CANCER TREATMENTS TARGETING CANCER STEM CELLS

Abstract

Disclosed are compounds, methods, compositions, uses, and kits that allow for treating cancer. In some embodiments, the compounds are used to treat diseases or disorders. The compounds may treat cancer by targeting cancer stem cells. In some embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, lymphoma, liver cancer, endometrial cancer, leukemia, or multiple myeloma. Disclosed are compounds, methods, compositions, uses, and kits that may be used in regenerative medicine. The compounds utilized in the disclosure are of Formula (0) and (I).

##STR00001##

Claims

1. A compound of Formula (0): ##STR00346## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R.sup.1 is substituted or unsubstituted, C.sub.1-12 alkyl or substituted or unsubstituted, C.sub.1-12 heteroalkyl; R.sup.2 is hydrogen, substituted or unsubstituted, C.sub.1-12 alkyl, substituted or unsubstituted, C.sub.1-12 heteroalkyl, substituted or unsubstituted, 3- to 13-membered heterocyclyl-C.sub.1-12-alkyl, substituted or unsubstituted, 3- to 13-membered carbocyclyl-C.sub.1-12-alkyl, or a nitrogen protecting group; when R.sup.2 is unsubstituted methyl, R.sup.1 is not unsubstituted ethyl; R.sup.3 is hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2; each instance of Ra is independently hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; each instance of R.sup.4 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2; each instance of R.sup.5 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2; R.sup.6 is hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, or a nitrogen protecting group; each instance of R.sup.1 is independently hydrogen, halogen, or substituted or unsubstituted, C.sub.1-6 alkyl; each instance of R.sup.9 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2, or two instances of R.sup.9 are joined to form a 3- to 13 membered heterocyclyl, 3- to 13 membered heterocyclyl, 6- to 12 membered aryl ring, or 5- to 14 membered heteroaryl ring; n is an integer from 0 to 4, inclusive; m is an integer from 0 to 3, inclusive; p is an integer from 0 to 3, inclusive; and q is an integer selected from 0 and 1; provided that the compound is not of the formula: ##STR00347## ##STR00348## ##STR00349##

2. The compound of claim 1, wherein the compound is of Formula (0a): ##STR00350## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

3. The compound of claim 1, wherein the compound is of Formula (0b): ##STR00351## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

4. The compound of claim 1, wherein the compound is of Formula (0c): ##STR00352## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

5. The compound of any one of claims 1-4, wherein q is 0.

6. The compound of any one of claims 1-4, wherein q is 1.

7. The compound of any one of claims 1-6, wherein two instances of R.sup.9 are joined to form a 5-membered heteroaryl ring or 5-membered heterocyclyl ring.

8. A compound of Formula (I): ##STR00353## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R.sup.1 is substituted or unsubstituted, C.sub.1-12 alkyl or substituted or unsubstituted, C.sub.1-12 heteroalkyl; R.sup.2 is hydrogen, substituted or unsubstituted, C.sub.1-12 alkyl, substituted or unsubstituted, C.sub.1-12 heteroalkyl, substituted or unsubstituted, 3- to 13-membered heterocyclyl-C.sub.1-12-alkyl, substituted or unsubstituted, 3- to 13-membered carbocyclyl-C.sub.1-12-alkyl, or a nitrogen protecting group; when R.sup.2 is unsubstituted methyl, R.sup.1 is not unsubstituted ethyl; R.sup.3 is hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2; each instance of Ra is independently hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; each instance of R.sup.4 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2; each instance of R.sup.5 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2; R.sup.6 is hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, or a nitrogen protecting group; each instance of R.sup.1 is independently hydrogen, halogen, or substituted or unsubstituted, C.sub.1-6 alkyl; each instance of R.sup.9 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2; n is an integer from 0 to 4, inclusive; m is an integer from 0 to 3, inclusive; and p is an integer from 0 to 3, inclusive; provided that the compound is not of the formula: ##STR00354## ##STR00355## ##STR00356##

9. The compound of claim 1 or 8, wherein the compound is of Formula (Iz): ##STR00357## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

10. The compound of any one of claims 1 and 8-9, wherein n is 0.

11. The compound of any one of claims 1 and 8-9, wherein n is 1.

12. The compound of any one of claims 1 and 8-9, wherein n is 2.

13. The compound of claim 1 or 8, wherein the compound is of Formula (Ia): ##STR00358## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

14. The compound of claim 1 or 8, wherein the compound is of Formula (Ib): ##STR00359## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

15. The compound of claim 1 or 8, wherein the compound is of Formula (Ic): ##STR00360## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

16. The compound of any one of claims 1-15, wherein each R.sup.9 is independently hydrogen, substituted or unsubstituted methyl, chloro, fluoro, methoxy, or —NH.sub.2.

17. The compound of any one of claims 1-16, wherein each R.sup.9 is independently substituted or unsubstituted methyl, chloro, fluoro, methoxy, or —NH.sub.2.

18. The compound of any one of claims 1-17, wherein R.sup.9 is methyl.

19. The compound of any one of claims 1-13 and 16-18, wherein R.sup.3 is hydrogen, substituted or unsubstituted methyl, fluoro, chloro, —CN, or —COOR.sup.a.

20. The compound of any one of claims 1-13 and 16-18, wherein R.sup.3 is hydrogen, substituted or unsubstituted methyl, chloro, bromo, iodo, —CN, or —COOR.sup.a.

21. The compound of any one of claims 1-13 and 16-18, wherein R.sup.3 is hydrogen, substituted or unsubstituted methyl, —CN, or —COOR.sup.a.

22. The compound of any one of claims 1-13 and 16-18, wherein R.sup.3 is methyl or chloro.

23. The compound of any one of claims 1-22, wherein R.sup.1 is substituted or unsubstituted, C.sub.1-3 alkyl.

24. The compound of any one of claims 1-22, wherein R.sup.1 is substituted or unsubstituted, C.sub.1 3 heteroalkyl.

25. The compound of any one of claims 1-22, wherein R.sup.1 is methyl or ethyl.

26. The compound of any one of claims 1-25, wherein R.sup.2 is substituted or unsubstituted, C.sub.1-6 alkyl or substituted or unsubstituted, C.sub.1-6 heteroalkyl.

27. The compound of any one of claims 1-25, wherein R.sup.2 is substituted or unsubstituted, 3- to 6-membered heterocyclyl-C.sub.1-6-alkyl, or substituted or unsubstituted, 3- to 6-membered carbocyclyl-C.sub.1-6-alkyl.

28. The compound of any one of claims 1-25, wherein R.sup.2 is substituted or unsubstituted propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted butyl, or substituted or unsubstituted isobutyl.

29. The compound of any one of claims 1-25, wherein R.sup.2 is substituted or unsubstituted 3- to 6-membered heterocyclyl-C.sub.1-alkyl, or substituted or unsubstituted, 3- to 6-membered carbocyclyl-C.sub.1-alkyl.

30. The compound of any one of claims 1-25, wherein R.sup.2 is substituted or unsubstituted, 3- to 6-membered carbocyclyl-C.sub.1-6-alkyl or substituted or unsubstituted, C.sub.1-6 alkyl.

31. The compound of any one of claims 1-25, wherein R.sup.2 is unsubstituted, 3- to 6-membered carbocyclyl-C.sub.1-2-alkyl or substituted C.sub.1-6 alkyl.

32. The compound of any one of claims 1-31, wherein R.sup.1 and R.sup.2 comprise a combined number of carbon atoms greater than or equal to 4.

33. The compound of any one of claims 1-31, wherein R.sup.1 and R.sup.2 comprise a combined number of non-hydrogen atoms greater than or equal to 4.

34. The compound of claim 8, wherein the compound is selected from the group consisting of: ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tatomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

35. The compound of claim 1 or 8, wherein the compound is selected from the group consisting of: I-466, I-467, I-468, I482, I-483, I-484, I-485, I-486, I-487, I-488, I-489, I-491, I-492, I-495, I-497, I-499, I-500, I-501, I-502, I-503, I-510, I-512, I-517, I-593, I-594, I-595, I-596, I-599, I-600, I-601, I-602, I-603, I-604, I-605, I-606, I-608, I-609, I-610, I-611, I-619, I-620, I-626, I-629, I-631, I-639, I-652, I-658, I-662, I-663, I-677, I-685, I-689, I-690, I-T2106, I-T2107, I-T2120, I-696, I-T2174, I-T2175, I-T2176, I-T2177, I-T2178, I-T2179, I-T2180, I-T2181, I-T2182, I-T2183, I-T2184, I-T2185, I-T2186, I-T2187, I-T2188, I-T2206, I-T2211, I-T2212, I-T2213, I-T2217, I-T2218, I-T2219, I-T2223, I-T2224, I-T2225, I-T2241, I-T2242, I-T2243, I-T2244, I-T2245, I-T2246, I-T2247, I-T2248, I-T2249, I-T2250, I-T2251, I-T2252, I-T2253, I-T2254, I-T2255, I-T2256, I-T2257, and I-T2258, or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

36. The compound of claim 1, wherein the compound is selected from the group consisting of: I-674, 1-676, I-679, I-681, I-683, I-684, I-687, I-T2101, I-T2102, I-T2109, I-T2135, I-T2136, I-693, I-T2157, I-T2158, I-T2159, I-T2160, I-T2173, I-T2189, I-T2190, I-T2191, I-T2192, I-T2193, I-T2194, I-T2195, I-T2196, I-T2197, I-T2198, I-T2199, I-T2200, I-T2208, I-T2209, I-T2210, I-T2214, I-T2215, I-T2216, I-T2220, I-T2221, I-T2222, I-T2226, I-T2227, I-T2228, I-698, I-T2230, I-T2231, I-T2232, I-T2233, I-T2234, I-T2235, I-T2236, I-T2237, I-T2238, I-T2239, and I-T2240, or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

37. The compound of claim 1, wherein the compound is selected from the group consisting of: ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373## or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

38. A compound selected from the group consisting of: ##STR00374## ##STR00375## a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

39. A compound selected from the group consisting of: ##STR00376## ##STR00377## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

40. A compound selected from the group consisting of: I-481, I-597, I-624, I-630, and I-675, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

41. A compound selected from the group consisting of: 1-331, I-496, I-511, I-450, and 1-527, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

42. A compound selected from the group consisting of: ##STR00378## or a pharmaceutically acceptable salt, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

43. A pharmaceutical composition comprising a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; and optionally, a pharmaceutically acceptable excipient.

44. The pharmaceutical composition of claim 43 further comprising an additional pharmaceutical agent.

45. The pharmaceutical composition of claim 44, wherein the additional pharmaceutical agent is a chemotherapeutic agent.

46. The pharmaceutical composition of claim 44, wherein the additional pharmaceutical agent is a differentiation agent.

47. A method of inhibiting NAMPT in a subject, the method comprising administering to the subject a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

48. A method of treating a disease or disorder in a subject by inhibiting NAMPT in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

49. A method of treating a disease or disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

50. The method of claim 49, wherein the disease or disorder is heart failure, dilated cardiomyopathy, pain, inflammation, acute respiratory distress syndrome, ventilator-induced lung injury, graft-versus-host disease (GCDH), pneumonia, pneumonitis, severe acute respiratory distress syndrome, arthritis, acute lung injury, colitis, inflammatory bowel disease (IBD), diabetes, obesity, axon degeneration, a tissue repair disorder, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, osteoporosis, fibrotic diseases, dermatosis, psoriasis, atopic dermatitis, ultra-violet induced skin damage, an autoimmune disease, Alzheimer's disease, stroke, atherosclerosis, restenosis, glomerulonephritis, cachexia, inflammation associated with infection, vascular inflammation, an atherothrombotic disease, Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, ataxia telangiectasia, atherogenic inflammatory disease, a cardiovascular disorder, a cerebrovascular disorder, acute coronary syndrome, polycystic ovary syndrome, preeclampsia, sepsis, septic shock, an intrauterine infection, Crohn's disease (CD), ulcerative colitis (UC), a neurodegenerative disorder, COVID-19, pulmonary inflammation, a coronavirus infection, or a tumor.

51. A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

52. The method of claim 51, wherein the cancer comprises cancer stem cells.

53. The method of any one of claims 51-52, wherein the cancer is gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, or prostate cancer.

54. The method of any one of claims 51-53, wherein the cancer is gastric cancer subtype GS or gastric cancer subtype CIN.

55. The method of any one of claims 51-53, wherein the cancer is colorectal cancer.

56. The method of claim 55, wherein the cancer is colorectal cancer subtype CMS2 or colorectal cancer subtype CMS4.

57. The method of any one of claims 51-52, wherein the cancer is testicular cancer.

58. The method of any one of claims 51-52, wherein the cancer is liver cancer.

59. The method of any one of claims 51-52, wherein the cancer is endometrial cancer.

60. The method of claim 59, wherein the cancer is uterine cancer.

61. The method of any one of claims 51-52, wherein the cancer is small cell lung cancer.

62. The method of any one of claims 51-52, wherein the cancer is lymphoma.

63. The method of claim 62, wherein the cancer is non-Hodgkin's lymphoma, B-cell lymphoma, large B-cell lymphoma, Burkitt's lymphoma, Burkitt's B-cell lymphoma, or large cell immunoblastic lymphoma.

64. The method of any one of claims 51-52, wherein the cancer is leukemia.

65. The method of claim 64, wherein the cancer is acute myeloid leukemia.

66. The method of claim 65, wherein the cancer is undifferentiated acute myeloblastic leukemia (M0), acute myeloblastic leukemia with minimal maturation (M1), acute myeloblastic leukemia with maturation (M2), acute promyelocytic leukemia (APL) (M3), acute myelomonocytic leukemia (M4), acute myelomonocytic leukemia with eosinophilia (M4 eos), acute monocytic leukemia (M5), acute erythroid leukemia (M6), or acute megakaryoblastic leukemia (M7).

67. The method of claim 64, wherein the cancer is acute monocytic leukemia, acute lymphocytic leukemia, or B-cell acute lymphocytic leukemia.

68. The method of claim 64, wherein the cancer is chronic myelocytic leukemia (CML) or chronic lymphocytic leukemia.

69. The method of claim 64, wherein the cancer is acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, or T-cell acute lymphoblastic leukemia.

70. The method of any one of claims 51-52, wherein the cancer is multiple myeloma.

71. The method of claim 70, wherein the cancer is B-cell myeloma.

72. The method of any one of claims 51-71, wherein the subject has or is undergoing one or more additional cancer therapies.

73. The method of any one of claims 51-72, wherein the subject is in need of a regenerative medicine.

74. A method comprising contacting a cell, tissue, or biological sample with an effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

75. The method of claim 74, wherein the cell is characterized by one or more embryonic, pluripotent, or adult stem cell properties.

76. The method of claim 74 or 75, wherein the cell is a cancer stem cell, an embryonic stem cell, an induced pluripotent stem cell, a neural stem cell, a differentiated cancer cell, or an adult stem cell.

77. The method of any one of claims 74-76, wherein the contacting reduces one or more embryonic properties or adult stem cell properties of the cell.

78. The method of any one of claims 74-77, wherein the contacting is in vitro or ex vivo.

79. The method of any one of claims 74-78, wherein the contacting reduces cell viability and/or prevents cell proliferation.

80. The method of any one of claims 74-79, wherein the contacting kills the cell.

81. The method of any one of claims 74-80, wherein the contacting inhibits tumor growth.

82. The method of any one of claims 74-81, wherein the contacting prevents metastasis.

83. The method of any one of claims 74-82, wherein the contacting differentiates one or more cells.

84. The method of any one of claims 74-83, wherein the contacting regenerates one or more cells.

85. A method comprising killing a cell with an effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

86. The method of claim 85, wherein the cell is characterized by one or more embryonic properties or adult stem cell properties.

87. The method of any one of claims claim 85 or 86, wherein the cell is a cancer stem cell, an embryonic stem cell, an induced pluripotent stem cell, a neural stem cell, an adult stem cell, or a differentiated cancer cell.

88. The method of any one of claims 85-87, wherein the contacting reduces one or more embryonic properties or adult stem cell properties of the cell.

89. The method of any one of claims 85-88, wherein the contacting is in vitro or ex vivo.

90. A method of inhibiting production of nicotinamide adenine dinucleotide in a subject, the method comprising administering to the subject a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

91. A method of treating a disease or disorder in a subject by inhibiting the production of nicotinamide adenine dinucleotide in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

92. A method of inhibiting production of nicotinamide mononucleotide in a subject, the method comprising administering to the subject a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

93. A method of treating a disease or disorder in a subject by inhibiting the production of nicotinamide mononucleotide in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

94. A method of reducing inflammatory cell infiltration in a subject, the method comprising administering to the subject a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

95. A method of treating a disease or disorder in a subject by reducing inflammatory cell infiltration in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

96. A method of reducing cell proliferation in a subject, the method comprising administering to the subject a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

97. A method of treating a disease or disorder in a subject by reducing cell proliferation in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

98. A method of reducing cellular metabolic activity or state in a subject, the method comprising administering to the subject a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

99. A method of treating a disease or disorder in a subject by reducing cellular metabolic activity or state in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

100. A method of decreasing inflammatory activity in a subject, the method comprising administering to the subject a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

101. A method of treating a disease or disorder in a subject by decreasing inflammatory activity in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

102. A method of decreasing NAMPT signaling in a subject, the method comprising administering to the subject a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

103. A method of treating a disease or disorder in a subject by decreasing NAMPT signaling in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

104. A method of inhibiting a NAMPT pathway in a subject, the method comprising administering to the subject a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

105. A method of treating a disease or disorder in a subject by inhibiting a NAMPT pathway in the subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

106. A method of inhibiting a NAMPT pathway in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

107. A method of decreasing NAMPT signaling in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

108. A method of decreasing inflammatory activity in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

109. A method of reducing cellular metabolic activity or state in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

110. A method of reducing cell proliferation in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

111. A method of reducing inflammatory cell infiltration in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

112. A method of inhibiting production of nicotinamide adenine dinucleotide in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

113. A method of inhibiting production of nicotinamide mononucleotide in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

114. A method of inhibiting NAMPT in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

115. The method of any one of claims 106-114, wherein the contacting is in vitro or ex vivo.

116. A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46, and an additional pharmaceutical agent.

117. The method of claim 116, wherein the additional pharmaceutical agent is administered, before, concurrently with, or after the compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or composition of any one of claims 43-46.

118. The method of any one of claims 48, 91, 93, 95, 97, 99, 101, 103, 105, and 116-117, wherein the disease or disorder is heart failure, dilated cardiomyopathy, pain, inflammation, acute respiratory distress syndrome, ventilator-induced lung injury, graft-versus-host disease (GCDH), pneumonia, pneumonitis, severe acute respiratory distress syndrome, arthritis, acute lung injury, colitis, inflammatory bowel disease (IBD), diabetes, obesity, axon degeneration, a tissue repair disorder, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, osteoporosis, fibrotic diseases, dermatosis, psoriasis, atopic dermatitis, ultra-violet induced skin damage, an autoimmune disease, Alzheimer's disease, stroke, atherosclerosis, restenosis, glomerulonephritis, cachexia, inflammation associated with infection, vascular inflammation, an atherothrombotic disease, Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, ataxia telangiectasia, atherogenic inflammatory disease, a cardiovascular disorder, a cerebrovascular disorder, acute coronary syndrome, polycystic ovary syndrome, preeclampsia, sepsis, septic shock, an intrauterine infection, Crohn's disease (CD), ulcerative colitis (UC), a neurodegenerative disorder, COVID-19, pulmonary inflammation, a coronavirus infection, or a tumor.

119. A kit comprising: a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; or a pharmaceutical composition of claim 43-46; and instructions for using the compound, pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, or pharmaceutical composition.

Description

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0169] Before the disclosed systems, compounds, compositions, methods, uses, and kits are described in more detail, it should be understood that the aspects described herein are not limited to specific embodiments, methods, systems, apparati, or configurations, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.

[0170] The compounds of the disclosure, and compositions and kits thereof, are useful for cancer treatment and the treatment of proliferative diseases or used for regenerative medicine. The compounds may differentiate embryonic-like cancer stem cells, kill differentiated cancer stem cells, disrupt their proliferation, and/or inhibit their ability to form new tumors. The compounds may inhibit tumor growth, regenerate or differentiate one or more cells, prevent metastasis, kill cancer cells, reduce embryonic properties or adult stem cell properties of one or more cells, reduce cell viability, and/or prevent cell proliferation. Embryonic-like properties, including embryonic gene expression patterns, are re-activated across a variety of different types of cancers. Additionally, the compounds may differentiate adult-like cancer stem cells, kill differentiated adult cancer stem cells, disrupt their proliferation, and/or inhibit their ability to form new tumors. Adult stem cells are also associated with a variety of different types of cancers. In certain embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, lymphoma, leukemia, or liver cancer. For example, embryonic-like properties have been found in cancer stem cells from solid tumors, such as colorectal cancer, gastric cancer, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, and prostate cancer..sup.10 Embryonic-like properties have been also found in cancer stem cells from hematopoietic cancers, such as leukemia and lymphoma..sup.14

[0171] Without wishing to be bound by a particular theory, the compounds and compositions disclosed herein are believed to modulate (e.g., inhibit) nicotinamide phosphoribosyltransferase (NAMPT), which is also referred to as Visfatin and Pre-B-Cell Colony-Enhancing Factor 1 (PBEF). NAMPT is an enzyme that catalyzes the first step in the biosynthesis of nicotinamide adenine dinucleotide (NAD) from nicotinamide..sup.15 Nicotinamide adenine dinucleotide is an essential cofactor for cellular metabolism. Nicotinamide mononucleotide (NMN) is the product of the NAMPT enzymatic reaction. NAMPT has been indicated in a wide variety of diseases and disorders, thus, modulation (i.e., inhibition) of NAMPT can treat a broad range of indications..sup.15,16,17 Further, NAMPT is also involved in signaling, displaying activity as an adipocytokine.sup.18 and immunomodulatory cytokine.sup.19. Increased levels of NAMPT have been described in (i) metabolic/inflammatory conditions including obesity, type 2 diabetes, metabolic syndromes, atherogenic inflammatory diseases, and cardio-cerebro-vascular disorders, (ii) non-metabolic chronic inflammatory diseases including osteoarthritis and acute lung injury, (iii) infections like sepsis or intrauterine infection, and (iv) autoimmune inflammatory diseases including psoriasis, rheumatoid arthritis, Crohn's disease, and ulcerative colitis..sup.15 Accordingly, the compounds of the disclosure, and compositions and kits thereof, are useful for treating or preventing a wide variety of diseases and disorders.

Compounds

[0172] In certain aspects, the present disclosure provides compounds of Formula (0) or (I). Additional compounds are also provided herein.

[0173] In certain embodiments, a compound of the disclosure is a compound (e.g. a compound of Formula (0) or (I), or compound as described in the Additional Compounds section below), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, a compound of the disclosure is a compound (e.g., a compound of Formula (0) or (I), or compound as described in the Additional Compounds section below), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a compound of the disclosure is a compound (e.g., a compound of Formula (0) or (I), or compound as described in the Additional Compounds section below), or a pharmaceutically acceptable salt thereof.

[0174] The compounds of the present disclosure may have a high aqueous solubility. Compared to certain similar known compounds, the compounds of the present disclosure may have a higher (e.g., at least 10%, at least 20%, at least 50%, at least 100%, at least 200%, at least 500%, or at least 1,000% higher) aqueous solubility.

[0175] The compounds of the present disclosure may have a high microsomal stability. Compared to certain similar known compounds, the compounds of the present disclosure may have a higher (e.g., at least 10%, at least 20%, at least 50%, at least 100%, at least 200%, at least 500%, or at least 1,000% higher) microsomal stability.

[0176] The compounds of the present disclosure may treat cancer. Compared to certain similar known compounds, the compounds of the present disclosure may be better at treating cancer (e.g., at least 10%, at least 20%, at least 50%, at least 100%, at least 200%, at least 500%, or at least 1,000% better), which may be evidenced by a decrease in cancer symptoms and/or tumor size.

Compounds of Formula (0) and (I)

[0177] In certain embodiments, provided herein is a compound of Formula (0):

##STR00008##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: [0178] R.sup.1 is substituted or unsubstituted, C.sub.1-12 alkyl or substituted or unsubstituted, C.sub.1-12 heteroalkyl; [0179] R.sup.2 is hydrogen, substituted or unsubstituted, C.sub.1-12 alkyl, substituted or unsubstituted, C.sub.1-12 heteroalkyl, substituted or unsubstituted, 3- to 13-membered heterocyclyl-C.sub.1-12-alkyl, substituted or unsubstituted, 3- to 13-membered carbocyclyl-C.sub.1-12-alkyl, or a nitrogen protecting group; [0180] when R.sup.2 is unsubstituted methyl, R.sup.1 is not unsubstituted ethyl; [0181] R.sup.3 is hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2; [0182] each instance of Ra is independently hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; [0183] each instance of R.sup.4 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2; [0184] each instance of R.sup.5 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2; [0185] R.sup.6 is hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, or a nitrogen protecting group; [0186] each instance of R.sup.8 is independently hydrogen, halogen, or substituted or unsubstituted, C.sub.1-6 alkyl; [0187] each instance of R.sup.9 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2, or two instances of R.sup.9 are joined to form a 3- to 13 membered heterocyclyl, 3- to 13 membered heterocyclyl, 6- to 12 membered aryl ring, or 5- to 14 membered heteroaryl ring; [0188] n is an integer from 0 to 4, inclusive; [0189] m is an integer from 0 to 3, inclusive; [0190] p is an integer from 0 to 3, inclusive; and [0191] q is an integer selected from 0 and 1.

[0192] In certain embodiments, a compound of Formula (0) is of Formula (0a):

##STR00009##

[0193] In certain embodiments, a compound of Formula (0) is of Formula (0b):

##STR00010##

[0194] In certain embodiments, a compound of Formula (0) is of Formula (0c):

##STR00011##

[0195] In certain embodiments, provided herein is a compound of Formula (I):

##STR00012##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: [0196] R.sup.1 is substituted or unsubstituted, C.sub.1-12 alkyl or substituted or unsubstituted, C.sub.1-12 heteroalkyl; [0197] R.sup.2 is hydrogen, substituted or unsubstituted, C.sub.1-12 alkyl, substituted or unsubstituted, C.sub.1-12 heteroalkyl, substituted or unsubstituted, 3- to 13-membered heterocyclyl-C.sub.1-12-alkyl, substituted or unsubstituted, 3- to 13-membered carbocyclyl-C.sub.1-12-alkyl, or a nitrogen protecting group; [0198] when R.sup.2 is unsubstituted methyl, R.sup.1 is not unsubstituted ethyl; [0199] R.sup.3 is hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2; [0200] each instance of Ra is independently hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; [0201] each instance of R.sup.4 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2; [0202] each instance of R.sup.5 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2; [0203] R.sup.6 is hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, or a nitrogen protecting group; [0204] each instance of R.sup.1 is independently hydrogen, halogen, or substituted or unsubstituted, C.sub.1-6 alkyl; [0205] each instance of R.sup.9 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2; [0206] n is an integer from 0 to 4, inclusive; [0207] m is an integer from 0 to 3, inclusive; and [0208] p is an integer from 0 to 3, inclusive.

[0209] In certain embodiments, a compound of Formula (I) is of Formula (Iz):

##STR00013##

[0210] In certain embodiments, a compound of Formula (I) is of Formula (Ia):

##STR00014##

[0211] In certain embodiments, a compound of Formula (I) is of Formula (Ib):

##STR00015##

[0212] In certain embodiments, a compound of Formula (I) is of Formula (Ic):

##STR00016##

[0213] In certain embodiments, R.sup.1 is substituted or unsubstituted, C.sub.1 12 alkyl. In certain embodiments, R.sup.1 is substituted C.sub.1-12 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1 12 alkyl. In certain embodiments, R.sup.1 is substituted or unsubstituted, 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 unsubstituted C.sub.1 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.2 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.3 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.4 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.5 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.6 alkyl. In certain embodiments, R.sup.1 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is substituted C.sub.1 alkyl. In certain embodiments, R.sup.1 is substituted C.sub.2 alkyl. In certain embodiments, R.sup.1 is substituted C.sub.3 alkyl. In certain embodiments, R.sup.1 is substituted C.sub.4 alkyl. In certain embodiments, R.sup.1 is substituted C.sub.5 alkyl. In certain embodiments, R.sup.1 is substituted C.sub.6 alkyl. In certain embodiments, R.sup.1 is fluorinated C.sub.1-6 alkyl (e.g., —CF.sub.3, —CHF.sub.2, —CH.sub.2F). In certain embodiments, R.sup.1 is methyl. In certain embodiments, R.sup.1 is ethyl. In some embodiments, R.sup.1 is propyl. In certain embodiments, R.sup.1 is substituted or unsubstituted, C.sub.1-12 heteroalkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.112 heteroalkyl. In certain embodiments, R.sup.1 is substituted C.sub.112 heteroalkyl. In certain embodiments, R.sup.1 is substituted or unsubstituted, C.sub.1-6 heteroalkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 heteroalkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1 heteroalkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.2 heteroalkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.3 heteroalkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.4 heteroalkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.5 heteroalkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.6 heteroalkyl. In certain embodiments, R.sup.1 is substituted C.sub.1-6 heteroalkyl. In certain embodiments, R.sup.1 is substituted C.sub.1 heteroalkyl. In certain embodiments, R.sup.1 is substituted C.sub.2 heteroalkyl. In certain embodiments, R.sup.1 is substituted C.sub.3 heteroalkyl. In certain embodiments, R.sup.1 is substituted C.sub.4 heteroalkyl. In certain embodiments, R.sup.1 is substituted C.sub.5 heteroalkyl. In certain embodiments, R.sup.1 is substituted C.sub.6 heteroalkyl. In some embodiments, R.sup.1 is methoxy, ethoxy, or propoxy. In certain embodiments, R.sup.1 is substituted with halo, —CN, —NRa.sub.2, —Co.sub.2R.sup.aa, —C(═O)R.sup.aa, OC(═O)R.sup.aa, OCO.sub.2R.sup.aa, —C(═O)N(R.sup.bb).sub.2, —OC(═O)N(R.sup.bb).sub.2, —NR.sup.bbC(═O)R.sup.aa, —NR.sup.bbCo.sub.2R.sup.aa, or —NR.sup.bbC(═O)N(R.sup.bb).sub.2. In certain embodiments, R.sup.1 is substituted with —CO.sub.2R.sup.aa, —OC(═O)R.sup.aa, OCO.sub.2R.sup.aa, —C(═O)N(R.sup.bb).sub.2, —OC(═O)N(R.sup.bb).sub.2, —NR.sup.bbC(═O)R.sup.aa, —NR.sup.bbCO.sub.2R.sup.aa, or —NR.sup.bbC(═O)N(R.sup.bb).sub.2.

[0214] In some embodiments, R.sup.bb is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, or pentyl.

[0215] In certain embodiments, the substituent on the R.sup.1 group is —CN, —F, —Cl, —N(R.sup.a)(C═O)OR.sup.a, or —COOR.sup.a. In certain embodiments, the substituent on the R.sup.1 group is —CN, —F, —C.sub.1, —NRa.sub.2, —N(R.sup.a)(C═O)OR.sup.a, —COOR.sup.a, or —(C═O)R.sup.a. In certain embodiments, the substituent on the R.sup.1 group is —CN, —F, —Cl, —NH.sub.2, —NHC(═O)OEt, —NHC(═O)OMe, —NHC(═O)O.sup.tBu, or —C(═O)CH.sub.3.

[0216] In certain embodiments, R.sup.2 is hydrogen. In certain embodiments, R.sup.2 is not hydrogen. In certain embodiments, R.sup.2 is substituted or unsubstituted, C.sub.1-12 alkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.1-12 alkyl. In certain embodiments, R.sup.2 is substituted C.sub.1-12 alkyl. In certain embodiments, R.sup.2 is Me. In certain embodiments, R.sup.2 is Et, Pr, or Bu. In certain embodiments, R.sup.2 is a nitrogen protecting group.

[0217] In certain embodiments, R.sup.2 is substituted or unsubstituted, C.sub.1-12 alkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.1-12 alkyl. In certain embodiments, R.sup.2 is substituted C.sub.1-12 alkyl. In certain embodiments, R.sup.2 is substituted or unsubstituted, C.sub.1-6 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 alkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.2 alkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.3 alkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.4 alkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.5 alkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.6 alkyl. In certain embodiments, R.sup.2 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is substituted C.sub.1 alkyl. In certain embodiments, R.sup.2 is substituted C.sub.2 alkyl. In certain embodiments, R.sup.2 is substituted C.sub.3 alkyl. In certain embodiments, R.sup.2 is substituted C.sub.4 alkyl. In certain embodiments, R.sup.2 is substituted C.sub.5 alkyl. In certain embodiments, R.sup.2 is substituted C.sub.6 alkyl. In certain embodiments, R.sup.2 is halogenated C.sub.1-12 alkyl. In certain embodiments, R.sup.2 is substituted C.sub.6 alkyl. In certain embodiments, R.sup.2 is fluorinated C.sub.1-6 alkyl (e.g., —CF.sub.3, —CHF.sub.2, —CH.sub.2F). In certain embodiments, R.sup.2 is methyl. In certain embodiments, R.sup.2 is ethyl. In some embodiments, R.sup.2 is propyl. In certain embodiments, R.sup.2 is substituted or unsubstituted, C.sub.1-12 heteroalkyl. In certain embodiments, R.sup.2 is substituted C.sub.1-12 heteroalkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.1-12 heteroalkyl. In certain embodiments, R.sup.2 is substituted or unsubstituted, C.sub.1-6 heteroalkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.1-6 heteroalkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.1 heteroalkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.2 heteroalkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.3 heteroalkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.4 heteroalkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.5 heteroalkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.6 heteroalkyl. In certain embodiments, R.sup.2 is substituted C.sub.1-6 heteroalkyl. In certain embodiments, R.sup.2 is substituted C.sub.1 heteroalkyl. In certain embodiments, R.sup.2 is substituted C.sub.2 heteroalkyl. In certain embodiments, R.sup.2 is substituted C.sub.3 heteroalkyl. In certain embodiments, R.sup.2 is substituted C.sub.4 heteroalkyl. In certain embodiments, R.sup.2 is substituted C.sub.5 heteroalkyl. In certain embodiments, R.sup.2 is substituted C.sub.6 heteroalkyl. In some embodiments, R.sup.2 is methoxy, ethoxy, or propoxy.

[0218] In certain embodiments, R.sup.2 is substituted or unsubstituted, 3- to 13-membered heterocyclyl-C.sub.1-12 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 13-membered heterocyclyl-C.sub.1-12 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 13-membered heterocyclyl-C.sub.1-12 alkyl. In certain embodiments, R.sup.2 is substituted or unsubstituted, 3- to 13-membered heterocyclyl-C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 6-membered heterocyclyl-C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 6-membered heterocyclyl-C.sub.1 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 6-membered heterocyclyl-C.sub.2 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 6-membered heterocyclyl-C.sub.3 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 6-membered heterocyclyl-C.sub.4 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 6-membered heterocyclyl-C.sub.5 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 6-membered heterocyclyl-C.sub.6 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 6-membered heterocyclyl-C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 6-membered heterocyclyl-C.sub.1 alkyl. In certain embodiments, R.sup.2 is substituted C.sub.2 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 6-membered heterocyclyl-C.sub.3 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 6-membered heterocyclyl-C.sub.4 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 6-membered heterocyclyl-C.sub.5 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 6-membered heterocyclyl-C.sub.6 alkyl. In certain embodiments, R.sup.2 is halogenated 3- to 6-membered heterocyclyl-C.sub.1-12 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 6-membered heterocyclyl-C.sub.6 alkyl.

[0219] In certain embodiments, R.sup.2 is substituted or unsubstituted, 3- to 13-membered carbocyclyl-C.sub.1-12 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 13-membered carbocyclyl-C.sub.1-12 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 13-membered carbocyclyl-C.sub.1-12 alkyl. In certain embodiments, R.sup.2 is substituted or unsubstituted, 3- to 13-membered carbocyclyl-C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 6-membered carbocyclyl-C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 6-membered carbocyclyl-C.sub.1 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 6-membered carbocyclyl-C.sub.2 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 6-membered carbocyclyl-C.sub.3 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 6-membered carbocyclyl-C.sub.4 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 6-membered carbocyclyl-C.sub.5 alkyl. In certain embodiments, R.sup.2 is unsubstituted 3- to 6-membered carbocyclyl-C.sub.6 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 6-membered carbocyclyl-C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 6-membered carbocyclyl-C.sub.1 alkyl. In certain embodiments, R.sup.2 is substituted C.sub.2 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 6-membered carbocyclyl-C.sub.3 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 6-membered carbocyclyl-C.sub.4 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 6-membered carbocyclyl-C.sub.5 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 6-membered carbocyclyl-C.sub.6 alkyl. In certain embodiments, R.sup.2 is halogenated 3- to 6-membered carbocyclyl-C.sub.1 12 alkyl. In certain embodiments, R.sup.2 is substituted 3- to 6-membered carbocyclyl-C.sub.6 alkyl.

[0220] In certain embodiments, R.sup.2 is substituted C.sub.6 heteroalkyl. In some embodiments, R.sup.2 is methoxy, ethoxy, or propoxy.

[0221] In certain embodiments, R.sup.2 is substituted with halo, —CN, —NR.sup.a.sub.2, —CO.sub.2R.sup.aa, C(═O)R.sup.aa, —OC(═O)R.sup.aa, —OCO.sub.2R.sup.aa, —C(═O)N(R.sup.bb).sub.2, —OC(═O)N(R.sup.bb).sub.2, —NR.sup.bbC(═O)R.sup.aa, —NR.sup.bbCO.sub.2R.sup.aa, or —NR.sup.bbC(═O)N(R.sup.bb).sub.2. In certain embodiments, R.sup.2 is substituted with —CO.sub.2R.sup.aa, OC(═O)R.sup.aa, —OCO.sub.2R.sup.aa, —C(═O)N(R.sup.bb).sub.2, —OC(═O)N(R.sup.bb).sub.2, —NR.sup.bbC(═O)R.sup.aa, —NR.sup.bbCO.sub.2R.sup.aa, or —NR.sup.bbC(═O)N(R.sup.bb).sub.2.

[0222] In some embodiments, R.sup.bb is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, or pentyl.

[0223] In certain embodiments, the substituent on the R.sup.2 group is —CN, —F, —Cl, —N(R.sup.a)(C═O)OR.sup.a, or COOR.sup.a.

[0224] In certain embodiments, the substituent on the R.sup.2 group is —CN, —F, —Cl, —N(R.sup.a)(C═O)OR.sup.a, or —COOR.sup.a. In certain embodiments, the substituent on the R.sup.2 group is —CN, —F, —Cl, —NR.sup.a.sub.2, —N(R.sup.a)(C═O)OR.sup.a, —COOR.sup.a, or —(C═O)R.sup.a. In certain embodiments, the substituent on the R.sup.1 group is —CN, —F, —Cl, —NH.sub.2, —NHC(═O)OEt, —NHC(═O)OMe, —NHC(═O)O.sup.tBu, or —C(═O)CH.sub.3.

[0225] In certain embodiments, when R.sup.2 is unsubstituted methyl, R.sup.1 is not unsubstituted ethyl. In some embodiments, when R.sup.2 is methyl, R.sup.1 is not ethyl.

[0226] In certain embodiments, when R.sup.2 is unsubstituted methyl, R.sup.1 is not unsubstituted n-propyl. In some embodiments, when R.sup.2 is methyl, R.sup.1 is not n-propyl.

[0227] In certain embodiments, when R.sup.2 is unsubstituted methyl, R.sup.1 is not unsubstituted ethoxy. In some embodiments, when R.sup.2 is methyl, R.sup.1 is not ethoxy.

[0228] In certain embodiments, R.sup.1 is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, methoxy, or ethoxy; and R.sup.2 is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted 3- to 6-membered carbocyclyl-C.sub.1 alkyl, substituted or unsubstituted 3- to 6-membered carbocyclyl-C.sub.2 alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl-C.sub.1 alkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl-C.sub.2 alkyl.

[0229] In certain embodiments, R.sup.2 is substituted C.sub.1-6 alkyl. In some embodiments, R.sup.2 is haloalkyl. In certain embodiments, R.sup.2 is difluoroethyl. In some embodiments, R.sup.2 is 2,2-difluoroethyl.

[0230] In some embodiments, R.sup.2 is substituted or unsubstituted 3- to 6-membered carbocyclyl-C.sub.1-6 alkyl. In some embodiments, R.sup.2 is substituted or unsubstituted 3- to 6-membered carbocyclyl-C.sub.1 alkyl. In some embodiments, R.sup.2 is cyclopropylmethyl.

[0231] In some embodiments, R.sup.3 is hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2. In some embodiments, R.sup.3 is hydrogen, chloro, bromo, iodo, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2. In some embodiments, R.sup.3 is hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2.

[0232] In some embodiments, R.sup.3 is hydrogen. In certain embodiments, R.sup.3 is halogen. In certain embodiments, R.sup.3 is chloro, bromo, or iodo. In certain embodiments, R.sup.3 is chloro. In certain embodiments, R.sup.3 is fluoro. In certain embodiments, R.sup.3 is —CN. In certain embodiments, R.sup.3 is substituted or unsubstituted, C.sub.1-6 alkyl (e.g., unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.3 is methyl. In certain embodiments, R.sup.3 is ethyl. In some embodiments, R.sup.3 is propyl or butyl. In certain embodiments, R.sup.3 is fluorinated C.sub.1-6 alkyl (e.g., fluorinated methyl, e.g., —CF.sub.3). In certain embodiments, R.sup.3 is —OR.sup.a. In certain embodiments, R.sup.3 is —OH. In certain embodiments, R.sup.3 is —O(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —OMe). In certain embodiments, R.sup.3 is —COOR.sup.a. In certain embodiments, R.sup.3 is —COOR.sup.a, where Ra is hydrogen or substituted or unsubstituted, C.sub.1-6 alkyl (e.g., —COOMe, —COOEt, —COO(CH.sub.2).sub.2CH.sub.3, —COO(CH.sub.2).sub.3CH.sub.3, or —COOC(CH.sub.3).sub.3. In certain embodiments, R.sup.3 is —COR.sup.a. In certain embodiments, R.sup.3 is —COR.sup.a where Ra is hydrogen or substituted or unsubstituted, C.sub.1-6 alkyl (e.g., —COMe, —COEt, —CO(CH.sub.2).sub.2CH.sub.3, —CO(CH.sub.2).sub.3CH.sub.3, or —COC(CH.sub.3).sub.3). In certain embodiments, R.sup.3 is —N(R.sup.a).sub.2. In certain embodiments, R.sup.3 is —NH.sub.2. In certain embodiments, R.sup.3 is —NHR.sup.a (e.g., —NH(substituted or unsubstituted, C.sub.1-6 alkyl), e.g., —NHMe). In certain embodiments, R.sup.3 is —N(substituted or unsubstituted, C.sub.1-6 alkyl).sub.2, e.g., —N(Me).sub.2). In certain embodiments, R.sup.3 is —C(═O)N(R.sup.a).sub.2. In certain embodiments, R.sup.3 is —C(═O)NH.sub.2. In certain embodiments, R.sup.3 is —C(═O)NHR.sup.a (e.g., —C(═O)NH(substituted or unsubstituted, C.sub.1-6 alkyl), e.g., —C(═O)NHMe). In certain embodiments, R.sup.3 is —C(═O)N(substituted or unsubstituted, C.sub.1-6 alkyl).sub.2, e.g., —C(═O)N(Me).sub.2). In some embodiments, R.sup.3 is halo or —COOR.sup.a. In some embodiments, R.sup.3 is chloro or —COOMe.

[0233] In certain embodiments, each instance of Ra is independently hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, each instance of Ra is hydrogen. In certain embodiments, no instance of Ra is hydrogen. In certain embodiments, at least one instance of Ra is substituted or unsubstituted, C.sub.1-6 alkyl (e.g., unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of Ra is Me. In certain embodiments, at least one instance of Ra is Et, Pr, or Bu. In certain embodiments, at least one instance of Ra is fluorinated C.sub.1-6 alkyl (e.g., fluorinated methyl, e.g., —CF.sub.3).

[0234] In some embodiments, R.sup.4 is hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2. In some embodiments, R.sup.4 is hydrogen. In certain embodiments, R.sup.4 is halogen. In certain embodiments, R.sup.4 is chloro. In certain embodiments, R.sup.4 is fluoro. In certain embodiments, R.sup.4 is —CN. In certain embodiments, R.sup.4 is substituted or unsubstituted, C.sub.1-6 alkyl (e.g., unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.4 is methyl. In certain embodiments, R.sup.4 is ethyl. In some embodiments, R.sup.4 is propyl or butyl. In certain embodiments, R.sup.4 is fluorinated C.sub.1-6 alkyl (e.g., fluorinated methyl, e.g., —CF.sub.3). In certain embodiments, R.sup.4 is —OR.sup.a. In certain embodiments, R.sup.4 is —OH. In certain embodiments, R.sup.4 is —O(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —OMe). In certain embodiments, R.sup.4 is —COOR.sup.a. In certain embodiments, R.sup.4 is —COOR.sup.a where Ra is hydrogen or substituted or unsubstituted, C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is —COR.sup.a. In certain embodiments, R.sup.4 is —COR.sup.a where Ra is hydrogen or substituted or unsubstituted, C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is —N(R.sup.a).sub.2. In certain embodiments, R.sup.4 is —NH.sub.2. In certain embodiments, R.sup.4 is —NHR.sup.a (e.g., —NH(substituted or unsubstituted, C.sub.1-6 alkyl)). In certain embodiments, R.sup.4 is —N(substituted or unsubstituted, C.sub.1-6 alkyl).sub.2, e.g., —N(Me).sub.2). In certain embodiments, R.sup.4 is —C(═O)N(R.sup.a).sub.2. In certain embodiments, R.sup.4 is —C(═O)N(R.sup.a).sub.2, where Ra is hydrogen or substituted or unsubstituted, C.sub.1-6 alkyl.

[0235] In certain embodiments, p is 0. In some embodiments, p is 1. In certain embodiments, p is 2. In some embodiments, p is 3.

[0236] In certain embodiments, the phenyl ring which bears R.sup.3 and optionally, bears R.sup.4 is represented

##STR00017##

In some embodiments, the phenyl ring which bears R.sup.3 and optionally, bears R.sup.4 is represented by:

##STR00018##

In certain embodiments, the
phenyl ring which bears R.sup.3 and optionally, bears R.sup.4 is represented by:

##STR00019##

In certain embodiments, the phenyl ring which bears R.sup.3 and optionally, bears R.sup.4 is represented by:

##STR00020##

[0237] In certain embodiments, each instance of R.sup.5 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —N(Ra).sub.2, or —CN. In certain embodiments, each instance of R.sup.5 is independently —COOR.sup.a, —COR.sup.a, or —(C═O)N(Ra).sub.2. In certain embodiments, at least one instance of R.sup.5 is hydrogen. In certain embodiments, each instance of R.sup.5 is hydrogen. In certain embodiments, at least one instance of R.sup.5 is not hydrogen. In certain embodiments, no instance of R.sup.5 is hydrogen. In certain embodiments, at least one instance of R.sup.5 is halogen. In certain embodiments, at least one instance of R.sup.5 is F. In certain embodiments, at least one instance of R.sup.5 is Cl. In certain embodiments, at least one instance of R.sup.5 is substituted or unsubstituted, C.sub.1-6 alkyl (e.g., unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.5 is Me. In certain embodiments, at least one instance of R.sup.5 is Et, Pr, or Bu. In certain embodiments, at least one instance of R.sup.5 is fluorinated C.sub.1-6 alkyl (e.g., fluorinated methyl, e.g., —CF.sub.3). In certain embodiments, at least one instance of R.sup.5 is —OR.sup.a. In certain embodiments, at least one instance of R.sup.5 is —OH. In certain embodiments, at least one instance of R.sup.5 is —O(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —OMe). In certain embodiments, at least one instance of R.sup.5 is —N(Ra).sub.2. In certain embodiments, at least one instance of R.sup.5 is —NH.sub.2. In certain embodiments, at least one instance of R.sup.5 is —NHR.sup.a (e.g., —NH(substituted or unsubstituted, C.sub.1-6 alkyl), e.g., —NHMe). In certain embodiments, at least one instance of R.sup.5 is —N(substituted or unsubstituted, C.sub.1-6 alkyl).sub.2, e.g., —N(Me).sub.2. In certain embodiments, at least one instance of R.sup.5 is —CN. In certain embodiments, at least one instance of R.sup.5 is halogen, substituted or unsubstituted, C.sub.1-6 alkyl, or —OR.sup.a.

[0238] In certain embodiments, m is 0. In some embodiments, m is 1. In certain embodiments, m is 2. In some embodiments, m is 3.

[0239] In some embodiments, m is 0, and p is 0. In some embodiments, m is 0, and p is 1. In some embodiments, m is 0, p is 0, and n is 0. In some embodiments, m is 0, p is 0, and n is 1. In some embodiments, m is 0, p is 1, and n is 1.

[0240] In certain embodiments, the central pyridinyl ring, which optionally bears R.sup.5, is represented by:

##STR00021##

In certain embodiments, the central pyridinyl ring, which optionally bears R.sup.5, is represented by:

##STR00022##

In certain embodiments, the central pyridinyl ring, which optionally bears R.sup.5, is represented by:

##STR00023##

In certain embodiments, the central pyridinyl ring, which optionally bears R.sup.5, is represented by:

##STR00024##

[0241] In certain embodiments, R.sup.6 is hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, R.sup.6 is hydrogen. In certain embodiments, R.sup.6 is substituted or unsubstituted, C.sub.1-6 alkyl. In some embodiments, R.sup.6 is substituted or unsubstituted methyl. In certain embodiments, R.sup.6 is substituted or unsubstituted ethyl. In some embodiments, R.sup.6 is nitrogen protecting group selected from tosyl, tert-butyloxycarbonyl, acetyl, or benzoyl.

[0242] In certain embodiments, each instance of R.sup.1 is independently hydrogen, halogen, or substituted or unsubstituted, C.sub.1-6 alkyl. In certain embodiments, each instance of R.sup.1 is hydrogen. In certain embodiments, one instance of R.sup.1 is hydrogen. In certain embodiments, at least one instance of R.sup.1 is halogen. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted, C.sub.1-6 alkyl.

[0243] In certain embodiments, at least one instance of R.sup.1 is unsubstituted C.sub.1-6 alkyl (e.g., methyl, ethyl, propyl). In certain embodiments, at least one instance of R.sup.1 is C.sub.1-6 alkyl substituted with at least one instance of halogen (e.g., F).

[0244] In certain embodiments, q is 0. In some embodiments, q is 1.

[0245] In some embodiments, q is 0 and n is 0, 1, or 2. In some embodiments, q is 1 and n is 0, 1, or 2.

[0246] In some embodiments, each instance of R.sup.9 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2, or two instances of R.sup.9 are joined to form a 3- to 13 membered heterocyclyl, 3- to 13 membered heterocyclyl, 6- to 12 membered aryl ring, or 5- to 14 membered heteroaryl ring. In certain embodiments, each instance of R.sup.9 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, —COOR.sup.a, —COR.sup.a, —N(R.sup.a).sub.2, —CN, or —(C═O)N(R.sup.a).sub.2. Each instance of R.sup.9 is independently hydrogen, halogen, substituted or unsubstituted, C.sub.1-6 alkyl, —OR.sup.a, or —N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.9 is hydrogen. In certain embodiments, each instance of R.sup.9 is hydrogen. In certain embodiments, at least one instance of R.sup.9 is not hydrogen. In certain embodiments, no instance of R.sup.9 is hydrogen. In certain embodiments, at least one instance of R.sup.9 is halogen. In certain embodiments, at least one instance of R.sup.9 is F. In certain embodiments, at least one instance of R.sup.9 is Cl. In certain embodiments, at least one instance of R.sup.9 is substituted or unsubstituted, C.sub.1-6 alkyl (e.g., unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.9 is Me. In certain embodiments, at least one instance of R.sup.9 is Et. In certain embodiments, at least one instance of R.sup.9 is Pr or Bu. In certain embodiments, at least one instance of R.sup.9 is fluorinated C.sub.1-6 alkyl (e.g., fluorinated methyl, e.g., —CF.sub.3). In certain embodiments, at least one instance of R.sup.9 is —OR.sup.a. In certain embodiments, at least one instance of R.sup.9 is —OH. In certain embodiments, at least one instance of R.sup.9 is —O(substituted or unsubstituted, C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.9 is —OMe. In certain embodiments, at least one instance of R.sup.9 is —N(R.sup.a).sub.2. In certain embodiments, at least one instance of R.sup.9 is —NH.sub.2. In certain embodiments, at least one instance of R.sup.9 is —NHR.sup.a (e.g., —NH(substituted or unsubstituted, C.sub.1-6 alkyl), e.g., —NHMe). In certain embodiments, at least one instance of R.sup.9 is —NHR.sup.a, wherein Ra is a substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.9 is —NHR.sup.a, wherein Ra is a C.sub.1-6 alkyl substituted with —NH.sub.2, —NHMe, or —NMe.sub.2. In certain embodiments, at least one instance of R.sup.9 is —NHR.sup.a, wherein Ra is an unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.9 is —N(substituted or unsubstituted, C.sub.1-6 alkyl).sub.2. In certain embodiments, at least one instance of R.sup.9 is —N(Me).sub.2. In certain embodiments, at least one instance of R.sup.9 is —CN. In certain embodiments, at least one instance of R.sup.9 is halogen, substituted or unsubstituted, C.sub.1-6 alkyl, or —OR.sup.a. In certain embodiments, more than one instance of R.sup.9 is C.sub.1-6 alkyl (e.g., two instances of R.sup.9 are methyl). In certain embodiments, more than one instance of R.sup.9 is halogen (e.g., two instances of R.sup.9 are fluoro). In some embodiments, one instance of R.sup.9 is C.sub.1-6 alkyl, and a second instance of R.sup.9 is halogen. In some embodiments, one instance of R.sup.9 is methyl, and a second instance of R.sup.9 is fluoro.

[0247] In certain embodiments, n is 0. In some embodiments, n is 1. In certain embodiments, n is 2. In some embodiments, n is 3. In certain embodiments, n is 4.

[0248] In certain embodiments, the terminal pyridinyl ring, which optionally bears R.sup.9, is represented by:

##STR00025##