Phenylsulfonamido-benzofuran derivatives and uses thereof in the treatment of proliferative diseases

Abstract

Described herein are phenylsulfonamido-benzofuran derivatives, and pharmaceutically acceptable salts thereof. Also provided are pharmaceutical compositions, methods, uses, and kits involving compounds of Formulae (I), (II), (III), (IV), (V), or (VI) for treating and/or preventing proliferative diseases (e.g. cancers, inflammatory diseases, and autoimmune diseases) in a subject. The compounds and pharmaceutical compositions as described herein inhibit at least one protein of the BCL-2 family in a biological sample or subject to treat and/or prevent a proliferative disease. In certain embodiments, compounds described herein are selective inhibitors of MCL-1, a BCL-2 family member protein. ##STR00001## ##STR00002##

Claims

1. A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (IV): ##STR00192## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is hydrogen or alkyl, wherein the alkyl is optionally substituted with one instance of —O—C.sub.1-6 alkyl; each instance of R.sup.3 is independently halogen, alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or acyl; each instance of R.sup.3A is independently hydrogen or alkyl; each instance of R.sup.3B is independently hydrogen or alkyl; n is 0, 1, 2, or 3; R.sup.4 is hydrogen, alkyl, or acyl; R.sup.7 is hydrogen or alkyl; R.sup.8 is hydrogen, halogen, or alkyl; R.sup.9 is alkyl or —OR.sup.2; R.sup.2 is hydrogen or alkyl; and wherein the cancer is lung cancer, colorectal cancer, multiple myeloma, or leukemia.

2. The method of claim 1, wherein the cancer is associated the addiction of a cell to a BCL-2 family member protein.

3. The method of claim 1 wherein the BCL-2 family member is an anti-apoptotic BCL-2 family member protein.

4. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R.sup.9 is —OR.sup.2.

5. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R.sup.7 is hydrogen.

6. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R.sup.8 is halogen.

7. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R.sup.8 is hydrogen.

8. The method of claim 1, wherein the compound of Formula (IV) is of Formula (III): ##STR00193## or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is C.sub.1-6 alkyl.

10. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is hydrogen.

11. The method of claim 1, wherein the compound is selected from the group consisting of: ##STR00194## and pharmaceutically acceptable salts thereof.

12. The method of claim 1, wherein the compound is selected from the group consisting of: ##STR00195## ##STR00196## and pharmaceutically acceptable salts thereof.

13. The method of claim 1, wherein the compound of Formula (IV) is of Formula (III-a): ##STR00197## or a pharmaceutically acceptable salt thereof.

14. The method of claim 1, wherein the compound of Formula (IV) is of Formula (III-b): ##STR00198## or a pharmaceutically acceptable salt thereof.

15. The method of claim 4 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is C.sub.1-6 alkyl.

16. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein at least one instance of R.sup.3 is C.sub.1-6 alkyl or —OR.sup.3A.

17. The method of claim 16 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein at least one instance of R.sup.3 is —OR.sup.3A; and R.sup.3A is C.sub.1-6 alkyl.

18. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein n is 1.

19. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is C.sub.1-6 acyl.

20. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is C.sub.1-6 alkyl; each instance of R.sup.3 is independently C.sub.1-6 alkyl or —OR.sup.3A; each instance of R.sup.3A is independently C.sub.1-6 alkyl; n is 1; R.sup.4 is hydrogen or —C(═O)C.sub.1-6 alkyl; R.sup.7 is hydrogen; R.sup.8 is hydrogen or halogen; R.sup.9 is —OR.sup.2; and R.sup.2 is C.sub.1-6 alkyl.

21. The method of claim 1, wherein the cancer is lung cancer.

22. The method of claim 1, wherein the cancer is colorectal cancer.

23. The method of claim 1, wherein the cancer is multiple myeloma.

24. The method of claim 1, wherein the cancer is leukemia.

25. The method of claim 1, wherein the cancer is associated with overexpression of a BCL-2 family member protein.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1A shows Compound 1 (“Mclin”) induces apoptosis with an EC50 of 0.6 μM in MCL-1-addicted cancer cell-line, H23. FIG. 1B shows 1 M of Compound 1 induces robust apoptosis in MCL-1-addicted cancer cell-lines, H23 and H82.

(2) FIG. 2A shows three cell lines, DMS53, SW1417, and H82, are selectively addicted to BCL-2, BCL-X.sub.L, and MCL-1, respectively. FIG. 2B shows apoptotic induction by Compound 1 (“Mclin”) and other BCL-2 and BCL-X.sub.L inhibitors in DMS53, SW1417, and H82 cell lines. Compound 1 (“Mclin”) selectively induces apoptosis in MCL-1 addicted cancer cell line over BCL-2 or BCL-X.sub.L addicted cancer cell lines.

(3) FIG. 3 shows the EC.sub.50 of the indicated compounds in triggering apoptosis in MCL-1-addicted cancer cell lines including H23 and H82. These compounds do not induce apoptosis in cells deficient for the essential apoptotic effectors, Bax and Bak.

(4) FIG. 4 shows the EC.sub.50 of the indicated compounds in triggering apoptosis in the MCL-1-addicted cancer cell line H23.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

(5) The present invention provides compounds of Formulae (I), (II), (V), and (VI), which are phenylsulfonamido-benzofuran derivatives. The compounds are inhibitors of BCL-2 family member proteins. In certain embodiments, the compounds are selective inhibitors of the BCL-2 family member protein MCL-1. These compounds and other compounds described herein may be useful in the prevention and/or treatment of a proliferative disease. Also provided are methods of using compounds of Formula (I), (II), (III), (IV), (V), or (VI) to treat and/or prevent proliferative diseases. Exemplary proliferative diseases include, but are not limited to, cancers, benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

(6) Compounds

(7) As generally described above, provided herein are compounds of Formula (I). The compounds are phenylsulfonamido-benzofuran derivatives. In certain embodiments, the present disclosure provides compounds of Formula (I):

(8) ##STR00017##
and pharmaceutically acceptable salts thereof,
wherein:

(9) R.sup.1 is hydrogen, halogen, or optionally substituted alkyl;

(10) each instance of R.sup.3 is independently halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl;

(11) n is 0, 1, 2, 3, 4, or 5;

(12) R.sup.4 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

(13) R.sup.5 is halogen or optionally substituted C.sub.1-6 alkyl;

(14) each of R.sup.2 and R.sup.3A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and

(15) R.sup.3B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.3B are taken together with the intervening atoms to form optionally substituted heterocyclyl.

(16) In certain embodiments, n is 1, and the compound of Formula (I) is of Formula (I-a):

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

(18) In certain embodiments, n is 1, and the compound of Formula (I) is of Formula (I-b):

(19) ##STR00019##
or a pharmaceutically acceptable salt thereof.

(20) In certain embodiments, n is 1, and the compound of Formula (I) is of Formula (I-c):

(21) ##STR00020##
or a pharmaceutically acceptable salt thereof.

(22) In certain embodiments, n is 1, and the compound of Formula (I) is of Formula (I-d):

(23) ##STR00021##
or a pharmaceutically acceptable salt thereof.

(24) In certain embodiments, n is 2, and the compound of Formula (I) is of the formula:

(25) ##STR00022##
or a pharmaceutically acceptable salt thereof.

(26) In certain embodiments, n is 2, and the compound of Formula (I) is of one of the following formulae:

(27) ##STR00023##
or a pharmaceutically acceptable salt thereof.

(28) In certain embodiments, n is 2, and the compound of Formula (I) is of the formula:

(29) ##STR00024##
or a pharmaceutically acceptable salt thereof.

(30) In certain embodiments, n is 2, and the compound of Formula (I) is of one of the following formulae:

(31) ##STR00025##
or a pharmaceutically acceptable salt thereof.

(32) In certain embodiments, n is 2, and the compound of Formula (I) is of the formula:

(33) ##STR00026##
or a pharmaceutically acceptable salt thereof.

(34) In certain embodiments, n is 2, and the compound of Formula (I) is of one of the following formulae:

(35) ##STR00027##
or a pharmaceutically acceptable salt thereof.

(36) In certain embodiments, n is 3, and the compound of Formula (I) is of the formula:

(37) ##STR00028##
or a pharmaceutically acceptable salt thereof.

(38) In certain embodiments, n is 3, and the compound of Formula (I) is of one of following formulae:

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

(40) In certain embodiments, n is 3, and the compound of Formula (I) is of the formula:

(41) ##STR00030##
or a pharmaceutically acceptable salt thereof.

(42) In certain embodiments, n is 3, and the compound of Formula (I) is of one of following formulae:

(43) ##STR00031##
or a pharmaceutically acceptable salt thereof.

(44) In certain embodiments, n is 3, and the compound of Formula (I) is of the formula:

(45) ##STR00032##
or a pharmaceutically acceptable salt thereof.

(46) In certain embodiments, n is 3, and the compound of Formula (I) is of one of following formulae:

(47) ##STR00033##
or a pharmaceutically acceptable salt thereof.

(48) In certain embodiments, n is 3, and the compound of Formula (I) is of the formula:

(49) ##STR00034##
or a pharmaceutically acceptable salt thereof.

(50) In certain embodiments, n is 3, and the compound of Formula (I) is of one of following formulae:

(51) ##STR00035##
or a pharmaceutically acceptable salt thereof.

(52) In certain embodiments, n is 3, and the compound of Formula (I) is of the formula:

(53) ##STR00036##
or a pharmaceutically acceptable salt thereof.

(54) In certain embodiments, n is 3, and the compound of Formula (I) is of one of following formulae:

(55) ##STR00037##
or a pharmaceutically acceptable salt thereof.

(56) In certain embodiments, n is 3, and the compound of Formula (I) is of the formula:

(57) ##STR00038##
or a pharmaceutically acceptable salt thereof.

(58) In certain embodiments, n is 3, and the compound of Formula (I) is of one of following formulae:

(59) ##STR00039##
or a pharmaceutically acceptable salt thereof.

(60) In certain embodiments, n is 3, and the compound of Formula (I) is of the formula:

(61) ##STR00040##
or a pharmaceutically acceptable salt thereof.

(62) In certain embodiments, n is 3, and the compound of Formula (I) is of one of following formulae:

(63) ##STR00041##
or a pharmaceutically acceptable salt thereof.

(64) In certain embodiments, n is 4, and the compound of Formula (I) is of one of the following formulae:

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

(66) In certain embodiments, n is 5, and the compound of Formula (I) is of the following formula:

(67) ##STR00043##
or a pharmaceutically acceptable salt thereof.

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

(69) ##STR00044##
or a pharmaceutically acceptable salt thereof.

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

(71) ##STR00045##
or a pharmaceutically acceptable salt thereof.

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

(73) ##STR00046##
or a pharmaceutically acceptable salt thereof.

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

(75) ##STR00047##
or a pharmaceutically acceptable salt thereof.

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

(77) ##STR00048##
or a pharmaceutically acceptable salt thereof.

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

(79) ##STR00049##
or a pharmaceutically acceptable salt thereof.

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

(81) ##STR00050##
or a pharmaceutically acceptable salt thereof.

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

(83) ##STR00051##
or a pharmaceutically acceptable salt thereof.

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

(85) ##STR00052##
or a pharmaceutically acceptable salt thereof.

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

(87) ##STR00053##
or a pharmaceutically acceptable salt thereof.

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

(89) ##STR00054##
or a pharmaceutically acceptable salt thereof.

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

(91) ##STR00055##
or a pharmaceutically acceptable salt thereof.

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

(93) ##STR00056##
or a pharmaceutically acceptable salt thereof.

(94) In certain embodiments, n is 1 and R.sup.3 is halogen. In certain embodiments, n is 1 and R.sup.3 is F. In certain embodiments, n is 1 and R.sup.3 is Cl. In certain embodiments, n is 1 and R.sup.3 is Br. In certain embodiments, n is 1 and R.sup.3 is I. In certain embodiments, n is 1 and R.sup.3 is optionally substituted alkyl. In certain embodiments, n is 1 and R.sup.3 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, n is 1 and R.sup.3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, n is 1 and R.sup.3 is methyl, ethyl, n-propyl, or iso-propyl. In certain embodiments, n is 1 and R.sup.3 is —OR.sup.3A and R.sup.3A is as defined herein. In certain embodiments, n is 1 and R.sup.3 is —OH. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is optionally substituted alkyl. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is optionally substituted C.sub.1-6 alkyl. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, n is 1 and R.sup.3 is —OCH.sub.3. In certain embodiments, n is 1 and R.sup.3 is —OEt. In certain embodiments, n is 1 and R.sup.3 is —OPr. In certain embodiments, n is 1 and R.sup.3 is —OPr or —OiPr. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is substituted C.sub.1-6 alkyl. In certain embodiments, n is 1; R.sup.3 is —N(R.sup.3B).sub.2; and each instance of R.sup.3B is as defined herein. In certain embodiments, n is 1; R.sup.3 is —N(R.sup.3B).sub.2; and each instance of R.sup.3B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, n is 1; R.sup.3 is —NHR.sup.3B; and R.sup.3B is as defined herein. In certain embodiments, n is 1; R.sup.3 is —NHR.sup.3B; and R.sup.3B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, n is 1 and R.sup.3 is —NH.sub.2. In certain embodiments, n is 1; R.sup.3 is —N(CH.sub.3)R.sup.3B; and R.sup.3B is as defined herein. In certain embodiments, n is 1; R.sup.3 is —N(CH.sub.3)R.sup.3B; and R.sup.3B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, n is 1 and R.sup.3 is —N(CH.sub.3).sub.2.

(95) In certain embodiments, n is 1; R.sup.3 is halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl; and R.sup.5 is independently halogen. In certain embodiments, n is 1; R.sup.3 is halogen; and R.sup.5 is independently halogen. In certain embodiments, n is 1; R.sup.3 is optionally substituted alkyl; and R.sup.5 is halogen. In certain embodiments, n is 1; R.sup.3 is optionally substituted C.sub.1-6 alkyl; and R.sup.5 is halogen. In certain embodiments, n is 1; R.sup.3 is substituted C.sub.1-6 alkyl; and R.sup.5 is halogen. In certain embodiments, n is 1; R.sup.3 is unsubstituted C.sub.1-6 alkyl; and R.sup.5 is halogen. In certain embodiments, n is 1; R.sup.3 is substituted C.sub.1-6 alkyl; and R.sup.5 is halogen. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; and R.sup.5 is halogen. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; R.sup.5 is halogen; and R.sup.3A is hydrogen or optionally substituted alkyl. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; R.sup.5 is halogen; and R.sup.3A is optionally substituted alkyl. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; R.sup.5 is halogen; and R.sup.3A is unsubstituted alkyl. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; R.sup.5 is halogen; and R.sup.3A is methyl or ethyl. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; R.sup.5 is halogen; and R.sup.3A is substituted alkyl. In certain embodiments, n is 1; R.sup.3 is —N(R.sup.3B).sub.2; and R.sup.5 is halogen. In certain embodiments, n is 1; R.sup.3 is —N(R.sup.3B).sub.2; R.sup.5 is halogen; and each instance of R.sup.3B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, n is 1; R.sup.3 is —NHR.sup.3B; R.sup.5 is halogen; and R.sup.3B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, n is 1; R.sup.3 is —N(CH.sub.3)R.sup.3B; R.sup.5 is halogen; and R.sup.3B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group.

(96) In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; n is 1; R.sup.3 is halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl; and R.sup.5 is independently halogen. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl; n is 1; R.sup.3 is halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl; and R.sup.5 is independently halogen. In certain embodiments, R.sup.1 is substituted C.sub.1-6 alkyl; n is 1; R.sup.3 is halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl; and R.sup.5 is independently halogen. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; n is 1; R.sup.3 is halogen, optionally substituted alkyl, or —OR.sup.3A; and R.sup.5 is independently halogen. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl; n is 1; R.sup.3 is halogen, optionally substituted alkyl, or —OR.sup.3A; and R.sup.5 is independently halogen. In certain embodiments, R.sup.1 is substituted C.sub.1-6 alkyl; n is 1; R.sup.3 is halogen, optionally substituted alkyl, —OR.sup.3A, or optionally substituted acyl; and R.sup.5 is independently halogen.

(97) In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is independently optionally substituted C.sub.1-6 alkyl; n is 1; R.sup.3 is halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl; and R.sup.5 is independently halogen. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl; R.sup.2 is independently unsubstituted C.sub.1-6 alkyl; n is 1; R.sup.3 is halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl; and R.sup.5 is independently halogen. In certain embodiments, R.sup.1 is substituted C.sub.1-6 alkyl; R.sup.2 is independently substituted C.sub.1-6 alkyl; n is 1; R.sup.3 is halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl; and R.sup.5 is independently halogen. In certain embodiments, R.sup.1 is substituted C.sub.1-6 alkyl; R.sup.2 is independently unsubstituted C.sub.1-6 alkyl; n is 1; R.sup.3 is halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl; and R.sup.5 is independently halogen.

(98) As generally described above, provided herein are compounds of Formula (II). The compounds are phenylsulfonamido-benzofuran derivatives. In certain embodiments, the present disclosure provides compounds of Formula (II):

(99) ##STR00057##
and pharmaceutically acceptable salts thereof,
wherein:

(100) R.sup.1 is hydrogen, halogen, or optionally substituted alkyl;

(101) each instance of R.sup.3 is independently halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl;

(102) n is 0, 1, 2, 3, 4, or 5;

(103) R.sup.4 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

(104) R.sup.5 is halogen or optionally substituted C.sub.1-6 alkyl;

(105) each of R.sup.2 and R.sup.3A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and

(106) R.sup.3B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.3B are taken together with the intervening atoms to form optionally substituted heterocyclyl.

(107) R.sup.6 is halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.6A, —N(R.sup.6B).sub.2, or optionally substituted acyl;

(108) R.sup.6A is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and

(109) each instance of R.sup.6B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.6B are taken together with the intervening atoms to form optionally substituted heterocyclyl.

(110) In certain embodiments, n is 1, and the compound of Formula (II) is of Formula (II-a):

(111) ##STR00058##
or a pharmaceutically acceptable salt thereof.

(112) In certain embodiments, n is 1, and the compound of Formula (II) is of Formula (II-b):

(113) ##STR00059##
or a pharmaceutically acceptable salt thereof.

(114) In certain embodiments, n is 1, and the compound of Formula (II) is of Formula (II-c):

(115) ##STR00060##
or a pharmaceutically acceptable salt thereof.

(116) In certain embodiments, n is 1, and the compound of Formula (II) is of Formula (II-d):

(117) ##STR00061##
or a pharmaceutically acceptable salt thereof.

(118) In certain embodiments, n is 2, and the compound of Formula (II) is of the formula:

(119) ##STR00062##
or a pharmaceutically acceptable salt thereof.

(120) In certain embodiments, n is 2, and the compound of Formula (II) is of one of the following formulae:

(121) ##STR00063##

(122) In certain embodiments, n is 2, and the compound of Formula (II) is of the formula:

(123) ##STR00064##
or a pharmaceutically acceptable salt thereof.

(124) In certain embodiments, n is 2, and the compound of Formula (II) is of one of the following formulae:

(125) ##STR00065##
or a pharmaceutically acceptable salt thereof.

(126) In certain embodiments, n is 2, and the compound of Formula (II) is of the formula:

(127) ##STR00066##
or a pharmaceutically acceptable salt thereof.

(128) In certain embodiments, n is 2, and the compound of Formula (II) is of one of the following formulae:

(129) ##STR00067##
or a pharmaceutically acceptable salt thereof.

(130) In certain embodiments, n is 3, and the compound of Formula (II) is of the formula:

(131) ##STR00068##
or a pharmaceutically acceptable salt thereof.

(132) In certain embodiments, n is 3, and the compound of Formula (II) is of one of following formulae:

(133) ##STR00069##
or a pharmaceutically acceptable salt thereof.

(134) In certain embodiments, n is 3, and the compound of Formula (II) is of the formula:

(135) ##STR00070##
or a pharmaceutically acceptable salt thereof.

(136) In certain embodiments, n is 3, and the compound of Formula (II) is of one of following formulae:

(137) ##STR00071##
or a pharmaceutically acceptable salt thereof.

(138) In certain embodiments, n is 3, and the compound of Formula (II) is of the formula:

(139) ##STR00072##
or a pharmaceutically acceptable salt thereof.

(140) In certain embodiments, n is 3, and the compound of Formula (II) is of one of following formulae:

(141) ##STR00073##
or a pharmaceutically acceptable salt thereof.

(142) In certain embodiments, n is 3, and the compound of Formula (II) is of the formula:

(143) ##STR00074##
or a pharmaceutically acceptable salt thereof.

(144) In certain embodiments, n is 3, and the compound of Formula (II) is of one of following formulae:

(145) ##STR00075##
or a pharmaceutically acceptable salt thereof.

(146) In certain embodiments, n is 3, and the compound of Formula (II) is of the formula:

(147) ##STR00076##
or a pharmaceutically acceptable salt thereof.

(148) In certain embodiments, n is 3, and the compound of Formula (II) is of one of following formulae:

(149) ##STR00077##
or a pharmaceutically acceptable salt thereof.

(150) In certain embodiments, n is 3, and the compound of Formula (II) is of the formula:

(151) ##STR00078##
or a pharmaceutically acceptable salt thereof.

(152) In certain embodiments, n is 3, and the compound of Formula (II) is of one of following formulae:

(153) ##STR00079##
or a pharmaceutically acceptable salt thereof.

(154) In certain embodiments, n is 3, and the compound of Formula (II) is of the formula:

(155) ##STR00080##
or a pharmaceutically acceptable salt thereof.

(156) In certain embodiments, n is 3, and the compound of Formula (II) is of one of following formulae:

(157) ##STR00081##
or a pharmaceutically acceptable salt thereof.

(158) In certain embodiments, n is 4, and the compound of Formula (II) is of one of the following formulae:

(159) ##STR00082##
or a pharmaceutically acceptable salt thereof.

(160) In certain embodiments, n is 5, and the compound of Formula (II) is of the following formula:

(161) ##STR00083##
or a pharmaceutically acceptable salt thereof.

(162) In another aspect, the present invention provides compounds of Formula (V):

(163) ##STR00084##
and pharmaceutically acceptable salts thereof, wherein:

(164) R.sup.1 is hydrogen, halogen, or optionally substituted alkyl;

(165) each instance of R.sup.3 is independently halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl;

(166) R.sup.3A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and

(167) R.sup.3B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.3B are taken together with the intervening atoms to form optionally substituted heterocyclyl.

(168) n is 0, 1, 2, 3, 4, or 5;

(169) R.sup.4 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

(170) R.sup.7 is hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.7A, —N(R.sup.7B).sub.2, or optionally substituted acyl;

(171) R.sup.7A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and

(172) R.sup.7B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.7B are taken together with the intervening atoms form optionally substituted heterocyclyl.

(173) R.sup.8 is hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.8A, —N(R.sup.8B).sub.2, or optionally substituted acyl;

(174) R.sup.8A is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;

(175) each instance of R.sup.8B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.8B are taken together with the intervening atoms to form optionally substituted heterocyclyl; and

(176) each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, —OR.sup.NA, —N(R.sup.NB).sub.2, or a nitrogen protecting group, or two R.sup.N are taken together with the intervening atoms form optionally substituted heterocyclyl;

(177) R.sup.NA is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and

(178) each instance of R.sup.NB is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.NB are taken together with the intervening atoms to form optionally substituted heterocyclyl;

(179) provided that at least one instance of R.sup.N is not hydrogen, —OH, or —NH.sub.2.

(180) In certain embodiments, the compound of Formula (V) is not one of the following:

(181) ##STR00085## ##STR00086## ##STR00087##

(182) In certain embodiments, n is 1, and the compound of Formula (V) is of Formula (V-a):

(183) ##STR00088##
or a pharmaceutically acceptable salt thereof.

(184) In certain embodiments, n is 1, and the compound of Formula (V) is of one of the following formulae:

(185) ##STR00089##
or a pharmaceutically acceptable salt thereof.

(186) In certain embodiments, n is 2, and the compound of Formula (V) is of one of the following formulae:

(187) ##STR00090## ##STR00091##
or a pharmaceutically acceptable salt thereof.

(188) In certain embodiments, n is 3, and the compound of Formula (V) is of one of the following formulae:

(189) ##STR00092## ##STR00093## ##STR00094## ##STR00095##
or a pharmaceutically acceptable salt thereof.

(190) In certain embodiments, n is 4, and the compound of Formula (V) is of one of the following formulae:

(191) ##STR00096##
or a pharmaceutically acceptable salt thereof.

(192) In certain embodiments, n is 5, and the compound of Formula (V) is of the following formula:

(193) ##STR00097##
or a pharmaceutically acceptable salt thereof.

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

(195) ##STR00098##
or a pharmaceutically acceptable salt thereof.

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

(197) ##STR00099##
or a pharmaceutically acceptable salt thereof.

(198) In certain embodiments, a compound of Formula (V) is of the following formula:

(199) ##STR00100##
or a pharmaceutically acceptable salt thereof.

(200) In certain embodiments, a compound of Formula (V) is of the following formula:

(201) ##STR00101##
or a pharmaceutically acceptable salt thereof.

(202) In certain embodiments, a compound of Formula (V) is of the following formula:

(203) ##STR00102##
or a pharmaceutically acceptable salt thereof.

(204) In certain embodiments, a compound of Formula (V) is of the following formula:

(205) ##STR00103##
or a pharmaceutically acceptable salt thereof.

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

(207) ##STR00104##
or a pharmaceutically acceptable salt thereof.

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

(209) ##STR00105##
or a pharmaceutically acceptable salt thereof.

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

(211) ##STR00106##
or a pharmaceutically acceptable salt thereof.

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

(213) ##STR00107##
or a pharmaceutically acceptable salt thereof.

(214) In another aspect, the present invention provides compounds of Formula (VI):

(215) ##STR00108##
and pharmaceutically acceptable salts thereof, wherein:

(216) R.sup.1 is hydrogen, halogen, or optionally substituted alkyl;

(217) each instance of R.sup.3 is independently halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl;

(218) R.sup.3A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and

(219) R.sup.3B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.3B are taken together with the intervening atoms to form optionally substituted heterocyclyl.

(220) n is 0, 1, 2, 3, 4, or 5;

(221) R.sup.4 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

(222) R.sup.7 is hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.7A, —N(R.sup.7B).sub.2, or optionally substituted acyl;

(223) R.sup.7A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and

(224) R.sup.7B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.7B are taken together with the intervening atoms form optionally substituted heterocyclyl.

(225) R.sup.8 is hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.8A, —N(R.sup.8B).sub.2, or optionally substituted acyl;

(226) R.sup.8A is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;

(227) each instance of R.sup.8B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.8B are taken together with the intervening atoms to form optionally substituted heterocyclyl; and

(228) R.sup.9 is 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.sup.2, or —N(R.sup.9B).sub.2;

(229) R.sup.2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;

(230) each instance of R.sup.9B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.9B are taken together with the intervening atoms to form optionally substituted heterocyclyl;

(231) R.sup.10 is optionally substituted alkyl or —OR.sup.10A; and

(232) R.sup.10A is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group.

(233) In certain embodiments, n is 1, and the compound of Formula (VI) is of Formula (VI-a):

(234) ##STR00109##
or a pharmaceutically acceptable salt thereof.

(235) In certain embodiments, n is 1, and the compound of Formula (VI) is of one of the following formulae:

(236) or a pharmaceutically acceptable salt thereof.

(237) ##STR00110##

(238) In certain embodiments, n is 2, and the compound of Formula (VI) is of one of the following formulae:

(239) ##STR00111## ##STR00112##
or a pharmaceutically acceptable salt thereof.

(240) In certain embodiments, n is 3, and the compound of Formula (VI) is of one of the following formulae:

(241) ##STR00113## ##STR00114## ##STR00115## ##STR00116##
or a pharmaceutically acceptable salt thereof.

(242) In certain embodiments, n is 4, and the compound of Formula (VI) is of one of the following formulae:

(243) ##STR00117##
or a pharmaceutically acceptable salt thereof.

(244) In certain embodiments, n is 5, and the compound of Formula (VI) is of the following formula:

(245) ##STR00118##
or a pharmaceutically acceptable salt thereof.

(246) In certain embodiments, a compound of Formula (VI) is of the following formula:

(247) ##STR00119##
or a pharmaceutically acceptable salt thereof.

(248) In certain embodiments, a compound of Formula (VI) is of the following formula:

(249) ##STR00120##
or a pharmaceutically acceptable salt thereof.

(250) In certain embodiments, a compound of Formula (VI) is of the following formula:

(251) ##STR00121##
or a pharmaceutically acceptable salt thereof.

(252) In certain embodiments, a compound of Formula (VI) is of the following formula:

(253) ##STR00122##
or a pharmaceutically acceptable salt thereof.

(254) In certain embodiments, a compound of Formula (VI) is of the following formula:

(255) ##STR00123##
or a pharmaceutically acceptable salt thereof.

(256) In certain embodiments, a compound of Formula (VI) is of the following formula:

(257) ##STR00124##
or a pharmaceutically acceptable salt thereof.

(258) In certain embodiments, a compound of Formula (VI) is of the following formula:

(259) ##STR00125##
or a pharmaceutically acceptable salt thereof.

(260) In certain embodiments, a compound of Formula (VI) is of the following formula:

(261) ##STR00126##
or a pharmaceutically acceptable salt thereof.

(262) In certain embodiments, a compound of Formula (VI) is of the following formula:

(263) ##STR00127##
or a pharmaceutically acceptable salt thereof.

(264) In certain embodiments, a compound of Formula (VI) is of the following formula:

(265) ##STR00128##
or a pharmaceutically acceptable salt thereof.

(266) For example, a compound of Formula (VI) may be of the following formula:

(267) ##STR00129##
or a pharmaceutically acceptable salt thereof.

(268) In certain embodiments, the following compounds are excluded from the present invention:

(269) ##STR00130##

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

(271) Group R.sup.1

(272) As generally defined herein, R.sup.1 is hydrogen, halogen, or optionally substituted alkyl.

(273) In certain embodiments, R.sup.1 is hydrogen. In certain embodiments, R.sup.1 is halogen. In certain embodiments, R.sup.1 is —Cl, —Br, —F, or —I. In certain embodiments, R.sup.1 is optionally substituted alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is methyl. In certain embodiments, R.sup.1 is ethyl. In certain embodiments, R.sup.1 is n-propyl. In certain embodiments, R.sup.1 is iso-propyl. In certain embodiments, R.sup.1 is n-butyl, iso-butyl, sec-butyl, or tert-butyl. In certain embodiments, R.sup.1 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is C.sub.1-6alkyl substituted with one instance of —O—C.sub.1-6alkyl. In certain embodiments, R.sup.1 is —C.sub.1-6alkyl-O—C.sub.1-6alkyl. In certain embodiments, R.sup.1 is —C.sub.1-3alkyl-O—C.sub.1-3alkyl. In certain embodiments, R.sup.1 is —C.sub.1-6alkyl-OCH.sub.3. In certain embodiments, R.sup.1 is —C.sub.1-3alkyl-OCH.sub.3. In certain embodiments, R.sup.1 is —CH.sub.2—O—C.sub.1-6alkyl. In certain embodiments, R.sup.1 is —CH.sub.2—O—C.sub.1-3alkyl. In certain embodiments, R.sup.1 is —CH.sub.2—O—CH.sub.3. In certain embodiments, R.sup.1 is —C.sub.1-6 alkyl-N.sub.3. In certain embodiments, R.sup.1 is —C.sub.1-3 alkyl-N.sub.3. In certain embodiments, R.sup.1 is —CH.sub.2N.sub.3. In certain embodiments, R.sup.1 is —C.sub.1-6 alkyl-CN. In certain embodiments, R.sup.1 is —C.sub.1-3 alkyl-CN. In certain embodiments, R.sup.1 is —CH.sub.2CN. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl-O—R.sup.1O, wherein R.sup.1O is hydrogen or optionally substituted alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl-O—R.sup.1O, wherein R.sup.1O is hydrogen or optionally substituted alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl-O—R.sup.1O, wherein R.sup.1O is hydrogen or optionally substituted alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-3 alkyl-O—R.sup.1O, wherein R.sup.1O is hydrogen or optionally substituted alkyl. In certain embodiments, R.sup.1 is-CH.sub.2—O—R.sup.1O, wherein R.sup.1O is hydrogen or optionally substituted alkyl. In certain embodiments, R.sup.1O is optionally substituted alkyl. In certain embodiments, R.sup.1O is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1O is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1O is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1O is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1O is methyl. In certain embodiments, R.sup.1O is ethyl. In certain embodiments, R.sup.1O is n-propyl. In certain embodiments, R.sup.1O is iso-propyl. In certain embodiments, R.sup.1O is n-butyl, iso-butyl, sec-butyl, or tert-butyl.

(274) Group R.sup.2

(275) As generally defined herein, each instance of R.sup.2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group. In certain embodiments, R.sup.2 is hydrogen. In certain embodiments, R.sup.2 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group. In certain embodiments, R.sup.2 is optionally substituted alkyl. In certain embodiments, R.sup.2 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.1-3alkyl. In certain embodiments, R.sup.2 is methyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is ethyl. In certain embodiments, R.sup.2 is n-propyl. In certain embodiments, R.sup.2 is iso-propyl. In certain embodiments, R.sup.2 is n-butyl, iso-butyl, sec-butyl, or tert-butyl. In certain embodiments, R.sup.2 is substituted C.sub.1-6 alkyl.

(276) Group R.sup.3

(277) As generally defined herein, each instance of R.sup.3 is independently halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl. 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 —F. In certain embodiments, at least one instance of R.sup.3 is —Cl. In certain embodiments, at least one instance of R.sup.3 is —Br. In certain embodiments, at least one instance of R.sup.3 is —I. 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 C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.3 is unsubstituted C.sub.1-6alkyl. In certain embodiments, at least one instance of R.sup.3 is optionally substituted C.sub.1-3alkyl. In certain embodiments, at least one instance of R.sup.3 is unsubstituted C.sub.1-3alkyl. In certain embodiments, at least one instance of R.sup.3 is methyl or ethyl. In certain embodiments, at least one instance of R.sup.3 is methyl. In certain embodiments, at least one instance of R.sup.3 is n-propyl. In certain embodiments, at least one instance of R.sup.3 is iso-propyl. In certain embodiments, at least one instance of R.sup.3 is n-butyl, iso-butyl, sec-butyl, or tert-butyl. In certain embodiments, at least one instance of R.sup.3 is substituted C.sub.1-6alkyl. In certain embodiments, at least one instance of R.sup.3 is —OR.sup.3A; and R.sup.3A is as defined herein. In certain embodiments, at least one instance of R.sup.3 is —OH. In certain embodiments, at least one instance of R.sup.3 is —OR.sup.3A; and R.sup.3A is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.3 is —OR.sup.3A; and R.sup.3A is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.3 is —OR.sup.3A; and R.sup.3A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.3 is —OR.sup.3A; and R.sup.3A is optionally substituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.3 is —OR.sup.3A; and R.sup.3A is unsubstituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.3 is —OCH.sub.3. In certain embodiments, at least one instance of R.sup.3 is —OEt. In certain embodiments, at least one instance of R.sup.3 is —OPr. In certain embodiments, at least one instance of R.sup.3 is —O.sup.iPr. In certain embodiments, at least one instance of R.sup.3 is —OR.sup.3A; and R.sup.3A is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.3 is —N(R.sup.3B).sub.2 and each instance of R.sup.3B is as defined herein. In certain embodiments, at least one instance of R.sup.3 is —N(R.sup.3B).sub.2; and each instance of R.sup.3B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, at least one instance of R.sup.3 is —NHR.sup.3B; and R.sup.3B is as defined herein. In certain embodiments, at least one instance of R.sup.3 is —NHR.sup.3B and R.sup.3B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, at least one instance of R.sup.3 is —NH.sub.2. In certain embodiments, at least one instance of R.sup.3 is —NHR.sup.3B and R.sup.3B is as defined herein. In certain embodiments, at least one instance of R.sup.3 is —NHR.sup.3B and R.sup.3B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, at least one instance of R.sup.3 is —NH.sub.2. In certain embodiments, at least one instance of R.sup.3 is —N(CH.sub.3)R.sup.3B; and R.sup.3B is as defined herein. In certain embodiments, at least one instance of R.sup.3 is —N(CH.sub.3)R.sup.3B; and R.sup.3B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, at least one instance of R.sup.3 is —NHCH.sub.3. In certain embodiments, at least one instance of R.sup.3 is —N(CH.sub.3)R.sup.3B and R.sup.3B is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.3 is —N(CH.sub.3)R.sup.3B and R.sup.3B is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.3 is —N(CH.sub.3)R.sup.3B and R.sup.3B is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.3 is —N(CH.sub.3).sub.2. In certain embodiments, at least one instance of R.sup.3 is —N(CH.sub.3)R.sup.3B and R.sup.3B is substituted C.sub.1-6 alkyl.

(278) As generally defined herein, each instance of R.sup.3A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group. In certain embodiments, R.sup.3A is hydrogen. In certain embodiments, R.sup.3A is optionally substituted alkyl. In certain embodiments, R.sup.3A is optionally substituted alkenyl. In certain embodiments, R.sup.3A is optionally substituted alkynyl. In certain embodiments, R.sup.3A is optionally substituted carbocyclyl. In certain embodiments, R.sup.3A is optionally substituted heterocyclyl. In certain embodiments, R.sup.3A is optionally substituted aryl. In certain embodiments, R.sup.3A is optionally substituted heteroaryl. In certain embodiments, R.sup.3A is an oxygen protecting group.

(279) As generally defined herein, each instance of R.sup.3B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.3B are taken together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.3B is hydrogen. In certain embodiments, R.sup.3B is optionally substituted alkyl. In certain embodiments, R.sup.3B is optionally substituted alkenyl. In certain embodiments, R.sup.3B is optionally substituted alkynyl. In certain embodiments, R.sup.3B is optionally substituted carbocyclyl. In certain embodiments, R.sup.3B is optionally substituted heterocyclyl. In certain embodiments, R.sup.3B is optionally substituted aryl. In certain embodiments, R.sup.3B is optionally substituted heteroaryl. In certain embodiments, R.sup.3B is or a nitrogen protecting group. In certain embodiments, two R.sup.3B are taken together with the intervening atoms to form optionally substituted heterocyclyl.

(280) Group R.sup.4

(281) As generally defined herein, R.sup.4 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R.sup.4 is hydrogen. In certain embodiments, R.sup.4 is optionally substituted alkyl or a nitrogen protecting group. In certain embodiments, R.sup.4 is optionally substituted alkyl. In certain embodiments, R.sup.4 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is methyl. In certain embodiments, R.sup.4 is ethyl. In certain embodiments, R.sup.4 is a nitrogen protecting group. In certain embodiments, R.sup.4 is optionally substituted acyl. In certain embodiments, R.sup.4 is acetyl (e.g., —C(═O)CH.sub.3. In certain embodiments, R.sup.4 is —C(═O)C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is —C(═O)C.sub.1-3 alkyl. In certain embodiments, R.sup.4 is —C(═O)CH.sub.2CH.sub.2CH.sub.3.

(282) Group R.sup.5

(283) As generally defined herein, R.sup.5 is halogen or optionally substituted alkyl. In certain embodiments, R.sup.5 is halogen. In certain embodiments, R.sup.5 is fluorine (—F). In certain embodiments, R.sup.5 is chlorine (—Cl). In certain embodiments, R.sup.5 is bromine (—Br). In certain embodiments, R.sup.5 is iodine (—I). In certain embodiments, R.sup.5 is optionally substituted alkyl. In certain embodiments, R.sup.5 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.5 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.5 is methyl. In certain embodiments, R.sup.5 is ethyl. In certain embodiments, R.sup.5 is a nitrogen protecting group. In certain embodiments, R.sup.5 is optionally substituted acyl. In certain embodiments, R.sup.5 is acetyl.

(284) Group R.sup.6

(285) As generally defined herein, R.sup.6 is halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.6A, —N(R.sup.6B).sub.2, or optionally substituted acyl. In certain embodiments, R.sup.6 is halogen. In certain embodiments, R.sup.6 is —F. In certain embodiments, R.sup.6 is —Cl. In certain embodiments, R.sup.6 is —Br. In certain embodiments, R.sup.6 is —I. In certain embodiments, R.sup.6 is optionally substituted alkyl. In certain embodiments, R.sup.6 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.6 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.6 is methyl or ethyl. In certain embodiments, R.sup.6 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.6 is —OR.sup.6A; and R.sup.6A is as defined herein. In certain embodiments, R.sup.6 is —OH. In certain embodiments, R.sup.6 is —OR.sup.6A; and R.sup.6A is optionally substituted alkyl. In certain embodiments, R.sup.3 is —OR.sup.6A; and R.sup.6A is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.6 is —OR.sup.6A; and R.sup.6A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.6 is —OCH.sub.3. In certain embodiments, R.sup.6 is —OEt. In certain embodiments, R.sup.6 is —OPr. In certain embodiments, R.sup.6 is —O.sup.iPr. In certain embodiments, R.sup.6 is —OR.sup.6A and R.sup.6A is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.6 is —N(R.sup.6B).sub.2 and each instance of R.sup.6B is as defined herein. In certain embodiments, R.sup.6 is —N(R.sup.6B).sub.2 and each instance of R.sup.6B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R.sup.6 is —NHR.sup.6B and R.sup.6B is as defined herein. In certain embodiments, R.sup.6 is —NHR.sup.6B and R.sup.6B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R.sup.6 is —NH.sub.2. In certain embodiments, R.sup.6 is —NHR.sup.6B and R.sup.6B is as defined herein. In certain embodiments, R.sup.6 is —NHR.sup.6B and R.sup.6B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R.sup.6 is —NH.sub.2. In certain embodiments, R.sup.6 is —N(CH.sub.3)R.sup.6B; and R.sup.6B is as defined herein. In certain embodiments, R.sup.6 is —N(CH.sub.3)R.sup.6B; and R.sup.6B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R.sup.6 is —NHCH.sub.3. In certain embodiments, R.sup.6 is —N(CH.sub.3)R.sup.6B; and R.sup.6B is optionally substituted alkyl. In certain embodiments, R.sup.6 is —N(CH.sub.3)R.sup.6B; and R.sup.6B is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.6 is —N(CH.sub.3)R.sup.6B; and R.sup.6B is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.6 is —N(CH.sub.3).sub.2. In certain embodiments, R.sup.6 is —N(CH.sub.3)R.sup.6B; and R.sup.6B is substituted C.sub.1-6 alkyl.

(286) As generally defined herein, each instance of R.sup.6A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group. In certain embodiments, R.sup.6A is hydrogen. In certain embodiments, R.sup.6A is optionally substituted alkyl. In certain embodiments, R.sup.6A is optionally substituted alkenyl. In certain embodiments, R.sup.6A is optionally substituted alkynyl. In certain embodiments, R.sup.6A is optionally substituted carbocyclyl. In certain embodiments, R.sup.6A is optionally substituted heterocyclyl. In certain embodiments, R.sup.6A is optionally substituted aryl. In certain embodiments, R.sup.6A is optionally substituted heteroaryl. In certain embodiments, R.sup.6A is an oxygen protecting group.

(287) As generally defined herein, each instance of R.sup.6B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.6B are taken together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.6B is hydrogen. In certain embodiments, R.sup.6B is optionally substituted alkyl. In certain embodiments, R.sup.6B is optionally substituted alkenyl. In certain embodiments, R.sup.6B is optionally substituted alkynyl. In certain embodiments, R.sup.6B is optionally substituted carbocyclyl. In certain embodiments, R.sup.6B is optionally substituted heterocyclyl. In certain embodiments, R.sup.6B is optionally substituted aryl. In certain embodiments, R.sup.6B is optionally substituted heteroaryl. In certain embodiments, R.sup.6B is or a nitrogen protecting group. In certain embodiments, two R.sup.6B are taken together with the intervening atoms to form optionally substituted heterocyclyl.

(288) Group R.sup.7

(289) As generally defined herein, R.sup.7 is hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.7A, —N(R.sup.7B).sub.2, or optionally substituted acyl. In certain embodiments, R.sup.7 is hydrogen. In certain embodiments, R.sup.7 is halogen. In certain embodiments, R.sup.7 is F. In certain embodiments, R.sup.7 is Cl. In certain embodiments, R.sup.7 is Br. In certain embodiments, R.sup.7 is I. In certain embodiments, R.sup.7 is —CN. In certain embodiments, R.sup.7 is —NO.sub.2. In certain embodiments, R.sup.7 is —N.sub.3. In certain embodiments, R.sup.7 is optionally substituted acyl. In certain embodiments, R.sup.7 is optionally substituted alkyl. In certain embodiments, R.sup.7 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.7 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.7 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.7 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.7 is methyl or ethyl. In certain embodiments, R.sup.7 is n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. In certain embodiments, R.sup.7 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.7 is —OR.sup.6A; and R.sup.6A is as defined herein. In certain embodiments, R.sup.7 is —OH. In certain embodiments, R.sup.7 is —OR.sup.7A; and R.sup.7A is optionally substituted alkyl. In certain embodiments, R.sup.7 is —OR.sup.7A; and R.sup.7A is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.7 is —OR.sup.7A; and R.sup.7A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.7 is —N(R.sup.7B).sub.2 and each instance of R.sup.7B is as defined herein. In certain embodiments, R.sup.7 is —N(R.sup.7B).sub.2 and each instance of R.sup.7B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R.sup.7 is —NHR.sup.7B and R.sup.7B is as defined herein. In certain embodiments, R.sup.7 is —NHR.sup.7B and R.sup.7B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R.sup.7 is —NH.sub.2. In certain embodiments, R.sup.7 is —NMe.sub.2.

(290) As generally defined herein, each instance of R.sup.7A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group. In certain embodiments, R.sup.7A is hydrogen. In certain embodiments, R.sup.7A is optionally substituted alkyl. In certain embodiments, R.sup.7A is optionally substituted alkenyl. In certain embodiments, R.sup.7A is optionally substituted alkynyl. In certain embodiments, R.sup.7A is optionally substituted carbocyclyl. In certain embodiments, R.sup.7A is optionally substituted heterocyclyl. In certain embodiments, R.sup.7A is optionally substituted aryl. In certain embodiments, R.sup.7A is optionally substituted heteroaryl. In certain embodiments, R.sup.7A is an oxygen protecting group.

(291) As generally defined herein, each instance of R.sup.7B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.7B are taken together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.7B is hydrogen. In certain embodiments, R.sup.7B is optionally substituted alkyl. In certain embodiments, R.sup.7B is optionally substituted alkenyl. In certain embodiments, R.sup.7B is optionally substituted alkynyl. In certain embodiments, R.sup.7B is optionally substituted carbocyclyl. In certain embodiments, R.sup.7B is optionally substituted heterocyclyl. In certain embodiments, R.sup.7B is optionally substituted aryl. In certain embodiments, R.sup.7B is optionally substituted heteroaryl. In certain embodiments, R.sup.7B is or a nitrogen protecting group. In certain embodiments, two R.sup.7B are taken together with the intervening atoms to form optionally substituted heterocyclyl.

(292) Group R.sup.8

(293) As generally defined herein, R.sup.8 is hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.8A, —N(R.sup.8B).sub.2, or optionally substituted acyl. In certain embodiments, R.sup.8 is hydrogen. In certain embodiments, R.sup.8 is halogen. In certain embodiments, R.sup.8 is F. In certain embodiments, R.sup.8 is Cl. In certain embodiments, R.sup.8 is Br. In certain embodiments, R.sup.8 is I. In certain embodiments, R.sup.8 is —CN. In certain embodiments, R.sup.8 is —NO.sub.2. In certain embodiments, R.sup.8 is —N.sub.3. In certain embodiments, R.sup.8 is optionally substituted acyl. In certain embodiments, R.sup.8 is optionally substituted alkyl. In certain embodiments, R.sup.8 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.8 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.8 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.8 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.8 is methyl or ethyl. In certain embodiments, R.sup.8 is n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. In certain embodiments, R.sup.8 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.8 is —OR.sup.8A; and R.sup.8A is as defined herein. In certain embodiments, R.sup.8 is —OH. In certain embodiments, R.sup.8 is —OR.sup.7A; and R.sup.8A is optionally substituted alkyl. In certain embodiments, R.sup.8 is —OR.sup.8A; and R.sup.8A is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.8 is —OR.sup.8A; and R.sup.8A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.8 is —N(R.sup.8B).sub.2 and each instance of R.sup.8B is as defined herein. In certain embodiments, R.sup.8 is —N(R.sup.8B).sub.2 and each instance of R.sup.8B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R.sup.8 is —NHR.sup.8B and R.sup.8B is as defined herein. In certain embodiments, R.sup.8 is —NHR.sup.8B and R.sup.8B is hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, R.sup.8 is —NH.sub.2. In certain embodiments, R.sup.8 is —NMe.sub.2.

(294) As generally defined herein, each instance of R.sup.8A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group. In certain embodiments, R.sup.8A is hydrogen. In certain embodiments, R.sup.8A is optionally substituted alkyl. In certain embodiments, R.sup.8A is optionally substituted alkenyl. In certain embodiments, R.sup.8A is optionally substituted alkynyl. In certain embodiments, R.sup.8A is optionally substituted carbocyclyl. In certain embodiments, R.sup.8A is optionally substituted heterocyclyl. In certain embodiments, R.sup.8A is optionally substituted aryl. In certain embodiments, R.sup.8A is optionally substituted heteroaryl. In certain embodiments, R.sup.8A is an oxygen protecting group.

(295) As generally defined herein, each instance of R.sup.8B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.8B taken together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.8B is hydrogen. In certain embodiments, R.sup.8B is optionally substituted alkyl. In certain embodiments, R.sup.8B is optionally substituted alkenyl. In certain embodiments, R.sup.8B is optionally substituted alkynyl. In certain embodiments, R.sup.8B is optionally substituted carbocyclyl. In certain embodiments, R.sup.8B is optionally substituted heterocyclyl. In certain embodiments, R.sup.8B is optionally substituted aryl. In certain embodiments, R.sup.8B is optionally substituted heteroaryl. In certain embodiments, R.sup.8B is or a nitrogen protecting group. In certain embodiments, two R.sup.8B are taken together with the intervening atoms to form optionally substituted heterocyclyl.

(296) Group R.sup.N

(297) As generally defined herein, each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, —OR.sup.NA, —N(R.sup.NB).sub.2, or a nitrogen protecting group or two R.sup.N taken together with the intervening atoms form optionally substituted heterocyclyl; provided that at least one instance of R.sup.N is not hydrogen, —OH, or —NH.sub.2. In certain embodiments, 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 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, at least one instance of R.sup.N is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.N is optionally substituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.N is unsubstituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.N is substituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.N is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. In certain embodiments, at least one instance of R.sup.N is —C.sub.1-6 alkyl-CN. In certain embodiments, at least one instance of R.sup.N is —C.sub.1-3 alkyl-CN. In certain embodiments, at least one instance of R.sup.N is —CH.sub.2CN. In certain embodiments, one instance of R.sup.N is —CH.sub.2CN. In certain embodiments, at least one instance of R.sup.N is —OR.sup.NA, and R.sup.NA is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.N is —OR.sup.NA, and R.sup.NA is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.N is —OR.sup.NA, and R.sup.NA is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.N is —OR.sup.NA, and R.sup.NA is optionally substituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.N is —OR.sup.NA, and R.sup.NA is unsubstituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.N is —OR.sup.NA, and R.sup.NA is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. In certain embodiments, one instance of R.sup.N is —OC.sub.1-6 alkyl. In certain embodiments, one instance of R.sup.N is —OC.sub.1-3 alkyl. In certain embodiments, one instance of R.sup.N is —OCH.sub.3.

(298) As generally defined herein, each instance of R.sup.NA is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group. In certain embodiments, R.sup.NA is hydrogen. In certain embodiments, R.sup.NA is optionally substituted alkyl. In certain embodiments, R.sup.NA is optionally substituted alkenyl. In certain embodiments, R.sup.NA is optionally substituted alkynyl. In certain embodiments, R.sup.NA is optionally substituted carbocyclyl. In certain embodiments, R.sup.NA is optionally substituted heterocyclyl. In certain embodiments, R.sup.NA is optionally substituted aryl. In certain embodiments, R.sup.NA is optionally substituted heteroaryl. In certain embodiments, R.sup.NA is an oxygen protecting group.

(299) As generally defined herein, each instance of R.sup.NB is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.NB are taken together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.NB is hydrogen. In certain embodiments, R.sup.NB is optionally substituted alkyl. In certain embodiments, R.sup.NB is optionally substituted alkenyl. In certain embodiments, R.sup.NB is optionally substituted alkynyl. In certain embodiments, R.sup.NB is optionally substituted carbocyclyl. In certain embodiments, R.sup.NB is optionally substituted heterocyclyl. In certain embodiments, R.sup.NB is optionally substituted aryl. In certain embodiments, R.sup.NB is optionally substituted heteroaryl. In certain embodiments, R.sup.NB is or a nitrogen protecting group. In certain embodiments, two R.sup.NB are taken together with the intervening atoms to form optionally substituted heterocyclyl.

(300) Group R.sup.9

(301) As generally defined herein, R.sup.9 is 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.sup.2, or —N(R.sup.9B).sub.2. In certain embodiments, R.sup.9 is hydrogen. In certain embodiments, R.sup.9 is hydrogen. In certain embodiments, R.sup.9 is optionally substituted alkyl. In certain embodiments, R.sup.9 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.9 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.9 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.9 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.9 is methyl or ethyl. In certain embodiments, R.sup.9 is n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. In certain embodiments, R.sup.9 is optionally substituted alkenyl. In certain embodiments, R.sup.9 is optionally substituted alkynyl. In certain embodiments, R.sup.9 is optionally substituted aryl. In certain embodiments, R.sup.9 is optionally substituted heteroaryl. In certain embodiments, R.sup.9 is optionally substituted carbocyclyl. In certain embodiments, R.sup.9 is optionally substituted heterocyclyl. In certain embodiments, R.sup.9 is optionally substituted acyl. In certain embodiments, R.sup.9 is —OR.sup.2. In certain embodiments, R.sup.9 is —OR.sup.2, and R.sup.2 is optionally substituted alkyl. In certain embodiments, R.sup.9 is —OR.sup.2, and R.sup.2 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.9 is —OR.sup.2, and R.sup.2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.9 is —OR.sup.2, and R.sup.2 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.9 is —OR.sup.2, and R.sup.2 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.9 is —OR.sup.2, and R.sup.2 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. In certain embodiments, R.sup.9 is —OCH.sub.3. In certain embodiments, R.sup.9 is —OCH.sub.2CH.sub.3. In certain embodiments, R.sup.9 is —N(R.sup.9B).sub.2.

(302) As generally defined herein, each instance of R.sup.9B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.9B are taken together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.9B is hydrogen. In certain embodiments, R.sup.9B is optionally substituted alkyl. In certain embodiments, R.sup.9B is optionally substituted alkenyl. In certain embodiments, R.sup.9B is optionally substituted alkynyl. In certain embodiments, R.sup.9B is optionally substituted carbocyclyl. In certain embodiments, R.sup.9B is optionally substituted heterocyclyl. In certain embodiments, R.sup.9B is optionally substituted aryl. In certain embodiments, R.sup.9B is optionally substituted heteroaryl. In certain embodiments, R.sup.9B is or a nitrogen protecting group. In certain embodiments, two R.sup.9B are taken together with the intervening atoms to form optionally substituted heterocyclyl.

(303) Group R.sup.10

(304) As generally defined herein, R.sup.10 is optionally substituted alkyl or —OR.sup.10A. In certain embodiments, R.sup.1′ is optionally substituted alkyl. In certain embodiments, R.sup.10 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.10 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.10 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.10 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.10 is methyl or ethyl. In certain embodiments, R.sup.10 is n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. In certain embodiments, R.sup.10 is —OR.sup.10A, and R.sup.10 is optionally substituted alkyl. In certain embodiments, R.sup.10 is —OR.sup.10A, and R.sup.10 is hydrogen. In certain embodiments, R.sup.10 is —OH. As generally defined herein, R.sup.10A is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group. In certain embodiments, R.sup.10A is hydrogen. In certain embodiments, R.sup.10A is optionally substituted alkyl. In certain embodiments, R.sup.10A is optionally substituted alkenyl. In certain embodiments, R.sup.10A is optionally substituted alkynyl. In certain embodiments, R.sup.10A is optionally substituted carbocyclyl. In certain embodiments, R.sup.10A is optionally substituted heterocyclyl. In certain embodiments, R.sup.10A is optionally substituted aryl. In certain embodiments, R.sup.10A is optionally substituted heteroaryl. In certain embodiments, R.sup.10A is an oxygen protecting group.

(305) Pharmaceutical Compositions, Kits, and Administration

(306) The present invention provides pharmaceutical compositions comprising a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, as described herein, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition of the invention comprises a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the compound of Formula (I), (II), (III), (IV), (V), or (VI), or a 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 a prophylactically effective amount. In certain embodiments, the provided pharmaceutical compositions can be used to treat a proliferative disease in a subject. In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is associated with aberrant activities of anti-apoptotic BCL-2 family proteins. In certain embodiments, the cancer is associated with aberrant activities of BCL-2. In certain embodiments, the cancer is associated with aberrant activities of BCL-X.sub.L. In certain embodiments, the cancer is associated with MCL-1. In certain embodiments, the cancer is associated with overexpression of BCL-2. In certain embodiments, the cancer is associated with overexpression of BCL-X.sub.L. In certain embodiments, the cancer is associated with overexpression of an anti-apoptotic BCL-2 family protein. In certain embodiments, the cancer is associated with overexpression of MCL-1. In certain embodiments, the proliferative disease is an inflammatory disease. In certain embodiments, the inflammatory disease is arthritis. In certain embodiments, the proliferative disease is an autoimmune disease. In certain embodiments, the autoimmune disease is autoimmune glomerulonephritis, immunoglobulinemia, or systemic lupus erythematosus (SLE).

(307) Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound of Formula (I), (II), (III), (IV), (V), or (VI) into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.

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

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

(310) 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.

(311) 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.

(312) 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.

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

(314) 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.

(315) Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal 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.

(316) 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.

(317) Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

(318) 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.

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

(320) 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.

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

(322) 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.

(323) 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.

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

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

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

(327) 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.

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

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

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

(331) 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.

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

(333) 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 embedding compositions which can be used include polymeric substances and waxes.

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

(335) 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. Jet injection devices which deliver liquid compositions 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. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration.

(336) 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.

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

(338) 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).

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

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

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

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

(343) 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.

(344) Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease 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.

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

(346) The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

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

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

(349) It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

(350) It will be also appreciated that a compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents. The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.

(351) The compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. 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 inventive compound with the additional pharmaceutical agents and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

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

(353) Also encompassed by the invention are kits (e.g., pharmaceutical packs). The inventive kits may be useful for preventing and/or treating a proliferative disease (e.g., cancer (e.g., leukemia, breast cancer, lung cancer, colon cancer, or cervical cancer), benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, or autoimmune disease). The inventive kits may also be useful for preventing and/or treating an infectious disease (e.g., a bacterial infection, a viral infection, a fungal infection, or a parasitic disease). The kits provided may comprise an inventive pharmaceutical composition or compound and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound. In some embodiments, the inventive pharmaceutical composition or compound provided in the container and the second container are combined to form one unit dosage form.

(354) Thus, in one aspect, provided are kits including a first container comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, and prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the kit of the invention includes a first container comprising a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the kits are useful in preventing and/or treating a proliferative disease in a subject. In certain embodiments, the kits are useful in preventing and/or treating an infectious disease in a subject. In certain embodiments, the kits further include instructions for administering the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, and prodrug thereof, or a pharmaceutical composition thereof, to a subject to prevent and/or treat a proliferative disease.

(355) Methods of Treatment and Uses

(356) The present invention also provides methods of using compounds of Formulae (I), (II), (III), (IV), (V), and (VI), 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 a proliferative disease such as cancer (e.g., leukemia, breast cancer, lung cancer, colon cancer, liver cancer, bladder cancer, multiple myeloma, or lymphoma), benign neoplasm, diseases related to angiogenesis, inflammatory disease, autoinflammatory disease, or autoimmune disease in a subject. Any of the compounds provided herein (including, but not limited to, the genera, subclasses, and species provided herein) can be used in the methods described herein.

(357) As described herein, the present invention provides methods of using compounds of Formula (IV), and pharmaceutically acceptable salts thereof, for the treatment and/or prevention of proliferative diseases. Provided herein are compounds of Formula (IV):

(358) ##STR00131##
and pharmaceutically acceptable salts thereof, wherein:

(359) R.sup.1 is hydrogen, halogen, or optionally substituted alkyl;

(360) each instance of R.sup.3 is independently halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl;

(361) R.sup.3A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and

(362) R.sup.3B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.3B are taken together with the intervening atoms to form optionally substituted heterocyclyl.

(363) n is 0, 1, 2, 3, 4, or 5;

(364) R.sup.4 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

(365) R.sup.7 is hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.7A, —N(R.sup.7B).sub.2, or optionally substituted acyl;

(366) R.sup.7A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and

(367) R.sup.7B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.7B taken together with the intervening atoms form optionally substituted heterocyclyl.

(368) R.sup.8 is hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.8A, —N(R.sup.8B).sub.2, or optionally substituted acyl;

(369) R.sup.8A is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;

(370) each instance of R.sup.8B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.8B taken together with the intervening atoms to form optionally substituted heterocyclyl; and

(371) R.sup.9 is 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.sup.2 or —N(R.sup.9B).sub.2;

(372) R.sup.2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and

(373) each instance of R.sup.9B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.9B taken together with the intervening atoms to form optionally substituted heterocyclyl.

(374) In certain embodiments, n is 1, and the compound of Formula (IV) is of Formula (IV-a):

(375) ##STR00132##
or a pharmaceutically acceptable salt thereof.

(376) In certain embodiments, n is 1, and the compound of Formula (IV) is of one of the following formulae:

(377) ##STR00133##
or a pharmaceutically acceptable salt thereof.

(378) In certain embodiments, n is 2, and the compound of Formula (IV) is of one of the following formulae:

(379) ##STR00134## ##STR00135##
or a pharmaceutically acceptable salt thereof.

(380) In certain embodiments, n is 3, and the compound of Formula (IV) is of one of the following formulae:

(381) ##STR00136## ##STR00137## ##STR00138## ##STR00139##
or a pharmaceutically acceptable salt thereof.

(382) In certain embodiments, n is 4, and the compound of Formula (IV) is of one of the following formulae:

(383) ##STR00140##
or a pharmaceutically acceptable salt thereof.

(384) In certain embodiments, n is 5, and the compound of Formula (IV) is of the following formula:

(385) ##STR00141##
or a pharmaceutically acceptable salt thereof.

(386) In certain embodiments, a compound of Formula (IV) is of the following formula:

(387) ##STR00142##
or a pharmaceutically acceptable salt thereof.

(388) In certain embodiments, a compound of Formula (IV) is of the following formula:

(389) ##STR00143##
or a pharmaceutically acceptable salt thereof.

(390) In certain embodiments, a compound of Formula (IV) is of the following formula:

(391) ##STR00144##
or a pharmaceutically acceptable salt thereof.

(392) In certain embodiments, a compound of Formula (IV) is of the following formula:

(393) ##STR00145##
or a pharmaceutically acceptable salt thereof.

(394) In certain embodiments, a compound of Formula (IV) is of the following formula:

(395) ##STR00146##
or a pharmaceutically acceptable salt thereof.

(396) In certain embodiments, a compound of Formula (IV) is of the following formula:

(397) ##STR00147##
or a pharmaceutically acceptable salt thereof.

(398) In certain embodiments, a compound of Formula (IV) is of the following formula:

(399) ##STR00148##
or a pharmaceutically acceptable salt thereof.

(400) Examples of compounds of Formula (IV) include the following:

(401) ##STR00149##
and pharmaceutically acceptable salts thereof.

(402) As described herein, the invention provides methods of using compounds of Formula (III), or 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 proliferative diseases. Provided herein are compounds of Formula (III):

(403) ##STR00150##

(404) and pharmaceutically acceptable salts thereof,

(405) wherein:

(406) R.sup.1 is hydrogen, halogen, or optionally substituted alkyl;

(407) each instance of R.sup.3 is independently halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl;

(408) n is 1, 2, 3, 4, or 5;

(409) R.sup.4 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;

(410) each of R.sup.2 and R.sup.3A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and

(411) R.sup.3B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group, or two R.sup.3B are taken together with the intervening atoms to form optionally substituted heterocyclyl.

(412) In certain embodiments, n is 1, and the compound of Formula (III) is of Formula (III-a):

(413) ##STR00151##
or a pharmaceutically acceptable salt thereof.

(414) In certain embodiments, n is 1, and the compound of Formula (III) is of Formula (I-b):

(415) ##STR00152##
or a pharmaceutically acceptable salt thereof.

(416) In certain embodiments, n is 1, and the compound of Formula (III) is of Formula (III-c):

(417) or a pharmaceutically acceptable salt thereof.

(418) ##STR00153##

(419) In certain embodiments, n is 1, and the compound of Formula (III) is of Formula (III-d):

(420) ##STR00154##
or a pharmaceutically acceptable salt thereof.

(421) In certain embodiments, n is 2, and the compound of Formula (III) is of the formula:

(422) ##STR00155##
or a pharmaceutically acceptable salt thereof.

(423) In certain embodiments, n is 2, and the compound of Formula (III) is of one of the following formulae:

(424) ##STR00156##
or a pharmaceutically acceptable salt thereof.

(425) In certain embodiments, n is 2, and the compound of Formula (III) is of the formula:

(426) ##STR00157##
or a pharmaceutically acceptable salt thereof.

(427) In certain embodiments, n is 2, and the compound of Formula (III) is of one of the following formulae:

(428) ##STR00158##
or a pharmaceutically acceptable salt thereof.

(429) In certain embodiments, n is 2, and the compound of Formula (III) is of the formula:

(430) ##STR00159##
or a pharmaceutically acceptable salt thereof.

(431) In certain embodiments, n is 2, and the compound of Formula (III) is of one of the following formulae:

(432) ##STR00160##
or a pharmaceutically acceptable salt thereof.

(433) In certain embodiments, n is 3, and the compound of Formula (III) is of the formula:

(434) ##STR00161##
or a pharmaceutically acceptable salt thereof.

(435) In certain embodiments, n is 3, and the compound of Formula (III) is of one of following formulae:

(436) ##STR00162##
or a pharmaceutically acceptable salt thereof.

(437) In certain embodiments, n is 3, and the compound of Formula (III) is of the formula:

(438) ##STR00163##
or a pharmaceutically acceptable salt thereof.

(439) In certain embodiments, n is 3, and the compound of Formula (III) is of one of following formulae:

(440) ##STR00164##
or a pharmaceutically acceptable salt thereof.

(441) In certain embodiments, n is 3, and the compound of Formula (III) is of the formula:

(442) ##STR00165##
or a pharmaceutically acceptable salt thereof.

(443) In certain embodiments, n is 3, and the compound of Formula (III) is of one of following formulae:

(444) ##STR00166##
or a pharmaceutically acceptable salt thereof.

(445) In certain embodiments, n is 3, and the compound of Formula (III) is of the formula:

(446) ##STR00167##
or a pharmaceutically acceptable salt thereof.

(447) In certain embodiments, n is 3, and the compound of Formula (III) is of one of following formulae:

(448) ##STR00168##
or a pharmaceutically acceptable salt thereof.

(449) In certain embodiments, n is 3, and the compound of Formula (III) is of the formula:

(450) ##STR00169##
or a pharmaceutically acceptable salt thereof.

(451) In certain embodiments, n is 3, and the compound of Formula (III) is of one of following formulae:

(452) ##STR00170##
or a pharmaceutically acceptable salt thereof.

(453) In certain embodiments, n is 3, and the compound of Formula (III) is of the formula:

(454) ##STR00171##
or a pharmaceutically acceptable salt thereof.

(455) In certain embodiments, n is 3, and the compound of Formula (III) is of one of following formulae:

(456) ##STR00172##
or a pharmaceutically acceptable salt thereof.

(457) In certain embodiments, n is 3, and the compound of Formula (III) is of the formula:

(458) ##STR00173##
or a pharmaceutically acceptable salt thereof.

(459) In certain embodiments, n is 3, and the compound of Formula (III) is of one of following formulae:

(460) ##STR00174##
or a pharmaceutically acceptable salt thereof.

(461) In certain embodiments, n is 4, and the compound of Formula (III) is of one of the following formulae:

(462) ##STR00175##
or a pharmaceutically acceptable salt thereof.

(463) In certain embodiments, n is 5, and the compound of Formula (III) is of the following formula:

(464) ##STR00176##

(465) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (III) is of the following formula:

(466) ##STR00177##
or a pharmaceutically acceptable salt thereof.

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

(468) ##STR00178##
or a pharmaceutically acceptable salt thereof.

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

(470) ##STR00179##
or a pharmaceutically acceptable salt thereof.

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

(472) ##STR00180##
or a pharmaceutically acceptable salt thereof.

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

(474) ##STR00181##
or a pharmaceutically acceptable salt thereof.

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

(476) ##STR00182##
or a pharmaceutically acceptable salt thereof.

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

(478) ##STR00183##
or a pharmaceutically acceptable salt thereof.

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

(480) or a pharmaceutically acceptable salt thereof.

(481) ##STR00184##

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

(483) ##STR00185##
or a pharmaceutically acceptable salt thereof.

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

(485) ##STR00186##
or a pharmaceutically acceptable salt thereof.

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

(487) ##STR00187##
or a pharmaceutically acceptable salt thereof.

(488) In certain embodiments, the compound of Formula (III) if of one of the following formulae:

(489) ##STR00188## ##STR00189##
or a pharmaceutically acceptable salt thereof.

(490) Formula (III) includes substituents R.sup.1, R.sup.2, R.sup.3, and R.sup.4; and variable n. In certain embodiments, n is 1, and R.sup.3 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, n is 1 and R.sup.3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, n is 1 and R.sup.3 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, n is 1 and R.sup.3 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, n is 1 and R.sup.3 is methyl, ethyl, n-propyl, or iso-propyl. In certain embodiments, n is 1 and R.sup.3 is methyl. In certain embodiments, n is 1; R.sup.3 is methyl; and R.sup.3 is para to the point of attachment of the sulfonamide group on the benzenoid ring. In certain embodiments, n is 1 and R.sup.3 is —OR.sup.3A and R.sup.3A is as defined herein. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is optionally substituted alkyl. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is optionally substituted C.sub.1-6 alkyl. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is optionally substituted C.sub.1-3 alkyl. In certain embodiments, n is 1; R.sup.3 is OR.sup.3A; and R.sup.3A is unsubstituted C.sub.1-3 alkyl. In certain embodiments, n is 1 and R.sup.3 is —OCH.sub.3. In certain embodiments, n is 1; R.sup.3 is —OCH.sub.3; and R.sup.3 is para to the point of attachment of the sulfonamide group on the benzenoid ring. In certain embodiments, n is 1 and R.sup.3 is —OEt. In certain embodiments, n is 1 and R.sup.3 is —OPr. In certain embodiments, n is 1 and R.sup.3 is —OPr or —O.sup.iPr. In certain embodiments, n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is substituted C.sub.1-6 alkyl.

(491) In certain embodiments, R.sup.1 is optionally substituted alkyl; n is 1; and R.sup.3 is halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; n is 1; and R.sup.3 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; n is 1; R.sup.3 is optionally substituted C.sub.1-6 alkyl; and R.sup.3 is para to the point of attachment of the sulfonamide group to the benzenoid ring. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl; n is 1; and R.sup.3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-3 alkyl; n is 1; and R.sup.3 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-3 alkyl; n is 1; and R.sup.3 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is methyl, ethyl, n-propyl, or iso-propyl; n is 1; and R.sup.3 is methyl, ethyl, n-propyl, or iso-propyl. In certain embodiments, R.sup.1 is methyl, ethyl, n-propyl, or iso-propyl; n is 1; R.sup.3 is methyl, ethyl, n-propyl, or iso-propyl; R.sup.3 is para to the point of attachment of the sulfonamide group to the benzenoid ring. In certain embodiments, n is 1 and R.sup.3 is methyl. In certain embodiments, R.sup.1 is methyl; n is 1; and R.sup.3 is methyl.

(492) In certain embodiments, R.sup.1 is optionally substituted alkyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is as defined herein. In certain embodiments, R.sup.1 is optionally substituted alkyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is optionally substituted alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; n is 1; R.sup.3 is —OR.sup.3A; R.sup.3A is optionally substituted C.sub.1-6 alkyl; and R.sup.3 is para to the point of attachment of the sulfonamide group to the benzenoid ring. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-3 alkyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-3 alkyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is methyl, ethyl, n-propyl, or iso-propyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is methyl, ethyl, n-propyl, or iso-propyl. In certain embodiments, R.sup.1 is methyl, ethyl, n-propyl, or iso-propyl; n is 1; R.sup.3 is —OR.sup.3A; R.sup.3A is methyl, ethyl, n-propyl, or iso-propyl; and R.sup.3 is para to the point of attachment of the sulfonamide group to the benzenoid ring. In certain embodiments, n is 1; R.sup.3 is —OCH.sub.3. In certain embodiments, R.sup.1 is methyl; n is 1; and R.sup.3 is —OCH.sub.3.

(493) In certain embodiments, R.sup.1 is alkyl substituted with one instance of —O—C.sub.1-6alkyl; n is 1; and R.sup.3 is halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl. In certain embodiments, R.sup.1 is C.sub.1-6alkyl substituted with one instance of —O—C.sub.1-6alkyl; n is 1; and R.sup.3 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is C.sub.1-6alkyl substituted with one instance of —O—C.sub.1-6alkyl; n is 1; R.sup.3 is optionally substituted C.sub.1-6 alkyl; and R.sup.3 is para to the point of attachment of the sulfonamide group to the benzenoid ring. In certain embodiments, R.sup.1 is —C.sub.1-6alkyl-O—C.sub.1-6alkyl; n is 1; and R.sup.3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is —C.sub.1-3alkyl-O—C.sub.1-3alkyl; n is 1; and R.sup.3 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is —C.sub.1-3alkyl-O—C.sub.1-3alkyl; n is 1; and R.sup.3 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is —C.sub.1-3alkyl-O—C.sub.1-3alkyl; n is 1; and R.sup.3 is methyl, ethyl, n-propyl, or iso-propyl. In certain embodiments, R.sup.1 is —C.sub.1-3alkyl-O—C.sub.1-3alkyl; n is 1; R.sup.3 is methyl, ethyl, n-propyl, or iso-propyl; R.sup.3 is para to the point of attachment of the sulfonamide group to the benzenoid ring. In certain embodiments, R.sup.1 is —CH.sub.2—O—CH.sub.3; n is 1; and R.sup.3 is methyl.

(494) In certain embodiments, R.sup.1 is optionally substituted alkyl; R.sup.2 is optionally substituted alkyl; n is 1; and R.sup.3 is —OR.sup.3A and R.sup.3A is as defined herein. In certain embodiments, R.sup.1 is optionally substituted alkyl; R.sup.2 is optionally substituted alkyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is optionally substituted alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; n is 1; R.sup.3 is —OR.sup.3A; R.sup.3A is optionally substituted C.sub.1-6 alkyl; and R.sup.3 is para to the point of attachment of the sulfonamide group to the benzenoid ring. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl; R.sup.2 is unsubstituted C.sub.1-6 alkyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-3 alkyl; R.sup.2 is optionally substituted C.sub.1-3alkyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-3 alkyl; R.sup.2 is unsubstituted C.sub.1-3alkyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is methyl, ethyl, n-propyl, or iso-propyl; R.sup.2 is methyl, ethyl, n-propyl, or iso-propyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is methyl, ethyl, n-propyl, or iso-propyl. In certain embodiments, R.sup.1 is methyl, ethyl, n-propyl, or iso-propyl; R.sup.2 is methyl, ethyl, n-propyl, or iso-propyl; n is 1; R.sup.3 is —OR.sup.3A; R.sup.3A is methyl, ethyl, n-propyl, or iso-propyl; and R.sup.3 is para to the point of attachment of the sulfonamide group to the benzenoid ring. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-3 alkyl; R.sup.2 is methyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-3 alkyl; R.sup.2 is ethyl; n is 1; R.sup.3 is —OR.sup.3A; and R.sup.3A is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is methyl; R.sup.2 is unsubstituted C.sub.1-3alkyl; n is 1; and R.sup.3 is —OCH.sub.3.

(495) In certain embodiments, R.sup.1 is optionally substituted alkyl; R.sup.2 is optionally substituted alkyl; n is 1; and R.sup.3 is halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; n is 1; and R.sup.3 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; n is 1; R.sup.3 is optionally substituted C.sub.1-6 alkyl; and R.sup.3 is para to the point of attachment of the sulfonamide group to the benzenoid ring. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl; R.sup.2 is unsubstituted C.sub.1-6 alkyl; n is 1; and R.sup.3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-3 alkyl; R.sup.2 is optionally substituted C.sub.1-3 alkyl; n is 1; and R.sup.3 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-3 alkyl; R.sup.2 is unsubstituted C.sub.1-3 alkyl; n is 1; and R.sup.3 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is methyl, ethyl, n-propyl, or iso-propyl; R.sup.2 is methyl, ethyl, n-propyl, or iso-propyl; n is 1; and R.sup.3 is methyl, ethyl, n-propyl, or iso-propyl. In certain embodiments, R.sup.1 is methyl, ethyl, n-propyl, or iso-propyl; R.sup.2 is methyl, ethyl, n-propyl, or iso-propyl; n is 1; R.sup.3 is methyl, ethyl, n-propyl, or iso-propyl; and R.sup.3 is para to the point of attachment of the sulfonamide group to the benzenoid ring. In certain embodiments, R.sup.1 is methyl; R.sup.2 is methyl; n is 1; and R.sup.3 is methyl. In certain embodiments, R.sup.1 is methyl; R.sup.2 is ethyl; n is 1; and R.sup.3 is methyl.

(496) In certain embodiments, R.sup.1 is alkyl substituted with one instance of —O—C.sub.1-6alkyl; R.sup.2 is optionally substituted alkyl; n is 1; and R.sup.3 is halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, —OR.sup.3A, —N(R.sup.3B).sub.2, or optionally substituted acyl. In certain embodiments, R.sup.1 is C.sub.1-6alkyl substituted with one instance of —O—C.sub.1-6alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; n is 1; and R.sup.3 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is C.sub.1-6alkyl substituted with one instance of —O—C.sub.1-6alkyl; R.sup.2 is optionally substituted C.sub.1-6 alkyl; n is 1; R.sup.3 is optionally substituted C.sub.1-6 alkyl; and R.sup.3 is para to the point of attachment of the sulfonamide group to the benzenoid ring. In certain embodiments, R.sup.1 is —C.sub.1-6alkyl-O—C.sub.1-6alkyl; n is 1; and R.sup.3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is —C.sub.1-3alkyl-O—C.sub.1-3alkyl; R.sup.2 is unsubstituted C.sub.1-6 alkyl; n is 1; and R.sup.3 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is —C.sub.1-3alkyl-O—C.sub.1-3alkyl; R.sup.2 is unsubstituted C.sub.1-3 alkyl; n is 1; and R.sup.3 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is —C.sub.1-3alkyl-O—C.sub.1-3alkyl; R.sup.2 is methyl, ethyl, n-propyl, or iso-propyl; n is 1; and R.sup.3 is methyl, ethyl, n-propyl, or iso-propyl. In certain embodiments, R.sup.1 is —C.sub.1-3alkyl-O—C.sub.1-3alkyl; R.sup.2 is methyl, ethyl, n-propyl, or iso-propyl; n is 1; R.sup.3 is methyl, ethyl, n-propyl, or iso-propyl; R.sup.3 is para to the point of attachment of the sulfonamide group to the benzenoid ring. In certain embodiments, R.sup.1 is —CH.sub.2—O—CH.sub.3; R.sup.2 is methyl; n is 1; and R.sup.3 is methyl. In certain embodiments, R.sup.1 is —CH.sub.2—O—CH.sub.3; R.sup.2 is ethyl; n is 1; and R.sup.3 is methyl.

(497) In some embodiments, a compound described herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is useful in treating a cancer. In some embodiments, a compound described herein is useful to delay the onset of, slow the progression of, or ameliorate the symptoms of cancer. In some embodiments, a compound described herein is administered in combination with another pharmaceutical agent to treat cancer.

(498) In some embodiments, compounds described herein (e.g., compounds of Formulae (I), (II), (III), (IV), (V), and (VI)) are useful for treating a cancer including, but not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarinoma), Ewing sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., “Waldenström's macroglobulinemia”), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM), a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumors), penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget's disease of the vulva).

(499) In some embodiments, a compound described herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is useful in treating a hematologic cancer. In certain embodiments, the hematologic cancer is a leukemia. In certain embodiments, the leukemia is AML. In certain embodiments, the leukemia is CML. In certain embodiments, the leukemia is CLL. In certain embodiments, the hematologic cancer is a lymphoma. In certain embodiments, the hematologic cancer is multiple myeloma. In some embodiments, a compound described herein is useful in treating a solid tumor. In certain embodiments, the solid tumor is lung cancer, pancreatic cancer, breast cancer, prostate cancer, colon cancer, liver cancer, or cervical cancer. In some embodiments, a compound described herein is useful in treating lung cancer. In some embodiments, a compound described herein is useful in treating pancreatic cancer. In some embodiments, a compound described herein is useful in treating breast cancer. In some embodiments, a compound described herein is useful in treating prostate cancer. In some embodiments, a compound described herein is useful in treating colon cancer. In some embodiments, a compound described herein is useful in treating cervical cancer. In some embodiments, a compound described herein is useful in treating liver cancer. In some embodiments, a compound described herein is useful in treating hepatocellular carcinoma. In some embodiments, a compound described herein is useful in treating lung cancer. In some embodiments, a compound described herein is useful in treating small cell lung cancer. In some embodiments, a compound described herein is useful in treating non-small cell lung cancer.

(500) In some embodiments, a compound described herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) is useful in treating advanced staged cancer. In some embodiments, a compound described herein is useful in treating metastatic cancer. In some embodiments, a compound described herein is useful in treating metastatic hematologic cancer (e.g., leukemia, lymphoma, or myeloma). In some embodiments, a compound described herein is useful in treating a metastatic solid tumor (e.g., lung cancer, pancreatic cancer, breast cancer, prostate cancer, colon cancer, lung cancer, or cervical cancer). In some embodiments, a compound described herein is useful in treating mutant cancer. In some embodiments, a compound described herein is useful in treating RAS mutant cancer. In some embodiments, a compound described herein is useful in treating K-RAS mutant cancer. In some embodiments, a compound described herein is useful in treating K-RAS mutant lung cancer.

(501) In some embodiments, the proliferative disease is a benign neoplasm. All types of benign neoplasms disclosed herein or known in the art are contemplated as being within the scope of the invention. In some embodiments, the proliferative disease is associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are contemplated as being within the scope of the invention. In certain embodiments, the proliferative disease is an inflammatory disease. All types of inflammatory diseases disclosed herein or known in the art are contemplated as being within the scope of the invention. In certain embodiments, the inflammatory disease is rheumatoid arthritis. In some embodiments, the proliferative disease is an autoinflammatory disease. All types of autoinflammatory diseases disclosed herein or known in the art are contemplated as being within the scope of the invention. In some embodiments, the proliferative disease is an autoimmune disease. All types of autoimmune diseases disclosed herein or known in the art are contemplated as being within the scope of the invention.

(502) The present invention also provides methods of inhibiting the activity of at least one BCL-2 family protein in a biological sample or a subject.

(503) As used herein, “BCL-2” encompasses “BCL-2” genes and “BCL-2 family proteins” that regulate apoptosis mainly by regulating the outer mitochondrial membrane integrity (Czabotar et al., Nat. Rev. Mol. Cell Biol., 2014, 15, 49-63). BCL-2 encompasses two classes: anti-apoptotic and pro-apoptotic. The BCL-2 anti-apoptotics (also called “BCL-2 pro-survival proteins”) include BCL-2, BCL-w, BCL-X.sub.L, MCL-1, A1 (BCL2A1) and BCL-B, all of which share up to four BH regions named BH1-4, and prevent cells from entering apoptosis. The BCL-2 pro-apoptotics can be further grouped into the multidomain pro-apoptotic and BH3-only proteins. The multidomain pro-apoptotic effectors, BAX and BAK, also contain four BH (BH1-4) regions and promote cell death by oligomerization-mediated mitochondria outer membrane permeabilization (MOMP). The BH3-only proteins share the BH3 region of sequence similarity. Members of this group include BID, BIM, BAD, BMF, BIK, PUMA, NOXA, HRK/DP5 (Harakiri), NIX, and BNIP3. The BH3 region is 16 to 25 amino acid residues long and some BH3 peptides can promote apoptosis when introduced into cells. The three groups of BCL-2 family proteins form a delicately balanced network of opposing functions that regulates the cell's fate. In certain embodiments, the BCL-2 is a BCL-2 anti-apoptotic. In certain embodiments, the BCL-2 anti-apoptotic is BCL-2, BCL-W, BCL-X.sub.L, or MCL-1. In certain embodiments, the BCL-2 anti-apoptotic is MCL-1. In certain embodiments, the compounds described herein may interact with at least one anti-apoptotic protein member of the BCL-2 family, thereby enhancing apoptosis. In certain embodiments, the compounds described herein may interact with at least one anti-apoptotic protein member of the BCL-2 family and induce its degradation. In certain embodiments, the compounds described herein may interact with at least one pro-apoptotic protein member of the BCL-2 family, thereby enhancing apoptosis. More specifically, such pro-apoptotic member of the BCL-2 family may be any one of BAX, BAK, BNIP3, NIX, BID, NOXA, PUMA and BAD.

(504) In certain embodiments, a compound described herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) modulates the activity of at least one anti-apoptotic BCL-2 family member (e.g., by binding to the hydrophobic dimerization groove of at least one anti-apoptotic BCL-2 family member protein). In certain embodiments, the compounds described herein modulate MCL-1 activity by binding to the hydrophobic dimerization groove of MCL-1. In certain embodiments, the compounds described herein inhibit the activity of at least one anti-apoptotic BCL-2 family protein by binding to the hydrophobic dimerization groove of the BCL-2 protein. In certain embodiments, the compounds described herein inhibit the activity of at least one anti-apoptotic BCL-2 family protein by binding to the hydrophobic dimerization groove of the BCL-X.sub.L protein. In certain embodiments, the compounds described herein can act as NOXA mimetics. NOXA is a pro-apoptotic BH3-only member of the BCL-2 protein family and has been shown to be involved in p53-mediated apoptosis and specifically antagonize MCL-1. In certain embodiments, the compounds described herein mimic NOXA and bind to the hydrophotic dimerization groove of MCL-1 and induce apoptosis in MCL-1 addicted cancer cells. In certain embodiments, the compounds described herein induce the degradation of MCL-1 and thereby trigger apoptotis in MCL-1 addicted cancer cells.

(505) In still another aspect, the present invention provides methods of inducing apoptosis of a cell in a biological sample or a subject.

(506) In certain embodiments, the compounds described herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI)) induce apoptosis of a cell by modulating at least one BCL-2 pathway. In certain embodiments, the compounds described herein induce apoptosis of a cell by modulating MCL-1 pathway. In certain embodiments, the compounds described herein induce apoptosis of a cell by inhibiting at least one BCL-2 pathway. In certain embodiments, the compounds described herein inhibit apoptosis of a cell by modulating MCL-1 pathway.

(507) It should be further noted that by inhibiting the anti-apoptotic action of BCL-2 family proteins, the compounds induce or enhance apoptosis. In certain embodiments, the compounds as described herein may lead to an increase, enhancement, induction, or elevation in apoptosis of treated cells. In certain embodiments, such increase, induction, or elevation of apoptosis may be an increase by about 1% to 99.9%. In certain embodiments, such increase, induction, or elevation of apoptosis may be an increase by about 1% to about 95%. In certain embodiments, such increase, induction, or elevation of apoptosis may be an increase by about 5% to 90%. In certain embodiments, such increase, induction, or elevation of apoptosis may be an increase by about 10% to 85%. In certain embodiments, such increase, induction, or elevation of apoptosis may be an increase by about 15% to 80%. In certain embodiments, such increase, induction, or elevation of apoptosis may be an increase by about 20% to 75%. In certain embodiments, such increase, induction, or elevation of apoptosis may be an increase by about 25% to 70%. In certain embodiments, such increase, induction, or elevation of apoptosis may be an increase by about 30% to 65%. In certain embodiments, such increase, induction, or elevation of apoptosis may be an increase by about 35% to 60%. In certain embodiments, such increase, induction, or elevation of apoptosis may be an increase by about 40% to 55%. In certain embodiments, such increase, induction, or elevation of apoptosis may be an increase by about 45% to 50%. In certain embodiments, such increase, induction, or elevation of apoptosis may be an increase by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99.9%. In certain embodiments, such increase, induction, or elevation of apoptosis may be an increase by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to untreated control.

(508) The cell described herein may be an abnormal cell. The cell may be in vitro or in vivo. In certain embodiments, the cell is a dividing cell. In certain embodiments, the cell is a blood cell. In certain embodiments, the cell is a lymphocyte. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cell is a leukemia cell. In certain embodiments, the cell is a melanoma cell. In certain embodiments, the cell is a multiple myeloma cell. In certain embodiments, the cell is a neoplastic cell. In certain embodiments, the cell is an endothelial cell. In certain embodiments, the cell is an immune cell.

(509) In certain embodiments, the methods described herein include administering to a subject or contacting a biological sample with an effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), 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 methods described herein include administering to a subject or contacting a biological sample with an effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

(510) In certain embodiments, the compound is administered in combination with one or more additional pharmaceutical agents described herein. Exemplary additional therapeutically active agents include, but are not limited to, anti-proliferative agents, antibiotics, anti-viral agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or non-steroidal anti-inflammatory agents, antihistamine, immunosuppressant agents, antigens, vaccines, antibodies, decongestant, sedatives, opioids, pain-relieving agents, analgesics, anti-pyretics, hormones, and prostaglandins, etc. Therapeutically active agents include small organic molecules such as drug compounds (e.g., compounds approved by the US 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.

(511) In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents. 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)). 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 (AGO 13736), 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®, SUl 1248), 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 (Semafoe) 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.

(512) In certain embodiments, the additional anti-cancer agent is an inhibitor of BCL-2. In certain embodiments, the additional anti-cancer agent is an inhibitor of BCL-X.sub.L. In certain embodiments, the additional anti-cancer agent is an inhibitor of an anti-apoptotic BCL-2 family protein. In certain embodiments, the additional anti-cancer agent is navitoclax, 4-[4-[[2-(4-Chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (ABT-263), (R)-4-(4-((4′-chloro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((-4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)benzamide (ABT-737), venetoclax (ABT-199), 1,1′,6,6′,7,7′-hexahydroxy-5,5′-diisopropyl-3,3′-dimethyl-[2,2′-binaphthalene]-8,8′-dicarbaldehyde (AT-101), (Z)-2-(2-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-3-methoxy-2H-pyrrol-5-yl)-1H-indole methanesulfonate (GX15-070), 5-(2-isopropylbenzyl)-N-(4-(2-tert-butylphenylsulfonyl)phenyl)-2,3,4-trihydroxybenzamide (TW-37), Gossypol, (−)-epigallocatechin gallate, obatoclax mesylate, licochalcone A, HA14-1, EM20-25, nilotinib, YCl37, 2-methoxy-antimycin A3, ABT-199, gambogic Acid, or nilotinib. In certain embodiments, the additional anti-cancer agent is an inhibitor of MCL-1. In certain embodiments, the additional anti-cancer agent is ABT-263. In certain embodiments, the additional anti-cancer agent is ABT-199.

(513) The compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. In will further be appreciated that the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved. In general, it is expected that additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

(514) In certain embodiments, the subject being treated is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent, dog, or non-human primate. In certain embodiments, the subject is a non-human transgenic animal such as a transgenic mouse or transgenic pig.

(515) In certain embodiments, the method of the invention may further comprise an additional determination of the anti-apoptotic BCL-2 family levels in the affected subject, such diagnostic step comprise (a) determining the level of expression of at least one BCL-2 pro-survival protein in at least one biological sample of the subject to obtain an expression value. The next step (b) involves determining if the expression value obtained in step (a) is any one of, positive or negative with respect to a predetermined standard expression value or to an expression value of said MCL-1 in a control sample. It should be noted that a positive expression value of said MCL-1 may indicate that the examined subjects may display a beneficial effect in response to compounds that reduce MCL-1 levels, and therefore may be administered with the provided compounds of the invention.

(516) Thus, in more specific embodiments, the invention further provides a method for treating and/or preventing an MCL-1 or other anti-apoptotic BCL-2 family protein over-expressing pathological disorder comprising the step of: First (a) determining the level of expression of at least one BCL-2 prosurvival protein in at least one biological sample of said subject to obtain an expression value. In the second step (b) determining if the expression value obtained in step (a) is any one of, positive or negative with respect to a predetermined standard expression value or to an expression value of said MCL-1 in a control sample. Finally, in step (c) administering to a subject displaying a positive expression value of MCL-1 as determined in step (b), a therapeutically effective amount of at least one compound as described herein.

EXAMPLES

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

(518) Synthesis of Compounds

(519) Compounds described herein can be prepared according to the example provided in Scheme 1. Scheme 1 shows the preparation of Compound 1 (“Mclin”).

(520) ##STR00190## ##STR00191##
Biological Activity

(521) Compounds described herein are anti-proliferative agents and induce apoptosis in cancer cells. Compound 1 (“Mclin”) induces apoptosis with an EC50 of 0.6 μM in MCL-1-addicted cancer cell-line, H23 (See, e.g., FIG. 1A). As a further example, 1 μM of Compound 1 induces robust apoptosis in MCL-1-addicted cancer cell-lines, H23 and H82 (See, e.g., FIG. 1B).

(522) Compounds provided herein are selective MCL-1 inhibitors and induce apoptosis in MCL-1 addicted cells over cells addicted to other BCL-2 family proteins. Compound 1 (“Mclin”), F.sub.9, A8, and M selectively induce apoptosis in MCL-1 addicted cancer cell line over BCL-2 or BCL-X.sub.L addicted cancer cell lines (See, e.g., FIG. 2B). FIG. 3 shows the EC.sub.50 of the indicated compounds in triggering apoptosis in MCL-1-addicted cancer cell lines including H23 and H82. These compounds do not induce apoptosis in cells deficient for the essential apoptotic effectors, Bax and Bak.

(523) Additional compounds have been shown to be effective anti-proliferative agents. FIG. 4 shows the EC.sub.50 of exemplary compounds in triggering apoptosis in the MCL-1-addicted cancer cell line H23.

EQUIVALENTS AND SCOPE

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

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

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

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