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Patent Searching and Data


Title:
BICYCLIC COMPOUNDS
Document Type and Number:
WIPO Patent Application WO/2021/030278
Kind Code:
A1
Abstract:
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions, including hepatitis B and hepatitis D, using a compound of Formula (I), or a pharmaceutical acceptable salt thereof.

Inventors:
VENDEVILLE SANDRINE (US)
Application Number:
PCT/US2020/045640
Publication Date:
February 18, 2021
Filing Date:
August 10, 2020
Export Citation:
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Assignee:
ALIGOS THERAPEUTICS INC (US)
International Classes:
C07D513/04; A61K31/549; A61P31/20
Domestic Patent References:
WO2019043139A12019-03-07
WO2000018762A12000-04-06
WO2008099020A12008-08-21
WO2003059356A22003-07-24
WO2007150001A12007-12-27
WO2008011337A12008-01-24
WO2004006913A12004-01-22
Foreign References:
US20080227774A12008-09-18
US20090062263A12009-03-05
Attorney, Agent or Firm:
MILLER, Kimberly J. (US)
Download PDF:
Claims:
WHAT IS CLAIMED IS: 1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure: wherein: n is 0 or 1; Z1 is –C(=O)–, –NH–C(=O)– or –O–C(=O)–; R1 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) and an optionally substituted heterocyclyl(C1-4 alkyl); R2 and R3 are independently selected from the group consisting of hydrogen, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) and an optionally substituted heterocyclyl(C1-4 alkyl); R4 and R5 are independently selected from the group consisting of hydrogen, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) and an optionally substituted heterocyclyl(C1-4 alkyl); R6 and R7 are independently selected from the group consisting of hydrogen, an unsubstituted C1-4 alkyl and an unsubstituted C1-4 haloalkyl; R8 is selected from the group consisting of hydrogen, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C1-4 alkyl), an optionally substituted cycloalkenyl(C1-4 alkyl), an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl), an optionally substituted heterocyclyl(C1-4 alkyl), –NR10R11, –C(=O)NR12R13 and –OR14; R9 is selected from the group consisting of hydrogen, an unsubstituted C1-4 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) and an optionally substituted heterocyclyl(C1-4 alkyl); R10 and R12 are independently hydrogen or an unsubstituted C1-4 alkyl; R11 and R13 are independently selected from the group consisting of hydrogen, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C1-4 alkyl), an optionally substituted cycloalkenyl(C1-4 alkyl), an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) and an optionally substituted heterocyclyl(C1-4 alkyl); or R10 and R11 are taken together along with the nitrogen to which R10 and R11 are attached to form an optionally substituted 4- to 8-membered monocyclic heterocyclyl, an optionally substituted 8- to 13-membered fused-bicyclic heterocyclyl or an optionally substituted 7- to 13-membered spiro-bicyclic heterocyclyl; R12 and R13 are taken together along with the nitrogen to which R12 and R13 are attached to form an optionally substituted 4- to 8-membered monocyclic heterocyclyl, an optionally substituted 8- to 13-membered fused-bicyclic heterocyclyl or an optionally substituted 7- to 13-membered spiro-bicyclic heterocyclyl; R14 is selected from the group consisting of hydrogen, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C1-4 alkyl), an optionally substituted cycloalkenyl(C1-4 alkyl), an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) and an optionally substituted heterocyclyl(C1-4 alkyl); R2 and R3 are taken together along with the carbon to which R2 and R3 are attached to form an optionally substituted monocyclic C3-6 cycloalkyl or an optionally substituted 3- to 6-membered monocyclic heterocyclyl; or R4 and R5 are taken together along with the carbon to which R4 and R5 are attached to form an optionally substituted monocyclic C3-6 cycloalkyl or an optionally 3- to 6-membered monocyclic heterocyclyl; or R2 and R4 are taken together along with the carbons to which R2 and R4 are each attached to form an optionally monocyclic C5-7 cycloalkyl or an optionally substituted 5- to 7-membered monocyclic heterocyclyl; or R3 and R5 are taken together along with the carbons to which R3 and R5 are each attached to form an optionally monocyclic C5-7 cycloalkyl or an optionally substituted 5- to 7-membered monocyclic heterocyclyl; or R6 and R7 are taken together along with the carbon to which R6 and R7 are attached to form an optionally substituted monocyclic C3-4 cycloalkyl, an optionally substituted oxetane or an optionally substituted thietane. 2. The compound of Claim 1, wherein n is 1. 3. The compound of Claim 2, wherein Z1 is –C(=O)–. 4. The compound of Claim 2, wherein Z1 is –NH–C(=O)–. 5. The compound of Claim 2, wherein Z1 is –O–C(=O)–. 6. The compound of Claim 1, wherein n is 0. 7. The compound of any one of Claims 1-6, wherein R1 is an optionally substituted aryl. 8. The compound of Claim 7, wherein R1 is an optionally substituted phenyl. 9. The compound of any one of Claims 1-6, wherein R1 is an optionally substituted heteroaryl. 10. The compound of Claim 9, wherein R1 is an optionally substituted monocyclic heteroaryl. 11. The compound of Claim 9, wherein R1 is an optionally substituted bicyclic heteroaryl. 12. The compound of any one of Claims 1-6, wherein R1 is an optionally substituted heterocyclyl.

13. The compound of Claim 12, wherein R1 is an optionally substituted monocyclic heterocyclyl. 14. The compound of Claim 12, wherein R1 is an optionally substituted bicyclic heterocyclyl. 15. The compound of any one of Claims 1-6, wherein R1 is an optionally substituted aryl(C1-4 alkyl). 16. The compound of any one of Claims 1-6, wherein R1 is an optionally substituted heteroaryl(C1-4 alkyl). 17. The compound of any one of Claims 1-6, wherein R1 is an optionally substituted heterocyclyl(C1-4 alkyl). 18. The compound of Claim 1, wherein n is 0; and R1 is wherein Ring A1 is an optionally substituted bicyclic heteroaryl or an optionally substituted bicyclic heterocyclyl. 19. The compound of any one of Claims 1-18, wherein R1 is substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 haloalkyl, an unsubstituted C1-6 alkoxy, an unsubstituted acyl, an unsubstituted C-amido, an unsubstituted sulfonyl, an unsubstituted amino, a mono-substituted amine and a di-substituted amine. 20. The compound of Claim 19, wherein Ring A1 is an optionally substituted bicyclic heteroaryl. 21. The compound of Claim 20, wherein Ring A1 is an optionally substituted nitrogen-containing bicyclic heteroaryl. 22. The compound of Claim 21, wherein Ring A1 is an optionally substituted nitrogen-containing, 9-membered bicyclic heteroaryl. 23. The compound of Claim 21, wherein Ring A1 is an optionally substituted nitrogen-containing, 10-membered bicyclic heteroaryl. 24. The compound of Claim 19, wherein Ring A1 is an optionally substituted bicyclic heterocyclyl.

25. The compound of Claim 24, wherein Ring A1 is an optionally substituted nitrogen-containing bicyclic heterocyclyl. 26. The compound of Claim 25, wherein Ring A1 is an optionally substituted nitrogen-containing, 9-membered bicyclic heterocyclyl. 27. The compound of Claim 25, wherein Ring A1 is an optionally substituted nitrogen-containing, 10-membered bicyclic heterocyclyl. 28. The compound of any one of Claims 1-27, wherein R2 is hydrogen. 29. The compound of any one of Claims 1-27, wherein R2 is an unsubstituted C1-4 alkyl. 30. The compound of any one of Claims 1-27, wherein R2 is an unsubstituted C1-4 haloalkyl. 31. The compound of any one of Claims 1-27, wherein R2 is an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl. 32. The compound of Claim 31, wherein R2 is an optionally substituted phenyl, an optionally substituted monocyclic heteroaryl or an optionally substituted monocyclic heterocyclyl. 33. The compound of any one of Claims 1-27, wherein R2 is an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) or an optionally substituted heterocyclyl(C1-4 alkyl). 34. The compound of any one of Claims 1-33, wherein R3 is hydrogen. 35. The compound of any one of Claims 1-33, wherein R3 is an unsubstituted C1-4 alkyl. 36. The compound of any one of Claims 1-33, wherein R3 is an unsubstituted C1-4 haloalkyl. 37. The compound of any one of Claims 1-33, wherein R3 is an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl. 38. The compound of Claim 37, wherein R3 is an optionally substituted phenyl, an optionally substituted monocyclic heteroaryl or an optionally substituted monocyclic heterocyclyl.

39. The compound of any one of Claims 1-33, wherein R3 is an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) or an optionally substituted heterocyclyl(C1-4 alkyl). 40. The compound of any one of Claims 1-27, wherein R2 and R3 are taken together along with the carbon to which R2 and R3 are attached to form an optionally substituted monocyclic C3-6 cycloalkyl or an optionally substituted 3- to 6-membered monocyclic heterocyclyl. 41. The compound of any one of Claims 1-40, wherein R4 is hydrogen. 42. The compound of any one of Claims 1-40, wherein R4 is an unsubstituted C1-4 alkyl. 43. The compound of any one of Claims 1-40, wherein R4 is an unsubstituted C1-4 haloalkyl. 44. The compound of any one of Claims 1-40, wherein R4 is an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl. 45. The compound of Claim 44, wherein R4 is an optionally substituted phenyl, an optionally substituted monocyclic heteroaryl or an optionally substituted monocyclic heterocyclyl. 46. The compound of any one of Claims 1-40, wherein R4 is an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) or an optionally substituted heterocyclyl(C1-4 alkyl). 47. The compound of any one of Claims 1-46, wherein R5 is hydrogen. 48. The compound of any one of Claims 1-46, wherein R5 is an unsubstituted C1-4 alkyl. 49. The compound of any one of Claims 1-46, wherein R5 is an unsubstituted C1-4 haloalkyl. 50. The compound of any one of Claims 1-46, wherein R5 is an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl. 51. The compound of Claim 50, wherein R5 is an optionally substituted phenyl, an optionally substituted monocyclic heteroaryl or an optionally substituted monocyclic heterocyclyl.

52. The compound of any one of Claims 1-46, wherein R5 is an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) or an optionally substituted heterocyclyl(C1-4 alkyl). 53. The compound of any one of Claims 1-40, wherein R4 and R5 are taken together along with the carbon to which R4 and R5 are attached to form an optionally substituted monocyclic C3-6 cycloalkyl or an optionally substituted 3- to 6-membered monocyclic heterocyclyl. 54. The compound of any one of Claims 1-27, 34-39 or 47-52, wherein R2 and R4 are taken together along with the carbons to which R2 and R4 are each attached to form an optionally monocyclic C5-7 cycloalkyl or an optionally substituted 5- to 7-membered monocyclic heterocyclyl. 55. The compound of any one of Claims 1-33 or 41-46, wherein R3 and R5 are taken together along with the carbons to which R3 and R5 are each attached to form an optionally monocyclic C5-7 cycloalkyl or an optionally substituted 5- to 7-membered monocyclic heterocyclyl. 56. The compound of any one of Claims 1-55, wherein R6 is hydrogen. 57. The compound of any one of Claims 1-55, wherein R6 is an unsubstituted C1-4 alkyl. 58. The compound of any one of Claims 1-55, wherein R6 is an unsubstituted C1-4 haloalkyl. 59. The compound of any one of Claims 1-58, wherein R7 is hydrogen. 60. The compound of any one of Claims 1-58, wherein R7 is an unsubstituted C1-4 alkyl. 61. The compound of any one of Claims 1-58, wherein R7 is an unsubstituted C1-4 haloalkyl. 62. The compound of any one of Claims 1-55, wherein R6 and R7 are taken together along with the carbon to which R6 and R7 are attached to form an optionally substituted monocyclic C3-4 cycloalkyl. 63. The compound of any one of Claims 1-55, wherein R6 and R7 are taken together along with the carbon to which R6 and R7 are attached to form an optionally substituted oxetane or an optionally substituted thietane.

64. The compound of any one of Claims 1-63, wherein R8 is hydrogen. 65. The compound of any one of Claims 1-63, wherein R8 is an unsubstituted C1-4 alkyl. 66. The compound of any one of Claims 1-63, wherein R8 is an unsubstituted C1-4 haloalkyl. 67. The compound of any one of Claims 1-63, wherein R8 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. 68. The compound of any one of Claims 1-63, wherein R8 is an optionally substituted aryl. 69. The compound of any one of Claims 1-63, wherein R8 is an optionally substituted heteroaryl. 70. The compound of any one of Claims 1-63, wherein R8 is an optionally substituted heterocyclyl. 71. The compound of any one of Claims 1-63, wherein R8 is an optionally substituted cycloalkyl(C1-4 alkyl) or an optionally substituted cycloalkenyl(C1-4 alkyl). 72. The compound of any one of Claims 1-63, wherein R8 is an optionally substituted aryl(C1-4 alkyl). 73. The compound of any one of Claims 1-63, wherein R8 is an optionally substituted heteroaryl(C1-4 alkyl). 74. The compound of any one of Claims 1-63, wherein R8 is an optionally substituted heterocyclyl(C1-4 alkyl), 75. The compound of any one of Claims 1-63, wherein R8 is –NR10R11. 76. The compound of Claim 75, wherein R10 is hydrogen. 77. The compound of Claim 75, wherein R10 is an unsubstituted C1-4 alkyl. 78. The compound of any one of Claims 75-77, wherein R11 is hydrogen. 79. The compound of any one of Claims 75-77, wherein R11 is an unsubstituted C1-4 alkyl. 80. The compound of any one of Claims 75-77, wherein R11 is an unsubstituted C1-4 haloalkyl. 81. The compound of any one of Claims 75-77, wherein R11 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.

82. The compound of any one of Claims 75-77, wherein R11 is an optionally substituted aryl. 83. The compound of Claim 82, wherein the optionally substituted aryl is optionally substituted phenyl. 84. The compound of any one of Claims 75-77, wherein R11 is an optionally substituted heteroaryl or an optionally substituted heterocyclyl. 85. The compound of any one of Claims 75-77, wherein R11 is an optionally substituted cycloalkyl(C1-4 alkyl) or an optionally substituted cycloalkenyl(C1-4 alkyl). 86. The compound of any one of Claims 75-77, wherein R11 is an optionally substituted aryl(C1-4 alkyl). 87. The compound of Claim 86, wherein the optionally substituted aryl(C1-4 alkyl) is an optionally substituted benzyl. 88. The compound of any one of Claims 75-77, wherein R11 is an optionally substituted heteroaryl(C1-4 alkyl) or an optionally substituted heterocyclyl(C1-4 alkyl). 89. The compound of Claim 75, wherein R10 and R11 are taken together along with the nitrogen to which R10 and R11 are attached to form an optionally substituted 4- to 8- membered monocyclic heterocyclyl, an optionally substituted 8- to 13-membered fused- bicyclic heterocyclyl or an optionally substituted 7- to 13-membered spiro-bicyclic heterocyclyl. 90. The compound of any one of Claims 1-70, wherein R8 is –C(=O)NR12R13. 91. The compound of Claim 90, wherein R12 is hydrogen. 92. The compound of Claim 90, wherein R12 is an unsubstituted C1-4 alkyl. 93. The compound of any one of Claims 90-92, wherein R13 is hydrogen. 94. The compound of any one of Claims 90-92, wherein R13 is an unsubstituted C1-4 alkyl or an unsubstituted C1-4 haloalkyl. 95. The compound of any one of Claims 90-92, wherein R13 is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl. 96. The compound of any one of Claims 90-92, wherein R13 is an optionally substituted cycloalkyl(C1-4 alkyl), an optionally substituted cycloalkenyl(C1-4 alkyl), an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) or an optionally substituted heterocyclyl(C1-4 alkyl). 97. The compound of Claim 90, wherein R12 and R13 are taken together along with the nitrogen to which R12 and R13 are attached to form an optionally substituted 4- to 8- membered monocyclic heterocyclyl, an optionally substituted 8- to 13-membered fused- bicyclic heterocyclyl or an optionally substituted 7- to 13-membered spiro-bicyclic heterocyclyl. 98. The compound of any one of Claims 1-70, wherein R8 is –OR14. 99. The compound of Claim 98, wherein R14 is hydrogen. 100. The compound of Claim 98, wherein R14 is an unsubstituted C1-4 alkyl. 101. The compound of Claim 98, wherein R14 is an unsubstituted C1-4 haloalkyl. 102. The compound of Claim 98, wherein R14 is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl. 103. The compound of Claim 98, wherein R14 is an optionally substituted cycloalkyl(C1-4 alkyl), an optionally substituted cycloalkenyl(C1-4 alkyl), an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) or an optionally substituted heterocyclyl(C1-4 alkyl). 104. The compound of any one of Claims 1-103, wherein R9 is hydrogen. 105. The compound of any one of Claims 1-103, wherein R9 is an unsubstituted C1- 4 alkyl. 106. The compound of any one of Claims 1-103, wherein R9 is an optionally substituted aryl. 107. The compound of Claim 106, wherein R9 is an unsubstituted phenyl or a substituted phenyl. 108. The compound of any one of Claims 1-103, wherein R9 is an optionally substituted heteroaryl. 109. The compound of any one of Claims 1-103, wherein R9 is an optionally substituted heterocyclyl. 110. The compound of Claim 109, wherein R9 is an unsubstituted monocyclic heterocyclyl or a substituted monocyclic heterocyclyl.

111. The compound of any one of Claims 1-103, wherein R9 is an optionally substituted aryl(C1-4 alkyl). 112. The compound of any one of Claims 1-103, wherein R9 is an optionally substituted heteroaryl(C1-4 alkyl). 113. The compound of any one of Claims 1-103, wherein R9 is an optionally substituted heterocyclyl(C1-4 alkyl). 114. The compound of Claim 1, wherein the compound is selected from the group consisting of: , or a pharmaceutically acceptable salt of any of the foregoing.

115. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-114, or a pharmaceutically acceptable salt thereof, and excipient.

116. Use of the compound of any one of Claims 1-114 in the preparation of a medicament for the treatment of hepatitis B.

117. Use of the compound of any one of Claims 1-114 in the preparation of a medicament for the treatment of hepatitis D.

118. The use of any one of Claims 116-117, wherein the use further comprises the use of an additional agent selected from the group consisting of an interferon, a nucleoside analog, a nucleotide analog, a sequence specific oligonucleotide, a nucleic acid polymer, an entry inhibitor and a small molecule immunomodulator.

119. The use of Claim 118, wherein the additional agent selected from the group consisting of recombinant interferon alpha 2b, IFN-a, PEG-IFN-a-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide and tenofovir disoproxil.

Description:
BICYCLIC COMPOUNDS INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS [0001] Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Application No.62/885,593, filed August 12, 2019. REFERENCE TO SEQUENCE LISTING [0002] The present application is filed with a Sequence Listing in Electronic format. The Sequence Listing is provided as a file entitled ALIG027.txt, created August 10, 2020, which is approximately 4 kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. BACKGROUND Field [0003] The present application relates to the fields of chemistry, biochemistry and medicine. Disclosed herein are compounds of Formula (I), or pharmaceutically acceptable salt thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also disclosed herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Description [0004] The hepatitis B virus (HBV) is a DNA virus and a member of the Hepadnaviridae family. HBV infects more than 300 million worldwide, and is a causative agent of liver cancer and liver disease such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Although there are approved drugs for treating HBV, by either boosting the immune system or slowing down the replication of the HBV virus, HBV continues to be a problem due to the drawbacks associated with each of the approved drugs. SUMMARY

[0005J Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0006] Some embodiments disclosed herein relate to a pharmaceutical composition that can contain an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0007] Some embodiments described herein relate to a method of treating a HBV and/or HDV infection that can include administering to a subject identified as suffering from the HBV and/or HDV infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of treating a HBV and/or HDV infection.

[0008] Some embodiments disclosed herein relate to a method of inhibiting replication of HBV and/or HDV that can include contacting a cell infected with the HBV and/or HDV with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of inhibiting the replication HBV and/or HDV.

[0009] These are other embodiments are described in greater detail below.

DETAILED DESCRIPTION

[0010] HBV is a partially double-stranded circular DNA of about 3.2 kilobase (kb) pairs, and is classified into eight genotypes, A to H. The HBV replication pathway has been studied in great detail. T.J. Liang, Hepatology (2009) 49(5 Suppl):S13-S21. On part of replication includes the formation of the covalently closed circular (cccDNA) form. The presence of the cccDNA gives rise to the risk of viral reemergence throughout the life of the host organism. HBV carriers can transmit the disease for many years. An estimated 300 million people are living with hepatitis B virus infection, and it is estimated that over 750,000 people worldwide die of hepatitis B each year. In addition, immunosuppressed individuals or individuals undergoing chemotherapy are especially at risk for reactivation of a HBV infection. HBV can be acute and/or chronic. Acute HBV infection can be either asymptomatic or present with symptomatic acute hepatitis. [0011] HBV can be transmitted by blood, semen, and/or another body fluid. This can occur through direct blood-to-blood contact, unprotected sex, sharing of needles, and from an infected mother to her baby during the delivery process. The HBV surface antigen (HBsAg) is most frequently used to screen for the presence of this infection. Currently available medications do not cure a HBV and/or HDV infection. Rather, the medications suppress replication of the virus. [0012] The hepatitis D virus (HDV) is a DNA virus, also in the Hepadnaviridae family of viruses. HDV can propagate only in the presence of HBV. The routes of transmission of HDV are similar to those for HBV. Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or in addition to chronic hepatitis B or hepatitis B carrier state (superinfection). Both superinfection and coinfection with HDV results in more severe complications compared to infection with HBV alone. These complications include a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased risk of developing liver cancer in chronic infections. In combination with hepatitis B, hepatitis D has the highest fatality rate of all the hepatitis infections, at 20%. There is currently no cure or vaccine for hepatitis D. Definitions [0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. [0014] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more of the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group. [0015] As used herein, “C a to C b ” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the aryl, ring of the heteroaryl or ring of the heterocyclyl can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “C 1 to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH 3 CH 2 CH(CH 3 )-, (CH 3 ) 2 CHCH 2 - and (CH 3 ) 3 C-. If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl or heterocyclyl group, the broadest range described in these definitions is to be assumed. [0016] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds may be designated as “C1-C4 alkyl” or similar designations. By way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted. [0017] As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. The length of an alkenyl can vary. For example, the alkenyl can be a C2-4 alkenyl, C2-6 alkenyl or C2-8 alkenyl. Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. An alkenyl group may be unsubstituted or substituted. [0018] As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. The length of an alkynyl can vary. For example, the alkynyl can be a C 2-4 alkynyl, C 2-6 alkynyl or C 2-8 alkynyl. Examples of alkynyls include ethynyl and propynyl. An alkynyl group may be unsubstituted or substituted. [0019] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s). 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. [0020] As used herein, “cycloalkenyl” refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi- electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkenyl group may be unsubstituted or substituted. [0021] As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C 6 -C 14 aryl group, a C 6 -C 10 aryl group, or a C 6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted. [0022] As used herein, “heteroaryl” refers to a monocyclic, bicyclic and tricyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1 to 5 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3- oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted. [0023] As used herein, “heterocyclyl” refers to a monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The number of atoms in the ring(s) of a heterocyclyl group can vary. For example, the heterocyclyl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocyclyl may be quaternized. Heterocyclyl groups may be unsubstituted or substituted. Examples of such “heterocyclyl groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2- dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3- dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4- piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and 3,4- methylenedioxyphenyl). [0024] As used herein, “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2- phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl). [0025] As used herein, “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to 2-thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl), and their benzo-fused analogs. [0026] A “(heterocyclyl)alkyl” refer to a heterocyclic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a heterocyclyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl) and 1,3-thiazinan-4-yl(methyl). [0027] “Lower alkylene groups” are straight-chained -CH 2 - tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-) and butylene (-CH2CH2CH2CH2-). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of “optionally substituted” and/or by substituting both hydrogens on the same carbon with a cycloalkyl group (e.g., or a monocyclic heterocyclyl (such as [0028] As used herein, “alkoxy” refers to the formula –OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso- butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted. [0029] As used herein, “acyl” refers to a hydrogen an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted. [0030] As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri- haloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted. [0031] As used herein, “haloalkoxy” refers to a O-alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2- fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted. [0032] A “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substituted or unsubstituted. [0033] A “sulfinyl” group refers to an “-S(=O)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted. [0034] A “sulfonyl” group refers to an “SO 2 R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted. [0035] An “O-carboxy” group refers to a “RC(=O)O-” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. An O-carboxy may be substituted or unsubstituted. [0036] The terms “ester” and “C-carboxy” refer to a “-C(=O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted. [0037] A “thiocarbonyl” group refers to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted. [0038] A “trihalomethanesulfonyl” group refers to an “X3CSO2-” group wherein each X is a halogen. [0039] A “trihalomethanesulfonamido” group refers to an “X3CS(O)2N(RA)-” group wherein each X is a halogen, and R A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). [0040] The term “amino” as used herein refers to a –NH2 group. [0041] As used herein, the term “hydroxy” refers to a –OH group. [0042] A “cyano” group refers to a “-CN” group. [0043] The term “azido” as used herein refers to a –N 3 group. [0044] An “isocyanato” group refers to a “-NCO” group. [0045] A “thiocyanato” group refers to a “-CNS” group. [0046] An “isothiocyanato” group refers to an “ -NCS” group. [0047] A “mercapto” group refers to an “-SH” group. [0048] A “carbonyl” group refers to a C=O group. [0049] An “S-sulfonamido” group refers to a “-SO 2 N(R A R B )” group in which R A and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An S-sulfonamido may be substituted or unsubstituted. [0050] An “N-sulfonamido” group refers to a “RSO 2 N(R A )-” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted. [0051] An “O-carbamyl” group refers to a “-OC(=O)N(RARB)” group in which R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted. [0052] An “N-carbamyl” group refers to an “ROC(=O)N(RA)-” group in which R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted. [0053] An “O-thiocarbamyl” group refers to a “-OC(=S)-N(RARB)” group in which R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted. [0054] An “N-thiocarbamyl” group refers to an “ROC(=S)N(RA)-” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted. [0055] A “C-amido” group refers to a “-C(=O)N(R A R B )” group in which R A and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted. [0056] An “N-amido” group refers to a “RC(=O)N(R A )-” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted. [0057] The term “halogen atom” or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine. [0058] Where the numbers of substituents is not specified (e.g. haloalkyl), there may be one or more substituents present. For example “haloalkyl” may include one or more of the same or different halogens. As another example, “C1-C3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms. [0059] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem.11:942-944 (1972)). [0060] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1 -C 7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine. [0061] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof. In addition, the term “comprising” is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

[0062] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality.

[0063] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of (Reconfiguration or (S)-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.

[0064] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).

[0065] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise. [0066] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments. Compounds [0067] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: n can be 0 or 1; Z 1 can be –C(=O)–, –NH–C(=O)– or –O–C(=O)–; R 1 can be selected from an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C 1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) and an optionally substituted heterocyclyl(C1-4 alkyl); R 2 and R 3 can be independently selected from hydrogen, an unsubstituted C 1-4 alkyl, an unsubstituted C1-4 haloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C 1-4 alkyl), an optionally substituted heteroaryl(C 1-4 alkyl) and an optionally substituted heterocyclyl(C 1- 4 alkyl); R 4 and R 5 can be independently selected from hydrogen, an unsubstituted C1-4 alkyl, an unsubstituted C 1-4 haloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) and an optionally substituted heterocyclyl(C1- 4 alkyl); R 6 and R 7 can be independently selected from hydrogen, an unsubstituted C 1-4 alkyl and an unsubstituted C1-4 haloalkyl; R 8 can be selected from hydrogen, an unsubstituted C1-4 alkyl, an unsubstituted C 1-4 haloalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C1-4 alkyl), an optionally substituted cycloalkenyl(C 1-4 alkyl), an optionally substituted aryl(C 1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl), an optionally substituted heterocyclyl(C1-4 alkyl), –NR 10 R 11 , –C(=O)NR 12 R 13 and –OR 14 ; R 9 can be selected from hydrogen, an unsubstituted C1-4 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C 1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) and an optionally substituted heterocyclyl(C1-4 alkyl); R 10 and R 12 can be independently hydrogen or an unsubstituted C1-4 alkyl; R 11 and R 13 can be independently selected from hydrogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-4 haloalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C1-4 alkyl), an optionally substituted cycloalkenyl(C1-4 alkyl), an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C 1-4 alkyl) and an optionally substituted heterocyclyl(C 1-4 alkyl); or R 10 and R 11 can be taken together along with the nitrogen to which R 10 and R 11 are attached to form an optionally substituted 4- to 8-membered monocyclic heterocyclyl, an optionally substituted 8- to 13-membered fused-bicyclic heterocyclyl or an optionally substituted 7- to 13- membered spiro-bicyclic heterocyclyl; R 12 and R 13 can be taken together along with the nitrogen to which R 12 and R 13 are attached to form an optionally substituted 4- to 8- membered monocyclic heterocyclyl, an optionally substituted 8- to 13-membered fused- bicyclic heterocyclyl or an optionally substituted 7- to 13-membered spiro-bicyclic heterocyclyl; R 14 can be selected from hydrogen, an unsubstituted C1-4 alkyl, an unsubstituted C 1-4 haloalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C 1-4 alkyl), an optionally substituted cycloalkenyl(C1-4 alkyl), an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) and an optionally substituted heterocyclyl(C1-4 alkyl); R 2 and R 3 can be taken together along with the carbon to which R 2 and R 3 are attached to form an optionally substituted monocyclic C3-6 cycloalkyl or an optionally substituted 3- to 6-membered monocyclic heterocyclyl; or R 4 and R 5 can be taken together along with the carbon to which R 4 and R 5 are attached to form an optionally substituted monocyclic C3-6 cycloalkyl or an optionally substituted 3- to 6-membered monocyclic heterocyclyl; or R 2 and R 4 can be taken together along with the carbons to which R 2 and R 4 are each attached to form an optionally monocyclic C5-7 cycloalkyl or an optionally substituted 5- to 7-membered monocyclic heterocyclyl; or R 3 and R 5 can be taken together along with the carbons to which R 3 and R 5 are each attached to form an optionally monocyclic C5-7 cycloalkyl or an optionally substituted 5- to 7-membered monocyclic heterocyclyl; or R 6 and R 7 can be taken together along with the carbon to which R 6 and R 7 are attached to form an optionally substituted monocyclic C3-4 cycloalkyl, an optionally substituted oxetane or an optionally substituted thietane. [0068] A variety of moieties can be present for Z 1 and R 1 . In some embodiments, n can be 0; and R 1 can be selected from an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C 1-4 alkyl), an optionally substituted heteroaryl(C 1-4 alkyl) and an optionally substituted heterocyclyl(C1-4 alkyl) such that Formula (I), and pharmaceutically acceptable salts thereof can be Formula (Ia), or a pharmaceutically acceptable salt thereof. In other embodiments, n can be 1; Z 1 can be –C(=O)–, –NH–C(=O)– or –O–C(=O)–; and R 1 can be selected from an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C 1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) and an optionally substituted heterocyclyl(C1-4 alkyl). As shown below, when Z 1 is –C(=O)–, –NH–C(=O)– or –O–C(=O)–, Formula (I) can be Formula (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof, respectively. As described herein, n can be 0 and R 1 can be an optionally substituted heteroaryl or an optionally substituted heterocyclyl. An example of n being 0; and R 1 being an optionally substituted heteroaryl or an optionally substituted heterocyclyl wherein Ring A 1 can be an optionally substituted bicyclic heteroaryl or an optionally substituted bicyclic heterocyclyl such that Formula (I), and pharmaceutically acceptable salts thereof can be Formula (Ie), or a pharmaceutically acceptable salt thereof. [0069] Various cyclic moieties can be present for R 1 . In some embodiments, R 1 can be an optionally substituted aromatic carbocyclic moiety, for example an optionally substituted aryl. For example, R 1 can be an optionally substituted phenyl. In some embodiments, R 1 can be an unsubstituted phenyl. In other embodiments, R 1 can be a substituted phenyl. When R 1 is a substituted phenyl, the phenyl can be mono-substituted. The mono-substituted phenyl can be a para-substituted phenyl, a meta-substituted phenyl or an ortho-substituted phenyl. The substituted phenyl can be substituted by multiple moieties, such as 2, 3 or 4 or more times. In some embodiments, R 1 can be a di-substituted phenyl. When more than one moiety is present, the moieties can be the same or different moieties can be different. In some embodiments, R 1 can be an unsubstituted or substituted naphthyl. [0070] As described herein, R 1 can be a monocyclic or multicyclic (for example, a bicyclic) moiety that includes one or more heteroatoms in the ring(s). In some embodiments, R 1 can be an optionally substituted heteroaryl. In some embodiments, R 1 can be an unsubstituted or a substituted monocyclic heteroaryl. For example, R 1 can be a 5- membered or 6-membered monocyclic heteroaryl, wherein the heteroaryl ring can be unsubstituted or substituted. In other embodiments, R 1 can be an unsubstituted or a substituted bicyclic heteroaryl. The bicyclic heteroaryl can be an unsubstituted or a substituted 9-membered or an unsubstituted or a substituted 10-membered heteroaryl. The heteroaryl can include one or more heteroatoms, such as N (nitrogen), O (oxygen) and/or S (sulfur). [0071] In some embodiments, R 1 can be an optionally substituted heterocyclyl. The heterocyclyl can be a monocyclic heterocyclyl or a bicyclic heterocyclyl. In some embodiments, R 1 can be an unsubstituted or a substituted monocyclic heterocyclyl, such as an unsubstituted or a substituted 5-membered or an unsubstituted or a substituted 6- membered monocyclic heterocyclyl. In other embodiments, R 1 can be an unsubstituted or a substituted bicyclic heterocyclyl, including an unsubstituted or a substituted 9-membered or an unsubstituted or a substituted 10-membered heterocyclyl. The number and types of heteroatoms that can be present in a heterocyclyl for R 1 can vary. For example, 1, 2, 3 or more than 3 heteroatoms, such as N (nitrogen), O (oxygen) and/or S (sulfur), can be present in a heterocyclyl of R 1 . [0072] In some embodiments, n can be 0; and R 1 can , wherein Ring A 1 can be an optionally substituted bicyclic heteroaryl. In other embodiments, R 1 can wherein Ring A 1 can be an optionally substituted bicyclic heterocyclyl. In some embodiments, Ring A 1 can be an optionally substituted nitrogen-containing, 9- membered bicyclic heteroaryl. In other embodiments, Ring A 1 can be an optionally substituted nitrogen-containing, 10-membered bicyclic heteroaryl. In still other embodiments, Ring A 1 can be an optionally substituted nitrogen-containing, 9-membered bicyclic heterocyclyl. In yet still other embodiments, Ring A 1 can be an optionally substituted nitrogen-containing, 10-membered bicyclic heterocyclyl. [0073] In some embodiments, R 1 can be a nitrogen-containing, bicyclic heteroaryl or a nitrogen-containing, bicyclic heterocyclyl. In some embodiments, R 1 can be selected from an unsubstituted or a substituted [5,5] bicyclic heteroaryl, an unsubstituted or a substituted [5,6] bicyclic heteroaryl, an unsubstituted or a substituted [6,5] bicyclic heteroaryl, an unsubstituted or a substituted [6,6] bicyclic heteroaryl, an unsubstituted or a substituted [5,5] bicyclic heterocyclyl, an unsubstituted or a substituted [5,6] bicyclic heterocyclyl, an unsubstituted or a substituted [6,5] bicyclic heterocyclyl and an unsubstituted or a substituted [6,6] bicyclic heterocyclyl. In some embodiments, R 1 can have the general structure 2 wherein Ring Y indicates the point of attachment to the remaining portion of Formula (I); and wherein Ring Y 1 and Ring Y 2 can be independently selected from phenyl, furan, furazan, thiophene, phthalazine, pyrrole, oxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,2,3,4-tetrazine, 2H-1,2-oxazine, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, thiazoline, thiazolidine, morpholine, piperidine, piperazine, pyrrolidine, pyrazoline, pyrazolidine and thiamorpholine, wherein Ring Y 1 and Ring Y 2 can be each optionally substituted. In some embodiments, Ring Y 1 can be selected from an optionally substituted phenyl, an optionally substituted pyridine, an optionally substituted pyridazine, an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted 1,2,3-triazine, an optionally substituted 1,2,4-triazine and an optionally substituted 1,2,3,4-tetrazine. In some embodiments, Ring Y 2 can be selected from an optionally substituted phenyl, an optionally substituted pyridine, an optionally substituted pyridazine, an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted 1,2,3-triazine, an optionally substituted 1,2,4-triazine and an optionally substituted 1,2,3,4-tetrazine. In other embodiments, Ring Y 2 can be selected from an optionally substituted furan, an optionally substituted thiophene, an optionally substituted pyrrole, an optionally substituted oxazole, an optionally substituted thiazole, an optionally substituted imidazole, an optionally substituted pyrazole, an optionally substituted isoxazole and an optionally substituted isothiazole. [0074] A variety of cyclic groups described herein for R 1 can be attached via a C1-4 alkyl linker. In some embodiments, R 1 can be an optionally substituted aryl(C1-4 alkyl), for example, an optionally substituted benzyl. In other embodiments, R 1 can be an optionally substituted heteroaryl(C 1-4 alkyl). In still other embodiments, R 1 can be an optionally substituted heterocyclyl(C1-4 alkyl). Examples of heteroaryls and heterocyclyls are described herein, and include those of the previous paragraph. As described herein, the linker can include 1 to 4 carbons. The aryl, heteroaryl, heterocyclyl and C1-4 alkyl of aryl(C1-4 alkyl), heteroaryl(C 1-4 alkyl) and heterocyclyl(C 1-4 alkyl) can be each unsubstituted or unsubstituted. When the C1-4 alkyl linker is substituted, one or more hydrogens can be replaced with a moiety, such as those provided in the definition of “optionally substituted,” and/or two or more hydrogens can be taken together along with the carbon to which the hydrogens are attached to form an optionally substituted C3-4 cycloalkyl or an optionally substituted 3-, 4- or 5-membered heterocyclyl. In some embodiments, the C 1-4 alkyl linker of aryl(C 1-4 alkyl), heteroaryl(C1-4 alkyl) and heterocyclyl(C1-4 alkyl) can be substituted with one or more moieties selected from halogen (such as F), cyano, C 1-2 haloalkyl (for example, –CHF 2 , – CH 2 F, –CF 3 , –CHClF, –CH 2 Cl, –CHCl 2 and –CCl 3 ), OH, an unsubstituted C 1-4 alkoxy and an unsubstituted C-amido (such as –C(=O)NH2, –C(=O)NH(C1-4 alkyl) and –C(=O)N(C1-4 alkyl) 2 ). In some embodiments, the C 1-4 alkyl linker for R 1 can be –CH 2 –, –CH 2 CH 2 –, – CH(CH 3 )CH 2 –, –CH 2 CH 2 CH 2 –, –CH 2 CH 2 CH 2 CH 2 –, [0075] As described herein, the R 1 groups can be unsubstituted or substituted. When R 1 is substituted, a variety of substituents can be present on a R 1 group described herein. In some embodiments, R 1 can be substituted with one or more substituents selected from deuterium, halogen (such as F, Cl and/or Br), cyano, an unsubstituted C1-6 alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight-changed or branched) and hexyl (straight-chained or branched)), an unsubstituted C 1-6 haloalkyl (such as –CHF 2 , –CH 2 F, –CF 3 , –CHClF, –CH 2 Cl, –CHCl 2 and –CCl 3 ), an unsubstituted C1-6 alkoxy (for example, methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy), an unsubstituted acyl (for example, –C(=O)-C1-4 alkyl), an unsubstituted C-amido (such as –C(=O)NH 2 , –C(=O)NH(C 1-4 alkyl) and –C(=O)N(C 1-4 alkyl)2), an unsubstituted sulfonyl (such as –S(=O)2-C1-4 alkyl), an unsubstituted amino, a mono-substituted amine (for example, an mono-alkyl substituted amine) and a di-substituted amine (such as a di-alkyl substituted amine). [0076] Exemplary R 1 groups include, but are not limited to, the following: wherein each of these moieties can be unsubstituted or substituted. Examples of substituted R 1 groups include , , [0077] As provided herein, R 8 can be selected from hydrogen, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C1-4 alkyl), an optionally substituted cycloalkenyl(C 1-4 alkyl), an optionally substituted aryl(C 1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl), an optionally substituted heterocyclyl(C1-4 alkyl), –NR 10 R 11 , –C(=O)NR 12 R 13 and –OR 14 . In some embodiments, R 8 can be hydrogen. In other embodiments, R 8 can be an unsubstituted C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. In still other embodiments, R 8 can be an unsubstituted C 1-4 haloalkyl. Exemplary unsubstituted C 1-4 haloalkyls include –CHF 2 , – CH2F, –CF3, –CHClF, –CH2Cl, –CHCl2 and –CCl3. [0078] Several cyclic moieties can be present at R 8 . For example, in some embodiments, R 8 can be an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. The optionally substituted cycloalkyl and the optionally substituted cycloalkenyl can be monocyclic, such as an optionally substituted monocyclic C3-6 cycloalkyl or an optionally substituted monocyclic C3-6 cycloalkenyl. Alternatively, the optionally substituted cycloalkyl and/or the optionally substituted cycloalkenyl can be multicyclic, for example, an optionally substituted fused-bicyclic cycloalkyl, an optionally substituted fused-bicyclic cycloalkenyl, an optionally substituted spiro-bicyclic cycloalkyl and an optionally substituted spiro-bicyclic cycloalkenyl. In other embodiments, R 8 can be an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl. Exemplary R 8 aryls, heteroaryls and heterocyclyls include, but are not limited to, phenyl, 5-membered monocyclic heteroaryls, 6-membered monocyclic heteroaryls, 5-membered monocyclic heterocyclyls and 6-membered monocyclic heterocyclyls, wherein each of the aforementioned moieties can be unsubstituted or substituted. The heteroatom(s) that can be present in an optionally substituted heteroaryl and an optionally substituted heterocyclyl for R 8 include N (nitrogen), O (oxygen) and/or S (sulfur). In some embodiments, R 8 can be an unsubstituted phenyl. In other embodiments, R 8 can be a substituted phenyl. [0079] The cyclic moieties described herein for R 8 can be attached via a C1-4 alkyl linker, such as those described herein. In some embodiments, R 8 can be an optionally substituted cycloalkyl(C1-4 alkyl). In other embodiments, R 8 can be an optionally substituted cycloalkenyl(C 1-4 alkyl). In still other embodiments, R 8 can be an optionally substituted aryl(C1-4 alkyl). In yet still other embodiments, R 8 can be an optionally substituted heteroaryl(C1-4 alkyl). In some embodiments, R 8 can be an optionally substituted heterocyclyl(C 1-4 alkyl). The cycloalkyls, cycloalkenyls, aryls, heteroaryls and heterocyclyls can be monocyclic or bicyclic (for example, fused bicyclic). For example, R 8 can be an optionally substituted monocyclic C 3-6 cycloalkyl(C 1-4 alkyl), an optionally substituted monocyclic C3-6 cycloalkenyl(C1-4 alkyl), an optionally substituted benzyl, an optionally substituted monocyclic heteroaryl(C 1-4 alkyl) (such as a 5-membered monocyclic heteroaryl(C 1-4 alkyl) or 6-membered monocyclic heteroaryl(C 1-4 alkyl)) or an optionally substituted monocyclic heterocyclyl(C1-4 alkyl) (such as a 5-membered monocyclic heterocyclyl(C 1-4 alkyl) or 6-membered monocyclic heterocyclyl(C 1-4 alkyl)). In some embodiments, R 8 can be an unsubstituted benzyl. In other embodiments, R 8 can be a substituted benzyl. [0080] The C1-4 alkyls of cycloalkyl(C1-4 alkyl), cycloalkenyl(C1-4 alkyl), aryl(C1- 4 alkyl), heteroaryl(C 1-4 alkyl) and heterocyclyl(C 1-4 alkyl) can be unsubstituted or substituted. When the C1-4 alkyl is substituted, one or more hydrogens can be replaced with a moiety, such as those provided in the definition of “optionally substituted,” and/or two or more hydrogens can be taken together along with the carbon to which the hydrogens are attached to form an optionally substituted C3-4 cycloalkyl or an optionally substituted 3-, 4- or 5-membered heterocyclyl. In some embodiments, the C1-4 alkyl linker of cycloalkyl(C1-4 alkyl), cycloalkenyl(C 1-4 alkyl), aryl(C 1-4 alkyl), heteroaryl(C 1-4 alkyl) and heterocyclyl(C 1-4 alkyl) can be substituted with one or more moieties selected from halogen (such as F), cyano, C 1-2 haloalkyl (for example, –CHF 2 , –CH 2 F, –CF 3 , –CHClF, –CH 2 Cl, –CHCl 2 and –CCl 3 ), OH, an unsubstituted C1-4 alkoxy and an unsubstituted C-amido (such as –C(=O)NH2, – C(=O)NH(C1-4 alkyl) and –C(=O)N(C1-4 alkyl)2). Exemplary linkers that can attached the cyclic moieties for R 8 include, but are not limited to, –CH 2 –, –CH 2 CH 2 –, –CH(CH 3 )CH 2 –, – CH 2 CH 2 CH 2 –, –CH 2 CH 2 CH 2 CH 2 – , and [0081] In some embodiments, R 8 can be –NR 10 R 11 . In other embodiments, R 8 can be –C(=O)NR 12 R 13 . In some embodiments, R 10 can be hydrogen. In other embodiments, R 10 can be an unsubstituted C 1-4 alkyl. In some embodiments, R 12 can be hydrogen. In other embodiments, R 12 can be an unsubstituted C1-4 alkyl. For example, R 10 and/or R 12 can be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl. [0082] In some embodiments, R 11 can be hydrogen. In other embodiments, R 11 can be an unsubstituted C 1-4 alkyl. For example, R 11 can be methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl. In still other embodiments, R 11 can be an unsubstituted C 1-4 haloalkyl. As described herein, R 11 can be various carbocyclic, heteroaryl or heterocyclic groups. In some embodiments, R 11 can be an optionally substituted cycloalkyl, for example, an optionally substituted C3-8 cycloalkyl. In other embodiments, R 11 can be an optionally substituted cycloalkenyl, such as an optionally substituted C 3-8 cycloalkenyl. In some embodiments, R 11 can be an optionally substituted aryl. For example, R 11 can be an unsubstituted or a substituted phenyl. In still other embodiments, R 11 can be an optionally substituted heteroaryl. The heteroaryl for R 11 can be an optionally substituted monocyclic heteroaryl (such as an optionally substituted 5- or 6-membered monocyclic heteroaryl) or an optionally substituted bicyclic heteroaryl (for example, an optionally substituted 9- or 10-membered bicyclic heteroaryl). In some embodiments, R 11 can be an optionally substituted heterocyclyl. [0083] A variety cyclic groups can be attached via a C1-4 alkyl linker for R 11 . Examples of C 1-4 alkyl linkers are described herein and include –CH 2 –, –CH 2 CH 2 –, – CH(CH 3 )CH 2 –, –CH 2 CH 2 CH 2 –, –CH 2 CH 2 CH 2 CH 2 –, As shown and described herei 11 n, the C1-4 alkyl linkers for R can be unsubstituted or substituted. When the C 1-4 alkyls for R 11 are substituted, one or more hydrogens can be replaced with a moiety, such as those provided in the definition of “optionally substituted,” and/or two or more hydrogens can be taken together along with the carbon to which the hydrogens are attached to form an optionally substituted C3-4 cycloalkyl or an optionally substituted 3-, 4- or 5-membered heterocyclyl. In some embodiments, the C 1-4 alkyl linker for the R 11 groups can be substituted with one or more moieties selected from halogen (such as F), cyano, C1-2 haloalkyl (for example, –CHF2, –CH2F, –CF3, – CHClF, –CH 2 Cl, –CHCl 2 and –CCl 3 ), OH, an unsubstituted C 1-4 alkoxy and an unsubstituted C-amido (such as –C(=O)NH2, –C(=O)NH(C1-4 alkyl) and –C(=O)N(C1-4 alkyl)2). In some embodiments, R 11 can be an optionally substituted cycloalkyl(C 1-4 alkyl), such as an optionally substituted monocyclic C3-8 cycloalkyl(C1-4 alkyl). In other embodiments, R 11 can be an optionally substituted cycloalkenyl(C1-4 alkyl), such as an optionally substituted monocyclic C 3-8 cycloalkenyl(C 1-4 alkyl). In still other embodiments, R 11 can be an optionally substituted aryl(C1-4 alkyl). As an example, R 11 can be an unsubstituted benzyl or a substituted benzyl. In yet still other embodiments, R 11 can be an optionally substituted heteroaryl(C1-4 alkyl). In some embodiments, R 11 can be an optionally substituted heterocyclyl(C 1-4 alkyl). The heteroaryl of the optionally substituted heteroaryl(C 1-4 alkyl) can be an optionally substituted monocyclic heteroaryl (such as a 5- or 6-membered monocyclic heteroaryl) or an optionally substituted bicyclic heteroaryl (such as a 9- or 10- membered bicyclic heteroaryl). [0084] In some embodiments, R 10 and R 11 can be taken together along with the nitrogen to which R 10 and R 11 are attached to form an optionally substituted 4- to 8-member monocyclic heterocyclyl. In other embodiments, R 10 and R 11 can be taken together along with the nitrogen to which R 10 and R 11 are attached to form an optionally substituted 8- to 13-membered fused-bicyclic heterocyclyl. In still other embodiments, R 10 and R 11 can be taken together along with the nitrogen to which R 10 and R 11 are attached to form an optionally substituted 7- to 13-membered spiro-bicyclic heterocyclyl. The 4- to 8-member monocyclic heterocyclyl, 8- to 13-membered fused-bicyclic heterocyclyl and/or 7- to 13- membered spiro-bicyclic heterocyclyl can include one or more ring nitrogens. [0085] As described herein, R 13 can be cyclic and non-cyclic moieties. In some embodiments, R 13 can be hydrogen. In other embodiments, R 13 can be an unsubstituted C1-4 alkyl. In still other embodiments, R 13 can be an unsubstituted C 1-4 haloalkyl. Various carbocyclic, heteroaryl or heterocyclic groups are suitable for R 13 . In some embodiments, R 13 can be an optionally substituted cycloalkyl, for example, an optionally substituted C 3-8 cycloalkyl. In other embodiments, R 13 can be an optionally substituted cycloalkenyl, such as an optionally substituted C3-8 cycloalkenyl. In some embodiments, R 13 can be an optionally substituted aryl. For example, R 13 can be an unsubstituted or a substituted phenyl. In still other embodiments, R 13 can be an optionally substituted heteroaryl. The heteroaryl for R 13 can be an optionally substituted monocyclic heteroaryl (such as an optionally substituted 5- or 6-membered monocyclic heteroaryl) or an optionally substituted bicyclic heteroaryl (for example, an optionally substituted 9- or 10-membered bicyclic heteroaryl). In some embodiments, R 13 can be an optionally substituted heterocyclyl. [0086] As described herein, R 13 can be an optionally substituted cycloalkyl(C 1-4 alkyl), an optionally substituted cycloalkenyl(C 1-4 alkyl), an optionally substituted aryl(C 1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) or an optionally substituted heterocyclyl(C 1-4 alkyl). Various C 1-4 alkyls are described herein for an optionally substituted cycloalkyl(C1-4 alkyl), an optionally substituted cycloalkenyl(C1-4 alkyl), an optionally substituted aryl(C 1-4 alkyl), an optionally substituted heteroaryl(C 1-4 alkyl) and/or an optionally substituted heterocyclyl(C1-4 alkyl) are described herein. For example, the C1-4 alkyl of an optionally substituted cycloalkyl(C1-4 alkyl), an optionally substituted cycloalkenyl(C1-4 alkyl), an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C 1-4 alkyl) and/or an optionally substituted heterocyclyl(C 1-4 alkyl) can be selected from –CH 2 –, –CH 2 CH 2 –, –CH(CH 3 )CH 2 –, –CH 2 CH 2 CH 2 –, –CH 2 CH 2 CH 2 CH 2 –, As shown and described herein, the C 1-4 alkyl linkers for R 13 can be unsubstituted or substituted. When the C1-4 alkyls for R 13 are substituted, one or more hydrogens can be replaced with a moiety, such as those provided in the definition of “optionally substituted,” and/or two or more hydrogens can be taken together along with the carbon to which the hydrogens are attached to form an optionally substituted C 3-4 cycloalkyl or an optionally substituted 3-, 4- or 5-membered heterocyclyl. In some embodiments, the C1-4 alkyl linker for the R 13 groups can be substituted with one or more moieties selected from halogen (such as F), cyano, C 1-2 haloalkyl (for example, –CHF 2 , –CH2F, –CF3, –CHClF, –CH2Cl, –CHCl2 and –CCl3), OH, an unsubstituted C1-4 alkoxy and an unsubstituted C-amido (such as –C(=O)NH2, –C(=O)NH(C1-4 alkyl) and –C(=O)N(C1-4 alkyl) 2 ). [0087] In some embodiments, R 13 can be an optionally substituted cycloalkyl(C1-4 alkyl), such as an optionally substituted monocyclic C 3-8 cycloalkyl(C 1-4 alkyl). In other embodiments, R 13 can be an optionally substituted cycloalkenyl(C1-4 alkyl), such as an optionally substituted monocyclic C 3-8 cycloalkenyl(C 1-4 alkyl). In some embodiments, R 13 can be an optionally substituted aryl(C1-4 alkyl). As an example, R 13 can be an optionally substituted benzyl. In other embodiments, R 13 can be an optionally substituted heteroaryl(C 1- 4 alkyl). In still other embodiments, R 13 can be an optionally substituted heterocyclyl(C 1-4 alkyl). The heteroaryl of the optionally substituted heteroaryl(C1-4 alkyl) can be an optionally substituted monocyclic heteroaryl (such as a 5- or 6-membered monocyclic heteroaryl) or an optionally substituted bicyclic heteroaryl (such as a 9- or 10-membered bicyclic heteroaryl). [0088] In some embodiments, R 12 and R 13 can be taken together along with the nitrogen to which R 12 and R 13 are attached to form an optionally substituted 4- to 8-member monocyclic heterocyclyl. In other embodiments, R 12 and R 13 can be taken together along with the nitrogen to which R 10 and R 11 are attached to form an optionally substituted 8- to 13-membered fused-bicyclic heterocyclyl. In still other embodiments, R 12 and R 13 can be taken together along with the nitrogen to which R 10 and R 11 are attached to form an optionally substituted 7- to 13-membered spiro-bicyclic heterocyclyl. The 4- to 8-member monocyclic heterocyclyl, 8- to 13-membered fused-bicyclic heterocyclyl and/or 7- to 13- membered spiro-bicyclic heterocyclyl can include one or more ring nitrogens. [0089] In some embodiments, R 10 can be hydrogen; and R 11 can be a non- hydrogen moiety described herein. For example, R 8 can be –NH(an unsubstituted C 1-4 alkyl), –NH(an optionally substituted phenyl) or –NH(an optionally substituted benzyl). [0090] As described herein, R 14 can be selected from hydrogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-4 haloalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C 1-4 alkyl), an optionally substituted cycloalkenyl(C1-4 alkyl), an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C 1-4 alkyl) and an optionally substituted heterocyclyl(C 1-4 alkyl). In some embodiments, R 14 can be hydrogen, such that R 8 can be OH. In other embodiments, R 14 can be an unsubstituted C1-4 alkyl, such as those described herein. In still other embodiments, R 14 can be an unsubstituted C 1-4 haloalkyl (for example, –CHF 2 , –CH 2 F, –CF3, –CHClF, –CH2Cl, –CHCl2 and –CCl3). In yet still other embodiments, R 14 can be a cyclic moiety selected from an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl. In some embodiments, R 14 can be a cyclic moiety connected via a C 1-4 alkyl linker, wherein the cyclic moiety is selected from an optionally substituted cycloalkyl(C1-4 alkyl), an optionally substituted cycloalkenyl(C1-4 alkyl), an optionally substituted aryl(C 1-4 alkyl), an optionally substituted heteroaryl(C 1-4 alkyl) and an optionally substituted heterocyclyl(C1-4 alkyl). The cyclic moiety that can be present at R 14 can be monocyclic or bicyclic. For example, R 14 can be an unsubstituted or a substituted monocyclic C3-8 cycloalkyl, an unsubstituted or a substituted bicyclic C3-8 cycloalkyl, an unsubstituted or a substituted monocyclic C3-8 cycloalkenyl, an unsubstituted or a substituted bicyclic C3-8 cycloalkenyl, an unsubstituted or a substituted phenyl, an unsubstituted or a substituted naphthyl, an unsubstituted or a substituted monocyclic heteroaryl (such as a 5- or 6-membered monocyclic heteroaryl), an unsubstituted or a substituted bicyclic heteroaryl (such as a 9- or 10-membered monocyclic heteroaryl), an unsubstituted or a substituted monocyclic heterocyclyl (such as a 5- or 6-membered monocyclic heterocyclyl) or an unsubstituted or a substituted bicyclic heterocyclyl (such as a 9- or 10-membered bicyclic heterocyclyl), wherein each of these aforementioned cyclic moieties can be directly attached via the oxygen of –OR 14 . [0091] The optionally substituted cycloalkyls, optionally substituted cycloalkenyls, optionally substituted aryls, optionally substituted heteroaryls and/or optionally substituted heterocyclyls of the aforementioned paragraph can be attached to the oxygen of –OR 14 via a C1-4 alkyl linker. In some embodiments, the C1-4 alkyl linker can be unsubstituted. In other embodiments, the C 1-4 alkyl linker can be substituted. For example, the C1-4 alkyl linker of R 14 can be substituted with one or more substituents selected from halogen (such as F), cyano, C1-2 haloalkyl (for example, CF3), OH and an unsubstituted C1-4 alkoxy. In some embodiments, the C 1-4 alkyl linker for R 14 can be –CH 2 –, –CH 2 CH 2 –, – CH(CH3)CH2–, –CH2CH2CH2–, –CH2CH2CH2CH2–, –CH(F)CH2–, –CH(CF3)CH2–, – CH(OH)CH 2 – or –CH(OCH 3 )CH 2 –. [0092] Various groups can be present for R 9 , including hydrogen, an unsubstituted C 1-4 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C 1-4 alkyl) and an optionally substituted heterocyclyl(C 1-4 alkyl). In some embodiment, R 9 can be hydrogen. In other embodiments, R 9 can be an unsubstituted C1-4 alkyl, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert- butyl. [0093] A variety of cyclic groups can be directly attached to the nitrogen to which R 9 is attached or the cyclic groups can be attached via a C 1-4 linker. In some embodiment, R 9 can be an optionally substituted aryl, for example, an optionally substituted phenyl or an optionally substituted naphthyl. In some embodiment, R 9 can be an optionally substituted heteroaryl. In other embodiments, R 9 can be an optionally substituted heterocyclyl. The heteroaryl can be a monocyclic or bicyclic heteroaryl (such as a fused bicyclic heteroaryl). For example, R 9 can be an unsubstituted or a substituted monocyclic 5- membered heteroaryl, an unsubstituted or a substituted monocyclic 6-membered heteroaryl, an unsubstituted or a substituted bicyclic 9-membered heteroaryl or an unsubstituted or a substituted bicyclic 10-membered heteroaryl. As additional examples, R 9 can be an unsubstituted or a substituted monocyclic 5-membered heterocyclyl, an unsubstituted or a substituted monocyclic 6-membered heterocyclyl, an unsubstituted or a substituted bicyclic 9-membered heterocyclyl or an unsubstituted or a substituted bicyclic 10-membered heterocyclyl. [0094] In some embodiments, R 9 can be an optionally substituted aryl(C 1-4 alkyl), for example, a substituted or an unsubstituted benzyl. In other embodiments, R 9 can be an optionally substituted heteroaryl(C 1-4 alkyl). In still other embodiments, R 9 can be an optionally substituted heterocyclyl(C1-4 alkyl). The C1-4 alkyl linkers for R 9 can be unsubstituted or substituted. When the C 1-4 alkyl linkers are substituted, one or more hydrogens can be replaced with a moiety, such as those provided in the definition of “optionally substituted,” and/or two or more hydrogens can be taken together along with the carbon to which the hydrogens are attached to form an optionally substituted C 3-4 cycloalkyl or an optionally substituted 3-, 4- or 5-membered heterocyclyl. In some embodiments, the C 1-4 alkyl linker for the R 9 groups can be substituted with one or more moieties selected from halogen (such as F and Cl), cyano, C1-2 haloalkyl (for example, CF3), OH, an unsubstituted C 1-4 alkoxy (for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy and tert-butoxy) and an unsubstituted C-amido (such as –C(=O)NH 2 , – C(=O)NH(C1-4 alkyl) and –C(=O)N(C1-4 alkyl)2). Exemplary C1-4 alkyl linkers include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, –CH(CH 3 )CH 2 -, . In some embodiments, R 9 can be an unsubstituted benzyl. In other embodiments, R 9 can be a substituted benzyl. The heteroaryls and heterocyclyls that can be present for R 9 and attached via a C1-4 alkyl linker include monocyclic and bicyclic heteroaryls and heterocyclyls. In some embodiments, R 9 can be an unsubstituted or a substituted monocyclic 5-membered heteroaryl or an unsubstituted or a substituted monocyclic 6-membered heteroaryl. In other embodiments, R 9 can be an unsubstituted or a substituted bicyclic 9-membered heteroaryl or an unsubstituted or a substituted bicyclic 10-membered heteroaryl. In still other embodiments, R 9 can be an unsubstituted or a substituted monocyclic 5-membered heterocyclyl or an unsubstituted or a substituted monocyclic 6-membered heterocyclyl. In yet still other embodiments, R 9 can be an unsubstituted or a substituted bicyclic 9-membered heterocyclyl or an unsubstituted or a substituted bicyclic 10-membered heterocyclyl, for example, an unsubstituted or a substituted fused-bicyclic 9-membered heterocyclyl or an unsubstituted or a substituted fused-bicyclic 10-membered heterocyclyl. [0095] A variety of groups can substitute a R 9 . R 11 , R 13 and/or R 14 group described herein. For example, R 9 . R 11 , R 13 and/or R 14 can be substituted one or more times with a group selected from deuterium, halogen (such as F, Cl and/or Br), cyano, an unsubstituted C 1-6 alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight-changed or branched) and hexyl (straight-chained or branched)), an unsubstituted C1-6 haloalkyl (such as –CHF2, –CH2F, –CF3, –CHClF, –CH2Cl, –CHCl 2 and –CCl 3 ), an unsubstituted C 1-6 alkoxy (for example, methoxy, ethoxy, iso- propoxy, n-butoxy, sec-butoxy, iso-butoxy and tert-butoxy), an unsubstituted acyl (such as – C(=O)-C 1-4 alkyl), an unsubstituted C-amido (such as –C(=O)NH 2 , –C(=O)NH(C 1-4 alkyl) and –C(=O)N(C1-4 alkyl)2), an unsubstituted sulfonyl (such as –S(=O)2-C1-4 alkyl), an unsubstituted S-sulfonamido (such as –S(=O) 2 NH 2, –S(=O) 2 NH(C 1-4 alkyl) and – S(=O) 2 N(C 1-4 alkyl) 2 ), an unsubstituted amino, a mono-substituted amine (for example, an mono-alkyl substituted amine) and a di-substituted amine (for example, a di-alkyl substituted amine).

[0096] Examples of R 9 groups include the following:

[0097] As provided herein, both hydrogen and non-hydrogen moieties can be present on the ring of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to which –(Z 1 )n-R 1 is attached. In some embodiments, R 2 can be hydrogen. In other embodiments, R 2 can be an unsubstituted C1-4 alkyl. In still other embodiments, R 2 can be an unsubstituted C 1-4 haloalkyl. For example, R 2 can be methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, tert-butyl, –CHF2, –CH2F, –CF3,–CH2Cl, –CHCl2 and –CCl3. In yet still other embodiments, R 2 can be an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl. In some embodiments, R 2 can be an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) or an optionally substituted heterocyclyl(C 1-4 alkyl). Exemplary R 2 groups include, but are not limited to, an optionally substituted phenyl, an optionally substituted benzyl, an optionally substituted monocyclic heteroaryl (an optionally substituted 5- or 6-membered monocyclic heteroaryl) or an optionally substituted monocyclic heterocyclyl (an optionally substituted 5- or 6-membered monocyclic heterocyclyl). [0098] As with R 2 , R 3 can be hydrogen or non-hydrogen moieties as described herein. In some embodiments, R 3 can be hydrogen. In other embodiments, R 3 can be an unsubstituted C1-4 alkyl, such as those described herein. In still other embodiments, R 3 can be an unsubstituted C1-4 haloalkyl, for example, –CHF2, –CH2F, –CF3,–CH2Cl, –CHCl2 and – CCl 3 . In yet still other embodiments, R 3 can be an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl. In some embodiments, R 3 can be an optionally substituted aryl(C 1-4 alkyl), an optionally substituted heteroaryl(C 1-4 alkyl) or an optionally substituted heterocyclyl(C1-4 alkyl). In other embodiments, R 3 can be an optionally substituted phenyl, an optionally substituted monocyclic heteroaryl or an optionally substituted monocyclic heterocyclyl. In other embodiments, R 2 and R 3 can be taken together along with the carbon to which R 2 and R 3 are attached to form an optionally substituted monocyclic C 3-6 cycloalkyl or an optionally substituted 3- to 6-member monocyclic heterocyclyl. For example, R 2 and R 3 can be taken together along with the carbon to which R 2 and R 3 are attached to form an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cyclohexyl, an optionally substituted oxetane, an optionally substituted thietane, an optionally substituted thietane oxide or an optionally substituted thietane dioxide. [0099] Each of R 4 and R 5 can be independently hydrogen or selected from the non-hydrogen moieties described herein. In some embodiments, R 4 can be hydrogen. In other embodiments, R 4 can be an unsubstituted C1-4 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. In still other embodiments, R 4 can be an unsubstituted C 1-4 haloalkyl. Exemplary unsubstituted C 1-4 haloalkyls are described herein, and include –CHF2, –CH2F, –CF3,–CH2Cl, –CHCl2 and –CCl3. In yet still other embodiments, R 4 can be an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl. In some embodiments, R 4 can be an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) or an optionally substituted heterocyclyl(C 1-4 alkyl). For example, R 4 can be an optionally substituted phenyl, an optionally substituted benzyl, an optionally substituted monocyclic heteroaryl (an optionally substituted 5- or 6-membered monocyclic heteroaryl) or an optionally substituted monocyclic heterocyclyl (an optionally substituted 5- or 6-membered monocyclic heterocyclyl). [0100] In some embodiments, R 5 can be hydrogen. In other embodiments, R 5 can be an unsubstituted C 1-4 alkyl. In still other embodiments, R 5 can be an unsubstituted C 1-4 haloalkyl. Exemplary unsubstituted C1-4 alkyls and unsubstituted C1-4 haloalkyls are described herein and include those described with respect to R 4 . In yet still other embodiments, R 5 can be an optionally substituted aryl (such as an optionally phenyl), an optionally substituted heteroaryl (such as an optionally substituted monocyclic heteroaryl) or an optionally substituted heterocyclyl (for example, an optionally substituted monocyclic heterocyclyl). The heteroaryl and heterocyclyl can include 3, 4, 5 or 6 ring(s) atoms and include 1, 2 or 3 heteroatoms such as N (nitrogen), O (oxygen) and S (sulfur). In some embodiments, R 5 can be an optionally substituted aryl(C 1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) or an optionally substituted heterocyclyl(C1-4 alkyl). For example, R 5 can be an unsubstituted or a substituted benzyl, an unsubstituted or a substituted 5-membered monocyclic heteroaryl, an unsubstituted or a substituted 6-memberd monocyclic heteroaryl, an unsubstituted or a substituted 5-membered monocyclic heterocyclyl or an unsubstituted or a substituted 6-membered monocyclic heterocyclyl. In some embodiments, R 4 and R 5 can be taken together along with the carbon to which R 4 and R 5 are attached to form an optionally substituted monocyclic C 3-6 cycloalkyl or an optionally substituted 3- to 6-member monocyclic heterocyclyl. Exemplary monocyclic C3-6 cycloalkyls and 3- to 6-member monocyclic heterocyclyls include, but are limited to, the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane, thietane, thietane oxide and thietane dioxide, each of the aforementioned can be optionally substituted. [0101] In some embodiments, R 3 and R 5 can be taken together along with the carbons to which R 3 and R 5 are each attached to form an optionally substituted monocyclic C 5-7 cycloalkyl. In other embodiments, R 3 and R 5 can be taken together along with the carbons to which R 3 and R 5 are each attached to form an optionally substituted 5- to 7- member monocyclic heterocyclyl. In some embodiments, R 2 and R 4 can be taken together along with the carbons to which R 2 and R 4 are each attached to form an optionally monocyclic C5-7 cycloalkyl. In other embodiments, R 2 and R 4 can be taken together along with the carbons to which R 2 and R 4 are each attached to form an optionally substituted 5- to 7-member monocyclic heterocyclyl. Exemplary 5- to 7-member monocyclic heterocyclyls include, but are not limited to, tetrahydrofuran, pyrrolidine, piperidine and tetrahydro-2H- pyran. [0102] In some embodiments, R 6 can be hydrogen. In other embodiments, R 6 can be an unsubstituted C1-4 alkyl. In still other embodiments, R 6 can be an unsubstituted C1-4 haloalkyl. Suitable unsubstituted C 1-4 alkyls and unsubstituted C 1-4 haloalkyls include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, –CHF2, –CH2F, – CF3,–CH2Cl, –CHCl2 and –CCl3. [0103] In some embodiments, R 7 can be hydrogen. In other embodiments, R 7 can be an unsubstituted C1-4 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl. In still other embodiments, R 7 can be an unsubstituted C 1-4 haloalkyl, for example, –CHF2, –CH2F, –CF3,–CH2Cl, –CHCl2 and –CCl3. In some embodiments, R 6 and R 7 are taken together along with the carbon to which R 6 and R 7 are attached to form an unsubstituted monocyclic C3-4 cycloalkyl. In other embodiments, R 6 and R 7 are taken together along with the carbon to which R 6 and R 7 are attached to form a substituted monocyclic C 3-4 cycloalkyl. In still other embodiments, R 6 and R 7 are taken together along with the carbon to which R 6 and R 7 are attached to form an unsubstituted oxetane or an unsubstituted thietane. In yet still other embodiments, R 6 and R 7 are taken together along with the carbon to which R 6 and R 7 are attached to form a substituted oxetane or a substituted thietane. [0104] In some embodiments, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 can be each hydrogen. In other embodiments, at least one of R 2 , R 3 , R 4 , R 5 , R 6 and R 7 can be a non-hydrogen group, such as those described herein in the previous paragraphs. In other embodiments, R 2 , R 3 , R 4 and R 5 can be each hydrogen, and R 6 and R 7 are taken together along with the carbon to which R 6 and R 7 are attached to form an optionally substituted monocyclic C 3-4 cycloalkyl. In still other embodiments, R 2 , R 3 , R 4 and R 5 can be each hydrogen, and R 6 and R 7 are taken together along with the carbon to which R 6 and R 7 are attached to form an unsubstituted or a substituted oxetane or an unsubstituted or a substituted thietane. [0105] Examples of compounds of Formula (I) include, but are not limited to, the following: , or a pharmaceutically acceptable salt of any of the foregoing. Synthesis [0106] Compounds of Formula (I) along with those described herein may be prepared in various ways. General synthetic routes for preparing compounds of Formula (I) are shown and described herein along with some examples of starting materials used to synthesize compounds described herein. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims. Scheme 1 [0107] Compounds of Formula (I), or a pharmaceutically acceptable salt thereof, can be prepared from an intermediate of Formula (aI). As an example, compounds of Formula (I) along with pharmaceutically acceptable salts thereof, wherein Z 1 represents – NH–C(=O)– and n = 1, can be obtained by reacting a compound of Formula (aI) with a phenyl carbamate of Formula R 1 -NH-C(=O)-O-phenyl or with an isocyanate of general Formula R 1 -N=C=O, in presence of a suitable base in a suitable solvent. An example of a suitable base is trimethylamine, and an example of suitable solvent is acetonitrile. [0108] Other compounds of Formula (I), along with pharmaceutically acceptable salts thereof, wherein Z 1 represents –C(=O)– and n = 1, can be obtained by reacting a compound of Formula (aI) with an acyl chloride of general formula R 1 -C(=O)-Cl in presence of a base in a suitable solvent. Other compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Z 1 represents –C(=O)– and n = 1, can be obtained by reacting compound of Formula (aI) with a carboxylic acid of formula R 1 -C(=O)-OH in presence of an amide coupling agent (such as HATU) in a suitable solvent. Other compounds of Formula (I) together with pharmaceutically acceptable salts thereof can be prepared from a compound of Formula (aI) using methods known in the art. Scheme 2 [0109] Compounds of Formula (aI) in which R 3 , R 5 and R 7 each represents H can be prepared from a compound of Formula (bI) as shown in Scheme 2. A compound of (bI) can be alkylated on the pyridine ring using 3,4-dimethoxybenzylbromide, in a suitable solvent (for example, acetonitrile) to afford a compound of Formula (IV). Reduction of the pyridinium intermediate of Formula (cI) can be achieved by methods known in the art. For instance, (cI) can be treated with sodium triacetoxyborohydride in a suitable solvent (such as 1,2-dichloroethane) to afford a compound of Formula (dI). The cleavage of the dimethoxybenzyl substituent of a compound of Formula (dI) can be achieved by methods known in the art, for instance, by treating (dI) with chloroethylchloroformate in presence of a base (for example, N,N-diisopropylethylamine) in a suitable solvent (such as 1,2- dichloroethane). The reaction mixture can be treated with MeOH to obtain a compound of Formula (aI) in which R 3 , R 5 and R 7 each represents H. Scheme 3 [0110] Compounds of Formula (bI) can be prepared from a compound of Formula (eI) using methods know in the art, for instance by treating (eI) with tetrabutylammoniumbromide, sodium metabisulfite (Na 2 SO 5 ), sodium formate, palladium acetate, triphenylphosphine, phenanthroline and dimethylsulphoxide. This mixture is then treated with an amine of general Formula R 9 -NH2, in presence of a suitable base (such as N,N-diisopropylethylamine) in a suitable solvent (such as THF) before being treated with N- chlorosuccinimide to afford a compound of Formula (fI). A compound of Formula (fI) can be reacted with ammonium hydroxide in a suitable solvent (for example, 1,4-dioxane) to afford a compound of Formula (gI). A compound of Formula (bI) in which R 8 represents - NR 10 R 11 , wherein R 10 represents H, can be prepared by reacting a compound of Formula (gI) with an isothiocyanate of general Formula R 11 -N=C=S in presence of a suitable base (such as sodium hydride) in a suitable solvent (such as DMF). Alternatively, a compound of Formula (bI) can be obtained by treating a compound of Formula (gI) with an aldehyde of general Formula R 8 -CHO, in presence of an acid, such as acetic acid in a suitable solvent (for example, ethanol), followed with a treatment with an oxidative agent (such as KMnO 4 ) in a suitable solvent (for example, acetonitrile). Other compounds of Formula (bI) can be obtained by methods known in the art. Pharmaceutical Compositions [0111] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of a compound described herein (e.g., a compound, or a pharmaceutically acceptable salt thereof, as described herein) and a pharmaceutically acceptable carrier, excipient or combination thereof. A pharmaceutical composition described herein is suitable for human and/or veterinary applications.

[0112] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0113] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.

[0114] As used herein, an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A “diluent” is a type of excipient.

[0115] Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, topical, aerosol, injection and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.

[0116] One may also administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the infected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes may be targeted to and taken up selectively by the organ. [0117] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. As described herein, compounds used in a pharmaceutical composition may be provided as salts with pharmaceutically compatible counterions.

Methods of Use

[0118] Some embodiments described herein relate to a method of treating a HBV and/or HDV infection that can include administering to a subject identified as suffering from the HBV and/or HDV infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a HBV and/or HDV infection. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a HBV and/or HDV infection.

[0119] Some embodiments disclosed herein relate to a method of treating a HBV and-'or HDV infection that can include contacting a cell infected with the HBV and/or HDV with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a HBV and/or HDV infection. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a HBV and/or HDV infection. [0120] Some embodiments disclosed herein relate to a method of inhibiting replication of HBV and/or HDV that can include contacting a cell infected with the HBV and/or HDV with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for inhibiting replication of HBV and/or HDV. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, for inhibiting replication of HBV and/or HDV. [0121] In some embodiments, the HBV infection can be an acute HBV infection. In some embodiments, the HBV infection can be a chronic HBV infection. [0122] Some embodiments disclosed herein relate to a method of treating liver cirrhosis that is developed because of a HBV and/or HDV infection that can include administering to a subject suffering from liver cirrhosis and/or contacting a cell infected with the HBV and/or HDV in a subject suffering from liver cirrhosis with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating liver cirrhosis with an effective amount of the compound, or a pharmaceutically acceptable salt thereof. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating liver cirrhosis. [0123] Some embodiments disclosed herein relate to a method of treating liver cancer (such as hepatocellular carcinoma) that is developed because of a HBV and/or HDV infection that can include administering to a subject suffering from the liver cancer and/or contacting a cell infected with the HBV and/or HDV in a subject suffering from the liver cancer with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating liver cancer (such as hepatocellular carcinoma). Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating liver cancer (such as hepatocellular carcinoma). [0124] Some embodiments disclosed herein relate to a method of treating liver failure that is developed because of a HBV and/or HDV infection that can include administering to a subject suffering from liver failure and/or contacting a cell infected with the HBV and/or HDV in a subject suffering from liver failure with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating liver failure. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating liver failure. [0125] Various indicators for determining the effectiveness of a method for treating an HBV and/or HDV infection are also known to those skilled in the art. Examples of suitable indicators include, but are not limited to, a reduction in viral load indicated by reduction in HBV DNA (or load) (e.g., reduction <10 5 copies/mL in serum), HBV surface antigen (HBsAg) and HBV e-antigen (HBeAg), a reduction in plasma viral load, a reduction in viral replication, a reduction in time to seroconversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy, an improvement in hepatic function, and/or a reduction of morbidity or mortality in clinical outcomes.

[0126J As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.

[0127] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject is human.

[0128] The term “effective amount” is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, an effective amount of compound can be the amount needed to alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

[0129] In some embodiments, an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein is an amount that is effective to achieve a sustained virologic response, for example, a sustained viral response 12 month after completion of treatment. [0130] Subjects who are clinically diagnosed with a HBV and/or HDV infection include “naive” subjects (e.g., subjects not previously treated for HBV and/or HDV) and subjects who have failed prior treatment for HBV and/or HDV (“treatment failure” subjects). Treatment failure subjects include “non-responders” (subjects who did not achieve sufficient reduction in ALT (alanine aminotransferase) levels, for example, subject who failed to achieve more than 1 log 10 decrease from base-line within 6 months of starting an anti-HBV and-'or anti-HDV therapy) and “relapsers” (subjects who were previously treated for HBV and/or HDV whose ALT levels have increased, for example, ALT > twice the upper normal limit and detectable serum HBV DNA by hybridization assays). Further examples of subjects include subjects with a HBV and/or HDV infection who are asymptomatic.

[0131] In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, as described herein can be provided to a treatment failure subject suffering from HBV and/or HDV. In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, as described herein can be provided to a non-responder subject suffering from HBV and/or HDV. In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, as described herein can be provided to a relapser subject suffering from HBV and/or HDV. In some embodiments, the subject can have HBeAg positive chronic hepatitis B. In some embodiments, the subject can have HBeAg negative chronic hepatitis B. In some embodiments, the subject can have liver cirrhosis. In some embodiments, the subject can be asymptomatic, for example, the subject can be infected with HBV and/or HDV but does not exhibit any symptoms of the viral infection. In some embodiments, the subject can be immunocompromised In some embodiments, the subject can be undergoing chemotherapy.

[0132] Examples of agents that have been used to treat HB V and/or HDV include immunomodulating agents, and nucleosides/nucleotides. Examples of immunomodulating agents include interferons (such as IFN-a and pegylated interferons that include PEG-IFN-a- 2a); and examples of nucleosides/nucleotides include lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide and tenofovir disoproxil. However, some of the drawbacks associated with interferon treatment are the adverse side effects, the need for subcutaneous administration and high cost. Potential advantages of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be less adverse side effects, delay in the onset of an adverse side effect and/or reduction in the severity of an adverse side effect. A drawback with nucleoside/nucleotide treatment can be the development of resistance, including cross-resistance. [0133] Resistance can be a cause for treatment failure. The term “resistance” as used herein refers to a viral strain displaying a delayed, lessened and/or null response to an anti-viral agent. In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, as described herein can be provided to a subject infected with an HBV and/or HDV strain that is resistant to one or more anti-HBV and/or anti-HDV agents. Examples of anti- viral agents wherein resistance can develop include lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide and tenofovir disoproxil. In some embodiments, development of resistant HBV and/or HDV strains is delayed when a subject is treated with a compound, or a pharmaceutically acceptable salt thereof, as described herein compared to the development of HBV and/or HDV strains resistant to other HBV and/or HDV anti-viral agents, such as those described. [0134] Previously known compounds, such as those provided in WO 2017/156255, were shown to form adducts with glutathione in in vitro assays. Formation of glutathione adducts can be a signal that a compound has the potential to induce liver injury. Thus, the formation of glutathione adducts can be used as a signal to predict safety. Unexpectedly, compounds described herein, such as many compounds of Formula (I), and pharmaceutically acceptable salts thereof, have been shown not to form adducts with glutathione in in vitro assays. Further, known compounds (for example, those described in WO 2017/156255), have demonstrated potency in a HepG2.2.15 cell-based assay with an EC 50 of >1000 pM. Many compounds described herein, such as compounds of Formula (I), and pharmaceutically acceptable salts thereof, unexpectedly show improved potency in a HepG2.2.15 cell-based assay with an EC50 <1000 pM range. Thus, compounds described herein, including compounds of Formula (I), and pharmaceutically acceptable salts thereof, can be at least 16 times more potent than previously known compounds. In some embodiments, improved potency can lead to a significantly lower dose requirement and therefore improve daily dose burden as well as lead to improved safety margins. Combination Therapies [0135] In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, as described herein can be used in combination with one or more additional agent(s) for treating and/or inhibiting replication HBV and/or HDV. Additional agents include, but are not limited to, an interferon, nucleoside/nucleotide analogs, a sequence specific oligonucleotide (such as anti-sense oligonucleotide and siRNA), nucleic acid polymers (NAPs, such as nucleic acid polymers that reduce HBsAg levels) an entry inhibitor and/or a small molecule immunomodulator. Examples of additional agents include recombinant interferon alpha 2b, IFN-a, PEG-IFN-a-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide and tenofovir disoproxil. Examples of NAPs include, but are not limited to, REP 2139, REP 2165 and those described in U.S. Application No. 62/757632, filed November 8, 2018, which is hereby incorporated by reference for the purpose of the NAPs described therein.

[0136] In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, as described herein can be administered with one or more additional agent(s) together in a single pharmaceutical composition. In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions. Further, the order of administration of a compound, or a pharmaceutically acceptable salt thereof, as described herein with one or more additional agent(s) can vary.

EXAMPLES

[0137] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.

Example 1 2-benzyl-6-(4-bromo-3-chlorobenzoyl)-3-(isopropylamino)-5H,7 H,8H-1l6-pyrido[3,4- e][1,2,4]thiadiazine-1,1-dione (1) [0138] A mixture of sodium metabisulfite (6.48 g, 34.1 mmol, 2.00 eq.), tetrabuylammonium bromide (5.50 g, 17.0 mmol, 1.00 eq.), sodium formate (2.32 g, 34.1 mmol, 2.00 eq.), palladium acetate (0.0383 g, 0.170 mmol, 0.01 eq.), triphenylphosphine (0.178 g, 0.682 mmol, 0.04 eq.), 1,10-phenanthroline (0.123 g, 0.682 mmol, 0.04 eq.), dimethyl sulphoxide (70 mL) and 4-bromo-3-fluoropyridine (3.00 g, 17.0 mmol, 1.00 eq.) was stirred for 4 h at 70 °C under a N 2 atmosphere. Benzylamine (1.83 g, 17.0 mmol, 1.00 eq.) and N,N-diisopropylethylamine (3.30 g, 25.6 mmol, 1.50 eq.) in THF (30 mL) were then added at room temperature (rt), and N-chlorosuccinimide (4.55 g, 34.1 mmol, 2.00 eq.) in tetrahydrofuran (70 mL) was added at 0 °C. The mixture was stirred overnight at rt and diluted with ethyl acetate (EA) (800 mL). The EA phase was washed with water (5 x 150 mL) and sat. NaCl (1 x 150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether (PE):EA (2:1) to afford the crude product. The crude product was purified by trituration with EA:PE (5:1) to afford N-benzyl-3- fluoropyridine-4-sulfonamide (2.41 g, 50% yield) as a white solid. LCMS (ESI, m/z): 267 [M+H] + , RT = 0.900 min. [0139] A mixture of N-benzyl-3-fluoropyridine-4-sulfonamide (2.41 g, 9.05 mmol, 1.00 eq.), dimethyl sulphoxide (24 mL) and ammonium hydroxide (12 mL) was stirred overnight at 100 °C. The mixture was diluted with EA (300 mL). The EA phase was washed with water (3 x 30 mL) and sat. NaCl (1 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by trituration with EA:PE (5:1) to afford 3-amino-N-benzylpyridine-4-sulfonamide (2.06 g, 82% yield) as a white solid. LCMS (ESI, m/z): 264 [M+H] + , RT = 0.697 min. [0140] A mixture of 3-amino-N-benzylpyridine-4-sulfonamide (1.25 g, 4.75 mmol, 1.00 eq.), N,N-dimethylformamide (13 mL), 2-isothiocyanatopropane (0.720 g, 7.12 mmol, 1.50 eq.) and potassium carbonate (1.31 g, 9.49 mmol, 2.00 eq.) was stirred overnight at 80 °C. The mixture was concentrated under reduced pressure, and then diluted with EA (200 mL). The EA phase was washed with water (3x20 mL) and sat. NaCl (1 x 20 mL), dried over anhydrous NaCl, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (2:1) to afford 2- benzyl-3-(isopropylamino)-1l6-pyrido[3,4-e][1,2,4]thiadiazin e-1,1-dione (0.240 g, 14% yield) as a white solid. LCMS (ESI, m/z): 331 [M+H] + , RT = 0.981 min. [0141] A mixture of 2-benzyl-3-(isopropylamino)-1l6-pyrido[3,4- e][1,2,4]thiadiazine-1,1-dione (210 mg, 0.636 mmol, 1.00 eq.), acetonitrile (10 mL) and 4- (bromomethyl)-1,2-dimethoxybenzene (147 mg, 0.636 mmol, 1.00 eq.) was stirred overnight at rt, and then concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with diethyl ether (2 x 5 mL) to afford the product 2-benzyl-6-[(3,4- dimethoxyphenyl)methyl]-3-(isopropylamino)-1,1-dioxo-1l6-pyr ido[3,4-e][1,2,4]thiadiazin- 6-ium bromide (510 mg, crude) as a yellow solid. LCMS (ESI, m/z): 481 [M-Br] + , RT = 1.365 min. [0142] A mixture of 2-benzyl-6-[(3,4-dimethoxyphenyl)methyl]-3- (isopropylamino)-1,1-dioxo-1l6-pyrido[3,4-e][1,2,4]thiadiazi n-6-ium bromide (0.510 g, 0.908 mmol, 1.00 eq.), sodium triacetoxyborohydride (1.16 g, 5.45 mmol, 6.00 eq.) and 1,2- dichloroethane (10 mL) was stirred for 1 h at 60 °C. The mixture was diluted with dichloromethane (200 mL). The dichloromethane phase was washed with water (2 x 50 mL) and sat. NaCl (1 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (1:1) to afford 2-benzyl-6-[(3,4-dimethoxyphenyl)methyl]-3- (isopropylamino)-5H,7H,8H-1l6-pyrido[3,4-e][1,2,4]thiadiazin e-1,1-dione (0.260 g, 56% yield) as a white solid. LCMS (ESI, m/z): 485 [M+H] + , RT = 0.882 min. [0143] A mixture of 2-benzyl-6-[(3,4-dimethoxyphenyl)methyl]-3- (isopropylamino)-5H,7H,8H-1l6-pyrido[3,4-e][1,2,4]thiadiazin e-1,1-dione (240 mg, 0.495 mmol, 1.00 eq.), N,N-diisopropylethylamine (96.0 mg, 0.743 mmol, 1.50 eq.), 1,2- dichloroethane (5 mL) and chloroethyl chloroformate (77.9 mg, 0.545 mmol, 1.10 eq.) was stirred for 1 h at rt. The mixture was concentrated under reduced pressure, and then methanol (5 mL) was added. The mixture was stirred for 1 h at 65 °C, and then concentrated under reduced pressure. The mixture was then diluted with MeOH:CH 2 Cl 2 (1:10, 30 mL). The mixture was purified by silica gel column chromatography, eluted with CH2Cl2:MeOH (1:10) to afford 2-benzyl-3-(isopropylamino)-5H,6H,7H,8H-1l6-pyrido[3,4- e][1,2,4]thiadiazine-1,1-dione (135 mg, 71% yield) as a light brown solid. LCMS (ESI, m/z): 335 [M+H] + , RT = 0.766 min. [0144] A mixture of 4-bromo-3-chlorobenzoic acid (105 mg, 0.449 mmol, 1.50 eq.), N,N-dimethylformamide (5.00 mL), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (86.0 mg, 0.449 mmol, 1.50 eq.), 1-hydroxybenzotrizole (60.6 mg, 0.449 mmol, 1.50 eq.), 2-benzyl-3-(isopropylamino)-5H,6H,7H,8H-1l6-pyrido[3,4- e][1,2,4]thiadiazine-1,1-dione (100 mg, 0.299 mmol, 1.00 eq.) and N,N- diisopropylethylamine (116 mg, 0.897 mmol, 3.00 eq.) was stirred overnight at rt. The mixture was diluted with EA (100 mL). The EA phase was washed with HCl (2 x 20 mL, 1 mol/L), sat. sodium bicarbonate (2 x 20 mL) and sat. NaCl (1 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted PE:EA (2:1) to afford a crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge C18 OBD Prep Column, 100 Å, 10 Pm, 19 mm x 250 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 65% B to 80% B in 7 min; 254 nm; RT:5.57 min to afford 2-benzyl-6-(4- bromo-3-chlorobenzoyl)-3-(isopropylamino)-5H,7H,8H-1l6-pyrid o[3,4-e][1,2,4]thiadiazine- 1,1-dione (105.8 mg, 73% yield) as a white solid. LCMS (ESI, m/z): 551 [M+H] + , RT = 1.702 min. 1 H NMR (400 MHz, CDCl3) į: 7.70 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.50-7.32 (m, 5H), 7.25-7.10 (m, 1H), 4.93 (s, 2H), 4.48-4.30 (m, 1H), 4.30-4.16 (m, 1H), 4.16-3.83 (m, 3H), 3.75-7.48 (m, 1H), 2.87-2.65 (m, 2H), 1.08-0.88 (m, 6H). Example 2 2-benzyl-6-(4-bromo-3-chlorobenzoyl)-3-(2-methylpropyl)-5H,7 H,8H-1l6-pyrido[3,4- e][1,2,4]thiadiazine-1,1-dione (2) [0145] A mixture of sodium metabisulfite (6.48 g, 34.1 mmol, 2.00 eq.), tetrabuylammonium bromide (5.50 g, 17.0 mmol, 1.00 eq.), sodium formate (2.32 g, 34.1 mmol, 2.00 eq.), palladium acetate (0.0383 g, 0.170 mmol, 0.01 eq.), triphenylphosphine (0.1789 mg, 0.682 mmol, 0.04 eq.), 1,10-phenanthroline (0.123 mg, 0.682 mmol, 0.04 eq.), dimethyl sulphoxide (50 mL) and 4-bromo-3-fluoropyridine (3.00 g, 17.0 mmol, 1.00 eq.) was stirred for 4 h at 70 °C under N 2 atmosphere. Benzylamine (1.83 g, 17.0 mmol, 1.00 eq.) and N,N-diisopropylethylamine (3.30 g, 25.6 mmol, 1.50 eq.) in THF (30 mL) were added at rt. N-chlorosuccinimide (4.55 g, 34.1 mmol, 2.00 eq.) in tetrahydrofuran (50 mL) was then added at 0 °C. The mixture was stirred overnight at rt and diluted with EA (800 mL). The EA phase was washed with water (5 x 150 mL) and sat. NaCl (1 x 150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (2:1) to afford N- benzyl-3-fluoropyridine-4-sulfonamide (1.37 g, 30% yield) as an off-white solid. LCMS (ESI, m/z): 267 [M+H] + , RT = 0.900 min. [0146] A mixture of N-benzyl-3-fluoropyridine-4-sulfonamide (1.37 g, 5.14 mmol, 1.00 eq.), dimethyl sulphoxide (14 mL) and ammonium hydroxide (7 mL) was stirred for 6 h at 100 °C. The mixture was diluted with EA (200 mL). The EA phase was washed with water (4 x 20 mL) and sat. NaCl (1 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by trituration EA:PE (5:1) to afford 3-amino-N-benzylpyridine-4-sulfonamide (1.11 g, 78% yield) as a white solid. LCMS (ESI, m/z): 264 [M+H] + , RT = 0.697 min. [0147] A mixture of 3-amino-N-benzylpyridine-4-sulfonamide (500 mg, 1.90 mmol, 1.00 eq.), ethanol (5 mL), isovaleraldehyde (327 mg, 3.80 mmol, 2.00 eq.) and acetic acid (5.0 mg, 0.0830 mmol, 0.04 eq.) was stirred overnight at 100 °C. The mixture was cool to rt. The solid was collected to obtain the product. The filtrate was purified by prep-HPLC (Column: YMC-Actus Triart C 18 , 30 x 250, 5 Pm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 .H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 95% B in 7 min; 220 nm; RT: 6.32 min to afford 2-benzyl-3-(2-methylpropyl)-3H,4H- 1l6-pyrido[3,4-e][1,2,4]thiadiazine-1,1-dione (350 mg, 53% yield) as a white solid. LCMS (ESI, m/z): 332 [M+H] + , RT = 1.179 min. [0148] A mixture of 2-benzyl-3-(2-methylpropyl)-3H,4H-1l6-pyrido[3,4- e][1,2,4]thiadiazine-1,1-dione (340 mg, 1.03 mmol, 1.00 eq.), acetonitrile (10 mL), potassium permanganate (324 mg, 2.05 mmol, 2.00 eq.) and silica gel (324 mg) was stirred overnight at 60 °C. The solid was removed, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (2:1) to afford 2-benzyl-3-(2-methylpropyl)-1l6-pyrido[3,4-e][1,2,4]thiadiaz ine-1,1-dione (80.0 mg, 22% yield) as a yellow solid. LCMS (ESI, m/z): 330 [M+H] + , RT = 1.151 min. [0149] A mixture of 2-benzyl-3-(2-methylpropyl)-1l6-pyrido[3,4- e][1,2,4]thiadiazine-1,1-dione (90.0 mg, 0.273 mmol, 1.00 eq.), acetonitrile (3 mL) and 4- (bromomethyl)-1,2-dimethoxybenzene (75.5 mg, 0.327 mmol, 1.20 eq.) was stirred overnight at 50 °C. The mixture was concentrated under reduced pressure to afford 2-benzyl-6-[(3,4- dimethoxyphenyl)methyl]-3-(2-methylpropyl)-1,1-dioxo-1l6-pyr ido[3,4-e][1,2,4]thiadiazin- 6-ium bromide (200 mg, crude) as a light yellow oil. LCMS (ESI, m/z): 480 [M-Br] + , RT = 0.967 min. [0150] A mixture of 2-benzyl-6-[(3,4-dimethoxyphenyl)methyl]-3-(2- methylpropyl)-1,1-dioxo-1l6-pyrido[3,4-e][1,2,4]thiadiazin-6 -ium bromide (200 mg, 0.357 mmol, 1.00 eq.), 1,2-dichloroethane (5 mL) and sodium triacetoxyborohydride (454 mg, 2.14 mmol, 6.00 eq.) was stirred for 1 h at 60 °C. The mixture was diluted with dichloromethane (200 mL). The dichloromethane phase was washed with water (3 x 40 mL) and sat. NaCl (1 x 40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (silica, PE:EA=2:1) to afford 2-benzyl-6- [(3,4-dimethoxyphenyl)methyl]-3-(2-methylpropyl)-5H,7H,8H-1l 6-pyrido[3,4- e][1,2,4]thiadiazine-1,1-dione (85.0 mg, 44% yield) as a light brown oil. LCMS (ESI, m/z): 484 [M+H] + , RT = 0.935 min. [0151] A mixture of 2-benzyl-6-[(3,4-dimethoxyphenyl)methyl]-3-(2- methylpropyl)-5H,7H,8H-1l6-pyrido[3,4-e][1,2,4]thiadiazine-1 ,1-dione (85.0 mg, 0.176 mmol, 1.00 eq.), 1,2-dichloroethane (3 mL), N,N-diisopropylethylamine (34.1 mg, 0.264 mmol, 1.50 eq.) and chloroethyl chloroformate (27.6 mg, 0.193 mmol, 1.10 eq.) was stirred for 1 h at rt. The mixture was concentrated under reduced pressure, and then MeOH (3 mL) was added. The mixture was stirred for 1 h at 70 °C, and then concentrated under reduced pressure to give 2-benzyl-3-(2-methylpropyl)-5H,6H,7H,8H-1l6-pyrido[3,4- e][1,2,4]thiadiazine-1,1-dione (58.0 mg, crude) as a light yellow oil. LCMS (ESI, m/z): 334 [M+H] + , RT = 0.822 min. [0152] A mixture of 4-bromo-3-chlorobenzoic acid (61.4 mg, 0.261 mmol, 1.50 eq.), N,N-dimethylformamide (5 mL), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (50.0 mg, 0.261 mmol, 1.50 eq.), 1-hydroxybenzotrizole (35.2 mg, 0.261 mmol, 1.50 eq.), 2-benzyl-3-(2-methylpropyl)-5H,6H,7H,8H-1l6-pyrido[3,4- e][1,2,4]thiadiazine-1,1-dione (58.0 mg, 0.174 mmol, 1.00 eq.) and N,N- diisopropylethylamine (67.4 mg, 0.522 mmol, 3.00 eq.) was stirred overnight at rt. The mixture was concentrated under reduced pressure, and then diluted with EA (100 mL). The EA phase was washed with HCl (2 x 20 mL, 1 mol/L), sat. sodium bicarbonate (2 x 20 mL) and sat. NaCl (1 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (silica, PE:EA=2:1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 Pm ; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 .H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 56% B to 77% B in 7 min; 220 nm; RT: 5.52 min to afford 2-benzyl-6-(4- bromo-3-chlorobenzoyl)-3-(2-methylpropyl)-5H,7H,8H-1l6-pyrid o[3,4-e][1,2,4]thiadiazine- 1,1-dione (19.9 mg, 21% yield) as a white solid. LCMS (ESI, m/z) = 550 [M+H] + , RT = 1.848 min. 1 H NMR (400 MHz, CDCl3) į: 7.70 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.42-7.30 (m, 3H), 7.27-7.20 (m, 3H), 5.06 (s, 2H), 4.62-4.32 (m, 1H), 4.32-4.10 (m, 1H), 4.10-3.85 (m, 1H), 3.85-3.39 (m, 1H), 3.00-2.55 (m, 2H), 2.42-2.20 (m, 2H), 2.20-1.92 (m, 1H), 0.99-0.77 (m, 6H). Example 3 6-(4-bromo-3-chlorobenzoyl)-3-(isopropylamino)-2-phenyl-5H,7 H,8H-1l6-pyrido[3,4- e][1,2,4]thiadiazine-1,1-dione (3) [0153] A mixture of sodium metabisulfite (6.48 g, 34.1 mmol, 2.00 eq.), tetrabuylammonium bromide (5.50 g, 17.0 mmol, 1.00 eq.), sodium formate (2.32 g, 34.1 mmol, 2.00 eq.), palladium acetate (0.383 mg, 0.170 mmol, 0.01 eq.), triphenylphosphine (0.179 mg, 0.682 mmol, 0.04 eq.), 1,10-phenanthroline (0.123 mg, 0.682 mmol, 0.04 eq.), dimethyl sulphoxide (60 mL) and 4-bromo-3-fluoropyridine (3.00 g, 17.0 mmol, 1.00 eq.) was stirred for 4 h at 70 °C. Aniline (1.59 g, 17.0 mmol, 1.00 eq.), N,N- diisopropylethylamine (3.30 g, 25.6 mmol, 1.50 eq.) in THF (30 mL) were added at rt. N- chlorosuccinimide (4.55 g, 34.1 mmol, 2.00 eq.) in THF (50 mL) was then added at 0 °C. The mixture was stirred overnight at rt, and then diluted with EA (600 mL). The EA phase was washed with water (5 x 50 mL) and sat. NaCl (1 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (4:1) to afford 3-fluoro-N-phenylpyridine-4- sulfonamide (840 mg, 15% yield) as an off-white solid. LCMS (ESI, m/z): 253 [M+H] + , RT = 0.877 min. [0154] A mixture of 3-fluoro-N-phenylpyridine-4-sulfonamide (1.28 g, 1.00 eq.), 1,4-dioxane (5 mL) and ammonium hydroxide (5 mL) was stirred for 2 days at 120 °C. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with PE:EA (1:3) to afford 3-amino-N-phenylpyridine-4- sulfonamide (230 mg, 22% yield) as a light yellow solid. LCMS (ESI, m/z): 250 [M+H] + , RT = 0.713 min. [0155] A mixture of 3-amino-N-phenylpyridine-4-sulfonamide (170 mg, 0.648 mmol, 1.00 eq.), N,N-dimethylformamide (3 mL), sodium hydride (51.8 mg, 1.29 mmol, 2.00 eq., 60% in mineral oil) and 2-isothiocyanatopropane (131 mg, 1.29 mmol, 2.00 eq.) was stirred overnight at rt, and then diluted with EA (100 mL). The mixture was washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (2:1) to afford 3-(isopropylamino)-2-phenyl-1l6-pyrido[3,4- e][1,2,4]thiadiazine-1,1-dione (110 mg, 49% yield) as a white solid. LCMS (ESI, m/z): 317 [M+H] + , RT = 0.958 min. [0156] A mixture of 3-(isopropylamino)-2-phenyl-1l6-pyrido[3,4- e][1,2,4]thiadiazine-1,1-dione (110 mg, 0.348 mmol, 1.00 eq.), acetonitrile (3 mL) and 4- (bromomethyl)-1,2-dimethoxybenzene (80.3 mg, 0.348 mmol, 1.00 eq.) was stirred overnight at rt. The mixture was concentrated under reduced pressure to afford 6-[(3,4- dimethoxyphenyl)methyl]-3-(isopropylamino)-1,1-dioxo-2-pheny l-1l6-pyrido[3,4- e][1,2,4]thiadiazin-6-ium bromide (200 mg, crude) as a light yellow oil. LCMS (ESI, m/z): 467 [M-Br] + , RT = 0.730 min. [0157] A mixture of 6-[(3,4-dimethoxyphenyl)methyl]-3-(isopropylamino)-1,1- dioxo-2-phenyl-1l6-pyrido[3,4-e][1,2,4]thiadiazin-6-ium bromide (200 mg, 0.365 mmol, 1.00 eq.), 1,2-dichloroethane (5.00 mL) and sodium triacetoxyborohydride (387 mg, 1.83 mmol, 5.00 eq.) was stirred for 1 h at 60 °C. The reaction was quenched with water (50 mL), and the resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (1:1) to afford 6-[(3,4-dimethoxyphenyl)methyl]-3-(isopropylamino)-2-phenyl- 5H,7H,8H-1l6- pyrido[3,4-e][1,2,4]thiadiazine-1,1-dione (85.0 mg, 47% yield) as a white solid. LCMS (ESI, m/z): 471 [M+H] + , RT = 0.848 min. [0158] A mixture of 6-[(3,4-dimethoxyphenyl)methyl]-3-(isopropylamino)-2- phenyl-5H,7H,8H-1l6-pyrido[3,4-e][1,2,4]thiadiazine-1,1-dion e (85.0 mg, 0.181 mmol, 1.00 eq.), 1,2-dichloroethane (1.5 mL), N,N-diisopropylethylamine (35.0 mg, 0.271 mmol, 1.50 eq.) and chloroethyl chloroformate (28.4 mg, 0.199 mmol, 1.10 eq.) was stirred for 1 h rt and then concentrated under reduced pressure. MeOH (3 mL) was added, and the mixture was stirred for 1 h at 70 °C. The residue was purified by silica gel column chromatography, eluted with CH2Cl2:MeOH (10:1) to afford 3-(isopropylamino)-2-phenyl-5H,6H,7H,8H-1l6- pyrido[3,4-e][1,2,4]thiadiazine-1,1-dione (57.0 mg, crude) as an off-white solid. LCMS (ESI, m/z): 321 [M+H] + , RT = 0.720 min. [0159] A mixture of 4-bromo-3-chlorobenzoic acid (54.4 mg, 0.231 mmol, 1.30 eq.), N,N-dimethylformamide (3 mL), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (44.3 mg, 0.231 mmol, 1.30 eq.), 1-hydroxybenzotrizole (31.2 mg, 0.231 mmol, 1.30 eq.), N,N-diisopropylethylamine (57.5 mg, 0.445 mmol, 2.50 eq.) and 3- (isopropylamino)-2-phenyl-5H,6H,7H,8H-1l6-pyrido[3,4-e][1,2, 4]thiadiazine-1,1-dione (57.0 mg, 0.178 mmol, 1.00 eq.) was stirred overnight at rt. The mixture was diluted with EA (100 mL). The mixture was washed with hydrochloric acid (2 x 20 mL, 1 mol/L), sat. sodium bicarbonate (2 x 20 mL) and sat. NaCl (1 x 20 mL) dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep- TLC (silica, PE:EA=2:1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 19 x 250 mm, 10 Pm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 53% B to 73% B in 7 min; 220 nm; RT: 6.98 min to afford 6-(4-bromo-3-chlorobenzoyl)-3-(isopropylamino)-2-phenyl-5H,7 H,8H- 1l6-pyrido[3,4-e][1,2,4]thiadiazine-1,1-dione (50.1 mg, 52% yield) as a white solid. LCMS (ESI, m/z): 537 [M+H] + , RT = 1.665 min. 1 H NMR (400 MHz, CDCl3) d: 7.71 (d, J = 8.0 Hz, 1H), 7.65-7.50 (m, 4H), 7.50-7.39 (m, 2H), 7.23 (s, 1H), 4.69-4.30 (m, 1H), 4.28-3.92 (m, 3H), 3.92-3.80 (m, 1H), 3.75-3.51 (m, 1H), 2.92-2.58 (m, 2H), 1.06 (s, 6H).

Example 4 6-(4-bromo-3-chlorobenzoyl)-3-[[(4-methoxyphenyl)methyl]amin o]-2-phenyl-5H,7H,8H- 1l6-pyrido[3,4-e][1,2,4]thiadiazine-1,1-dione (4) [0160] A mixture of sodium metabisulfite (7.56 g, 39.8 mmol, 2.00 eq.), tetrabuylammonium bromide (6.41 g, 19.9 mmol, 1.00 eq.), sodium formate (2.70 g, 39.8 mmol, 2.00 eq.), palladium acetate (0.0446 mg, 0.199 mmol, 0.01 eq.), triphenylphosphine (0.208 mg, 0.796 mmol, 0.04 eq.), 1,10-phenanthroline (0.143 g, 0.796 mmol, 0.04 eq.), dimethyl sulphoxide (50 mL) and 4-bromo-3-fluoropyridine (3.50 g, 19.9 mmol, 1.00 eq.) was stirred for 4 h at 70 °C under N2 atmosphere. Aniline (1.85 g, 19.9 mmol, 1.00 eq.) and N,N-diisopropylethylamine (3.86 g, 29.8 mmol, 1.50 eq.) in THF (50 mL) were added at rt, and N-chlorosuccinimide (5.31 g, 39.8 mmol, 2.00 eq.) in THF (30 mL) was added at 0 °C. The mixture was stirred overnight at rt, and then diluted with EA (800 mL). The mixture was washed with water (4 x 100 mL) and sat. NaCl (1 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (4:1) to afford 3-fluoro-N- phenylpyridine-4-sulfonamide (830 mg, 14% yield) as an off-white solid. LCMS (ESI, m/z): 253 [M+H] + , RT = 0.877 min. [0161] A mixture of 3-fluoro-N-phenylpyridine-4-sulfonamide (830 mg, 3.29 mmol, 1.00 eq.), dioxane (6 mL) and ammonium hydroxide (6 mL) was stirred overnight at 120 °C, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (1:3) to afford 3-amino-N-phenylpyridine-4- sulfonamide (510 mg, 59% yield) as a white solid. LCMS (ESI, m/z): 250 [M+H] + , RT = 0.713 min. [0162] A mixture of 3-amino-N-phenylpyridine-4-sulfonamide (100 mg, 0.401 mmol, 1.00 eq.), N,N-dimethylformamide (5 mL), potassium carbonate (138 mg, 1.00 mmol, 2.50 eq.) and 1-(isothiocyanatomethyl)-4-methoxybenzene (144 mg, 0.802 mmol, 2.00 eq.) was stirred overnight at 80 °C, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (2:1) to afford 3-[[(4- methoxyphenyl)methyl]amino]-2-phenyl-1l6-pyrido[3,4-e][1,2,4 ]thiadiazine-1,1-dione (120 mg, 36% yield) as an off-white solid. LCMS (ESI, m/z): 395 [M+H] + , RT = 1.557 min. [0163] A mixture of 3-[[(4-methoxyphenyl)methyl]amino]-2-phenyl-1l6- pyrido[3,4-e][1,2,4]thiadiazine-1,1-dione (90.0 mg, 0.228 mmol, 1.00 eq.), acetonitrile (5 mL) and 4-(bromomethyl)-1,2-dimethoxybenzene (79.1 mg, 0.342 mmol, 1.50 eq.) was stirred overnight at 60 °C, and then concentrated under reduced pressure to afford 6-[(3,4- dimethoxyphenyl)methyl]-3-[[(4-methoxyphenyl)methyl]amino]-1 ,1-dioxo-2-phenyl-1l6- pyrido[3,4-e][1,2,4]thiadiazin-6-ium bromide (140 mg, crude) as a yellow solid. LCMS29 (ESI, m/z): 545 [M-Br] + , RT = 0.916 min. [0164] A mixture of 6-[(3,4-dimethoxyphenyl)methyl]-3-[[(4- methoxyphenyl)methyl]amino]-1,1-dioxo-2-phenyl-1l6-pyrido[3, 4-e][1,2,4]thiadiazin-6-ium bromide (140 mg, 0.224 mmol, 1.00 eq.), 1,2-dichloroethane (5 mL) and sodium triacetoxyborohydride (237 mg, 1.12 mmol, 5.00 eq.) was stirred for 1.5 h at 60 °C. The reaction was quenched with water (20 mL). The mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (silica, PE:EA=1:1) to afford 6-[(3,4-dimethoxyphenyl)methyl]-3-[[(4- methoxyphenyl)methyl]amino]-2-phenyl-5H,7H,8H-1l6-pyrido[3,4 -e][1,2,4]thiadiazine-1,1- dione (40.0 mg, 28% yield) as an off-white solid. LCMS (ESI, m/z): 549 [M+H] + , RT = 0.897 min. [0165] A mixture of 6-[(3,4-dimethoxyphenyl)methyl]-3-[[(4- methoxyphenyl)methyl]amino]-2-phenyl-5H,7H,8H-1l6-pyrido[3,4 -e][1,2,4]thiadiazine-1,1- dione (30.0 mg, 0.0480 mmol, 1.00 eq., 87%), 1,2-dichloroethane (3 mL), N,N- diisopropylethylamine (10.6 mg, 0.0820 mmol, 1.50 eq.) and chloroethyl chloroformate (8.60 mg, 0.0600 mmol, 1.10 eq.) was stirred for 1 h at rt. The mixture was concentrated under reduced pressure, and then MeOH (3 mL) was added. The mixture was stirred for 1 h at 70 °C, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2:MeOH (10:1) to afford 3-[[(4- methoxyphenyl)methyl]amino]-2-phenyl-5H,6H,7H,8H-1l6-pyrido[ 3,4-e][1,2,4]thiadiazine- 1,1-dione (20.0 mg, crude) as an off-white solid. LCMS (ESI, m/z): 399 [M+H] + , RT = 0.785 min. [0166] A mixture of 4-bromo-3-chlorobenzoic acid (14.2 mg, 0.0600 mmol, 1.20 eq.), N,N-dimethylformamide (5 mL), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (11.5 mg, 0.0600 mmol, 1.20 eq.), 1-hydroxybenzotrizole (8.14 mg, 0.0600 mmol, 1.20 eq.), N,N-diisopropylethylamine (19.5 mg, 0.151 mmol, 3.00 eq.) and 3-[[(4- methoxyphenyl)methyl]amino]-2-phenyl-5H,6H,7H,8H-1l6-pyrido[ 3,4-e][1,2,4]thiadiazine- 1,1-dione (20.0 mg, 0.0500 mmol, 1.00 eq.) was stirred overnight at rt. The mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 19 x 250 mm, 10 Pm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 56% B to 76% B in 7 min; 220 nm; RT: 6.88 min to afford 6-(4-bromo-3-chlorobenzoyl)-3-[[(4- methoxyphenyl)methyl]amino]-2-phenyl-5H,7H,8H-1l6-pyrido[3,4 -e][1,2,4]thiadiazine-1,1- dione (21.8 mg, 74% yield) as a white solid. LCMS (ESI, m/z): 615 [M+H] + , RT = 1.717 min. 1 H NMR (400 MHz, CDCl 3 ) į: 7.78-7.65 (m, 1H), 7.63-7.50 (m, 4H), 7.50-7.38 (m, 2H), 7.28-7.18 (m, 1H), 7.18-6.93 (m, 2H), 6.90-6.69 (m, 2H), 4.68-4.29 (m, 4H), 4.28-4.08 (m, 1H), 4.08-3.89 (m, 1H), 3.77 (s, 3H), 3.71-3.52 (m, 1H), 2.90-2.60 (m, 2H). Example 5 Synthesis of (4-bromo-3-chlorophenyl)(3-(isopropylamino)-2-(4-methoxyphen yl)-1,1- dioxido-7,8-dihydro-2H-pyrido[3,4-e][1,2,4]thiadiazin-6(5H)- yl)methanone (5) [0167] Compound 5 was synthetized according to the pathway described for the synthesis of compound 4, using 4-methoxyaniline in place of aniline in the first step, and 2- isothiocyanatopropane in place of 1-(isothiocyanatomethyl)-4-methoxybenzene in the cyclization step. Compound 5 was obtained as a white powder. LCMS (ESI, m/z): 568 [M+H] + , RT = 1.770 min. 1 H NMR (400 MHz, CDCl 3 ) į: 7.13 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H), 7.39 (d, J = 9.0 Hz, 2H), 7.27-7.17 (m, 1H), 7.06 (d, J = 9.0 Hz, 2H), 4.68-4.38 (m, 1H), 4.31-3.80 (m, 7H), 3.78-3.49 (m, 1H), 2.68-2.48 (m, 2H), 1.08 (s, 6H). Example 6 Synthesis of (4-bromo-3-chloro-phenyl)-[2-(2-chloro-4-methoxy-phenyl)-3- (isopropylamino)-1,1-dioxo-7,8-dihydro-5H-pyrido[3,4-e][1,2, 4]thiadiazin-6-yl]methanone (6) [0168] Compound 6 was synthetized according to the pathway described for the synthesis of compound 4, using 2-chloro-4-methoxyaniline in place of aniline in the first step, and 2-isothiocyanatopropane in place of 1-(isothiocyanatomethyl)-4-methoxybenzene in the cyclization step. Compound 6 was obtained as a white powder. LCMS (ESI, m/z): 602.95 [M+H] + , RT = 1.62 min. 1 H NMR (400 MHz, CDCl 3 ) į: 7.71 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 6.4 Hz, 2H), 7.25-7.18 (m, 1H), 7.11 (d, J = 2.8 Hz, 1H), 7.00-6.90 (m, 1H), 4.61-4.30 (m, 1H), 4.28-4.00 (m, 2H), 3.92-3.81 (m, 4H), 3.80-3.51 (m, 2H), 2.89-2.60 (m, 2H), 1.18-0.95 (m, 6H). EXAMPLE A HBV-DNA Antiviral Assay using HepG2.117 cells [0169] The following assay procedure describes the HBV antiviral assay, using HepG2.117 cells, which carry a stably integrated genotype D HBV genome under the control of a Tet-off promoter, and intracellular HBV DNA quantification as endpoint. Cell viability is assessed in parallel by measuring the intracellular ATP content using ATPlite (Perkin Elmer). [0170] On day 0, HepG2.117 cells (which are maintained in routine cell culture with doxycycline present in the medium at a final concentration of 1 mg/mL) were seeded in 96-well plates (white with clear bottom) at a density of 2.0 x 10 4 cells/well (0.1 mL/well) in medium without doxycycline to induce pgRNA transcription and subsequent formation of HBV particles. The cells were incubated at 37 qC and 5% CO 2 . [0171] On day 1, medium was removed from each well, the test articles were diluted in culture medium without doxcycyline and 100 mL was added to cell culture wells (9 concentrations, 4-fold dilution). For each plate, 6 untreated (merely DMSO) wells were included. The final concentration of DMSO in the culture medium was 2%. Each plate was prepared in duplicate (one for HBV DNA extraction, one for ATPlite measurement). The cells were incubated at 37 °C and 5% CO 2 for 3 days. [0172] On day 4, cell viability was assessed using ATPlite and cell lysates were prepared for HBV DNA extraction and subsequent quantification by qPCR. HBV DNA quantification by qPCR [0173] Medium was removed from each well and 100 mL of 0.33% NP-40 in H 2 O was added to each well. Plates were sealed, incubated at 4 °C for 5 mins, vortexed extensively and centrifuged briefly. Next, 35 mL of lysate was added to 65 mL QuickExtract DNA Extraction Solution (Epicentre) in a PCR plate for each well. PCR plate was incubated at 65 °C for 6 mins, 98 °C for 2 mins and finally cooled to 4 °C. HBV DNA was then quantified by qPCR with HBV-specific primers and probes as specified in Table 1 using the Bio-Rad SSOAdvanced Universal Probes Supermix on a CFX96 machine (Bio-Rad). The PCR cycle program consisted of 95 °C for 3 mins, followed by 40 cycles at 95 °C for 10 sec and 60 °C for 30 sec. Table 1: HBV DNA Primers and Probe for HepG2.117 assay [0174] A DNA standard was prepared by dilution of an IDT gBlock corresponding to the amplicon with concentrations ranging from 10^2 to 10^8 copies/input (i.e. per 4 mL) and used to generate a standard curve by plotting Cq values vs. HBV DNA standard concentration. The quantity of HBV DNA in each sample was determined by interpolating from the standard curve. Cell viability [0175] Using the other plates, the cell viability was quantified by ATPlite according to the manufacturer’s manual. In brief, 50 ^L of cell lysis solution was added to the culture plates and shaken for 5’, followed by addition of 50 ^L substrate into each well and further shaking. The plates were incubated at room temperature for 10 mins and luminescence signal was subsequently measured on a VarioSkan Lux (ThermoFisher) plate reader. Data analysis [0176] Cell viability was calculated as follows: % Cell viability = (luminescence value of test sample) / (average luminescence value of 2% DMSO control) x 100%. HBV DNA inhibition was calculated as follows: 100 - (HBV DNA copy number of test sample)/ (average HBV DNA copy number of 2% DMSO control) x 100%. No normalization to entecavir was required due to the excellent dynamic window of this assay. The CC50, EC50 and EC90 values were determined by dose-response curves fitted by GraphPad Prism using "log (agonist) vs. response -- Variable slope ". [0177] Compounds of Formula (I) are active against HBV as shown in Table 2, where ‘A’ indicates an EC 50 < 1 nM, ‘B’ indicates an EC 50 of ³1 nM and < 10 nM, ‘C’ indicates an EC50 ³ 10 nM and < 100 nM, ‘D’ indicates an EC50 ³ 100 nM and < 1000 nM, and ‘E’ indicates an EC50 > 1000 nM. Table 2 [0178] Although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.