or R.sup.S, taken together with the sulfur atom to which it is attached forms a disulfide group substituted with hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl, provided that

[0121] when L1 is optionally substituted C.sub.1-2 alkylene, at least one instance of Y.sup.2 is —NR.sup.N—, R.sup.2 is optionally substituted aryl or optionally substituted heteroaryl,

[0122] when L.sup.1 is optionally substituted C.sub.1-2 alkylene, at least one instance of Y.sup.2 is —NR.sup.N—, R.sup.2 is not optionally substituted carbocyclyl,

[0123] when L.sup.1 is optionally substituted C.sub.1-4 alkylene, at least one instance of Y.sup.2 is —NR.sup.N—,

[0124] when L.sup.1 is optionally substituted C.sub.2 alkylene and at least one instance of Y.sup.2 is —NR.sup.N—, R.sup.2 is optionally substituted aryl or optionally substituted heteroaryl,

[0125] when L.sup.1 is optionally substituted C.sub.2 alkylene and at least one instance of Y.sup.2 is —NR.sup.N—, R.sup.2 is not optionally substituted carbocyclyl,

[0126] when R.sup.1 is optionally substituted C.sub.1 alkylene, at least one instance of Y.sup.2 is —NR.sup.N—,

[0127] when R.sup.1 is optionally substituted alkylene, L.sup.1 is optionally substituted C.sub.2 alkylene, each instance of Y2 is a bond, and L2 is a bond, R.sup.2 is not optionally substituted aryl,

[0128] where R.sup.1 is halo, L.sup.1 is optionally substituted C.sub.2 alkylene, one of Y.sup.2 is —NR.sup.N— and the other is a bond, and L.sup.2 is a bond, R.sup.2 is not optionally substituted carbocyclyl,

[0129] when R.sup.1 is halo, L.sup.1 is optionally substituted C.sub.2 alkylene, one of Y.sup.2 is —NR.sup.N— and the other is a bond, and L.sup.2 is a bond, R.sup.2 is not cyclopentyl,

[0130] and when L.sup.1 and L.sup.2 are optionally substituted C.sub.1 alkylene, Y.sup.1 is O, one of Y.sup.2 is a bond and the other is O, R.sup.2 is a phenyl, R.sup.1 is not optionally substituted oxazolidinone.

[0131] In certain embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; provided that when L.sup.1 is optionally substituted C.sub.1-2 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—; and R.sup.2 is optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, when L.sub.1 is optionally substituted C.sub.1-2 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—; and R.sup.2 is not optionally substituted carbocyclyl. In certain embodiments, when L.sub.1 is optionally substituted C.sub.1-2 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—; and R.sup.2 is not cyclopentyl.

[0132] In certain embodiments, when L.sup.1 is optionally substituted C.sub.1-4 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—. In certain embodiments, when L.sup.1 is optionally substituted C.sub.1 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—. In certain embodiments, when L.sub.1 is unsubstituted C.sub.4 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—. In certain embodiments, when L.sub.1 is optionally substituted C.sub.2 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—; and R.sup.2 is optionally substituted aryl. In certain embodiments, when L.sub.1 is optionally substituted C.sub.2 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—; and R.sup.2 is optionally substituted heteroaryl. In certain embodiments, when L.sup.1 is optionally substituted C.sub.2 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—; and R.sup.2 is not optionally substituted carbocyclyl. In certain embodiments, when L.sup.1 is optionally substituted C.sub.2 alkylene, then at least one instance of Y.sup.2 is —NR.sup.N—; and R.sup.2 is not cyclopentyl.

[0133] In certain embodiments, when R.sup.1 is optionally substituted C.sub.1 alkyl, then at least one instance of Y.sup.2 is —NR.sup.N—.

[0134] In certain embodiments, when R.sup.1 is optionally substituted alkyl, L.sup.1 is optionally substituted C.sub.2 alkyl, each instance of Y2 is a bond, and L2 is a bond, then R.sup.2 is not optionally substituted aryl.

[0135] In certain embodiments, where R.sup.1 is halo, L.sub.1 is optionally substituted C.sub.2 alkyl, one of Y.sup.2 is —NR.sup.N—, and the other is a bond, and L.sup.2 is a bond, then R.sup.2 is not optionally substituted carbocyclyl. In certain embodiments, where R.sup.1 is halo, L.sup.1 is optionally substituted C.sub.2 alkyl, one of Y.sup.2 is —NR.sup.N—, and the other is a bond, and L.sup.2 is a bond, then R.sup.2 is not cyclopentyl.

[0136] In certain embodiments, the compound is not any one of the following structures:

##STR00012##

[0137] In certain embodiments, R.sup.1 does not include an oxazolidinone.

[0138] In certain embodiments, the compound of Formula (I) is of Formula (I-i), (I-ii), or (I-iii):

##STR00013##

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

[0139] In certain embodiments, the compound of Formula (I) is of Formula (I-a):

##STR00014##

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; wherein:

[0140] p is an integer from 1 to 6, inclusive.

[0141] In certain embodiments, the compound of Formula (I) is of Formula (I-a-1) or (I-a-2):

##STR00015##

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

[0142] In certain embodiments, the compound of Formula (I) is of Formula (I-a-3) or (I-a-4):

##STR00016##

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; wherein:

[0143] s is an integer from 1 to 6, inclusive.

[0144] In certain embodiments, the compound of Formula (I) is of Formula (I-a-5):

##STR00017##

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

[0145] In certain embodiments, the compound of Formula (I) is of Formula (I-b):

##STR00018##

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; wherein:

[0146] each instance of R.sup.4 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; and

[0147] w is 0, or an integer from 1 to 4, inclusive.

[0148] In certain embodiments, the compound of Formula (I) is of Formula (I-b-1) or (I-b-2):

##STR00019##

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

[0149] In certain embodiments, the compound of Formula (I) is of Formula (I-b-3) or (I-b-4):

##STR00020##

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; wherein:

[0150] s is an integer from 1 to 6, inclusive.

[0151] In certain embodiments, the compound of Formula (I) is of Formula (I-b-5) or (I-b-6):

##STR00021##

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

[0152] In certain embodiments, the compound of Formula (I) is of Formula (I-c):

##STR00022##

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; wherein:

[0153] each instance of R.sup.4 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; and

[0154] t is 0, or an integer from 1 to 2, inclusive.

[0155] In certain embodiments, the compound of Formula (I) is of Formula (I-c-1):

##STR00023##

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

[0156] In certain embodiments, the compound of Formula (I) is of Formula (I-c-2):

##STR00024##

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

[0157] In certain embodiments, the compound of Formula (I) is of Formula (I-c-3):

##STR00025##

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; wherein:

[0158] s is an integer from 1 to 6, inclusive.

[0159] In certain embodiments, the compound of Formula (I) is of Formula (I-c-4):

##STR00026##

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

[0160] In certain embodiments, the compound of Formula (I) is of Formula (I-c-5):

##STR00027##

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

[0161] In certain embodiments, the compound of Formula (I) is of Formula (I-c-6):

##STR00028##

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

[0162] In certain embodiments, the compound of Formula (I) is of Formula (I-c-7):

##STR00029##

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; wherein:

[0163] s is an integer from 1 to 6, inclusive.

[0164] In certain embodiments, the compound of Formula (I) is of Formula (I-c-8):

##STR00030##

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

[0165] In certain embodiments, the compound of Formula (I) is represented by any one of structures:

##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049##

and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof.

Compounds of Formula (II)

[0166] Other inventive compounds are represented by Formula (II):

##STR00050##

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

[0167] each instance of R.sup.A is independently optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or —N(R.sup.N).sub.2;

[0168] each instance of R.sup.8 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S;

[0169] x is 0, or an integer from 1-3, inclusive;

[0170] Y.sup.4 is —C(R.sup.C).sub.2—, —O—, —NR.sup.N—, or —S—;

[0171] each instance of R.sup.9 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S;

[0172] y is 0, or an integer from 1 to 9, inclusive;

[0173] each instance of r is independently 0 or 1;

[0174] R.sup.5 is hydrogen, —OH, —NO.sub.2, —N(R.sup.N1).sub.2, —C(═O)N(R.sup.N1).sub.2, —C(═O)OR.sup.O1, or —C(═O)R.sup.C1;

[0175] each instance of R.sup.N1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, or a nitrogen protecting group; or two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;

[0176] each instance of R.sup.O1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group;

[0177] each instance of R.sup.C1 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; or two R.sup.C bonded to the same carbon are taken together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl;

[0178] each instance of R.sup.6 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S;

[0179] q is 0, or an integer from 1 to 4, inclusive;

[0180] each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;

[0181] each instance of R.sup.C is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; or two R.sup.C bonded to the same carbon are taken together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl;

[0182] each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, or an oxygen protecting group; and

[0183] each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a sulfur protecting group, or R.sup.S, taken together with the sulfur atom to which it is attached forms a disulfide group substituted with hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl, provided that

[0184] when Y.sup.4 is —NH—, each instance of r is 1, and R.sup.5 is —N(Me).sub.2, R.sup.A is not optionally substituted pyridyl,

[0185] when Y.sup.4 is —NR.sup.N—, each instance of r is 1, and R.sup.5 is —N(R.sup.N1).sub.2, R.sup.A is not optionally substituted pyridyl,

[0186] when Y.sup.4 is —NH—, each instance of r is 1, and R.sup.5 is —N(Me).sub.2, R.sup.A is not optionally substituted heteroaryl, and

[0187] when Y.sup.4 is —NR.sup.N—, each instance of r is 1, and R.sup.5 is —N(R.sup.N1).sub.2, R.sup.A is not optionally substituted heteroaryl.

[0188] In certain embodiments, when Y.sup.4 is —NH—, each instance of r is 1, and R.sup.5 is —N(Me).sub.2, then R.sup.A is not optionally substituted pyridyl. In certain embodiments, when Y.sup.4 is —NR.sup.N—, each instance of r is 1, and R.sup.5 is —N(R.sup.N1).sub.2, then R.sup.A is not optionally substituted pyridyl. In certain embodiments, when Y.sup.4 is —NH—, each instance of r is 1, and R.sup.5 is —N(Me).sub.2, then R.sup.A is not optionally substituted heteroaryl. In certain embodiments, when Y.sup.4 is —NR.sup.N—, each instance of r is 1, and R.sup.5 is —N(R.sup.N1).sub.2, then R.sup.A is not optionally substituted heteroaryl.

[0189] In certain embodiments, when Y.sup.4 is —NH—, each instance of r is 1, and R.sup.5 is —N(Me).sub.2, then R.sup.A is optionally substituted aryl. In certain embodiments, when Y.sup.4 is —NR.sup.N—, each instance of r is 1, and R.sup.5 is —N(R.sup.N1).sub.2, R.sup.A is optionally substituted aryl. In certain embodiments, when Y.sup.4 is —NH—, each instance of r is 1, and R.sup.5 is —N(Me).sub.2, then R.sup.A is optionally substituted phenyl. In certain embodiments, when Y.sup.4 is —NR.sup.N—, each instance of r is 1, and R.sup.5 is —N(R.sup.N1).sub.2, R.sup.A is optionally substituted phenyl.

[0190] In certain embodiments, the compound is not of the formula:

##STR00051##

[0191] In certain embodiments, the compound of Formula (II) is of Formula (II-i):

##STR00052##

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

[0192] In certain embodiments, the compound of Formula (II) is of Formula (II-ii):

##STR00053##

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

[0193] In certain embodiments, the compound of Formula (II) is of Formula (II-iii):

##STR00054##

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

[0194] In certain embodiments, the compound of Formula (II) is of Formula (II-a):

##STR00055##

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; wherein:

[0195] each instance of R.sup.7 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; and

[0196] v is 0, or an integer from 1 to 5, inclusive.

[0197] In certain embodiments, the compound of Formula (II) is of Formula (II-a-1) or (II-a-2):

##STR00056##

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

[0198] In certain embodiments, the compound of Formula (II) is of Formula (II-a-3) or (II-a-4):

##STR00057##

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

[0199] In certain embodiments, the compound of Formula (II) is of Formula (II-a-5) or (II-a-6):

##STR00058##

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

[0200] In certain embodiments, the compound of Formula (II) is represented by any one of structures:

##STR00059## ##STR00060## ##STR00061## ##STR00062##

and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

Group Definitions

[0201] The following definitions and embodiments apply to all formulas provided herein.

L.SUP.1 .and p

[0202] As defined herein, L.sup.1 is optionally substituted C.sub.1-6 alkylene, optionally substituted C.sub.2-6 alkenylene, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylene, or optionally substituted heteroarylene. In certain embodiments, L.sup.1 is optionally substituted C.sub.1-6 alkylene, optionally substituted C.sub.2-6 alkenylene, optionally substituted arylene, or optionally substituted heteroarylene. In certain embodiments, L.sup.1 is optionally substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.1 is optionally substituted C.sub.2-6 alkenylene. In certain embodiments, L.sup.1 is optionally substituted arylene. In certain embodiments, L.sup.1 is optionally substituted heteroarylene. In certain embodiments, L.sup.1 is optionally substituted carbocyclyl. In certain embodiments, L.sup.1 is optionally substituted heterocyclyl,

[0203] In certain embodiments, L.sup.1 is optionally substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.1 is optionally substituted C.sub.2-3 alkylene. In certain embodiments, L.sup.1 is optionally substituted C.sub.2 alkylene. In certain embodiments, L.sup.1 is optionally substituted C.sub.3 alkylene. In certain embodiments, L.sup.1 is of structure:

##STR00063##

In certain embodiments, L.sup.1 is of the formula —CH.sub.2CH.sub.2—. In certain embodiments, L.sup.1 is of the formula —CH.sub.2CH.sub.2CH.sub.2—.

[0204] As defined herein, p is an integer from 1 to 6, inclusive (i.e., 1, 2, 3, 4, 5, or 6). In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6.

[0205] In certain embodiments, L.sup.1 is optionally substituted arylene. In certain embodiments, L.sup.1 is optionally substituted phenylene. In certain embodiments, L.sup.1 is unsubstituted phenylene. In certain embodiments, L.sup.1 is of structure:

##STR00064##

In certain embodiments, L.sup.1 is of one of the following structures:

##STR00065##

In certain embodiments, L.sup.1 is one of the following structures:

##STR00066##

In certain embodiments, L.sup.1 is one of the following structures:

##STR00067##

In certain embodiments, L.sup.1 is of the following structure:

##STR00068##

In certain embodiments, L1 is of the following structure:

##STR00069##

In certain embodiments, L.sup.1 is of one of the following structures:

##STR00070##

In certain embodiments, L.sup.1 is of one of the following structures:

##STR00071##

[0206] In certain embodiments, L.sup.1 is optionally substituted C.sub.2-6 alkenylene. In certain embodiments, L.sup.1 is of structure:

##STR00072##

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

##STR00073##

In certain embodiments, L.sup.1 is of structure:

##STR00074##

R.SUP.4., w, and t

[0207] As defined herein, each instance of R.sup.4 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S. In certain embodiments, at least one instance of R.sup.4 is hydrogen. In certain embodiments, at least one instance of R.sup.4 is halogen. In certain embodiments, at least one instance of R.sup.4 is —CN. In certain embodiments, at least one instance of R.sup.4 is —N.sub.3. In certain embodiments, at least one instance of R.sup.4 is —NO.sub.2. In certain embodiments, at least one instance of R.sup.4 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted sulfonyl. In certain embodiments, at least one instance of R.sup.4 is optionally substituted sulfinyl. In certain embodiments, at least one instance of R.sup.4 is —OR.sup.O. In certain embodiments, at least one instance of R.sup.4 is —N(R.sup.N).sub.2. In certain embodiments, at least one instance of R.sup.4 is —SR.sup.S.

[0208] In certain embodiments, each instance of R.sup.4 is hydrogen.

[0209] In certain embodiments, at least one instance of R.sup.4 is halogen. In certain embodiments, at least one instance of R.sup.4 is —F.

[0210] In certain embodiments, at least one instance of R.sup.4 is optionally substituted C.sub.1-6 acyl. In certain embodiments, at least one instance of R.sup.4 is —CO.sub.2alkyl. In certain embodiments, at least one instance of R.sup.4 is —CO.sub.2Et.

[0211] As defined herein, w is 0, or an integer from 1 to 4, inclusive (i.e., 0, 1, 2, 3, or 4). In certain embodiments, w is 0. In certain embodiments, w is 1. In certain embodiments, w is 2. In certain embodiments, w is 3. In certain embodiments, w is 4.

[0212] As defined herein, t is 0, 1, or 2. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2.

Y.sup.1 and Y.sup.2

[0213] As defined herein, Y.sup.1 is —C(R.sup.C).sub.2—, —O—, —NR.sup.N—, or —S—. In certain embodiments, Y.sup.1 is —C(R.sup.C).sub.2—. In certain embodiments, Y.sup.1 is —CH.sub.2—. In certain embodiments, Y.sup.1 is —S—. In certain embodiments, Y.sup.1 is —O—. In certain embodiments, Y.sup.1 is —NR.sup.N—. In certain embodiments, Y.sup.1 is —NH—.

[0214] As defined herein, each instance of Y.sup.2 is independently a bond, —O—, or —NR.sup.N—. In certain embodiments, at least one instance of Y.sup.2 is a bond. In certain embodiments, at least one instance of Y.sup.2 is —O—. In certain embodiments, at least one instance of Y.sup.2 is —N(R.sup.N)—. In certain embodiments, at least one instance of Y.sup.2 is —NH—.

[0215] In certain embodiments, one instance of Y.sup.2 is —N(R.sup.N)—; and the other instance is a bond. In certain embodiments, the instance of Y.sup.2 proximal to R.sup.2 is —N(R.sup.N)—; and the other instance is a bond. In certain embodiments, the instance of Y.sup.2 distal to R.sup.2 is —N(R.sup.N)—; and the other instance is a bond. In certain embodiments, one instance of Y.sup.2 is —NH—; and the other instance is a bond. In certain embodiments, the instance of Y.sup.2 proximal to R.sup.2 is —NH—; and the other instance is a bond. In certain embodiments, the instance of Y.sup.2 distal to R.sup.2 is —NH—; and the other instance is a bond.

L.SUP.2 .and s

[0216] As defined herein, L.sup.2 is a bond, optionally substituted C.sub.1-6 alkylene, optionally substituted C.sub.1-6 heteroalkylene, optionally substituted C.sub.2-6 alkenylene, optionally substituted C.sub.2-6 alkynylene, optionally substituted C.sub.1-6 acylene, or a combination thereof. In certain embodiments, L.sup.2 is a bond. In certain embodiments, L.sup.2 is optionally substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.2 is optionally substituted C.sub.1-6 heteroalkylene. In certain embodiments, L.sup.2 is optionally substituted C.sub.2-6 alkenylene. In certain embodiments, L.sup.2 is optionally substituted C.sub.2-6 alkynylene. In certain embodiments, L.sup.2 is optionally substituted C.sub.1-6 acylene.

[0217] In certain embodiments, L.sup.2 is optionally substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.2 is optionally substituted C.sub.2-3 alkylene. In certain embodiments, L.sup.2 is optionally substituted C.sub.2 alkylene. In certain embodiments, L.sup.2 is optionally substituted C.sub.3 alkylene. In certain embodiments, L.sup.2 is of structure:

##STR00075##

In certain embodiments, L.sup.2 is of the formula —CH.sub.2CH.sub.2—. In certain embodiments, L.sup.2 is of the formula —CH.sub.2CH.sub.2CH.sub.2—.

[0218] As defined herein, s is an integer from 1 to 6, inclusive (i.e., 1, 2, 3, 4, 5, or 6). In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6.

R.sup.1, n, R.sup.2, and R.sup.A

[0219] As defined herein, each instance of R.sup.1 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S. In certain embodiments, at least one instance of R.sup.1 is hydrogen. In certain embodiments, at least one instance of R.sup.1 is halogen. In certain embodiments, at least one instance of R.sup.1 is —CN. In certain embodiments, at least one instance of R.sup.1 is —N.sub.3. In certain embodiments, at least one instance of R.sup.1 is —NO.sub.2. In certain embodiments, at least one instance of R.sup.1 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.1 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.1 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.1 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.1 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.1 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.1 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.1 is optionally substituted morpholinyl. In certain embodiments, at least one instance of R.sup.1 is optionally substituted piperidinyl. In certain embodiments, at least one instance of R.sup.1 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.1 is optionally substituted sulfonyl. In certain embodiments, at least one instance of R.sup.1 is optionally substituted sulfinyl. In certain embodiments, at least one instance of R.sup.1 is —OR.sup.O. In certain embodiments, at least one instance of R.sup.1 is —N(R.sup.N).sub.2. In certain embodiments, at least one instance of R.sup.1 is —SR.sup.S.

[0220] In certain embodiments, at least one instance of R.sup.1 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.1 is optionally substituted phenyl. In certain embodiments, at least one instance of R.sup.1 is of structure:

##STR00076##

In certain embodiments, at least one instance of R.sup.1 is of structure:

##STR00077##

In certain embodiments, at least one instance of R.sup.1 is of the structure:

##STR00078##

In certain embodiments, at least one instance of R.sup.1 is of the structure:

##STR00079##

and each instance of R.sup.7 is independently optionally substituted alkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, or —N(R.sup.N).sub.2. In certain embodiments, at least one instance of R.sup.1 is of the structure:

##STR00080##

and at least one instance of R.sup.7 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.1 is of the structure:

##STR00081##

and at least one instance of R.sup.7 is haloalkyl. In certain embodiments, at least one instance of R.sup.1 is of the structure:

##STR00082##

and at least one instance of R.sup.7 is alkyl-heterocyclyl. In certain embodiments, at least one instance of R.sup.1 is of the structure:

##STR00083##

and at least one instance of R.sup.7 is alkyl-morpholinyl. In certain embodiments, at least one instance of R.sup.1 is of the structure:

##STR00084##

and at least one instance of R.sup.7 is alkyl-piperidinyl. In certain embodiments, at least one instance of R.sup.1 is of the structure:

##STR00085##

and at least one instance of R.sup.7 is —NHC(O)-alkyl. In certain embodiments, at least one instance of R.sup.1 is of the structure:

##STR00086##

and at least one instance of R.sup.7 is —NHC(O)-alkyl-CO(O)H. In certain embodiments, at least one instance of R.sup.1 is of the structure:

##STR00087##

and at least one instance of R.sup.7 is —NHC(O)-alkyl-CO(O)alkyl.

[0221] In certain embodiments, at least one instance of R.sup.1 is hydrogen. In certain embodiments, each instance of R.sup.1 is hydrogen.

[0222] In certain embodiments, at least one instance of R.sup.1 is haloalkyl. In certain embodiments, at least one instance of R.sup.1 is —CF.sub.3. In certain embodiments, at least one instance of R.sup.1 is —CH.sub.2F. In certain embodiments, at least one instance of R.sup.1 is —CHF.sub.2. In certain embodiments, at least one instance of R.sup.1 is —OCF.sub.3.

[0223] As defined herein, n is 0, or an integer from 1 to 4, inclusive (i.e., 0, 1, 2, 3, or 4). 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.

[0224] As defined herein, R.sup.2 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl. In certain embodiments, R.sup.2 is optionally substituted aryl. In certain embodiments, R.sup.2 is optionally substituted heteroaryl. In certain embodiments, R.sup.2 is optionally substituted carbocyclyl. In certain embodiments, R.sup.2 is optionally substituted heterocyclyl.

[0225] In certain embodiments, R.sup.2 is optionally substituted aryl. In certain embodiments, R.sup.2 is optionally substituted phenyl. In certain embodiments, R.sup.2 is of the structure:

##STR00088##

In certain embodiments, R.sup.2 is of the structure:

##STR00089##

and at least one instance of R.sup.7 is halo. In certain embodiments, R.sup.2 is of the structure:

##STR00090##

and at least one instance of R.sup.7 is optionally substituted alkyl. In certain embodiments, R.sup.2 is of the structure:

##STR00091##

In certain embodiments, R.sup.2 is of the structure:

##STR00092##

In certain embodiments, R.sup.2 is of the structure:

##STR00093##

In certain embodiments, R.sup.2 is of the structure:

##STR00094##

In certain embodiments, R.sup.2 is of the structure:

##STR00095##

[0226] As defined herein, R.sup.A optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or —N(R.sup.N).sub.2. In certain embodiments, R.sup.A is optionally substituted aryl. In certain embodiments, R.sup.A is optionally substituted heteroaryl. In certain embodiments, R.sup.A is optionally substituted carbocyclyl. In certain embodiments, R.sup.A is optionally substituted heterocyclyl. In certain embodiments, R.sup.A is —N(R.sup.N).sub.2.

[0227] In certain embodiments, R.sup.A is optionally substituted aryl. In certain embodiments, R.sup.A is optionally substituted phenyl. In certain embodiments, R.sup.A is of the structure:

##STR00096##

In certain embodiments, R.sup.A is of the structure:

##STR00097##

In certain embodiments, R.sup.A is of the structure

##STR00098##

R.SUP.7 .and v

[0228] As defined herein, each instance of R.sup.7 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S. In certain embodiments, at least one instance of R.sup.7 is hydrogen. In certain embodiments, at least one instance of R.sup.7 is halogen. In certain embodiments, at least one instance of R.sup.7 is —CN. In certain embodiments, at least one instance of R.sup.7 is —N.sub.3. In certain embodiments, at least one instance of R.sup.7 is —NO.sub.2. In certain embodiments, at least one instance of R.sup.7 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.7 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.7 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.7 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.7 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.7 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.7 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.7 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.7 is optionally substituted sulfonyl. In certain embodiments, at least one instance of R.sup.7 is optionally substituted sulfinyl. In certain embodiments, at least one instance of R.sup.7 is —OR.sup.O. In certain embodiments, at least one instance of R.sup.7 is —N(R.sup.N).sub.2. In certain embodiments, at least one instance of R.sup.7 is —SR.sup.S.

[0229] In certain embodiments, at least one instance of R.sup.7 is —N(R.sup.N).sub.2. In certain embodiments, at least one instance of R.sup.7 is —N(Me).sub.2. In certain embodiments, one instance of R.sup.7 is —N(R.sup.N).sub.2. In certain embodiments, one instance of R.sup.7 is —N(Me).sub.2. In certain embodiments, one instance of R.sup.7 is Br. In certain embodiments, one instance of R.sup.7 is methyl.

[0230] As defined herein, v is 0, or an integer from 1 to 5, inclusive (i.e., 0, 1, 2, 3, 4, or 5). In certain embodiments, v is 0. In certain embodiments, v is 1. In certain embodiments, v is 2. In certain embodiments, v is 3. In certain embodiments, v is 4. In certain embodiments, v is 5.

R.SUP.3.. m, and r

[0231] As defined herein, each instance of R.sup.3 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S. In certain embodiments, at least one instance of R.sup.3 is hydrogen. In certain embodiments, at least one instance of R.sup.3 is halogen. In certain embodiments, at least one instance of R.sup.3 is —CN. In certain embodiments, at least one instance of R.sup.3 is —N.sub.3. In certain embodiments, at least one instance of R.sup.3 is —NO.sub.2. In certain embodiments, at least one instance of R.sup.3 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.3 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.3 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.3 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.3 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.3 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.3 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.3 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.3 is —OR.sup.O. In certain embodiments, at least one instance of R.sup.3 is —N(R.sup.N).sub.2. In certain embodiments, at least one instance of R.sup.3 is —SR.sup.S.

[0232] In certain embodiments, at least one instance of R.sup.3 is hydrogen. In certain embodiments, each instance of R.sup.3 is hydrogen.

[0233] As defined herein, m is 0, or an integer from 1 to 5, inclusive (i.e., 0, 1, 2, 5, 4, or 5). In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5.

[0234] As defined herein, each instance of r is independently 0 or 1.

[0235] In certain embodiments, each instance of r is 1. In certain embodiments, one instance of r is 1; and the other instance is 0. In certain embodiments, each instance of r is 0.

R.sup.5 and R.sup.N1

[0236] As defined herein, R.sup.5 is —NO.sub.2, —N(R.sup.N1).sub.2, or —C(═O)N(R.sup.N1).sub.2. In certain embodiments, R.sup.5 is —NO.sub.2. In certain embodiments, R.sup.5 is —N(R.sup.N1).sub.2. In certain embodiments, R.sup.5 is —NH.sub.2. In certain embodiments, R.sup.5 is —C(═O)N(R.sup.N1).sub.2. In certain embodiments, R.sup.5 is —C(═O)NH.sub.2. In certain embodiments, R.sup.5 is —C(═O)OH. In certain embodiments, R.sup.5 is —C(═O)OEt. In certain embodiments, R.sup.5 is —NHC(═O)CH.sub.3.

[0237] As defined herein, each instance of R.sup.N1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, or a nitrogen protecting group; or two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.N1 is hydrogen. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted sulfonyl. In certain embodiments, at least one instance of R.sup.N1 is optionally substituted sulfinyl. In certain embodiments, at least one instance of R.sup.N1 is a nitrogen protecting group. In certain embodiments, two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, two R.sup.N1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heteroaryl.

[0238] In certain embodiments, each instance of R.sup.N1 is hydrogen. In certain embodiments, each instance of R.sup.N1 is optionally substituted aryl. In certain embodiments, each instance of R.sup.N1 is optionally substituted phenyl.

R.SUP.6 .and q

[0239] As defined herein, each instance of R.sup.6 is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S. In certain embodiments, at least one instance of R.sup.6 is hydrogen. In certain embodiments, at least one instance of R.sup.6 is halogen. In certain embodiments, at least one instance of R.sup.6 is —CN. In certain embodiments, at least one instance of R.sup.6 is —N.sub.3. In certain embodiments, at least one instance of R.sup.6 is —NO.sub.2. In certain embodiments, at least one instance of R.sup.6 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.6 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.6 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.6 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.6 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.6 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.6 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.6 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.6 is optionally substituted sulfonyl. In certain embodiments, at least one instance of R.sup.6 is optionally substituted sulfinyl. In certain embodiments, at least one instance of R.sup.6 is —OR.sup.O. In certain embodiments, at least one instance of R.sup.6 is —N(R.sup.N).sub.2. In certain embodiments, at least one instance of R.sup.6 is —SR.sup.S.

[0240] In certain embodiments, at least one instance of R.sup.6 is optionally substituted C.sub.1-6 acyl. In certain embodiments, one instance of R.sup.6 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.6 is —CO.sub.2alkyl. In certain embodiments, at least one instance of R.sup.6 is —CO.sub.2Et. In certain embodiments, at least one instance of R.sup.6 is —CO.sub.2H. In certain embodiments, one instance of R.sup.6 is —CO.sub.2alkyl. In certain embodiments, one instance of R.sup.6 is —CO.sub.2Et. In certain embodiments, one instance of R.sup.6 is —CO.sub.2H.

[0241] In certain embodiments, at least one instance of R.sup.6 is —N(R.sup.N).sub.2. In certain embodiments, one instance of R.sup.6 is —N(R.sup.N).sub.2. In certain embodiments, at least one instance of R.sup.6 is —NHC(O)Me. In certain embodiments, one instance of R.sup.6 is —NHC(O)Me.

[0242] In certain embodiments, at least one instance of R.sup.6 is halogen. In certain embodiments, one instance of R.sup.6 is halogen. In certain embodiments, at least one instance of R.sup.6 is —C.sub.1. In certain embodiments, one instance of R.sup.6 is —C.sub.1.

[0243] In certain embodiments, at least one instance of R.sup.6 is para relative to R.sup.5. In certain embodiments, at least one instance of R.sub.6 is meta relative to R.sup.5. In certain embodiments, at least one instance of R.sub.6 is ortho relative to R.sup.5. In certain embodiments, q is 1 and R.sup.6 is para relative to R.sup.5. In certain embodiments, q is 1 and R.sub.6 is meta relative to R.sup.5. In certain embodiments, q is 1 and R.sub.6 is ortho relative to R.sup.5.

[0244] In certain embodiments, q is 0, or an integer from 1 to 4, inclusive (i.e., 0, 1, 2, 3, or 4). In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4.

R.sup.C, R.sup.N, R.sup.O, and R.sup.S

[0245] As defined herein, each instance of R.sup.C is independently hydrogen, halogen, —CN, —N.sub.3, —NO.sub.2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR.sup.O, —N(R.sup.N).sub.2, or —SR.sup.S; or two R.sup.C bonded to the same carbon are taken together with the intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, or ═O. In certain embodiments, at least one instance of R.sup.C is hydrogen. In certain embodiments, at least one instance of R.sup.C is halogen. In certain embodiments, at least one instance of R.sup.C is —CN. In certain embodiments, at least one instance of R.sup.C is —N.sub.3. In certain embodiments, at least one instance of R.sup.C is —NO.sub.2. In certain embodiments, at least one instance of R.sup.C is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.C is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.C is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.C is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.C is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.C is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.C is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.C is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.C is optionally substituted sulfonyl. In certain embodiments, at least one instance of R.sup.C is optionally substituted sulfinyl. In certain embodiments, at least one instance of R.sup.C is —OR.sup.O. In certain embodiments, at least one instance of R.sup.C is —N(R.sup.N).sub.2. In certain embodiments, at least one instance of R.sup.C is or —SR.sup.S. In certain embodiments, two R.sup.C bonded to the same carbon are taken together with the intervening atoms to form optionally substituted carbocyclyl. In certain embodiments, two R.sup.C bonded to the same carbon are taken together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, two R.sup.C bonded to the same carbon are joined together to form ═O.

[0246] In certain embodiments, each instance of R.sup.C is hydrogen.

[0247] As defined herein, each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.N is hydrogen. In certain embodiments, at least one instance of R.sup.N is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.N is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.N is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.N is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.N is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.N is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.N is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.N is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.N is optionally substituted sulfonyl. In certain embodiments, at least one instance of R.sup.N is optionally substituted sulfinyl. In certain embodiments, at least one instance of R.sup.N is a nitrogen protecting group. In certain embodiments, two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heteroaryl.

[0248] In certain embodiments, each instance of R.sup.N is hydrogen. In certain embodiments, at least one instance of R.sup.N is optionally substituted C.sub.1-6 alkyl. In certain embodiments, each instance of R.sup.N is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.N is unsubstituted C.sub.1-6 alkyl. In certain embodiments, each instance of R.sup.N is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.N is unsubstituted C.sub.1-3 alkyl. In certain embodiments, each instance of R.sup.N is unsubstituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.N is methyl. In certain embodiments, each instance of R.sup.N is methyl. In certain embodiments, each instance of R.sup.N is acetyl.

[0249] As defined herein, each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, at least one instance of R.sup.O is hydrogen. In certain embodiments, at least one instance of R.sup.O is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.O is optionally substituted methyl. In certain embodiments, at least one instance of R.sup.O is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.O is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.O is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.O is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.O is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.O is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.O is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.O is optionally substituted acetyl. In certain embodiments, at least one instance of R.sup.O is an oxygen protecting group.

[0250] In certain embodiments, each instance of R.sup.O is hydrogen.

[0251] As defined herein, each instance of R.sup.S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group. In certain embodiments, at least one instance of R.sup.S is hydrogen. In certain embodiments, at least one instance of R.sup.S is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.S is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.S is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.S is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.S is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.S is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.S is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.S is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.S is an oxygen protecting group.

[0252] In certain embodiments, each instance of R.sup.S is hydrogen.

L1, Y2, and L2

[0253] In certain embodiments,

##STR00099##

is represented by one of structures:

##STR00100##

In certain embodiments,

##STR00101##

is represented by structure:

##STR00102##

In certain embodiments,

##STR00103##

is represented by any one of structures:

##STR00104##

In certain embodiments,

##STR00105##

is represented by any one of the structures:

##STR00106##

In certain embodiments,

##STR00107##

is represented by one of structures:

##STR00108##

In certain embodiments,

##STR00109##

is represented by any one of structures:

##STR00110##

In certain embodiments,

##STR00111##

is represented by any one of structures:

##STR00112##

[0254] Yet other inventive compounds are represented by the following structures 1-22:

##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118##

and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

Pharmaceutical Compositions, Kits, and Administration

[0255] The present disclosure provides pharmaceutical compositions comprising a compound of Formula (I) or (II), or any one of compounds 1-22, 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 any one of compounds 1-22, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0256] In certain embodiments, an inventive compound, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is an amount effective for treating a proliferative disease (e.g., cancer) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a cardiovascular disease in a subject in need thereof. In certain embodiments, the effective amount is a prophylactically effective amount.

[0257] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing an inventive compound (also referred to as 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.

[0258] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0259] 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.

[0260] 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.

[0261] Non-limiting 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.

[0262] Non-limiting 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.

[0263] Non-limiting 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.

[0264] Non-limiting 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.

[0265] Non-limiting 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.

[0266] Non-limiting 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.

[0267] Non-limiting 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. Non-limiting 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.

[0268] Non-limiting 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. Non-limiting exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0269] Non-limiting 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.

[0270] Other non-limiting exemplary 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®.

[0271] Non-limiting 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.

[0272] Non-limiting exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0273] Non-limiting exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Non-limiting exemplary synthetic oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0274] Non-limiting exemplary 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, by way of non-limiting 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, non-limiting examples of which include 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, non-limiting examples of which include Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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, (0 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.

[0280] 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.

[0281] 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.

[0282] Dosage forms for topical and/or transdermal administration of an inventive compound 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.

[0283] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0284] 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.

[0285] 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. 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).

[0286] 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.

[0287] 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.

[0288] 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.

[0289] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other ophthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

[0290] 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.

[0291] Inventive compounds 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.

[0292] The inventive compounds and compositions can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0293] The exact amount of an inventive compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0294] 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.

[0295] An inventive compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including an inventive compound and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of an inventive compound and the additional pharmaceutical agent, but not both.

[0296] An inventive compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., a proliferative disease, e.g., cancer). Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0297] 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.

[0298] Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents. Non-limiting exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g. HERCEPTIN® (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX® (cetuximab), VECTIBIX® (panitumumab), RITUXAN® (rituximab), BEXXAR® (tositumomab)).

[0299] Non-limiting exemplary chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g. busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide), platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g. 5-fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g. cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g. 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g. verapamil), Ca.sup.2+ ATPase inhibitors (e.g. thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE®)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech™), SF1126 (Semafore) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethyl melamine.

[0300] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise an inventive compound or a pharmaceutical composition 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. Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., proliferative disease, e.g., cancer) in a subject in need thereof.

[0301] In certain embodiments, a kit described herein further includes instructions for using the kit and its component(s). A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., proliferative disease, e.g., cancer) in a subject in need thereof.

Methods of Treatment and Uses

[0302] The present disclosure also provides methods of using the inventive compounds and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the treatment and/or prevention of diseases or conditions. In certain embodiments, the disease or condition is a genetic disease, proliferative disease (e.g., cancer), a disease associated with angiogenesis, a neoplasm, inflammatory disease, autoimmune disease, liver disease, spleen disease, pulmonary disease, hematological disease, neurological disease, painful condition, psychiatric disorder, cardiovascular disease, or a metabolic disorder (e.g., a diabetic condition). In certain embodiments, the disease or condition is associated with overexpression and/or aberrant activity of a KDM (e.g., KDM3). In certain embodiments, the disease or condition is associated with overexpression of a KDM (e.g., KDM3). In certain embodiments, the disease or condition is associated with aberrant activity (e.g., increased activity) of a KDM (e.g., KDM3). In certain embodiments, the KDM is KDM3. In certain embodiments, the KDM is one or more of KDM2/7, KDM3, KDM4, KDM5, or KDM6. In certain embodiments, the KDM is one or more of KDM5A, KDM5B, or KDM5C. In certain embodiments, the KDM is one or more of KDM3A, KDM3B, or Jumonji domain containing 1C (JMJD1C).

[0303] Provided herein are methods for treating a proliferative disease (e.g., cancer) in a subject, the methods comprising administering to the subject a compound of Formula (I) or (II), or any one of compounds 1-22, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formulas (I) and (II), and compounds 1-22, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, or a pharmaceutical compositions thereof, for use in treating proliferative diseases (e.g., cancer) in a subject. Furthermore, also provided herein are uses of the compounds of Formulas (I) and (II), and compounds 1-22, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, or a pharmaceutical compositions thereof, for the manufacture of medicaments for treating proliferative diseases (e.g., cancer). In certain embodiments, the proliferative disease is a proliferative disease associated with overexpression and/or aberrant activity (e.g., increased activity) of a KDM (e.g., KDM3). In certain embodiments, the proliferative disease is a proliferative disease associated with the overexpression of a KDM (e.g., KDM3). In certain embodiments, the proliferative disease is a proliferative disease associated with aberrant activity (e.g., increased activity) of a KDM (e.g., KDM3).

[0304] In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, ovarian cancer, colon cancer, or colorectal cancer. In certain embodiments, the cancer is a carcinoma. In certain embodiments, the carcinoma is a carcinoma of the breast, liver, lung, pancreas, stomach, colon, or prostate. The cancer may be any other cancer described herein. In certain embodiments, the cancer is associated with overexpression and/or aberrant activity of a KDM (e.g., KDM3). In certain embodiments, the cancer associated with overexpression of a KDM (e.g., KDM3). In certain embodiments, the cancer is associated with aberrant activity (e.g., increased activity) of a KDM (e.g., KDM3 and/or KDM5).

[0305] Provided herein are methods for treating a cardiovascular disease in a subject, the methods comprising administering to the subject a compound of Formula (I) or (II), or any one of compounds 1-22, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formulas (I) and (II) and compounds 1-22, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, or a pharmaceutical compositions thereof, for use in treating cardiovascular diseases in a subject. Furthermore, also provided herein are uses of the compounds of Formulas (I) and (II), and compounds 1-22, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, or a pharmaceutical compositions thereof, for the manufacture of medicaments for treating cardiovascular diseases. In certain embodiments, the cardiovascular disease is associated with overexpression and/or aberrant activity of a KDM (e.g., KDM3). In certain embodiments, the cardiovascular disease is associated with overexpression of a KDM (e.g., KDM3). In certain embodiments, the cardiovascular disease is associated with aberrant activity (e.g., increased activity) of a KDM (e.g., KDM3).

[0306] In certain embodiments, the methods described herein comprise administering to a subject a therapeutically effective amount of a compound of Formula (I) or (II), or any one of compounds 1-22, 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, a therapeutically effective amount is an amount sufficient for treating a disease (e.g., proliferative disease (e.g., cancer) or cardiovascular disease). In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a proliferative disease (e.g., cancer). In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting the activity of a KDM (e.g., KDM3).

[0307] In certain embodiments, the methods described herein comprise administering to a subject a prophylactically effective amount compound of Formula (I) or (II), or any one of compounds 1-22, 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, a prophylactically effective amount is an amount sufficient for preventing a disease (e.g., proliferative disease or cardiovascular disease). In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing the recurrence of cancer in a subject. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting the activity of KDM (e.g., KDM3).

[0308] Also provided herein are methods of inhibiting the activity of a KDM (e.g., KDM3) comprising contacting the KDM enzyme with a compound of Formula (I) or (II), or any one of compounds 1-22, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formulas (I) and (II), and compounds 1-22, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in inhibiting the activity of a KDM (e.g., KDM3). Furthermore, also provided herein compounds of Formulas (I) and (II), and compounds 1-22, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in the manufacture of medicaments for inhibiting the activity of a KDM (e.g., KDM3). In certain embodiments, the inhibiting is in a subject, and the method or use comprises administering to the subject a compound of Formula (I) or (II), or any one of compounds 1-22, 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 inhibiting is in a biological sample, and the method or use comprises contacting the biological sample with a compound of Formula (I) or (II), or any one of compounds 1-22, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[0309] In certain embodiments, the KDM is a KDM1, KDM2, KDM3, KDM4, KDM5, or KDM6. In certain embodiments, the KDM is a KDM3. In certain embodiments, the KDM3 is KDM3A, KDM3B, or JMJD1C. In certain embodiments, the KDM3 is KDM3A. In certain embodiments, the KDM3 is KDM3B. In certain embodiments, the KDM3 is JMJD1C.

[0310] In certain embodiments, an inventive compound or pharmaceutical composition selectively inhibits one KDM over others. In certain embodiments, a compound or pharmaceutical composition described herein selectively inhibits KDM3. The selectivity of an inventive compound or pharmaceutical composition in inhibiting the activity of a KDM over a different histone demethylase (e.g., a different KDM) may be measured by the quotient of the IC.sub.50 value of the compound or pharmaceutical composition in inhibiting the activity of the different histone demethylase over the IC.sub.50 value of the compound or pharmaceutical composition in inhibiting the activity of the histone demethylase. The selectivity of a compound or pharmaceutical composition described herein for a histone demethylase (e.g., KDM (e.g., KDM3)) over a different histone demethylase may also be measured by the quotient of the K.sub.d value of an adduct of the inventive compound or pharmaceutical composition and the different protein over the K.sub.d value of an adduct of the compound or pharmaceutical composition and the histone demethylase. In certain embodiments, the selectivity is at least 2-fold, at least 3-fold, at least 5-fold, at least 10-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 300-fold, at least 500-fold, at least 1,000-fold, at least 3,000-fold, at least 5,000-fold, at least 10,000-fold, at least 30,000-fold, at least 50,000-fold, or at least 100,000-fold. In certain embodiments, the selectivity is not more than 100,000-fold, not more than 10,000-fold, not more than 1,000-fold, not more than 100-fold, not more than 10-fold, or not more than 2-fold. Combinations of the above-referenced ranges (e.g., at least 2-fold and not more than 10,000-fold) are also within the scope of the disclosure.

[0311] Also provided herein are methods of inducing apoptosis in a cell, the methods comprising contacting the cell with a compound of Formula (I) or (II), or any one of compounds 1-22, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formulas (I) and (II), and compounds 1-22, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in inducing apoptosis in a cell. Furthermore, also provided herein are uses of compounds of Formulas (I) and (II), and compounds 1-22, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for inducing apoptosis in a cell. In certain embodiments, the cell is in a subject, and the method or use comprises administering to the subject a compound of Formula (I) or (II), or any one of compounds 1-22, 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 cell is in a biological sample, and the method or use comprises contacting the biological sample with a compound of Formula (I) or (II), or any one of compounds 1-22, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[0312] In certain embodiments, the provided methods and uses comprise contacting a cell with an effective amount of an inventive compound, or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition, as described herein. The cell may be contacted in vitro or in vivo. In certain embodiments, the contacting is in vivo. In certain embodiments, the contacting is in vitro. In certain embodiments, the cell is a cancer cell.

EXAMPLES

[0313] These and other aspects of the present disclosure will be further appreciated upon consideration of the following Examples, which are intended to illustrate certain particular embodiments of the present disclosure but are not intended to limit its scope, as defined by the claims.

Example 1: KDM3 Alphascreen Assays

[0314] AlphaScreen assays were performed in 384-well plate format using white AlphaPlate™ (PerkinElmer®, USA), and transfer of pre-diluted compound (100 nL) was performed using a Janus® Workstation (PerkinElmer®, USA). All subsequent steps were carried out in assay buffer (50 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.5, 0.1% (wt/vol) bovine serum albumin (BSA) and 0.01% (vol/vol) Tween®20). In brief, 10 μL of assay buffer containing demethylase enzyme (2 nM Final) was pre-incubated for 15 min with dilutions of compound. The enzyme reaction was initiated by the addition of substrate (5 μL) consisting of L-ascorbic acid (100 μM Final), 2-oleoylglycerol (OG) (5 μM Final), FAS (10 μM Final) and histone H3(1-21)K9Me3-GGK Biotin (100 nM Final). The enzyme reaction was allowed to proceed for 30 minutes and was stopped by the addition of 5 μL of assay buffer containing ethylenediaminetetraacetic acid (EDTA) (40 mM) and NaCl (1,200 mM). The final concentration of DMSO was 1%. Streptavidin donor beads (0.08 mg/ml) and protein-A-conjugated acceptor beads (0.08 mg/ml) were preincubated for 1 h with antibody to methyl mark (300 ng/mL Final), and the presence of histone H3 product methyl mark was detected using the preincubated AlphaScreen™ beads (5 μL). Detection was allowed to proceed for 2 h at room temperature, and the assay plates were read on the EnVision® 2104 plate reader. Data were normalized to the (no-enzyme) control, and the IC.sub.50 values were determined via nonlinear regression curve fit using GraphPad Prism 7.

[0315] Results from KDM3B AlphaScreen™ assays are shown in Table 1 below. Data are expressed as IC.sub.50 (μM). 2,4-pyridinedicarboxylic acid (PDCA), shown below, was used as a standard:

##STR00119##

TABLE-US-00001 TABLE 1 KDM3B AlphaScreen ™ Assays Compound IC.sub.50 (μM) ASSAY 1 2,4 PDCA 6.02 JADA69 27.93 JADA84 52.99 JADA92 8.78 JADA94 (mixture of JADA94-1 and JADA94-2) 3.54 ASSAY 2 2,4 PDCA 8.22 JADA 92 13.69 JADA94 (mixture of JADA94-1 and JADA94-2) 8.03 ASSAY 3 JADA133 18.56 JADA142 (mixture of JADA142-1 and JADA142-2) 40.39 JADA143 (mixture of JADA143-1 and JADA143-2) 38.23 JADA144 (mixture of JADA144-1 and JADA144-2) 10 JADA146 (mixture of JADA146-1 and JADA146-2) 12.23 JADA147 (mixture of JADA147-1 and JADA 147-2) 113.1 JADA148 (mixture of JADA148-1 and JADA148-2) 8.87 JADA149 (mixture of JADA149-1 and JADA 149-2) 8.77 2,4 PDCA 4.54 ASSAY 4 KDM3-16 (mixture of KDM3-16-1 and KDM3-16-2) 30.08 KDM3-17 (mixture of KDM3-17-1 and KDM3-17-2) 39.2 2,4 PDCA 4.45 ASSAY 5 KDM3-18 (mixture of KDM3-18-1 and KDM3-18-2) 15.75 KDM3-19 (mixture of KDM3-19-1 and KDM3-19-2) 3.4 KDM3-23 4.78 KDM3-24 10.86 JADA 94 (mixture of JADA94-1 and JADA94-2) 3.53 2,4 PDCA 6.23 ASSAY 6 KDM3-26 74.32 KDM3-27 11.31 KDM3-31 9.43 2,4 PDCA 1.87 ASSAY 7 KDM3-31 8.26 KDM3-38 5.65 KDM3-39 10.92 JADA92 9.79 JADA94 (mixture of JADA94-1 and JADA94-2) 5.52 JADA144 (mixture of JADA144-1 and JADA144-2) 8.57 2,4 PDCA 3.2 ASSAY 8 KDM3-31 10.81 KDM3-39 19.23 KDM3-40 22.41 KDM3-41 49.39 KDM3-42 11.78 KDM3-43 61.01 KDM3-44 91.31 JADA94 (mixture of JADA94-1 and JADA94-2) 6.96 2,4 PDCA 5.22

[0316] The data illustrated in Table 1 show that inventive compounds, including JADA94 (mixture of JADA94-1 and JADA94-2), KDM3-19 (mixture of KDM3-19-1 and KDM3-19-2), and KDM3-23, are potent KDM3B inhibitors. Inventive compounds JADA94, KDM3-19 and KDM3-23 showed better IC.sub.50 than control compound 2,4, PDCA, indicating that they are strong KDM3 binders. Structure activity relationship (SAR) analysis results are also illustrated in Table 1.

TABLE-US-00002 TABLE 2 KDM3 AlphaScreen ™ Assays ASSAY 9 Compound IC.sub.50 (μM) JADA196 15.97 JADA201 24.34  5 7.65 11 33.59 KDM3-47 12.98 KDM3-51 13.99 KDM3-53 20.02 KDM3-56 8.83 KDM3-59 23.63 KDM3-60 34.96 JADA94 (mixture of 21.34 JADA94-1 and JADA94-2) 2,4 PDCA 13.82

[0317] The data illustrated in Table 2 show that inventive compounds, including compounds 5, 11, and KDM3-56, are potent KDM3A inhibitors. Inventive compounds 5, 11, and KDM3-56 showed better IC.sub.50 than control compound 2,4, PDCA, indicating that they are strong KDM3 binders. Structure activity relationship (SAR) analysis results are also illustrated in Table 2.

Example 2: Synthesis of Compounds

[0318] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures or methods known in the art. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures.

[0319] Non-limiting exemplary synthetic routes to compounds described herein are shown, below.

Example 2-1: Synthesis of 3-(4-(dimethylamino)phenyl)-N-(2-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)-4-fluorophenyl)propanamide (KDM3-23)

[0320] ##STR00120## ##STR00121##

##STR00122##

[0321] A mixture of SM-1 (356 mg, 1.00 mmol), SM-2 (181 mg, 1.1 mmol), BrettPhos Pd G3 catalyst (93 mg, 0.1 mmol), and K.sub.2CO.sub.3 (345 mg, 2.5 mmol) in THF (3 mL) was stirred in a 10-mL flask under N.sub.2 atmosphere at 65° C. for 16 hours (h). After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified via ISCO chromatography (DCM/MeOH=20/1) to give the Int-1 (210 mg, 53% yield).

##STR00123##

[0322] A solution of Int-1 (210 mg, 0.52 mmol) in DCM (5 mL) and TFA (1.5 mL) in a 10-mL flask was stirred at 25° C. for 6 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was purified via ISCO chromatography (regular 12 g column, DCM/MeOH=10/1) to give the Int-2 (135 mg, 87% yield).

##STR00124##

[0323] To a solution of Int-2 (29.7 mg, 0.1 mmol) and SM-3 (17 mg, 0.11 mmol) in DMF (1 mL), DIPEA (64.5 mg, 0.5 mmol) and HATU (46.6 mg, 0.12 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (3 mL). The mixture was washed with H.sub.2O (3 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-80/20) to give Int-3 (23 mg, 55% yield).

##STR00125##

[0324] To a solution of Int-3 (23 mg, 0.05 mmol) and SM-4 (10.5 mg, 0.06 mmol) in DMF (0.5 mL), N,N-diisopropylethylamine (DIPEA) (27.8 mg, 0.2 mmol) and 1-[bis (dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU) (24 mg, 0.06 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (2 mL). The mixture was washed with H.sub.2O (2 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-90/10) to give KDM3-23 (12 mg, 40% yield).

Example 2-2: Synthesis of 3-(4-(dimethylamino)phenyl)-N-(2-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)-5-fluorophenyl)propanamide (KDM3-51

[0325] ##STR00126##

[0326] KDM3-51 was prepared in an analogous manner to KDM3-23 in Example 2-1 (11.6 mg, 37% yield).

Example 2-3: Synthesis of methyl 4-(3-(4-(dimethylamino)phenyl)propanamido)-3-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzoate (KDM3-52)

[0327] ##STR00127##

[0328] KDM3-52 was prepared in an analogous manner to KDM3-23 in Example 2-1 (11 mg, 35% yield).

Example 2-4: 3-(4-(dimethylamino)phenyl)-N-(2-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)-4-(trifluoromethyl)phenyl)propanamide (KDM3-53)

[0329] ##STR00128##

[0330] KDM3-53 was prepared in an analogous manner to KDM3-23 in Example 2-1 (10 mg, 30% yield).

Example 2-5: Synthesis of 3-(4-(dimethylamino)phenyl)-N-(2-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)-4-(trifluoromethoxy)phenyl)propanamide (KDM3-59)

[0331] ##STR00129##

[0332] KDM3-59 was prepared in an analogous manner to KDM3-23 in Example 2-1 (7.3 mg, 18% yield).

Example 2-6: Synthesis of 3-(4-(dimethylamino)phenyl)-N-(3-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)naphthalen-2-yl)propanamide (KDM3-69)

[0333] ##STR00130##

[0334] KDM3-69 was prepared in an analogous manner to KDM3-23 in Example 2-1 (5.3 mg, 11% yield).

Example 2-7: Synthesis of 3-(4-(dimethylamino)phenyl)-N-(2-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)pyridin-3-yl)propanamide (KDM3-76)

[0335] ##STR00131##

[0336] KDM3-76 was prepared in an analogous manner to KDM3-23 in Example 2-1 (6.0 mg, 10% yield).

Example 2-8: Synthesis of N-(4-(dimethylamino)phenethyl)-2-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)-4-fluorobenzamide (JADA94-1) and N-(4-(dimethylamino)phenethyl)-2-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)-5-fluorobenzamide (JADA94-2)

[0337] ##STR00132##

##STR00133##

[0338] To a solution of Int-2 (29.7 mg, 0.1 mmol) and SM-5 (17 mg, 0.11 mmol) in MeCN (1 mL), TEA (50.5 mg, 0.5 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to concentration of crude mixture under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-80/20) to give Int-4 (35 mg, 75% yield).

##STR00134##

[0339] To a solution of Int-4 (23 mg, 0.05 mmol) and SM-6 (9.8 mg, 0.06 mmol) in DMF (0.5 mL), DIPEA (27.8 mg, 0.2 mmol) and HATU (24 mg, 0.06 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (2 mL). The mixture was washed with H.sub.2O (2 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-90/10) to give a mixture of JADA94-1 and JADA94-2 (10.6 mg, 35% yield).

Example 2-9: Synthesis of N-(4-(dimethylamino)phenethyl)-2-(4-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)-4-fluorobenzamide (JADA142-1) and N-(4-(dimethylamino)phenethyl)-2-(4-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)-5-fluorobenzamide (JADA142-2)

[0340] ##STR00135##

[0341] JADA142-1 and JADA142-2 were prepared as a mixture in an analogous manner to JADA94-1 and JADA94-2 in Example 2-8 (9.3 mg, 33% yield).

Example 2-10: Synthesis of N-(4-(dimethylamino)phenethyl)-4-fluoro-2-(4-((5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (JADA143-1) and N-(4-(dimethylamino)phenethyl)-5-fluoro-2-(4-((5-(4-(methylsulfonyl)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (JADA143-2)

[0342] ##STR00136##

[0343] JADA143-1 and JADA143-2 were prepared as a mixture in an analogous manner to JADA94-1 and JADA94-2 in Example 2-8 (7.3 mg, 21% yield).

Example 2-11: Synthesis of N-(4-(dimethylamino)phenethyl)-4-fluoro-2-(4-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (JADA144-1) and N-(4-(dimethylamino)phenethyl)-5-fluoro-2-(4-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (JADA144-2)

[0344] ##STR00137##

[0345] JADA144-1 and JADA144-2 were prepared as a mixture in an analogous manner to JADA94-1 and JADA94-2 in Example 2-8 (9.3 mg, 29% yield).

Example 2-12: Synthesis of N-(4-(dimethylamino)phenethyl)-4-fluoro-2-(4-((5-(4-(morpholinomethyl)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (JADA146-1) and N-(4-(dimethylamino)phenethyl)-5-fluoro-2-(4-((5-(4-(morpholinomethyl)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (JADA146-2)

[0346] ##STR00138##

[0347] JADA146-1 and JADA146-2 were prepared as a mixture in an analogous manner to JADA94-1 and JADA94-2 in Example 2-8 (12.1 mg, 36% yield).

Example 2-13: Synthesis of N-(4-(dimethylamino)phenethyl)-4-fluoro-2-(4-((5-(2-(trifluoromethoxy)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (JADA148-1) and N-(4-(dimethylamino)phenethyl)-5-fluoro-2-(4-((5-(2-(trifluoromethoxy)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (JADA148-2)

[0348] ##STR00139##

[0349] JADA148-1 and 2 were prepared as a mixture in an analogous manner to JADA94-1 and JADA94-2 in Example 2-8 (8.1 mg, 26% yield).

Example 2-14: Synthesis of N-(4-(dimethylamino)phenethyl)-4-fluoro-2-(4-((5-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (JADA149-1) and N-(4-(dimethylamino)phenethyl)-5-fluoro-2-(4-((5-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (JADA149-2)

[0350] ##STR00140##

[0351] JADA149-1 and JADA149-2 were prepared as a mixture in an analogous manner to JADA94-1 and JADA94-2 in Example 2-8 to (8.3 mg, 28% yield).

Example 2-15: Synthesis of N-(4-(dimethylamino)phenethyl)-4-fluoro-2-(4-((5-morpholinopyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide(KDM3-16-1) and N-(4-(dimethylamino)phenethyl)-5-fluoro-2-(4-((5-morpholinopyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (KDM3-16-2)

[0352] ##STR00141##

[0353] KDM3-16-1 and KDM3-16-2 were prepared as a mixture in an analogous manner to JADA94-1 and JADA94-2 in Example 2-8 (11.5 mg, 40% yield).

Example 2-16: Synthesis of N-(4-(dimethylamino)phenethyl)-2-(4-((5-(dimethylamino)pyridin-2-yl)oxy)piperidine-1-carbonyl)-4-fluorobenzamide (KDM3-17-1) and N-(4-(dimethylamino)phenethyl)-2-(4-((5-(dimethylamino)pyridin-2-yl)oxy)piperidine-1-carbonyl)-5-fluorobenzamide (KDM3-17-2)

[0354] ##STR00142##

[0355] KDM3-17-1 and KDM3-17-2 were prepared as a mixture in an analogous manner to JADA94-1 and JADA94-2 in Example 2-8 (13.5 mg, 50% yield).

Example 2-17: Synthesis of ethyl 4-((4-(dimethylamino)phenethyl)carbamoyl)-3-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzoate (KDM3-19-1) and ethyl 3-((4-(dimethylamino)phenethyl)carbamoyl)-4-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzoate (KDM3-19-2)

[0356] ##STR00143##

[0357] KDM3-19-1 and KDM3-19-2 were prepared as a mixture in an analogous manner to JADA94-1 and JADA94-2 in Example 2-8 (12.5 mg, 38% yield).

Example 2-18: Synthesis of N-(4-(dimethylamino)phenethyl)-4-fluoro-2-(4-((5-(4-(phenoxymethyl)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (KDM3-45-1)N-(4-(dimethylamino)phenethyl)-5-fluoro-2-(4-((5-(4-(phenoxymethyl)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (KDM3-45-2)

[0358] ##STR00144##

[0359] KDM3-45-1 and KDM3-45-2 were prepared as a mixture in an analogous manner to JADA94-1 and JADA94-2 in Example 2-8 (10.1 mg, 30% yield).

Example 2-19: Synthesis of N-(3-(4-(dimethylamino)phenyl)propyl)-2-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)-4-fluorobenzamide (KDM3-56-1) and N-(3-(4-(dimethylamino)phenyl)propyl)-2-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)-5-fluorobenzamide (KDM3-56-2)

[0360] ##STR00145##

[0361] KDM3-56-1 and KDM3-56-2 were prepared as a mixture in an analogous manner to JADA94-1 and JADA94-2 in Example 2-8 (9.6 mg, 31% yield).

Example 2-20: Synthesis of N-(4-(dimethylamino)phenethyl)-4-fluoro-2-(4-((5-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (KDM3-68-1) and N-(4-(dimethylamino)phenethyl)-5-fluoro-2-(4-((5-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzamide (KDM3-68-2)

[0362] ##STR00146##

[0363] KDM3-68-1 and KDM3-68-2 were prepared as a mixture in an analogous manner to JADA94-1 and JADA94-2 in Example 2-8 to (12.0 mg, 36% yield).

Example 2-21: Synthesis of (R)—N-(4-(dimethylamino)phenethyl)-4-fluoro-2-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidine-1-carbonyl)benzamide (KDM3-35-1) and (R)—N-(4-(dimethylamino)phenethyl)-5-fluoro-2-(3-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidine-1-carbonyl)benzamide(KDM3-35-2)

[0364] ##STR00147##

##STR00148##

[0365] To a solution of SM-7 (23.2 mg, 0.1 mmol) and SM-5 (17 mg, 0.11 mmol) in MeCN (1 mL), TEA (50.5 mg, 0.5 mmol) was added. The reaction was stirred at 25° C. for 6 h prior to concentration of crude mixture under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-70/30) to give Int-5 (31 mg, 79% yield).

##STR00149##

[0366] To a solution of Int-5 (19 mg, 0.05 mmol) and SM-6 (9.8 mg, 0.06 mmol) in DMF (0.5 mL), DIPEA (27.8 mg, 0.2 mmol) and HATU (24 mg, 0.06 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (2 mL). The mixture was washed with H.sub.2O (2 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-90/10) to give a mixture of KDM35-1 and KDM35-2 (13.6 mg, 51% yield).

Example 2-22: Synthesis of (S)—N-(4-(dimethylamino)phenethyl)-4-fluoro-2-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidine-1-carbonyl)benzamide (KDM3-36-1) and (S)—N-(4-(dimethylamino)phenethyl)-5-fluoro-2-(3-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidine-1-carbonyl)benzamide(KDM3-36-2)

[0367] ##STR00150##

[0368] KDM3-36-1 and KDM3-36-2 were prepared as a mixture in an analogous manner to KDM3-35-1 and KDM3-35-2 in Example 2-21 (13.0 mg, 35% yield).

Example 2-23: Synthesis of N-(4-(dimethylamino)phenethyl)-4-fluoro-2-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)azetidine-1-carbonyl)benzamide (KDM3-37-1) and N-(4-(dimethylamino)phenethyl)-5-fluoro-2-(3 #5-(trifluoromethyl)pyridin-2-yl)oxy)azetidine-1-carbonyl)benzamide (KDM3-37-2)

[0369] ##STR00151##

[0370] KDM3-37-1 and KDM3-37-2 were prepared as a mixture in an analogous manner to KDM3-35-1 and KDM3-35-2 in Example 2-21 (10.0 mg, 34% yield).

Example 2-24: Synthesis of 3-(4-(dimethylamino)phenyl)-N-(4-fluoro-2-(4-((4-morpholinopyridin-2-yl)oxy)piperidine-1-carbonyl)phenyl)propanamide (KDM3-26)

[0371] ##STR00152##

##STR00153##

[0372] To a solution of SM-8 (26.3 mg, 0.1 mmol) and SM-3 (17 mg, 0.11 mmol) in DMF (1 mL), DIPEA (64.5 mg, 0.5 mmol) and HATU (46.6 mg, 0.12 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (3 mL). The mixture was washed with H.sub.2O (3 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-85/15) to give Int-6 (24 mg, 60% yield).

##STR00154##

[0373] To a solution of Int-6 (20 mg, 0.05 mmol) and SM-4 (10.5 mg, 0.06 mmol) in DMF (0.5 mL), DIPEA (27.8 mg, 0.2 mmol) and HATU (24 mg, 0.06 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (2 mL). The mixture was washed with H.sub.2O (2 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-90/10) to give KDM3-26 (9.5 mg, 36% yield).

Example 2-25: Synthesis of 3-(4-(dimethylamino)phenyl)-N-(4-fluoro-2-(4-((4-(piperidin-1-yl)pyridin-2-yl)oxy)piperidine-1-carbonyl)phenyl)propanamide (KDM3-27)

[0374] ##STR00155##

[0375] KDM3-27 was prepared in an analogous manner to KDM3-26 in Example 2-24 (12.6 mg, 44% yield).

Example 2-26: Synthesis of ethyl 4-amino-3-(4-((4-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzoate (KDM3-31)

[0376] ##STR00156##

##STR00157##

[0377] Int-7 was prepared in an analogous manner to Int-2 in Example 2-1 (131 mg, 85% yield).

##STR00158##

[0378] To a solution of Int-7 (20 mg, 0.05 mmol) and SM-10 (12.5 mg, 0.06 mmol) in DMF (0.5 mL), DIPEA (27.8 mg, 0.2 mmol) and HATU (24 mg, 0.06 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (2 mL). The mixture was washed with H.sub.2O (2 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-80/20) to give KDM3-31 (12.5 mg, 50% yield).

Example 2-27: Synthesis of ethyl 4-amino-3-(4-((4-(dimethylamino)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzoate (KDM3-32)

[0379] ##STR00159##

[0380] KDM3-32 was prepared in an analogous manner to KDM3-31 in Example 2-26 (6.3 mg, 33% yield).

Example 2-28: Synthesis of ethyl 4-amino-3-(4-((5-(dimethylamino)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzoate (KDM3-33)

[0381] ##STR00160##

[0382] KDM3-33 was prepared in an analogous manner to KDM3-31 in Example 2-26 (7.3 mg, 35% yield).

Example 2-29: Synthesis of (4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidin-1-yl)(2-nitrophenyl)methanone (KDM3-39)

[0383] ##STR00161##

##STR00162##

[0384] To a solution of Int-2 (15 mg, 0.05 mmol) and SM-10 (9.1 mg, 0.06 mmol) in DMF (0.5 mL), DIPEA (27.8 mg, 0.2 mmol) and HATU (24 mg, 0.06 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (2 mL). The mixture was washed with H.sub.2O (2 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-80/20) to give KDM3-31 (2.5 mg, 12% yield).

Example 2-30: Synthesis of N-(3-amino-4-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)phenyl)acetamide (KDM3-40)

[0385] ##STR00163##

[0386] KDM3-40 was prepared in an analogous manner to KDM3-39 in Example 2-29 (5.4 mg, 23% yield).

Example 2-31: Synthesis of (3-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)azetidin-1-yl)(2-nitrophenyl)methanone (KDM3-42)

[0387] ##STR00164##

[0388] KDM3-42 was prepared in an analogous manner to KDM3-39 in Example 2-29 (3.1 mg, 15% yield).

Example 2-32: Synthesis of (3-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)azetidin-1-yl)(2-nitrophenyl)methanone (KDM3-44)

[0389] ##STR00165##

[0390] KDM3-44 was prepared in an analogous manner to KDM3-39 in Example 2-29 (3.7 mg, 19% yield).

Example 2-33: Synthesis of 4-amino-3-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzoic acid (KDM3-41)

[0391] ##STR00166##

##STR00167##

[0392] Int-8 was prepared in an analogous manner to KDM3-31 in Example 2-26 (12.6 mg, 28% yield).

##STR00168##

[0393] To a solution of Int-8 (9.5 mg, 0.02 mmol) in a 1:1:1 mixture of THF/MeOH/H2O (1.5 mL), KOH (5.6 mg, 0.1 mmol) was added. The solution was stirred at 25° C. for 24 h. After pH adjustment (pH 4-5) with HCl (1M), the resulting mixture was extracted with EtOAc (1 mL×3) and concentrated under reduced pressure. The crude product was purified by ISCO (CH.sub.2Cl.sub.2/MeOH=100/0˜70/30) to give KDM3-41 (4.6 mg, yield 50%).

Example 2-34: Synthesis of 4-amino-3-(4-((4-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)benzoic acid (KDM3-43)

[0394] ##STR00169##

[0395] KDM3-43 was prepared in an analogous manner to KDM3-41 in Example 2-33 (4.2 mg, 40% yield).

Example 2-35: Synthesis of (Z)-N-(4-(dimethylamino)phenethyl)-4-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidin-1-yl)-4-oxobut-2-enamide (KDM3-38)

[0396] ##STR00170##

##STR00171##

[0397] To a solution of Int-2 (29.7 mg, 0.1 mmol) and SM-12 (10.8 mg, 0.11 mmol) in MeCN (1 mL), TEA (50.5 mg, 0.5 mmol) was added. The reaction was stirred at 25° C. for 6 h prior to concentration of crude mixture under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-70/30) to give Int-9 (31 mg, 80% yield).

##STR00172##

[0398] To a solution of Int-9 (19.5 mg, 0.05 mmol) and SM-6 (9.6 mg, 0.06 mmol) in DMF (0.5 mL), DIPEA (27.8 mg, 0.2 mmol) and HATU (24 mg, 0.06 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (2 mL). The mixture was washed with H.sub.2O (2 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-90/10) to give KDM3-38 (9.5 mg, 35% yield).

Example 2-36: Synthesis of (Z)-4-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidin-1-yl)-N-((1-methylpiperidin-4-yl)methyl)-4-oxobut-2-enamide (KDM3-46)

[0399] ##STR00173##

[0400] KDM3-46 was prepared in an analogous manner to KDM3-38 in Example 2-35 (10.2 mg, 40% yield).

Example 2-37: Synthesis of (Z)-N-(4-(dimethylamino)benzyl)-4-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidin-1-yl)-4-oxobut-2-enamide (KDM3-47)

[0401] ##STR00174##

[0402] KDM3-47 was prepared in an analogous manner to KDM3-38 in Example 2-35 (8.4 mg, 32% yield).

Example 2-38: Synthesis of (Z)-N-(2-(dimethylamino)ethyl)-4-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidin-1-yl)-4-oxobut-2-enamide (KDM3-48)

[0403] ##STR00175##

[0404] KDM3-48 was prepared in an analogous manner to KDM3-38 in Example 2-35 (6.9 mg, 31% yield).

Example 2-39: Synthesis of (Z)-N-(2-(dimethylamino)ethyl)-4-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidin-1-yl)-N-ethyl-4-oxobut-2-enamide (KDM3-49)

[0405] ##STR00176##

[0406] KDM3-49 was prepared in an analogous manner to KDM3-38 in Example 2-35 (7.9 mg, 34% yield).

Example 2-40: Synthesis of (Z)-4-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidin-1-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-4-oxobut-2-enamide (KDM3-50)

[0407] ##STR00177##

[0408] KDM3-50 was prepared in an analogous manner to KDM3-38 in Example 2-35 (7.3 mg, 28% yield).

Example 2-41: Synthesis of N-(4-(dimethylamino)phenethyl)-4-oxo-4-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)butanamide (JADA69)

[0409] ##STR00178##

##STR00179##

[0410] To a solution of SM-13 (24.6 mg, 0.1 mmol) and SM-14 (11.2 mg, 0.11 mmol) in MeCN (1 mL), TEA (50.5 mg, 0.5 mmol) was added. The reaction was stirred at 25° C. for 6 h prior to concentration of crude mixture under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-70/30) to give Int-10 (35 mg, 85% yield).

##STR00180##

[0411] To a solution of Int-10 (19.5 mg, 0.05 mmol) and SM-6 (9.6 mg, 0.06 mmol) in DMF (0.5 mL), DIPEA (27.8 mg, 0.2 mmol) and HATU (24 mg, 0.06 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (2 mL). The mixture was washed with H.sub.2O (2 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-85/15) to give JADA69 (9.6 mg, 39% yield).

Example 2-42: Synthesis of N-(4-(dimethylamino)phenethyl)-4-(4-((4-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidin-1-yl)-4-oxobutanamide (JADA84)

[0412] ##STR00181##

[0413] JADA84 was prepared in an analogous manner to JADA69 in Example 2-41 (11.3 mg, 41% yield).

Example 2-43: Synthesis of N-(4-(dimethylamino)phenethyl)-4-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidin-1-yl)-4-oxobutanamide (JADA92)

[0414] ##STR00182##

[0415] JADA92 was prepared in an analogous manner to JADA69 in Example 2-41 (9.7 mg, 36% yield).

Example 2-44: Synthesis of N-(4-(dimethylamino)phenethyl)-4-oxo-4-(4-((5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl) amino)piperidin-1-yl)butanamide (JADA112)

[0416] ##STR00183##

[0417] JADA112 was prepared in an analogous manner to JADA69 in Example 2-41 (9.0 mg, 31% yield).

Example 2-45: Synthesis of 3-(4-bromophenyl)-N-(2-(4-((5-bromopyridin-2-yl)oxy)piperidine-1-carbonyl)-4-fluorophenyl)propanamide (KDM3-20)

[0418] ##STR00184##

##STR00185##

[0419] To a solution of SM-15 (25.6 mg, 0.1 mmol) and SM-3 (17 mg, 0.11 mmol) in DMF (1 mL), DIPEA (64.5 mg, 0.5 mmol) and HATU (46.6 mg, 0.12 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (3 mL). The mixture was washed with H.sub.2O (3 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-90/10) to give Int-11 (24 mg, 61% yield).

##STR00186##

[0420] To a solution of Int-11 (20 mg, 0.05 mmol) and SM-16 (13.5 mg, 0.06 mmol) in DMF (0.5 mL), DIPEA (27.8 mg, 0.2 mmol) and HATU (24 mg, 0.06 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (2 mL). The mixture was washed with H.sub.2O (2 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under vacuum. The residue was purified by ISCO (DCM/MeOH=100/0-90/10) to give KDM3-20 (9.6 mg, 32% yield).

Example 2-46: Synthesis of N-(2-(4-((5-bromopyridin-2-yl)oxy)piperidine-1-carbonyl)-4-fluorophenyl)-3-(p-tolyl)propanamide (KDM3-21)

[0421] ##STR00187##

[0422] KDM3-21 was prepared in an analogous manner to KDM3-20 in Example 2-45 (10.2 mg, 38% yield).

Example 2-47: Synthesis of N-(2-(4-((5-bromopyridin-2-yl)oxy)piperidine-1-carbonyl)-4-fluorophenyl)-3-(pyridin-3-yl)propanamide (KDM3-22)

[0423] ##STR00188##

[0424] KDM3-22 was prepared in an analogous manner to KDM3-20 in Example 2-45 (10.2 mg, 38% yield).

Example 2-48: Synthesis of (2-((4-(dimethylamino)benzyl)amino)-5-fluorophenyl)(4-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)oxy)piperidin-1-yl)methanone (KDM3-64)

[0425] ##STR00189##

##STR00190##

[0426] To a solution of SM-17 (25.6 mg, 0.1 mmol) and SM-3 (17 mg, 0.11 mmol) in DMF (1 mL), DIPEA (64.5 mg, 0.5 mmol) and HATU (46.6 mg, 0.12 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (3 mL). The mixture was washed with H.sub.2O (3 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-90/10) to give Int-12 (26.6 mg, 65% yield).

##STR00191##

[0427] A solution of Int-12 (8.2 mg, 0.02 mmol) and SM-18 (2.9 mg, 0.025 mmol) in CH.sub.2Cl.sub.2 (1 mL) was stirred at 25° C. for 3 h prior to addition of NaBH(AcO).sub.3 (6.3 mg, 0.03 mmol) in portions. The reaction was stirred at 25° C. for 9 h. The crude mixture was concentrated under reduced pressure, and the resulting residue was purified by ISCO (CH.sub.2Cl.sub.2/MeOH=100/0˜80/20) to give KDM3-64 (8.1 mg, 71% yield).

Example 2-49: Synthesis of (2-((4-(dimethylamino)benzyl)amino)-5-fluorophenyl)(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidin-1-yl)methanone (KDM3-65)

[0428] ##STR00192##

[0429] KDM3-65 was prepared in an analogous manner to KDM3-64 in Example 2-48 (7.8 mg, 69% yield).

Example 2-50: Synthesis of (4-((5-bromopyridin-2-yl)oxy)piperidin-1-yl)(2-((4-(dimethylamino)benzyl)amino)-5-fluorophenyl)methanone (KDM3-66)

[0430] ##STR00193##

[0431] KDM3-66 was prepared in an analogous manner to KDM3-64 in Example 2-48 (8.1 mg, 77% yield).

Example 2-51: Synthesis of (2-((2,4-dihydroxybenzyl)amino)-5-fluorophenyl)(4-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)oxy)piperidin-1-yl)methanone (KDM3-67)

[0432] ##STR00194##

[0433] KDM3-67 was prepared in an analogous manner to KDM3-64 in Example 2-48 (2.1 mg, 21% yield).

Example 2-52: Synthesis of 4-(6-((1-(2-((4-(dimethylamino)benzyl)amino)-5-fluorobenzoyl)piperidin-4-yl)oxy)pyridin-3-yl)-N,N-dimethylbenzamide (KDM3-68)

[0434] ##STR00195##

[0435] KDM3-68 was prepared in an analogous manner to KDM3-64 in Example 2-48 (4.9 mg, 46% yield).

Example 2-53: Synthesis of 2-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)phenyl 2-hydroxybenzoate (JADA196)

[0436] ##STR00196##

##STR00197##

[0437] To a solution of Int-2 (29.7 mg, 0.1 mmol) and SM-19 (14.5 mg, 0.11 mmol) in DMF (1 mL), DIPEA (64.5 mg, 0.5 mmol) and HATU (46.6 mg, 0.12 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (3 mL). The mixture was washed with H.sub.2O (3 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-80/20) to give Int-13 (21.6 mg, 51% yield).

##STR00198##

[0438] To a solution of Int-13 (20.8 mg, 0.05 mmol) and SM-19 (7.9 mg, 0.06 mmol) in DMF (0.5 mL), DIPEA (27.8 mg, 0.2 mmol) and HATU (24 mg, 0.06 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (2 mL). The mixture was washed with H.sub.2O (2 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-90/10) to give JADA196 (8.8 mg, 33% yield).

Example 2-54: Synthesis of 2-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)phenyl morpholine-4-carboxylate (JADA200)

[0439] ##STR00199##

##STR00200##

[0440] Int-13 was prepared in an analogous manner to JADA196 in Example 2-53 (21.6 mg, 51% yield).

##STR00201##

[0441] To a solution of Int-13 (20.9 mg, 0.05 mmol) and SM-20 (8.1 mg, 0.06 mmol) in MeCN (1 mL), TEA (50.5 mg, 0.5 mmol) was added. The reaction was stirred at 25° C. for 12 h prior to concentration of crude mixture under vacuum. The resulting residue was purified by ISCO (DCM/MeOH=100/0-80/20) to give JADA200 (12.2 mg, yield 46%).

Example 2-55: Synthesis of 2-((2-(4-((5-(4-(dimethylamino)phenyl)pyridin-2-yl)oxy)piperidine-1-carbonyl)phenoxy)carbonyl)phenyl morpholine-4-carboxylate (JADA201)

[0442] ##STR00202##

[0443] Int-13 was prepared in an analogous manner to JADA200 in Example 2-54 (2.14 mg, 33% yield).

Example 2-56: Synthesis of methyl 6-((1-(5-fluoro-2-(morpholine-4-carboxamido)benzoyl)piperidin-4-yl)oxy)nicotinate (JADA210)

[0444] ##STR00203##

[0445] JADA210 was prepared in an analogous manner to JADA200 in Example 2-54 (1.94 mg, 40% yield).

Example 2-57: Synthesis of methyl 6-((1-(5-fluoro-2-(morpholine-4-carboxamido)benzoyl)piperidin-4-yl)oxy)nicotinate (JADA236)

[0446] ##STR00204##

[0447] JADA236 was prepared in an analogous manner to JADA196 in Example 2-53 (1.19 mg, 21% yield).

Example 2-58: Synthesis of (2-((4-(dimethylamino)benzyl)amino)-5-fluorophenyl)(4-(4-(dimethylamino)benzyl)piperazin-1-yl)methanone (5)

[0448] ##STR00205##

##STR00206##

[0449] To a solution of SM-3 (155.0 mg, 1 mmol) and SM-21 (204.5 mg, 1.1 mmol) in DMF (1.5 mL), DIPEA (645 mg, 5 mmol) and HATU (466 mg, 1.2 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (5 mL). The mixture was washed with H.sub.2O (5 mL), and the aqueous phase was extracted with additional EtOAc (2×3 mL). The combined organic phases were concentrated under reduced pressure. The residue was purified by ISCO (DCM/MeOH=100/0-80/20) to give Int-14 (171.6 mg, 53% yield).

##STR00207##

[0450] A solution of Int-14 (161 mg, 0.5 mmol) in DCM (5 mL) and TFA (1.5 mL) in a 10-mL flask was stirred at 25° C. for 12 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was purified via ISCO chromatography (DCM/MeOH=100/0˜60/40) to give the Int-15 (92.5 mg, 83% yield).

##STR00208##

[0451] A solution of Int-15 (11.2 mg, 0.05 mmol) and SM-18 (22.4 mg, 0.15 mmol) in CH.sub.2Cl.sub.2 (2 mL) was stirred at 25° C. for 3 h prior to addition of NaBH(AcO).sub.3 (42.2 mg, 0.2 mmol) in portions. The solution was stirred at 25° C. for 9 h. The crude mixture was concentrated under reduced pressure, and the resulting residue was purified by ISCO (CH.sub.2Cl.sub.2/MeOH=100/0˜80/20) to give compound 5 (5.6 mg, 23% yield).

Example 2-59: Synthesis of (3-((4-(dimethylamino)benzyl)amino)pyridin-2-yl)(4-(4-(dimethylamino)benzyl)piperazin-1-yl)methanone (15)

[0452] ##STR00209##

[0453] Compound 15 was prepared in an analogous manner to compound 5 in Example 2-58 (3.7 mg, yield 16%).

Example 2-60: Synthesis of (3-((4-(dimethylamino)benzyl)amino)thiophen-2-yl)(4-(4-(dimethylamino)benzyl)piperazin-1-yl)methanone (16)

[0454] ##STR00210##

[0455] Compound 16 was prepared in an analogous manner to compound 5 in Example 2-58 (2.6 mg, yield 11% yield).

Example 2-61: Synthesis of 2-(4-(4-(dimethylamino)benzyl)piperazine-1-carbonyl)-N-(4-(dimethylamino)phenethyl)-4-fluorobenzamide (7) and 2-(4-(4-(dimethylamino)benzyl)piperazine-1-carbonyl)-N-(4-(dimethylamino)phenethyl)-5-fluorobenzamide (8)

[0456] ##STR00211##

##STR00212##

[0457] A solution of SM-18 (1.49 g, 10 mmol) and SM-22 (2.58 g, 30 mmol) in CH.sub.2Cl.sub.2 (50 mL) was stirred at 25° C. for 3 h prior to addition of NaBH(AcO).sub.3 (4.22 g, 20 mmol) in portions. The reaction was stirred at 25° C. for 9 h. The crude mixture was concentrated under reduced pressure, and the resulting residue was purified by ISCO (CH.sub.2Cl.sub.2/MeOH=100/0˜60/40) to give Int-16 (1.42 g, 65% yield).

##STR00213##

[0458] To a solution of Int-16 (24.6 mg, 0.1 mmol) and SM-5 (18.2 mg, 0.11 mmol) in MeCN (1 mL), TEA (50.5 mg, 0.5 mmol) was added. The reaction was stirred at 25° C. for 6 h. The crude mixture was concentrated under reduced pressure, and the resulting residue was purified by ISCO (DCM/MeOH=100/0˜70/30) to give Int-17 (36.1 mg, 86% yield).

##STR00214##

[0459] To a solution of Int-17 (21.0 mg, 0.05 mmol) and SM-6 (18.0 mg, 0.06 mmol) in DMF (0.5 mL), DIPEA (64.5 mg, 0.5 mmol) and HATU (46.6 mg, 0.12 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (2 mL). The mixture was washed with H.sub.2O (2 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-80/20) to give a mixture of compounds 7 and 8 (7.2 mg, 29% yield).

Example 2-62: Synthesis of 2-(4-(4-(dimethylamino)benzyl)piperazine-1-carbonyl)-N-(3-(4-(dimethylamino)phenyl)propyl)-4-fluorobenzamide (9) and 2-(4-(4-(dimethylamino)benzyl)piperazine-1-carbonyl)-N-(3-(4-(dimethylamino)phenyl)propyl)-5-fluorobenzamide (10)

[0460] ##STR00215##

[0461] Compounds 9 and 10 were prepared in an analogous manner to compounds 7 and 8 in Example 2-61 (6.2 mg, 25% yield).

Example 2-63: Synthesis of (2-((2,4-diisopropoxybenzyl)amino)-5-fluorophenyl)(4-(4-(dimethylamino)benzyl)piperazin-1-yl)methanone (13)

[0462] ##STR00216##

##STR00217##

[0463] To a solution of Int-16 (21.3 mg, 0.1 mmol) and SM-3 (17.5 mg, 0.11 mmol) in DMF (0.5 mL), DIPEA (64.5 mg, 0.5 mmol) and HATU (46.6 mg, 0.12 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (3 mL). The mixture was washed with H.sub.2O (2 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-70/30) to give Int-18 (16.3 mg, 46% yield).

##STR00218##

[0464] A solution of Int-18 (10.6 mg, 0.03 mmol) and SM-23 (8.9 mg, 0.04 mmol) in CH.sub.2Cl.sub.2 (1 mL) was stirred at 25° C. for 3 h prior addition of NaBH(AcO).sub.3 (10.55 mg, 0.05 mmol) in portions. The reaction was stirred at 25° C. for 9 h. The crude mixture was concentrated under reduced pressure, and the resulting residue was purified by ISCO (CH.sub.2Cl.sub.2/MeOH=100/0˜90/10) to give compound 13 (3.9 mg, 21% yield).

Example 2-64: Synthesis of 4-(((2-(4-(4-(dimethylamino)benzyl)piperazine-1-carbonyl)-4-fluorophenyl)amino)methyl)-1,3-dimethyl-1,3-dihydro-2H-imidazol-2-one (14)

[0465] ##STR00219##

[0466] Compound 14 was prepared in an analogous manner to compound 13 in Example 2-63 (3.7 mg, 23% yield).

Example 2-65: Synthesis of (2-((4-(dimethylamino)benzyl)amino)-5-fluorophenyl)(4-(3-((dimethylamino)methyl)-4-hydroxy benzyl)piperazin-1-yl)methanone (17)

[0467] ##STR00220##

[0468] Compound 17 was prepared in an analogous manner to compound 13 in Example 2-63 (1.73 mg, 11% yield).

Example 2-66: Synthesis of (2-((4-(dimethylamino)benzyl)amino)-5-fluorophenyl)(4-((4-(dimethylamino)benzyl)amino)piperidin-1-yl)methanone (18)

[0469] ##STR00221## ##STR00222##

##STR00223##

[0470] A solution of SM-18 (1.49 g, 10 mmol) and SM-24 (4.0 g, 20 mmol) in CH.sub.2Cl.sub.2 (30 mL) was stirred at 25° C. for 3 h prior to addition of NaBH(AcO).sub.3 (4.22 g, 20 mmol) in portions. The reaction was stirred at 25° C. for 9 h. The crude mixture was concentrated under reduced pressure, and the resulting residue was purified by ISCO (CH.sub.2Cl.sub.2/MeOH=100/0˜70/30) to give Int-19 (2.32 g, 70% yield).

##STR00224##

[0471] To a solution of Int-19 (1.66 g, 5 mmol) in THF: H.sub.2O (100 mL: 10 mL), NaHCO.sub.3 (0.86 g, 10 mmol) and FmocCl (1.54 g, 6 mmol) were added. The reaction was stirred at 25° C. for 16 h. The reaction mixture was evaporated under reduced pressure and then extracted with EA (50 mL×2). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (CH.sub.2Cl.sub.2/MeOH=100/0˜95/5) to afford Int-20 (1.94 g, 70% yield).

##STR00225##

[0472] A solution of Int-14 (555 mg, 1 mmol) in DCM (5 mL) and TFA (1.5 mL) in a 10-mL flask was stirred at 25° C. for 12 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was purified via ISCO chromatography (DCM/MeOH=100/0˜80/20) to give Int-21 (364.5 mg, 80% yield).

##STR00226##

[0473] To a solution of Int-21 (91.0 mg, 0.2 mmol) and SM-3 (23.5 mg, 0.15 mmol) in DMF (0.5 mL), DIPEA (64.5 mg, 0.5 mmol) and HATU (76.0 mg, 0.12 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (3 mL). The mixture was washed with H.sub.2O (2 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-70/30) to give Int-22 (58.3 mg, 65% yield).

##STR00227##

[0474] A solution of Int-22 (29.6 mg, 0.05 mmol) and SM-18 (8.9 mg, 0.06 mmol) in CH.sub.2Cl.sub.2 (1 mL) was stirred at 25° C. for 3 h prior to addition of NaBH(AcO).sub.3 (10.55 mg, 0.05 mmol) in portions. The reaction was stirred at 25° C. for 9 h. The crude mixture was concentrated under reduced pressure, and the resulting residue was purified by ISCO (CH.sub.2Cl.sub.2/MeOH=100/0˜90/10) to give Int-23 (25.7 mg, 71% yield).

##STR00228##

[0475] A solution of Int-23 (14.3 mg, 0.002 mmol) and piperidine (8.6 mg, 0.01 mmol) in DCM (2 mL) was stirred at 25° C. for 6 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was purified via ISCO chromatography (DCM/MeOH=100/0˜80/20) to give compound 18 (5.5 mg, 60% yield).

Example 2-67: Synthesis of N-(2-((4-(dimethylamino)benzyl)(methyl)amino)ethyl)-2-((4-(dimethylamino)benzyl)amino)-5-fluoro-N-methylbenzamide (19)

[0476] ##STR00229##

##STR00230##

[0477] To a solution of Int-3 (235.0 mg, 1.5 mmol) and SM-25 (264.5 mg, 3 mmol) in DMF (1.5 mL), DIPEA (129 mg, 10 mmol) and HATU (760 mg, 2 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (5 mL). The mixture was washed with H.sub.2O (5 mL), and the aqueous phase was extracted with additional EtOAc (2×3 mL). The combined organic phases were concentrated under reduced. The resulting residue was purified by ISCO (DCM/MeOH=100/0-60/40) to give Int-24 (212.3 mg, 63% yield).

##STR00231##

[0478] A solution of SM-18 (29.8 mg, 0.2 mmol) and Int-24 (11.5 mg, 0.05 mmol) in CH.sub.2Cl.sub.2 (1 mL) was stirred at 25° C. for 3 h prior to addition of NaBH(AcO).sub.3 (31.6 mg, 0.15 mmol) in portions. The solution was stirred at 25° C. for 9 h. The crude mixture solution was concentrated under reduced pressure, and the resulting residue was purified by ISCO (CH.sub.2Cl.sub.2/MeOH=100/0˜70/30) to give compound 19 (7.3 mg, 30% yield).

Example 2-68: Synthesis of N-(2-((4-((dimethylamino)methyl)benzyl)(methyl)amino)ethyl)-2-((4-((dimethylamino)methyl)benzyl)amino)-5-fluoro-N-methylbenzamide (20)

[0479] ##STR00232##

[0480] Compound 20 was prepared in an analogous manner to compound 19 in Example 2-67 (2.7 mg, 11.5% yield).

Example 2-69: Synthesis of (E)-N-(4-(dimethylamino)benzyl)-4-(4-(4-(dimethylamino)benzyl)piperazin-1-yl)-4-oxobut-2-enamide (21)

[0481] ##STR00233##

##STR00234##

[0482] To a solution of Int-16 (21.9 mg, 0.1 mmol) and SM-12 (10.8 mg, 0.11 mmol) in MeCN (1 mL), TEA (50.5 mg, 0.5 mmol) was added. The reaction was stirred at 25° C. for 6 h prior to concentration of crude mixture under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-70/30) to give Int-25 (23.1 mg, 73% yield).

##STR00235##

[0483] To a solution of Int-25 (15.5 mg, 0.05 mmol) and SM-6 (9.6 mg, 0.06 mmol) in DMF (0.5 mL), DIPEA (27.8 mg, 0.2 mmol) and HATU (24 mg, 0.06 mmol) were added. The reaction was stirred at 25° C. for 6 h prior to dilution with EtOAc (2 mL). The mixture was washed with H.sub.2O (2 mL), and the aqueous phase was extracted with additional EtOAc (2×2 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by ISCO (DCM/MeOH=100/0-90/10) to give compound 21 (4.2 mg, 19% yield).

Example 2-70: Synthesis of (E)-4-(4-(4-(dimethylamino)benzyl)piperazin-1-yl)-N-(4-(dimethylamino)phenyl)-4-oxobut-2-enamide (22)

[0484] ##STR00236##

[0485] Compound 22 was prepared in an analogous manner to compound 21 in Example 2-69 (3.7 mg, yield 17%).

Equivalents and Scope

[0486] 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 present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0487] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the present disclosure or aspects of the present disclosure 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 present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0488] This application refers to various issued patents, published patent applications, journal articles, and other publications, the contents of all of which are incorporated herein by reference in their entireties. If there is a conflict between any of the incorporated publication and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0489] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.