KARANICOLAS JOHN (US)
YEN TIMOTHY J (US)
CORY MICHAEL (US)
PARRY CHRIS (US)
PRASAD RAHUL (US)
US20110190302A1 | 2011-08-04 |
What is Claimed is: 1. A compound having Formula I: (I) or a pharmaceutically acceptable salt thereof, wherein: R10 X is or ; each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine, substituted or unsubstituted alkylamino, substituted or unsubstituted aminoalkoxy, and substituted or unsubstituted alkylthio; R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine, substituted or unsubstituted alkylamino, and substituted or unsubstituted aminoalkoxy; each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, and substituted or unsubstituted amine; and R10 and R11 are, independently, selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl. R10 R 2. The compound of claim 1, wherein X is 3. The compound of claim 2, wherein each of R1, R2, R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine. 4. The compound of claim 2, wherein each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted C1-3alkyl, and substituted or unsubstituted C1-3alkoxy. 5. The compound of claim 2, wherein each of R1, R2, R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C1-3alkoxy. 6. The compound of claim 2, wherein each of R1, R2 R3, R4, and R5 is, independently, hydrogen or unsubstituted C1-3alkoxy. 7. The compound of claim 2, wherein each of R1, R2, R3, R4, and R5 is, independently, hydrogen or -OCH3. 8. The compound of claim 2, wherein R2 and R4 are -OCH3, and R1, R3, and R5 are hydrogen. 9. The compound of claim 2, wherein R2 and R3 are -OCH3, and R1, R4, and R5 are hydrogen. 10. The compound of claim 2, wherein R1 and R2 are -OCH3, and R3, R4, and R5 are hydrogen. 11. The compound of claim 2, wherein R1 and R4 are -OCH3, and R2, R3, and R5 are hydrogen. 12. The compound of any one of claims 2 to 11, wherein R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy. 13. The compound of any one of claims 2 to 11, wherein R6 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-4alkyl, and substituted or unsubstituted C1-4alkoxy. 14. The compound of any one of claims 2 to 11, wherein R6 is selected from the group consisting of hydrogen, unsubstituted C1-3alkyl, and unsubstituted C1-3alkoxy. 15. The compound of any one of claims 2 to 11, wherein R6 is selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, -OCH(CH3)2. 16. The compound of any one of claims 2 to 15, wherein each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro. 17. The compound of any one of claims 2 to 15, wherein each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl. 18. The compound of any one of claims 2 to 15, wherein each of R7, R8, R9, and R12 is, independently, hydrogen or halogen. 19. The compound of any one of claims 2 to 18, wherein R10 and R11 are, independently, selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form a substituted or unsubstituted heterocycloalkyl. 20. The compound of any one of claims 2 to 18, wherein R10 and R11 are, independently, selected from the group consisting of hydrogen, unsubstituted C1-4alkyl, and unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form an unsubstituted heterocycloalkyl. 21. The compound of any one of claims 2 to 18, wherein R10 and R11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH3)3, or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. 22. The compound of claim 2, wherein: each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine; R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro; and R10 and R11 are, independently, selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form a substituted or unsubstituted heterocycloalkyl. 23. The compound of claim 2, wherein: each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted C1-3alkyl, and substituted or unsubstituted C1-3alkoxy; R6 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-4alkyl, and substituted or unsubstituted C1-4alkoxy; each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl; and R10 and R11 are, independently, selected from the group consisting of hydrogen, unsubstituted C1-4alkyl, and unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form an unsubstituted heterocycloalkyl. 24. The compound of claim 2, wherein: each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C1-3alkoxy; R6 is selected from the group consisting of hydrogen, unsubstituted C1-3alkyl, and unsubstituted C1-3alkoxy; each of R7, R8, R9, and R12 is, independently, hydrogen or halogen; and R10 and R11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH3)3, or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. 25. The compound of claim 2, wherein: each of R1, R2, R3, R4, and R5 is, independently, hydrogen or unsubstituted C1-3alkoxy; R6 is selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, -OCH(CH3)2; each of R7, R8, R9, and R12 is, independently, hydrogen or halogen; and R10 and R11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH3)3, or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. 26. The compound of claim 2, wherein: each of R1, R2 R3, R4, and R5 is, independently, hydrogen or -OCH3; R6 is selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, -OCH(CH3)2; each of R7, R8, R9, and R12 is, independently, hydrogen or halogen; and R10 and R11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH3)3, or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. 27. The compound of claim 26, wherein R2 and R4 are -OCH3, and R1, R3, and R5 are hydrogen. 28. The compound of claim 26, wherein R2 and R3 are -OCH3, and R1, R4, and R5 are hydrogen. 29. The compound of claim 26, wherein R1 and R2 are -OCH3, and R3, R4, and R5 are hydrogen. 30. The compound of claim 26, wherein R1 and R4 are -OCH3, and R2 R3, and R5 are hydrogen. 31. The compound of claim 2, wherein the compound is selected from the group consisting of OCH3 H3CO OCH3 and . 32. The compound of claim 1, wherein X is 33. The compound of claim 32, wherein eac h of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine. 34. The compound of claim 32, wherein each of R1, R2, R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted C1-3alkyl, and substituted or unsubstituted C1-3alkoxy. 35. The compound of claim 32, wherein each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C1-3alkoxy. 36. The compound of claim 32, wherein each of R1, R2, R3, R4, and R5 is, independently, hydrogen or unsubstituted C1-3alkoxy. 37. The compound of claim 32, wherein each of R1, R2, R3, R4, and R5 is, independently, hydrogen or -OCH3. 38. The compound of claim 32, wherein R2 and R4 are -OCH3, and R1, R3, and R5 are hydrogen. 39. The compound of claim 32, wherein R2 and R3 are -OCH3, and R1, R4, and R5 are hydrogen. 40. The compound of claim 32, wherein R1 and R2 are -OCH3, and R3, R4, and R5 are hydrogen. 41. The compound of claim 32, wherein R1 and R4 are -OCH3, and R2 R3, and R5 are hydrogen. 42. The compound of any one of claims 32 to 41, wherein each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro. 43. The compound of any one of claims 32 to 41, wherein each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl. 44. The compound of any one of claims 32 to 41, wherein each of R7, R8, R9, and R12 is, independently, hydrogen or halogen. 45. The compound of claim 32, wherein: each of R1, R2, R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine; and each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro. 46. The compound of claim 32, wherein: each of R1, R2, R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C1-3alkoxy; and each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl. 47. The compound of claim 32, wherein: each of R1, R2 R3, R4, and R5 is, independently, hydrogen or unsubstituted C1-3alkoxy; and each of R7, R8, R9, and R12 is, independently, hydrogen or halogen. 48. The compound of claim 32, wherein: each of R1, R2 R3, R4, and R5 is, independently, hydrogen or -OCH3; and each of R7, R8, R9, and R12 is, independently, hydrogen or halogen. 49. The compound of claim 48, wherein R2 and R4 are -OCH3, and R1, R3, and R5 are hydrogen. 50. The compound of claim 48, wherein R2 and R3 are -OCH3, and R1, R4, and R5 are hydrogen. 51. The compound of claim 48, wherein R1 and R2 are -OCH3, and R3, R4, and R5 are hydrogen. 52. The compound of claim 48, wherein R1 and R4 are -OCH3, and R2 R3, and R5 are hydrogen. H3CO OCH3 53. The compound of claim 32, wherein the compound is 54. A pharmaceutical composition comprising the compo und of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 55. The pharmaceutical composition of claim 54, wherein the pharmaceutical composition is an oral formulation, an intravenous formulation, a topical formulation, an intraperitoneal formulation, an intrapleural formulation, an intravesical formulation, or an intrathecal formulation. 56. The pharmaceutical composition of claim 55, wherein the oral formulation is a pill, tablet, capsule, cachet, gel-cap, pellet, powder, granule, or liquid. 57. A method of treating a mammal having cancer comprising administering to the mammal in need thereof a compound having Formula I: (I) or a pharmaceutically acceptable salt thereof, wherein: X is or ; each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine, substituted or unsubstituted alkylamino, substituted or unsubstituted aminoalkoxy, and substituted or unsubstituted alkylthio; R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine, substituted or unsubstituted alkylamino, and substituted or unsubstituted aminoalkoxy; each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, and substituted or unsubstituted amine; and R10 and R11 are, independently, selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl; wherein the cancer is selected from the group consisting of melanoma, prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, ovarian cancer, and glioblastoma. R10 58. The method of claim 57, wherein X is . 59. The method of claim 58, wherein each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine. 60. The method of claim 58, wherein each of R1, R2, R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted C1-3alkyl, and substituted or unsubstituted C1-3alkoxy. 61. The method of claim 58, wherein each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C1-3alkoxy. 62. The method of claim 58, wherein each of R1, R2 R3, R4, and R5 is, independently, hydrogen or unsubstituted C1-3alkoxy. 63. The method of claim 58, wherein each of R1, R2 R3, R4, and R5 is, independently, hydrogen or -OCH3. 64. The method of claim 58, wherein R2 and R4 are -OCH3, and R1, R3, and R5 are hydrogen. 65. The method of claim 58, wherein R2 and R3 are -OCH3, and R1, R4, and R5 are hydrogen. 66. The method of claim 58, wherein R1 and R2 are -OCH3, and R3, R4, and R5 are hydrogen. 67. The method of claim 58, wherein R1 and R4 are -OCH3, and R2, R3, and R5 are hydrogen. 68. The method of any one of claims 58 to 67, wherein R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy. 69. The method of any one of claims 58 to 67, wherein R6 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-4alkyl, and substituted or unsubstituted C1-4alkoxy. 70. The method of any one of claims 58 to 67, wherein R6 is selected from the group consisting of hydrogen, unsubstituted C1-3alkyl, and unsubstituted C1-3alkoxy. 71. The method of any one of claims 58 to 67, wherein R6 is selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, -OCH(CH3)2. 72. The method of any one of claims 58 to 71, wherein each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro. 73. The method of any one of claims 58 to 71, wherein each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl. 74. The method of any one of claims 58 to 71, wherein each of R7, R8, R9, and R12 is, independently, hydrogen or halogen. 75. The method of any one of claims 58 to 74, wherein R10 and R11 are, independently, selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form a substituted or unsubstituted heterocycloalkyl. 76. The method of any one of claims 58 to 74, wherein R10 and R11 are, independently, selected from the group consisting of hydrogen, unsubstituted C1-4alkyl, and unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form an unsubstituted heterocycloalkyl. 77. The method of any one of claims 58 to 74, wherein R10 and R11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH3)3, or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. 78. The method of claim 58, wherein: each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine; R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro; and R10 and R11 are, independently, selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form a substituted or unsubstituted heterocycloalkyl. 79. The method of claim 58, wherein: each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted C1-3alkyl, and substituted or unsubstituted C1-3alkoxy; R6 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-4alkyl, and substituted or unsubstituted C1-4alkoxy; each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl; and R10 and R11 are, independently, selected from the group consisting of hydrogen, unsubstituted C1-4alkyl, and unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form an unsubstituted heterocycloalkyl. 80. The method of claim 58, wherein: each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C1-3alkoxy; R6 is selected from the group consisting of hydrogen, unsubstituted C1-3alkyl, and unsubstituted C1-3alkoxy; each of R7, R8, R9, and R12 is, independently, hydrogen or halogen; and R10 and R11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH3)3, or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. 81. The method of claim 58, wherein: each of R1, R2, R3, R4, and R5 is, independently, hydrogen or unsubstituted C1-3alkoxy; R6 is selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, -OCH(CH3)2; each of R7, R8, R9, and R12 is, independently, hydrogen or halogen; and R10 and R11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH3)3, or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. 82. The method of claim 58, wherein: each of R1, R2, R3, R4, and R5 is, independently, hydrogen or -OCH3; R6 is selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, -OCH(CH3)2; each of R7, R8, R9, and R12 is, independently, hydrogen or halogen; and R10 and R11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH3)3, or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. 83. The method of claim 82, wherein R2 and R4 are -OCH3, and R1, R3, and R5 are hydrogen. 84. The method of claim 82, wherein R2 and R3 are -OCH3, and R1, R4, and R5 are hydrogen. 85. The method of claim 82, wherein R1 and R2 are -OCH3, and R3, R4, and R5 are hydrogen. 86. The method of claim 82, wherein R1 and R4 are -OCH3, and R2 R3, and R5 are hydrogen. 87. The method of claim 58, wherein the compound is selected from the group consisting of OCH3 88. The method of claim 57, wherein X is . 89. The method of claim 88, wherein each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine. 90. The method of claim 88, wherein each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted C1-3alkyl, and substituted or unsubstituted C1-3alkoxy. 91. The method of claim 88, wherein each of R1, R2, R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C1-3alkoxy. 92. The method of claim 88, wherein each of R1, R2 R3, R4, and R5 is, independently, hydrogen or unsubstituted C1-3alkoxy. 93. The method of claim 88, wherein each of R1, R2 R3, R4, and R5 is, independently, hydrogen or -OCH3. 94. The method of claim 88, wherein R2 and R4 are -OCH3, and R1, R3, and R5 are hydrogen. 95. The method of claim 88, wherein R2 and R3 are -OCH3, and R1, R4, and R5 are hydrogen. 96. The method of claim 88, wherein R1 and R2 are -OCH3, and R3, R4, and R5 are hydrogen. 97. The method of claim 88, wherein R1 and R4 are -OCH3, and R2, R3, and R5 are hydrogen. 98. The method of any one of claims 88 to 97, wherein each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro. 99. The method of any one of claims 88 to 97, wherein each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl. 100. The method of any one of claims 88 to 97, wherein each of R7, R8, R9, and R12 is, independently, hydrogen or halogen. 101. The method of claim 88, wherein: each of R1, R2, R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine; and each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro. 102. The method of claim 88, wherein: each of R1, R2 R3, R4, and R5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C1-3alkoxy; and each of R7, R8, R9, and R12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl. 103. The method of claim 88, wherein: each of R1, R2, R3, R4, and R5 is, independently, hydrogen or unsubstituted C1-3alkoxy; and each of R7, R8, R9, and R12 is, independently, hydrogen or halogen. 104. The method of claim 88, wherein: each of R1, R2, R3, R4, and R5 is, independently, hydrogen or -OCH3; and each of R7, R8, R9, and R12 is, independently, hydrogen or halogen. 105. The method of claim 104, wherein R2 and R4 are -OCH3, and R1, R3, and R5 are hydrogen. 106. The method of claim 104, wherein R2 and R3 are -OCH3, and R1, R4, and R5 are hydrogen. 107. The method of claim 104, wherein R1 and R2 are -OCH3, and R3, R4, and R5 are hydrogen. 108. The method of claim 104, wherein R1 and R4 are -OCH3, and R2 R3, and R5 are hydrogen. H3CO OCH3 109. The method of claim 88, wherein the compound is 110. The method of any one of claims 57 to 109, wherein the amount of the compound administered to the mammal is from about 0.1 mg to about 500 mg. 111. The method of any one of claims 57 to 110, wherein the mammal is human. 112. The method of any one of claims 57 to 111, wherein the mammal is also administered radiation therapy, a chemotherapeutic agent, a biologic agent, or any combination thereof. |
(I), or a pharmaceutically acceptable salt thereof, wherein: R 10 X is ; each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine, substituted or unsubstituted alkylamino, substituted or unsubstituted aminoalkoxy, and substituted or unsubstituted alkylthio; R 6 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine, substituted or unsubstituted alkylamino, and substituted or unsubstituted aminoalkoxy; each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, and substituted or unsubstituted amine; and R 10 and R 11 are, independently, selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl. R 10 R 9 O In some embodiments, X is . In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted C 1-3 alkyl, and substituted or unsubstituted C 1-3 alkoxy. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C 1-3 alkoxy. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, hydrogen or unsubstituted C 1-3 alkoxy. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, hydrogen or -OCH 3 . In some embodiments, R 2 and R 4 are -OCH 3 , and R 1 , R 3 , and R 5 are hydrogen. In some embodiments, R 2 and R 3 are -OCH 3 , and R 1 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 2 are -OCH 3 , and R 3 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 4 are -OCH 3 , and R 2 , R 3 , and R 5 are hydrogen. In any of these embodiments, R 6 is selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy. In some embodiments, R 6 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-4 alkyl, and substituted or unsubstituted C 1-4 alkoxy. In some embodiments, R 6 is selected from the group consisting of hydrogen, unsubstituted C 1-3 alkyl, and unsubstituted C 1-3 alkoxy. In some embodiments, R 6 is selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, -OCH(CH 3 ) 2 . In any of these embodiments, each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro. In some embodiments, each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl. In some embodiments, each of R 7 , R 8 , R 9 , and R 12 is, independently, hydrogen or halogen. In any of these embodiments, R 10 and R 11 are, independently, selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form a substituted or unsubstituted heterocycloalkyl. In some embodiments, R 10 and R 11 are, independently, selected from the group consisting of hydrogen, unsubstituted C 1-4 alkyl, and unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form an unsubstituted heterocycloalkyl. In some embodiments, R 10 and R 11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH 3 ) 3 , or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine; R 6 is selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro; and R 10 and R 11 are, independently, selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form a substituted or unsubstituted heterocycloalkyl. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted C 1-3 alkyl, and substituted or unsubstituted C 1-3 alkoxy; R 6 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-4 alkyl, and substituted or unsubstituted C 1- 4alkoxy; each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl; and R 10 and R 11 are, independently, selected from the group consisting of hydrogen, unsubstituted C 1-4 alkyl, and unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form an unsubstituted heterocycloalkyl. In some embodiments, each of R 1 , R 2 , R 3 , R 4, and R 5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C 1-3 alkoxy; R 6 is selected from the group consisting of hydrogen, unsubstituted C 1-3 alkyl, and unsubstituted C 1- 3 alkoxy; each of R 7 , R 8 , R 9 , and R 12 is, independently, hydrogen or halogen; and R 10 and R 11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH 3 ) 3 , or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, hydrogen or unsubstituted C 1-3 alkoxy; R 6 is selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ; each of R 7 , R 8 , R 9 , and R 12 is, independently, hydrogen or halogen; and R 10 and R 11 are, independently, selected from the group consisting of hydrogen, ethyl, or - C(CH 3 ) 3 , or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, hydrogen or - OCH 3 ; R 6 is selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, -OCH(CH 3 ) 2 ; each of R 7 , R 8 , R 9 , and R 12 is, independently, hydrogen or halogen; and R 10 and R 11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH 3 ) 3 , or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. In some embodiments, R 2 and R 4 are -OCH 3 , and R 1 , R 3 , and R 5 are hydrogen. In some embodiments, R 2 and R 3 are -OCH 3 , and R 1 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 2 are - OCH 3 , and R 3 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 4 are -OCH 3 , and R 2 , R 3 , and R 5 are hydrogen. In some embodiments, the compound is selected from the group consisting of OCH 3 In some embodiments, X is . In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted C 1-3 alkyl, and substituted or unsubstituted C 1-3 alkoxy. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C 1-3 alkoxy. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, hydrogen or unsubstituted C 1-3 alkoxy. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, hydrogen or -OCH 3 . In some embodiments, R 2 and R 4 are -OCH 3 , and R 1 , R 3 , and R 5 are hydrogen. In some embodiments, R 2 and R 3 are -OCH 3 , and R 1 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 2 are -OCH 3 , and R 3 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 4 are -OCH 3 , and R 2 R 3 , and R 5 are hydrogen. In any of these embodiments, each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro. In some embodiments, each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl. In some embodiments, each of R 7 , R 8 , R 9 , and R 12 is, independently, hydrogen or halogen. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine; and each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C 1-3 alkoxy; and each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, hydrogen or unsubstituted C 1-3 alkoxy; and each of R 7 , R 8 , R 9 , and R 12 is, independently, hydrogen or halogen. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, hydrogen or -OCH 3 ; and each of R 7 , R 8 , R 9 , and R 12 is, independently, hydrogen or halogen. In some embodiments, R 2 and R 4 are -OCH 3 , and R 1 , R 3 , and R 5 are hydrogen. In some embodiments, R 2 and R 3 are -OCH 3 , and R 1 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 2 are -OCH 3 , and R 3 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 4 are -OCH 3 , and R 2 R 3 , and R 5 are hydrogen. H 3 CO OCH 3 In some embodiments, the compound is . The present disclosure also provides pha rmaceutical compositions comprising any one or more of the compounds of Formula I described herein, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is an oral formulation, an intravenous formulation, a topical formulation, an intraperitoneal formulation, an intrapleural formulation, an intravesical formulation, or an intrathecal formulation. In some embodiments, the oral formulation is a pill, tablet, capsule, cachet, gel-cap, pellet, powder, granule, or liquid. In some embodiments, the oral formulation is a pill, tablet, capsule, gel-cap, or liquid. In some embodiments, the pharmaceutical composition further comprises an anti-cancer agent. As used herein, the phrase “anti-cancer agent” is meant to include all forms of treatment of cancer including, but not limited to, traditional chemotherapy (i.e., chemotherapeutic agents, whether they are administered parenterally or orally), immunotherapeutic agents, small molecule enzyme or kinase inhibitors, intravesical therapeutic agents, antibody inhibitors of receptors or kinases, antibody-drug conjugates, and radiation therapy. Examples of chemotherapeutic agents include, but are not limited to, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, methotrexate, vincristine, doxorubicin, tunicamycin, oligomycin, bortezomib, MG132, 5-flurouracil, sorafenib, flavopiridol, gemcitabine, taxol, mercaptopurine, thioguanine, hydroxyurea, cytarabine, mitomycin, cyclophosphamide, ifosfamide, nitrosourea, dacarbazine, procarbizine, an etoposide, a campathecin, bleomycin, idarubicin, daunorubicin, dactinomycin, distamycin A, etidium, netropsin, auristatin, amsacrine, prodigiosin, bortexomib, pibenzimol, tomaymycin, duocarmycin SA, plicamycin, mitoxantrone, asparaginase, vinblastine, vinorelbine, paclitaxel, docetaxel, CPT-11, gleevec, erlotinib, gefitinib, ibrutinib, crizotinib, ceritinib, lapatinib, navitoclax, and regorafenib, or any combination thereof. In some embodiments, the chemotherapeutic agent is a combination of agents, such as, for example, methotrexate/vincristine/doxorubicin/cisplatin (MVAC) or gemcitabine/cisplatin. Examples of immunotherapeutic agents include, but are not limited to, OPDIVO ® (nivolumab), KEYTRUDA ® (pembrolizumab), TECENTRIQ ® (atezolizumab), IMFINZI ® (durvalumab), YERVOY ® (ipilumumab), ERBITUX ® (cetuximab), AVASTIN ® (bevacizumab), HERCEPTIN ® (trastuzumab), PERJETA ® (pertuzumab), VECTIBIX ® (panitumumab), PORTRAZZA™ (necitumumab), UNITUXIN™ (dinutuximab), CIRAMZA ® (ramucirumab), LARTRUVO ® (olaratumab), KADCYLA ® (ado-trastuzumab emtansineb), XGEVA ® (denosumab), and BAVENCIO ® (avelumab), or any combination thereof. In some embodiments, the immunotherapeutic agent is nivolumab, pembrolizumab, atezolizumab, durvalab, ipilumumab, cetuximab, bevacizumab, trastuzumab, pertuzumab, panitumumab, necitumumab, dinutuximab, ramucirumab, olaratumab, ado-trastuzumab emtansineb, denosumab, or avelumab, or any combination thereof. In some embodiments, the immunotherapeutic agent is nivolumab, pembrolizumab, atezolizumab, durvalab, ipilumumab, cetuximab, bevacizumab, or trastuzumab, or any combination thereof. In some embodiments, the immunotherapeutic agents include immune checkpoint inhibitors. Examples of immune checkpoint inhibitors include, but are not limited to, YERVOY ® (Ipilimumab), tremelimumab, MGA271, MGA271, indoximod, INCB024360, BMS-986016, or any combination thereof. In some embodiments, the immunotherapeutic agents include PD-1 and/ or PD-L1 inhibitors. Examples of PD-1 and PD-L1 inhibitors include but are not limited to OPDIVO ® (nivolumab), KEYTRUDA ® (pembrolizumab), TECENTRIQ ® (atezolizumab), BAVENCIO ® (avelumab), IMFINZI ® (durvalumab), LIBTAYO ® (cemiplimab) JTX-4014, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, pidilizumab, INCMGA00012, AMP-224, AMP-514, KN035, CK-301, AUNP12, CA-170, and BMS986189, or any combination thereof. In some embodiments, the ratio of the compound having Formula I to the anti-cancer agent in the pharmaceutical composition is from about 0.01:1 to about 100:1 w/w. The pharmaceutical compositions described herein can be administered to a patient in need thereof in an oral formulation, an intravenous formulation, a topical formulation, an intraperitoneal formulation, an intrapleural formulation, an intravesical formulation, or an intrathecal formulation. The compositions may be formulated in a suitable controlled-release vehicle, with an adjuvant, or as a depot formulation. In some embodiments, the carrier is a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include, but are not limited to, aqueous vehicles such as water, alcohol (e.g., ethanol or glycol), saline solutions, dextrose solutions, and balanced salt solutions, as well as nonaqueous vehicles such as alcohols and oils, including plant or vegetable- derived oils such as olive oil, cottonseed oil, corn oil, canola oil, sesame oil, and other non-toxic oils. The compositions may also comprise one or more pharmaceutically acceptable excipients. The compositions may be formulated for administration to a subject in any suitable dosage form. The compositions may be formulated for oral, buccal, nasal, transdermal, parenteral, injectable, intravenous, subcutaneous, intramuscular, rectal, or vaginal administration. The compositions may be formulated in a suitable controlled-release vehicle, with an adjuvant, or as a depot formulation. Preparations for parenteral administration include, but are not limited to, sterile solutions ready for injection, sterile dry soluble products ready to be combined with a solvent just prior to use, including, but not limited to, hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. Solid dosage forms include, but are not limited to, tablets, pills, powders, bulk powders, capsules, granules, and combinations thereof. Solid dosage forms may be prepared as compressed, chewable lozenges and tablets which may be enteric-coated, sugar coated or film- coated. Solid dosage forms may be hard or encased in soft gelatin, and granules and powders may be provided in non-effervescent or effervescent form. Solid dosage forms may be prepared for dissolution or suspension in a liquid or semi-liquid vehicle prior to administration. Solid dosage forms may be prepared for immediate release, controlled release, or any combination thereof. Controlled release includes, but is not limited to, delayed release, sustained release, timed pulsatile release, and location-specific pulsatile release, and combinations thereof. Liquid dosage forms include, but are not limited to, aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, but are not limited to, elixirs and syrups. Emulsions may be oil-in water or water-in-oil emulsions. Pharmaceutically acceptable excipients utilized in solid dosage forms include, but are not limited to, coatings, binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, preservatives, sweeteners, and wetting agents. Enteric-coated tablets, due to their enteric-coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines. Other examples of coatings include, but are not limited to, sugar coatings and polymer coatings. Sweetening agents are useful in the formation of chewable tablets and lozenges. Pharmaceutically acceptable excipients used in liquid dosage forms include, but are not limited to, solvents, suspending agents, dispersing agents, emulsifying agents, surfactants, emollients, coloring agents, flavoring agents, preservatives, and sweeteners. Suitable examples of binders include, but are not limited to, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste. Suitable examples of lubricants include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Suitable examples of diluents include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Suitable examples of disintegrating agents include, but are not limited to, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Suitable examples of emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suitable examples of suspending agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, veegum and acacia. Suitable examples of coloring agents include, but are not limited to, any of the approved certified water soluble FD and C dyes, mixtures thereof, and water insoluble FD and D dyes suspended on alumina hydrate. Suitable examples of sweetening agents include, but are not limited to, dextrose, sucrose, fructose, lactose, mannitol and artificial sweetening agents such as saccharin, aspartame, sucralose, acelsulfame potassium, and other artificial sweeteners. Suitable examples of flavoring agents include, but are not limited to, synthetic flavors and natural flavors extracted from plants such as fruits and mints, and synthetic blends of compounds which produce a pleasant sensation. Suitable examples of wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether. Suitable examples of enteric-coatings include, but are not limited to, fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Suitable examples of film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Suitable examples of preservatives include, but are not limited to, glycerin, methyl and propylparaben, ethylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben, citrate, benzoic acid, sodium benzoate and alcohol. Suitable examples of elixirs include, but are not limited to, clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Suitable examples of syrups include, but are not limited to, concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two- phase system in which one liquid is dispersed throughout another liquid. Pharmaceutically acceptable carriers used in emulsions can also include emulsifying agents and preservatives. Suspensions may use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form, include, but are not limited to, diluents, sweeteners, and wetting agents. Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form, include, but are not limited to, organic acids and a source of carbon dioxide. Sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate. Coloring and flavoring agents may be used in all such dosage forms. Additional excipients that may be included in any dosage forms include, but are not limited to, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetic agents, sequestering or chelating agents, analgesic agents, antiemetic agents, and other agents to enhance selected characteristics of the formulation. Antimicrobial agents may be cidal or static, and may be antimicrobial, antifungal, antiparasitic, or antiviral. Suitable examples of commonly used antimicrobial agents include, but are not limited to, phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Acidic or basic pH may be used for antimicrobial effects in some aspects. Suitable examples of isotonic agents include, but are not limited to, sodium chloride and dextrose. Suitable examples of buffers include, but are not limited to, phosphate and citrate buffers. A non- limiting example of a chelating agent for metal ions is EDTA. The present disclosure also provides methods of treating a mammal having cancer comprising administering to the mammal in need thereof a compound having Formula I: (I), or a pharmaceutically acceptable salt thereof, wherein: X is each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine, substituted or unsubstituted alkylamino, substituted or unsubstituted aminoalkoxy, and substituted or unsubstituted alkylthio; R 6 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine, substituted or unsubstituted alkylamino, and substituted or unsubstituted aminoalkoxy; each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, and substituted or unsubstituted amine; and R 10 and R 11 are, independently, selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocycloalkyl; wherein the cancer is selected from the group consisting of melanoma, prostate cancer, pancreatic cancer, breast cancer, colon and rectal cancer, lung cancer, ovarian cancer, endometrial cancer, cervical cancer, esophageal cancer, stomach cancer, thyroid cancer, kidney cancer, liver cancer, mesothelioma, skin cancer, and brain cancer, such as glioblastoma. In addition, the cancer can be selected from a leukemia, a lymphoma, a myeloma (such as multiple myeloma), and a myelodysplastic neoplasm/myeloproferative disease. R 10 R In some embodiments, X is In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted C 1-3 alkyl, and substituted or unsubstituted C 1-3 alkoxy. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C 1-3 alkoxy. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, hydrogen or unsubstituted C 1-3 alkoxy. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, hydrogen or -OCH 3 . In some embodiments, R 2 and R 4 are -OCH 3 , and R 1 , R 3 , and R 5 are hydrogen. In some embodiments, R 2 and R 3 are -OCH 3 , and R 1 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 2 are -OCH 3 , and R 3 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 4 are -OCH 3 , and R 2 R 3 , and R 5 are hydrogen. In any of these embodiments, R 6 is selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy. In some embodiments, R 6 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-4 alkyl, and substituted or unsubstituted C1-4alkoxy. In some embodiments, R 6 is selected from the group consisting of hydrogen, unsubstituted C 1-3 alkyl, and unsubstituted C 1-3 alkoxy. In some embodiments, R 6 is selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, -OCH(CH 3 ) 2 . In any of these embodiments, each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro. In some embodiments, each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl. In some embodiments, each of R 7 , R 8 , R 9 , and R 12 is, independently, hydrogen or halogen. In any of these embodiments, R 10 and R 11 are, independently, selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form a substituted or unsubstituted heterocycloalkyl. In some embodiments, R 10 and R 11 are, independently, selected from the group consisting of hydrogen, unsubstituted C 1-4 alkyl, and unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form an unsubstituted heterocycloalkyl. In some embodiments, R 10 and R 11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH 3 ) 3 , or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine; R 6 is selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro; and R 10 and R 11 are, independently, selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form a substituted or unsubstituted heterocycloalkyl. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted C 1-3 alkyl, and substituted or unsubstituted C 1-3 alkoxy; R 6 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-4 alkyl, and substituted or unsubstituted C 1-4 alkoxy; each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl; and R 10 and R 11 are, independently, selected from the group consisting of hydrogen, unsubstituted C 1-4 alkyl, and unsubstituted cycloalkyl, or together with the nitrogen to which they are bonded form an unsubstituted heterocycloalkyl. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C 1-3 alkoxy; R 6 is selected from the group consisting of hydrogen, unsubstituted C 1-3 alkyl, and unsubstituted C 1-3 alkoxy; each of R 7 , R 8 , R 9 , and R 12 is, independently, hydrogen or halogen; and R 10 and R 11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH3)3, or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, hydrogen or unsubstituted C 1-3 alkoxy; R 6 is selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, -OCH(CH3)2; each of R 7 , R 8 , R 9 , and R 12 is, independently, hydrogen or halogen; and R 10 and R 11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH 3 ) 3 , or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, hydrogen or -OCH 3 ; R 6 is selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, -OCH(CH3)2; each of R 7 , R 8 , R 9 , and R 12 is, independently, hydrogen or halogen; and R 10 and R 11 are, independently, selected from the group consisting of hydrogen, ethyl, or -C(CH 3 ) 3 , or together with the nitrogen to which they are bonded form piperidine or pyrrolidine. In some embodiments, R 2 and R 4 are -OCH 3 , and R 1 , R 3 , and R 5 are hydrogen. In some embodiments, R 2 and R 3 are -OCH 3 , and R 1 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 2 are -OCH 3 , and R 3 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 4 are -OCH 3 , and R 2 , R 3 , and R 5 are hydrogen. In some embodiments, the compound is selected from the group consisting of OCH 3 In some embodiments, X is In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, substituted or unsubstituted C 1-3 alkyl, and substituted or unsubstituted C 1-3 alkoxy. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C 1-3 alkoxy. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, hydrogen or unsubstituted C 1-3 alkoxy. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, hydrogen or -OCH 3 . In some embodiments, R 2 and R 4 are -OCH 3 , and R 1 , R 3 , and R 5 are hydrogen. In some embodiments, R 2 and R 3 are -OCH 3 , and R 1 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 2 are -OCH 3 , and R 3 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 4 are -OCH 3 , and R 2 R 3 , and R 5 are hydrogen. In any of these embodiments, each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro. In some embodiments, each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl. In some embodiments, each of R 7 , R 8 , R 9 , and R 12 is, independently, hydrogen or halogen. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amine; and each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and nitro. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C 1-3 alkoxy; and each of R 7 , R 8 , R 9 , and R 12 is, independently, selected from the group consisting of hydrogen, halogen, and hydroxyl. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, hydrogen or unsubstituted C 1-3 alkoxy; and each of R 7 , R 8 , R 9 , and R 12 is, independently, hydrogen or halogen. In some embodiments, each of R 1 , R 2 R 3 , R 4 , and R 5 is, independently, hydrogen or -OCH 3 ; and each of R 7 , R 8 , R 9 , and R 12 is, independently, hydrogen or halogen. In some embodiments, R 2 and R 4 are -OCH 3 , and R 1 , R 3 , and R 5 are hydrogen. In some embodiments, R 2 and R 3 are -OCH 3 , and R 1 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 2 are -OCH 3 , and R 3 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 and R 4 are -OCH 3 , and R 2 R 3 , and R 5 are hydrogen. H 3 CO OCH 3 In some embodiments, the compound is . The amount of the compound having Fo rmula I to be administered may be that amount which is therapeutically effective. The dosage to be administered may depend on the characteristics of the subject being treated, e.g., the particular animal treated, age, weight, health, types of concurrent treatment, if any, and frequency of treatments, and on the nature and extent of the cancer, and can be easily determined by one skilled in the art (e.g., by the clinician). The selection of the specific dose regimen can be selected or adjusted or titrated by the clinician according to methods known to the clinician to obtain the desired clinical response. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions may also depend on the route of administration, and should be decided according to the judgment of the practitioner and each patient’s circumstances. The compositions may be prepared to provide from about 0.05 mg to about 500 mg of the compound having Formula I, or pharmaceutically acceptable salt thereof. In some embodiments, the compositions may comprise from about 1 mg to about 200 mg, from about 10 mg to about 200 mg, from about 10 mg to about 100 mg, from about 50 mg to about 100 mg, from about 20 mg to about 400 mg, from about 100 mg to about 300 mg, or from about 50 mg to about 250 mg of the compound of Formula I, or an isomer, tautomer, or solvate thereof, or a pharmaceutically acceptable salt thereof. Suitable dosage ranges for oral administration include, but are not limited to, from about 0.001 mg/kg body weight to about 200 mg/kg body weight, from about 0.01 mg/kg body weight to about 100 mg/kg body weight, from about 0.01 mg/kg body weight to about 70 mg/kg body weight, from about 0.1 mg/kg body weight to about 50 mg/kg body weight, from 0.5 mg/kg body weight to about 20 mg/kg body weight, or from about 1 mg/kg body weight to about 10 mg/kg body weight. In some embodiments, the oral dose is about 5 mg/kg body weight. Suitable dosage ranges for intravenous administration include, but are not limited to, from about 0.01 mg/kg body weight to about 500 mg/kg body weight, from about 0.1 mg/kg body weight to about 100 mg/kg body weight, from about 1 mg/kg body weight to about 50 mg/kg body weight, or from about 10 mg/kg body weight to about 35 mg/kg body weight. Suitable dosage ranges for other routes of administration can be calculated based on the forgoing dosages as known by one skilled in the art. For example, recommended dosages for intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, intracerebral, transdermal, or inhalation are in the range from about 0.001 mg/kg body weight to about 200 mg/kg body weight, from about 0.01 mg/kg body weight to about 100 mg/kg body weight, from about 0.1 mg/kg body weight to about 50 mg/kg body weight, or from about 1 mg/kg body weight to about 20 mg/kg body weight. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Such animal models and systems are well known in the art. In some embodiments, the amount of the compound administered to the mammal is from about 0.1 mg to about 500 mg, from about 1 mg to about 250 mg, from about 5 mg to about 400 mg, from about 10 mg to about 250 mg, from about 20 mg to about 200 mg, or from about 40 mg to about 100 mg. In some embodiments, the amount of the compound administered to the mammal is from about 0.1 mg to about 500 mg. In some embodiments, the amount of the compound administered to the mammal is from about 1 mg to about 250 mg. In some embodiments, the amount of the compound administered to the mammal is from about 5 mg to about 400 mg. In some embodiments, the amount of the compound administered to the mammal is from about 10 mg to about 250 mg. In some embodiments, the amount of the compound administered to the mammal is from about 20 mg to about 200 mg. In some embodiments, the amount of the compound administered to the mammal is from about 40 mg to about 100 mg. In some embodiments, the mammal is human. In some embodiments, the mammal is also administered radiation therapy, a chemotherapeutic agent, an immunotherapeutic agent, a biologic agent, or any combination thereof. The present disclosure also provides methods for inhibiting genome-wide hypomethylation. Such methods may comprise treatment methods, by which inhibiting genome- wide hypomethylation treats any condition in which genome-wide hypomethylation plays a role, including cancer. In some embodiments, the methods of treatment further comprise administering another therapy to the subject. In some embodiments, the another therapy is radiation therapy, chemotherapy, immunotherapy, or a combination thereof. In some embodiments, the another therapy is administered to the subject at a lower level compared to the level when administered in the absence of the compound of Formula I. In some embodiments, the methods comprise contacting a cell with genome-wide hypomethylation with an effective amount of a compound or composition comprising Formula I, or any pharmaceutically acceptable salt thereof. The composition may comprise any dosage form and/or any excipients, including those described or exemplified herein. In some embodiments, the methods comprise contacting a cancer cell with an effective amount of a compound or composition comprising any of Formula I, or any pharmaceutically acceptable salt thereof. The composition may comprise any dosage form and/or any excipients, including those described or exemplified herein. In some embodiments, the methods comprise contacting a cell having genome-wide hypomethylation with an effective amount of a compound or composition comprising any of, or any combination thereof, or any pharmaceutically acceptable salt thereof. The composition may comprise any dosage form and/or any excipients, including those described or exemplified herein. In contacting the cell in this manner, the compound or composition inhibits genome-wide hypomethylation. The cell may be within the body of a subject. The cell may be a cancer cell, such as a prostate cancer cell, a breast cancer cell, a kidney cancer cell, an ovarian cancer cell, a lymphoma cell, a melanoma cell, a leukemia cell, or a glioblastoma cell. In some embodiments, methods for treating a cancer patient comprise administering to the patient a compound or composition comprising any of Formula I, or any combination thereof, or any pharmaceutically acceptable salt thereof, in an amount effective to treat the cancer. In some embodiments, the effective amount is an amount effective to inhibit genome- wide hypomethylation in cancer cells within the patient’s body. In some embodiments, the patient is a human cancer patient. In some embodiments, the cancer is associated with genome- wide hypomethylation. The cancer may be any cancer in which genome-wide hypomethylation occurs including, but are not limited to, prostate cancer, breast cancer, kidney cancer, ovarian cancer, lymphoma, leukemia, melanoma, or glioblastoma. In some embodiments, the cancer is selected from the group consisting of a carcinoma, a sarcoma, a colorectal cancer, a lymphoma, a leukemia, a blastoma, a germ cell cancer, a breast cancer, a lung cancer, a pancreatic cancer, a stomach cancer, a bone cancer, an ovarian cancer, a prostate cancer, a head and neck cancer, a bladder cancer, a cervical cancer, a colon cancer, a skin cancer, a gliobastoma cancer, an esophageal cancer, an oral cancer, a gallbladder cancer, a liver cancer, a testicular cancer, a uterine cancer, a thyroid cancer, and a throat cancer. In some embodiments, the cancer is a colorectal cancer, a head and neck cancer, a pancreatic cancer, a breast cancer, a colon cancer, a lung cancer, or a gliobastoma cancer. In some embodiments, the cancer is melanoma, prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, ovarian cancer, or glioblastoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is glioblastoma. Administration may be according to any technique or route suitable to the cancer being treated or the patient’s needs. Administration may be, for example, oral, parenteral, or via direct injection. Administration may be directly to the tumor or to a location proximal to the tumor. Delivery may be via the bloodstream. Delivery may include active targeting, for example, by conjugating the compound to an antibody that binds to an antigen on the tumor being treated. Delivery may also be passive. The present disclosure also provides uses of any one or more of these compounds, or a pharmaceutically acceptable salt thereof, or a composition comprising any one or more of these compounds, or a pharmaceutically acceptable salt thereof, for treating a mammal having cancer. The present disclosure also provides uses of any one or more of these compounds, or a pharmaceutically acceptable salt thereof, or a composition comprising any one or more of these compounds, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a mammal having cancer. In order that the subject matter disclosed herein may be more efficiently understood, examples are provided below. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the claimed subject matter in any manner. Examples Example 1: TET-TDG Demethylation in a Subset of Metastatic Melanomas Characterized by Prominent DNA Hypomethylation The TCGA SKCM Infinium 450K methylation array data was mined, and 1,028 CpG sites that are candidate targets of TDG-mediated DNA demethylation in metastatic melanoma were identified. These CpG sites divided metastatic melanomas in two dominant clusters, with the “burgundy” cluster showing prominent genome hypomethylation as opposed to the “green” cluster that had less hypomethylation (data not shown). Remarkably, not only TDG, but also TET1-3 mRNA expression levels were higher in the burgundy cluster enriched for hypomethylated sites (Figure 1), suggesting activation of both TET and TDG promotes DNA demethylation in this cluster of metastatic SKCM. Importantly, these hypomethylated CpG sites are enriched for melanoma enhancers (Fontanals-Cirera et al., Mol. Cell, 2017, 68, 731-744) (permutation test p-values=0.0229). Pathway analysis of nearby genes revealed enrichment of GO terms of cell proliferation, transcriptional dysregulation in cancer, kinase activity, RAS signaling, EMT, cell motility, and wound healing. Thus, upregulation of the TET-TDG axis leads to hypomethylation of enhancers, promoters and other regulatory elements, leading to transcriptional activation of oncogenes and other genes that ultimately provide a survival/proliferative/invasive advantage to melanoma cells. Example 2: TET1 and TDG Demethylation in Hypomethylated Lung Cancer By mining the Infinium 450K methylation array data in the TCGA LC databases LUAD (lung adenocarcinomas) and LUSC (lung squamous cell carcinoma), CpG sites were identified that are candidate targets of TET1-TDG-mediated DNA demethylation. These CpG sites divided LUAD and LUSC cases in two dominant clusters, with the “burgundy” cluster showing prominent genome hypomethylation as opposed to the “green” cluster that had less hypomethylation (data not shown). Thus, approximately a fifth and a seventh of LUSC and LUAD cases, respectively, have a marked signature of TET1-TDG-mediated DNA hypomethylation. Example 3: TDG Knockdown Partially Corrects the Altered Methylome of Melanoma To assess the possibility that TDG knockdown partially corrects the altered methylome of melanoma, the methylation values in the top and bottom quartile (TDG.High/TDG.Low) of metastatic SKCM were compared for all Illumina 450K probes matching one of the DREAM probes in the SK28 methylome. The results revealed that CpG sites undergoing hypermethylation in TDG knockdown SK28 cells were significantly associated with hypomethylated CpG sites in metastatic SKCM cases with high TDG expression (p-value = 1.536e-14 by Fisher’s Exact Test). Example 4: Identification of a First-in-class TDG Inhibitor, MC1 A virtual screen was carried out using an approach developed previously (Johnson et al., J. Chem. Inf. Model, 2016, 56, 399-411). From the structure of TDG in complex with a 5-carboxylcytosine (5caC)-containing DNA segment (substrate) (Zhang et al., Nat. Chem. Biol., 2012, 8, 328-330), key interactions with drug-like small molecules were recapitulated. This pilot screen used a virtual library of about 15 million compounds, from which the top-scoring 19 computational hits were obtained and characterized them in an enzyme assay (Mancuso et al., Oncogene, 2019, 38, 3710-3728), modified to work on a self-assembled monolayers for matrix- assisted laser desorption/ionization (SAMDI) mass spectrometry platform. TDG reactions were optimized through assay development to understand the Km of the substrate and enzyme linearity, DMSO tolerance, and assay performance. The final conditions were performed with 10 nM APE1 and 5 nM TDG, 200 nM hairpin G:U mismatched substrate (sequence of the substrate: biotinylated CCACTUGTGAATTGACAGCCCATGTGCATCAATT CACGAGTGG; SEQ ID NO:1) and 100 nM internal standard (sequence of the standard: biotinylated TTTTT; SEQ ID NO:2)(input sequences) in 1X optimized buffer (1X BER buffer, 1.2 mM MgC1 2 , 0.01% Bovine Skin Gelatin, 0.6 mM DTT). The reactions were run in 20 µL volume in 384-well polypropylene microplates (Greiner Bio-One) at ambient temperature and quenched by the addition of 100 mM EDTA (final). At defined times, a 2 µL sample of the quenched reactions was then transferred using a 384-channel pipette station to SAMDI 384- biochip arrays functionalized with self-assembled monolayers presenting Neutravidin. The SAMDI arrays were incubated for 1 hour in a humidified chamber to enable immobilization of the substrate, product, and internal standard. The samples were purified by washing the SAMDI biochip arrays with water and dried under compressed air. A matrix comprising 2-hydroxy-5- methoxybenzoic acid in acetonitrile (30 mg/mL) and ascorbic acid in aqueous citrate (500 mM) was applied by dispensing 350 nL of each spot in the array. SAMDI mass spectrometry (MS) was performed using the reflector-negative mode on an AB Sciex TOF/TOF 5800 System, a matrix-assisted laser desorption ionization (MALDI) mass spectrometer (AB Sciex, Framingham, MA). The conversion of substrate to product was calculated by using the ratio of product area under the curve (AUC) divided by the AUC of the internal standard. In this assay, a TDG inhibitor, MC1, was identified which had acceptable potency, with an IC50 of 50 µM (see, Figure 2). Example 5: MC1 Phenocopies TDG Knockdown and has On-Target Activity, as Demonstrated by Elevation of 5fC and 5caC MC1 recapitulated morphological changes previously described for TDG knockdown, and augmented cellular 5fC and 5caC levels (see, Figure 3), a strong indication of on-target inhibition, as TDG is the main activity involved in 5caC removal (He et al., Science, 2011, 333, 1303-1307; and Maiti et al., J. Biol. Chem., 2011, 286, 35334-35338). Example 6: MC1 has On-Target Activity, as Demonstrated by Increased Cytotoxicity on Hemizygous vs. Normal TDG Content Cells To further assess MC1 on-target activity in vivo, a pair of isogenic cell lines were generated from a tumor that originated spontaneously in a mouse containing an inducible Tdg deletion cassette. This allowed for direct comparison between normal TDG gene dosage (Tdg flox/flox genotype) and hemizygous TDG gene dosage (Tdg flox/- genotype). It was confirmed in the hemizygous cell line, Mft68 flox/- , a 50% reduction in TDG protein level relative to the flox cell line, Mft68 flox/flox . The cell viability in the presence of increasing concentrations of MC1 was determined using a commercial assay. In keeping with on-target activity of MC1, the hemizygous Tdg cell line was more sensitive to MC1, with visible morphologic differences accompanying the reduction in cell viability (see, Figure 4). These data are consistent with the fact that MC1 phenotypes are determined specifically by TDG protein inhibition. Example 7: MC1 Induces Senescence of Cancer Cells MC1 induced senescence, as detected by senescence-associated ^-gal staining (see, Figure 5, Panel A). Senescence is also linked to dramatic alterations of the chromatin landscape that is reorganized in facultative repressive structures known as senescence-associated heterochromatin foci (SAHF) (Narita et al., Cell, 2003, 113, 703-716; and Zhang et al., Mol. Cell. Biol., 2007, 27, 2343-2358). Senescent cells exhibited increased levels of repressive marks, such as H3K9me2/3 and H3K27me2/3 (Narita et al., Cell, 2003, 113, 703-716; and Ito et al., Cell Rep., 2018, 22, 3480-3492), which would predict decreased activating marks at these sites. Importantly, MC1 also induced SAHF, detected by immunofluorescence for H3K9me3 (see, Figure 5, Panel B). Example 8: MC1 Decreases Clonogenic Capacity of Cancer Cells MC1 treatment of the TDG-dependent H23 cell line, but not of the TDG-independent line A548, decreased clonogenic capacity, as colonies were reduced in number and size. Cells at the periphery of the colonies exhibited features of senescence (see, Figure 6). MC1 treatment of MiaPaCa-2 pancreatic cancer cells also reduced clonogenic survival (see, Figure 7). Example 9: TDG is an Immunomodulator that Suppresses Immune Response to Tumors Cluster analysis of metastatic SKCM methylation with 1,028 CpG sites demethylated in a TDG-dependent fashion was carried out. Two dominant clusters were apparent which differ in the extent of TDG-mediated hypomethylation (Figure 8, Panel A). The gene set variance analysis (GSVA) demonstrated that inflammatory genesets are under-represented (Figure 8, Panel B) and their score is lower (Figure 8, Panel C) in the prominently hypomethylated melanomas. These data show that that melanomas with pervasive DNA hypomethylation are depleted of hallmarks of inflammatory signaling, JAK-STAT signaling and TNF signaling, thus confirming that prominent DNA hypomethylation driven by elevated TET-TDG activity correlates with immunoevasion, “cold” tumor status and resistance to immunotherapy. These data further support and strengthen TDG status as an immunomodulatory target. Example 10: TDG Inhibitor Renders Cancer Cells Susceptible to Innate Anti-Tumor Immune Response Melanoma SK28 cells and lung cancer H23 and H358 cells that are treated for 72 hours with the TDG inhibitor MC1 were killed more rapidly by the natural killer line NK92 than untreated samples. H23 lung cancer cells were treated with DMSO or MC1 for 3 days, and then incubated or not with NK92 natural killer cells, and monitored in real-time for loss (cytotoxicity) of the adherent H23 cells, as indicated. Experiments were performed in duplicate and are presented as average ± standard deviation (Figure 9, Panel A). The results were further confirmed in SK28 melanoma cells, which were treated with DMSO or MC1 for 3 days, and then incubated or not with NK92 natural killer cells for 5 hours. Melanoma cells were spindle- shaped, whereas NK cells were smaller and round (Figure 9, Panel B). Similar results were obtained with the lung cancer line H358. These results suggest that inhibition of TDG can reprogram the hypomethylated epigenome of melanoma, induce senescence and proimmunogenic inflammation, thus sensitizing ICB-resistant cases to anti-PD1 immunotherapy. Various modifications of the described subject matter, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference (including, but not limited to, journal articles, U.S. and non-U.S. patents, patent application publications, international patent application publications, gene bank accession numbers, and the like) cited in the present application is incorporated herein by reference in its entirety.
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