SMITH DAVID (US)
ZHANG QINGLING (US)
DEBING YANNICK (US)
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)– or –NH–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 hydrogen or an unsubstituted C1-4 alkyl; R4, R5, R6 and R7 are each hydrogen; R8 is –NR10AR10B or an optionally substituted C2-12 alkynyl, wherein the C2-12 alkynyl is optionally substituted with one or more substituents selected from the group consisting of amino, –NH–C(=O)(an unsubstituted C1-4 alkyl), hydroxy, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 haloalkyl, an unsubstituted C3-4 monocyclic cycloalkyl, a fluoro-substituted C3-4 monocyclic cycloalkyl, a hydroxy-substituted C3-4 monocyclic cycloalkyl an unsubstituted 4-6 membered monocyclic heterocyclyl, an optionally substituted aryl and an optionally substituted 5-6 membered monocyclic heteroaryl; R9 is a substituted phenyl, a substituted monocyclic heteroaryl or a substituted fused- bicyclic heteroaryl, wherein the substituted phenyl, the substituted monocyclic heteroaryl or the substituted fused-bicyclic heteroaryl is substituted with –C(=O)NR11R12 and the substituted phenyl, the substituted monocyclic heteroaryl or the substituted fused-bicyclic heteroaryl is optionally further substituted; R10A is hydrogen, an unsubstituted C1-6 alkyl, a monocyclic C3-6 cycloalkyl optionally substituted with one or two halogens, an optionally substituted 5-6 membered monocyclic heteroaryl, an optionally substituted 4-6 membered monocyclic heterocyclyl or an optionally substituted monocyclic C3-6 cycloalkyl(C1-4 alkyl); R10B is selected from the group consisting of an optionally substituted C2-8 alkenyl, an optionally substituted C2-8 alkynyl, an optionally substituted aryl, an optionally substituted aryl(C1-4 alkyl), an optionally substituted heteroaryl(C1-4 alkyl) and an optionally substituted heterocyclyl(C1-4 alkyl), wherein the C2-8 alkenyl and the C2-8 alkynyl is optionally substituted with one or more substituents selected from the group consisting of amino, hydroxy, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 haloalkyl, an unsubstituted C3-4 monocyclic cycloalkyl, a fluoro-substituted C3-4 monocyclic cycloalkyl, a hydroxy-substituted C3-4 monocyclic cycloalkyl and an unsubstituted 4-6 membered monocyclic heterocyclyl; and R11 is H or an unsubstituted C1-4 alkyl; R12 is –(C(=O)–O–CR13AR13B)p–R14; p is 0 or 1; R13A and R13B are independently H or an unsubstituted C1-4 alkyl; and R14 is selected from the group consisting -linked D-amino acid, –CH2–O-linked D-amino acid, a hydroxy-substituted C1-4 alkyl, –O–(C=O)–CH(OH)–CH(OH)–C(=O)OH, –O–(C=O)– CH2–CH(OH)–C(=O)OH, –O–(C=O)–CH=CH–C(=O)OH and –(C=O)–(an unsubstituted or a substituted monocyclic heterocyclyl). 2. The compound of Claim 1, wherein n is 1; and Z1 is –C(=O)–. 3. The compound of Claim 1, wherein n is 1; and Z1 is –NH–C(=O)–. 4. The compound of any one of Claims 1-3, wherein R1 is an optionally substituted aryl. 5. The compound of Claim 4, wherein R1 is an optionally substituted phenyl. 6. The compound of Claim 5, wherein R1 is a di-substituted phenyl. 7. The compound of Claim 6, wherein R1 is selected from the group consisting of: The compound of Claim 6, wherein R1 is . . The compound of any one of Claims 1-3, 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 1-3, 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 1-3, wherein R1 is an optionally substituted aryl(C1-4 alkyl). 16. The compound of Claim 15, wherein R1 is an optionally substituted benzyl. 17. The compound of any one of Claims 1-3, wherein R1 is an optionally substituted heteroaryl(C1-4 alkyl). 18. The compound of any one of Claims 1-3, wherein R1 is an optionally substituted heterocyclyl(C1-4 alkyl). 19. The compound of any one of Claims 1-18, wherein R2 is hydrogen. 20. The compound of any one of Claims 1-18, wherein R2 is an unsubstituted C1-4 alkyl. 21. The compound of any one of Claims 1-20, wherein R8 is –NR10AR10B. 22. The compound of Claim 21, wherein R10A is hydrogen. 23. The compound of Claim 21, wherein R10A is an unsubstituted C1-6 alkyl. 24. The compound of Claim 21, wherein R10A is a monocyclic C3-6 cycloalkyl optionally substituted with one or two halogens or an optionally substituted 4-6 membered monocyclic heterocyclyl. 25. The compound of Claim 21, wherein R10A is an optionally substituted 5-6 membered monocyclic heteroaryl. 26. The compound of Claim 21 wherein R10A is an optionally substituted monocyclic C3-6 cycloalkyl(C1-4 alkyl). 27. The compound of any one of Claims 21-26, wherein R10B is an optionally substituted C2-8 alkenyl. 28. The compound of any one of Claims 21-26, wherein R10B is an optionally substituted C2-8 alkynyl. 29. The compound of any one of Claims 21-26, wherein R10B is an optionally substituted aryl. 30. The compound of any one of Claims 21-26, wherein R10B is an optionally substituted aryl(C1-4 alkyl). 31. The compound of any one of Claims 21-26, wherein R10B is an optionally substituted heteroaryl(C1-4 alkyl). 32. The compound of any one of Claims 21-26, wherein R10B is an optionally substituted heterocyclyl(C1-4 alkyl). 33. The compound of any one of Claims 1-20, wherein R8 is an unsubstituted C2-12 alkynyl. 34. The compound of any one of Claims 1-20, wherein R8 is a substituted C2-12 alkynyl substituted one or more substituents selected from the group consisting of amino, – NH–C(=O)(an unsubstituted C1-4 alkyl), hydroxy, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 haloalkyl, an unsubstituted C3-4 monocyclic cycloalkyl, a fluoro-substituted C3-4 monocyclic cycloalkyl, a hydroxy-substituted C3-4 monocyclic cycloalkyl, an unsubstituted 4-6 membered monocyclic heterocyclyl, an optionally substituted aryl and an optionally substituted 5-6 membered monocyclic heteroaryl. 35. The compound of any one of Claims 1-34, wherein R9 is a substituted phenyl. 36. The compound of any one of Claims 1-34, wherein R9 is a substituted monocyclic heteroaryl. 37. The compound of any one of Claims 1-34, wherein R9 is a substituted monocyclic 5- or 6-membered heteroaryl. 38. The compound of any one of Claims 1-34, wherein R9 is a substituted fused- bicyclic heteroaryl. 39. The compound of any one of Claims 1-34, wherein R9 is a substituted fused- bicyclic 9- or 10-membered heteroaryl. 40. The compound of any one of Claims 1-39, wherein R11 is H. 41. The compound of any one of Claims 1-39, wherein R11 is an unsubstituted C1-4 alkyl. 42. The compound of any one of Claims 1-41, wherein . 43. The compound of any one of Claims 1-41, wherein O O P OH OH . 44. The compound of any one of Claims 1-41, wherein R14 is –O-linked D-amino acid or –CH2–O-linked D-amino acid. 45. The compound of any one of Claims 1-41, wherein R14 is –O–(C=O)–CH(OH)– CH(OH)–C(=O)OH. 46. The compound of any one of Claims 1-41, wherein R14 is –O–(C=O)–CH2– CH(OH)–C(=O)OH. 47. The compound of any one of Claims 1-41, wherein R14 is –O–(C=O)–CH=CH– C(=O)OH. 48. The compound of any one of Claims 1-41, wherein R14 is –(C=O)–(an unsubstituted or a substituted monocyclic heterocyclyl). 49. The compound of any one of Claims 1-48, wherein p is 0. 50. The compound of any one of Claims 1-48, wherein p is 1. 51. The compound of Claim 50, wherein R13A is H. 52. The compound of Claim 50, wherein R13A is an unsubstituted C1-4 alkyl. 53. The compound of any one of Claims 50-52, wherein R13B is H. 54. The compound of any one of Claims 50-52, wherein R13B is an unsubstituted C1-4 alkyl. 55. The compound of any one of Claims 40-54, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is , or a pharmaceutically acceptable salt thereof. 56. The compound of Claim 1 selected from the group consisting of: , , , , , , , acceptable salt of any of the foregoing. 57. The compound of Claim 1 selected from the group consisting of: , , , , , , , , , , , , acceptable salt of any of the foregoing. 58. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-57, or a pharmaceutically acceptable salt thereof, and excipient. 59. Use of the compound of any one of Claims 1-57, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of hepatitis B. 60. Use of the compound of any one of Claims 1-57 or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of hepatitis D. 61. The use of any one of Claims 59-60, 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. 62. The use of Claim 61, wherein the additional agent selected from the group consisting of recombinant interferon alpha 2b, IFN-D, PEG-IFN-D-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, tenofovir disoproxil and a siRNA selected from the group consisting of SEQ. ID. Nos. 1-618 of WO 2021/178885. 63. A compound of any one of Claims 1-57, or a pharmaceutically acceptable salt thereof, for use in treating hepatitis B. 64. A compound of any one of Claims 1-57, or a pharmaceutically acceptable salt thereof, for use in treating hepatitis D. 65. The compound of any one of Claims 63-64, wherein the compound is used in combination with 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. 66. The compound of Claim 65, wherein the additional agent is selected from the group consisting of recombinant interferon alpha 2b, IFN-D, PEG-IFN-D-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, tenofovir disoproxil and a siRNA selected from the group consisting of SEQ. ID. Nos. 1-618 of WO 2021/178885. 67. A method for treating hepatitis B in a subject comprising administering to the subject in need thereof an effective amount of a compound of any one of Claims 1-57, or a pharmaceutically acceptable salt thereof, suffering from hepatitis B. 68. A method for treating hepatitis D in a subject comprising administering to the subject in need thereof an effective amount of a compound of any one of Claims 1-57, or a pharmaceutically acceptable salt thereof, suffering from hepatitis D. 69. The method of any one of Claims 67-68, further comprising administering 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. 70. The method of Claim 69, wherein the additional agent selected from the group consisting of recombinant interferon alpha 2b, IFN-D, PEG-IFN-D-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, tenofovir disoproxil and a siRNA selected from the group consisting of SEQ. ID. Nos. 1-618 of WO 2021/178885. |
[0094] As provided herein, R 9 can be a cyclic moiety that is substituted with –C(=O)NR 11 R 12 . For example, in some embodiments, R 9 can be a substituted phenyl. In other embodiments, R 9 can be a heteroaryl (monocyclic or fused-bicyclic heteroaryl). The heteroaryl can have one or more heteroatoms present, for example, 1, 2 or 3 heteroatoms. Exemplary heteroatoms include, but are not limited to, N (nitrogen), O (oxygen) and S (sulfur). The size of the heteroaryl can vary. In some embodiments, R 9 can be a substituted monocyclic heteroaryl. The monocyclic heteroaryl can be a 5- or 6-membered heteroaryl. In other embodiments, R 9 can be a substituted fused-bicyclic heteroaryl. The number of ring atoms of the fused-bicyclic heteroaryl can be 9 or 10 such that R 9 can be a substituted fused-bicyclic 9- or 10-membered heteroaryl. Examples of suitable heteroaryls for R 9 include pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, indazole, benzo[d]imidazole and imidazo[4,5-b]pyridine. In some embodiments, R 9 can be selected from: , , wherein each of the aforementioned can be unsubstituted or substituted as described herein. In some embodiment, R 9 can . [0095] As provided herein, R 9 is substituted with –C(=O)NR 11 R 12 , and can be optionally further substituted. Additionally substituents that can be present on R 9 in addition to –C(=O)NR 11 R 12 include, but are not limited to, halogen (such as F, Cl or Br), an unsubstituted C 1-4 alkyl, a cyano-substituted C 1-4 alkyl, an unsubstituted C 1-4 haloalkyl, an unsubstituted C 1-4 alkoxy, a hydroxy-substituted C 1-4 alkoxy, an optionally substituted monocyclic C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), an optionally substituted monocyclic heteroaryl, an optionally substituted monocyclic heterocyclyl, amino, a mono-substituted amine and a di-substituted amine. Examples of an unsubstituted C1-4 alkyl and an unsubstituted C1-4 alkoxy include the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, iso-butoxy and tert-butoxy. Exemplary unsubstituted C1-4 haloalkyls include –CHF 2 , –CH 2 F, –CF 3 , –CH 2 Cl, –CHCl 2 , –CCl 3 , –CH 2 CF 3 , –CH 2 CHF 2 , – CH 2 CCl 3 and –CH 2 CHCl 2 . A non-limiting list of cyano-substituted C 1-4 alkyls include – CH 2 CN, –CH 2 CH 2 CN, –CH 2 CH(CH 3 )CN and –CH 2 C(CH 3 ) 2 CN. Examples of hydroxy- substituted C1-4 alkoxy include –OCH2CH2OH, –OCH2CH(CH3)OH and –OCH2C(CH3)2OH. The number of additional substituents that can be present on R 9 can vary. In some embodiments, 1 additional substituent can be present on R 9 . In some embodiments, 2 additional substituents can be present on R 9 . [0096] An R 9 group described herein, can be substituted with an unsubstituted or a substituted monocyclic heteroaryl, such as a 5- or 6-membered monocyclic heteroaryl that includes one or more heteroatoms (such as 1, 2 or 3) selected from O (oxygen), S (sulfur) and N (nitrogen). Suitable monocyclic heteroaryls that can be present on R 9 are described herein, and include pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, pyridazine, pyridazine, 1,2,3-trizole and 1,2,4-triazole. In some embodiments, an unsubstituted or a substituted heterocyclyl (such as a 5- or 6-membered heterocyclyl) can be substituted on an R 9 group described herein. The heteroatoms present in an unsubstituted or a substituted heterocyclyl that can be substituted on an R 9 group described herein can vary, and include O (oxygen), S (sulfur) and N (nitrogen). Exemplary unsubstituted or a substituted heterocyclyls that can be present on an R 9 group described herein include morpholine, piperidine, piperazine, pyrrolidine, 1,2,4-oxadiazol-5(2H)-one, 1,2,4-oxadiazol-5(4H)-one, 2,4-dihydro-3H-1,2,4- triazol-3-one, azetidine and oxetane. The substituted heteroaryls and/or substituted heterocyclyls that can be substituted on an R 9 group described herein can be substituted with one or more moieties (for example, 1, 2 or 3 moieties) such as those described herein for “optionally substituted.” In some embodiments, the substituted heteroaryls and/or substituted heterocyclyls that can be substituted on an R 9 group described herein can be substituted with halogen, amino, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl (for example, CF3, CHF2, CH2F) and/or an unsubstituted C1-4 alkoxy. Suitable halogens, unsubstituted C1-4 alkyls, unsubstituted C1-4 haloalkyls and/or unsubstituted C1-4 alkoxys are described herein, such as those described in this paragraph. [0097] In some embodiments, R 11 can be hydrogen; p can be 1; and R 12 can be – C(=O)–O–CR 13A R 13B –R 14 . In other embodiments, R 11 can be an unsubstituted C 1-4 alkyl; p can be 1; and R 12 can be –C(=O)–O–CR 13A R 13B –R 14 . In some embodiments, including those of this paragraph, R 13A can be hydrogen. In other embodiments, including those of this paragraph, R 13A can be unsubstituted C1-4 alkyl. In some embodiments, including those of this paragraph, R 13B can be hydrogen. In other embodiments, including those of this paragraph, R 13B can be unsubstituted C1-4 alkyl. Examples of unsubstituted C1-4 alkyls include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. [0098] In some embodiments, R 11 can be hydrogen; p can be 1; and R 12 can be – C(=O)–O–CHR 13B –R 14 . In other embodiments, R 11 can be an unsubstituted C 1-4 alkyl; p can be 1; and R 12 can be –C(=O)–O–CHR 13B –R 14 . In some embodiments, R 11 can be methyl; p can be 1; and R 12 can be –C(=O)–O–CR 13A R 13B –R 14 . In some embodiments, R 11 can be methyl; p can be 1; and R 12 can be –C(=O)–O–CHR 13B –R 14 . In some embodiments of this paragraph, R 13B can be unsubstituted C1-4 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl and tert-butyl. [0099] A variety of moieties can be present for R 12 . In some embodiments, R 12 can be –C(=O)–O–CH 2 –R 14 . In some embodiments, R 12 can be –C(=O)–O–CH(an unsubstituted C 1-4 alkyl)–R 14 . Suitable unsubstituted C 1-4 alkyls are provided herein. In some embodiments, R 12 can be –C(=O)–O–CH(CH3)–R 14 . [0100] In some embodiments, R 11 can be hydrogen; p can be 0; and R 12 can be –R 14 . In other embodiments, R 11 can be an unsubstituted C1-4 alkyl; p can be 0; and R 12 can be –R 14 . [0101] Various moieties can be present for R 14 . In some embodiments, R 14 can be a phosphate. In other embodiments, R 14 can be a phosphate connected via a lower alkylene. For example, R 14 can be . As with a phosphate, R 14 can be –O-linked D-amino acid or an –O-linked D-amino acid linked via a lower alkylene. In some embodiments, R 14 can be –O-linked D- amino acid. In other embodiments, R 14 can be –CH2–O-linked D-amino acid. Examples of D- amino acids include arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine and tryptophan. In some embodiments, the O- linked amino acid can
amino acid, except for glycine, has a chiral center. In some embodiment, the chiral center of an D-amino acid may be a (R)-chiral center. In other embodiments, the chiral center of an D- amino acid may be a (S)-chiral center. [0102] In some embodiments, R 14 can be a hydroxy-substituted C 1-4 alkyl. For example, R 14 can be –CH 2 –OH, –CH 2 CH 2 –OH, –CH 2 CH 2 CH 2 –OH, –CH 2 CH 2 CH 2 CH 2 –OH or –CH(OH)–CH 2 CH 3 , –CH(CH 3 )–CH 2 OH In other embodiments, R 14 can be –O–(C=O)– CH(OH)–CH(OH)–C(=O)OH. In still other embodiments, R 14 can be –O–(C=O)–CH 2 – CH(OH)–C(=O)OH. In yet still other embodiments, R 14 can be –O–(C=O)–CH=CH– C(=O)OH. In some embodiments, R 14 can be –(C=O)–(an unsubstituted or a substituted monocyclic heterocyclyl). A variety of monocyclic heterocyclyls can be part of –(C=O)–(an unsubstituted or a substituted monocyclic heterocyclyl) for R 14 . For example, the monocyclic heterocyclyl can be a 5- or 6-membered monocyclic heterocyclyl. A variety of heteroatoms can be in the ring of a monocyclic heterocyclyl, such as N (nitrogen), O (oxygen) and S (sulfur). Additionally, the number of heteroatoms present in the ring of a monocyclic heterocyclyl can vary. For example, a monocyclic heterocyclyl of –(C=O)–(an unsubstituted or a substituted monocyclic heterocyclyl) for R 14 can include 1 or 2 heteroatoms. In some embodiments, the monocyclic heterocyclyl of –(C=O)–(an unsubstituted or a substituted monocyclic heterocyclyl) for R 14 can be a 5- or 6-membered monocyclic heterocyclyl that includes 1 or 2 nitrogens and optionally 1 heteroatom selected from O (oxygen) and S (sulfur). A non-limiting list of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, morpholinyl and thiomorpholinyl. [0103] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be where n can be 1; Z 1 is –C(=O)–; R 1 can be ; R 2 can be an unsubstituted C 1-4 alkyl (such as methyl); R 3 , R 4 , R 5 , R 6 and R 7 can each be hydrogen; R 8 can be –NHR 10B ; R 9 can be a substituted phenyl, wherein the phenyl is substituted with – C(=O)NHR 12 ; and R 10B can be an unsubstituted C 2-8 alkenyl. In some embodiments, a compound of Formula (I) , or a pharmaceutically acceptable salt thereof, can be where n can be 1; Z 1 is –C(=O)–; R 1 can be ; R 2 can be an unsubstituted C 1-4 alkyl (such as methyl); R 3 , R 4 , R 5 , R 6 and R 7 can each be hydrogen; R 8 can be –NHR 10B ; R 9 can be a substituted phenyl, wherein the phenyl is substituted with –C(=O)NHR 12 ; and R 10B can be an unsubstituted C2-8 alkynyl. In some embodiments, a compound of Formula (I) , or a pharmaceutically acceptable salt thereof, can be where n can be 1; Z 1 is –C(=O)–; R 1 can be ; R 2 can be an unsubstituted C1-4 alkyl (such as methyl); R 3 , R 4 , R 5 , R 6 and R 7 can each be hydrogen; R 8 can be –NHR 10B ; R 9 can be a substituted phenyl, wherein the phenyl is substituted with –C(=O)NHR 12 ; and R 10B can be an unsubstituted C2-8 alkenyl or an unsubstituted C2-8 alkynyl. [0104] Examples of compounds of Formula (I), including pharmaceutically acceptable salts thereof, include: ,
, , , ,
,
, acceptable salt of any of the foregoing. [0105] Additional examples of compounds of Formula (I), including pharmaceutically acceptable salts thereof, include: ,
, , , ,
, , , ,
, ,
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. [0107] Compounds of Formula (I) can be prepared from an intermediate of Formula (II), in which PG represents an amino protecting group such as Boc. The PG group can be cleaved from a compound of Formula (II) using methods known in the art. For example, when PG represents a Boc group, PG can be cleaved using acidic conditions, for example, in the presence of HCl in a suitable solvent (such as 1,4-dioxane) or in the presence of copper triflate. The coupling of the intermediate of Formula (III) with a suitable agent can afford a compound of Formula (I), along with pharmaceutically acceptable salts thereof. 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 (III) with a phenyl carbamate of general formula R 1 -NH-C(=O)-O-phenyl or with an isocyanate of general formula R 1 -N=C=O, in the presence of a suitable base in a suitable solvent. An example of a suitable base is triethylamine, 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 (III) with an acyl chloride of general formula R 1 -C(=O)-Cl in the presence of a base in a suitable solvent. Additional 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 (III) with a carboxylic acid of general formula R 1 - C(=O)-OH in the presence of an amide coupling agent (such as HATU) in a suitable solvent. Further compounds of Formula (I), along with pharmaceutically acceptable salts thereof, can be prepared from a compound of Formula (III) using methods known in the art. Scheme 2 [0109] Compounds of Formula (I), including pharmaceutically acceptable salts thereof, can also be prepared from an intermediate of Formula (IV), in which LG represents a leaving group (such as sulfhydryl, methylsulfoxide or halo, in particular chloro or bromo). A compound of Formula (I) in which R 8 represents –NR 10A R 10B can be prepared from a compound of Formula (IV) in which LG represents methylsulfoxide by reacting an amine of Formula HNR 10A R 10B , in the presence of a base (such as diisopropylethylamine (DIPEA) or sodium bicarbonate) in a suitable solvent (such as 1,4-dioxane or acetonitrile), optionally in the presence of a catalyst (for example, DMAP). A compound of Formula (I) in which R 8 represents –NR 10A R 10B can be prepared from a compound of Formula (IV) in which LG represents chloro by reacting an amine of Formula HNR 10A R 10B , in the presence of a base (for example, triethylamine, sodium bicarbonate or DIPEA) in a suitable solvent (such as acetonitrile, n-butanol or dioxane), optionally in the presence of a catalyst, such as DMAP. Scheme 3 [0110] Compounds of Formula (I) in which R 8 represents –NR 10A R 10B can be prepared from an intermediate of Formula (VI) and an amine of general formula HNR 10A R 10B , in the presence of tert-Butyl hydroperoxide (TBHP) in a suitable solvent (such as acetonitrile). Scheme 4 [0111] Compounds of Formula (I), including pharmaceutically acceptable salts thereof, in which R 9 represents a phenyl substituted with –C(=O)NHR 12 can be prepared from an acid intermediate of general formula (VIIa) and an amine of Formula NH 2 -R 12 , using a peptide coupling agent (such as CDI) in the presence of a base (for example, DBU) in a suitable solvent, such as acetonitrile or DMF. Compounds of Formula (I), along with pharmaceutically acceptable salts thereof, in which R 9 represents a phenyl substituted with –C(=O)NHR 12 can be prepared from an ester intermediate of Formula (VIIb) and an amine of general formula NH2-R 12 in a suitable solvent (such as acetonitrile). Scheme 5 [0112] Intermediate of Formula (II) in which R 8 represents –NR 10A R 10B can be prepared from a compound of Formula (XI) using methyl iodide or methyl bromide, in the presence of a base, such as DBU, in a suitable solvent, such as DMF, to afford an intermediate of Formula (XII). Oxidation of an intermediate of Formula (XII) to a sulfoxide intermediate of Formula (XIII) can be achieved by a treatment with an oxidative agent (such as m-CPBA) in the presence of MgSO 4 and NaOAc in a suitable solvent (such as dichloromethane). Treatment of intermediate of Formula (XIII) with an amine of general formula HNR 10A R 10B in the presence of a base (such as DIPEA) in the presence of a catalyst (for example, DMAP) in a suitable solvent (such as 1,4-dioxane) can afford an intermediate of Formula (II) in which R 8 represents –NR 10A R 10B . [0113] Intermediates of Formula (IV) in which the leaving group LG represents a methylsulfoxide can be prepared from an intermediate of Formula (VI) using methyl iodide or methyl bromide, in the presence of a base (for example, DBU) in a suitable solvent, such as DMF, to afford an intermediate of Formula (XIV). Oxidation of an intermediate of Formula (XIV) to a sulfoxide intermediate of Formula (IV) can be achieved using an oxidative agent, such as m-CPBA, in the presence of MgSO 4 and NaOAc in a suitable solvent, such as dichloromethane. Scheme 7 [0114] Intermediates of Formula (IV) in which the leaving group LG represents a chloro can be prepared from an intermediate of Formula (VI) using thiophosgene in a suitable solvent (such as 1,4-dioxane). Scheme 8 [0115] Intermediate of Formula (VI) can be prepared from an intermediate of Formula (XV) in the presence of a strong base, such as NaH, in a suitable solvent (for example, THF or 2-methylTHF) followed by the subsequent addition of an isothiocyanate of general formula R 9 -NCS to afford an intermediate of Formula (XVI). The Boc group of an intermediate of Formula (XVI) can be obtained in the presence of an acid (such as HCl or TFA) in a suitable solvent (for example, 1,4-dioxane) to afford an intermediate of Formula (XVII). Intermediates of Formula (VI) can be prepared from an intermediate of Formula (XVII) following several conditions known to those skilled in the art. For example, compounds of Formula (XVII), wherein Z 1 represents –NH–C(=O)– and n = 1, can be obtained by reacting a compound of Formula (XVII) with a phenyl carbamate of general formula R 1 -NH-C(=O)-O- phenyl or with an isocyanate of general formula R 1 -N=C=O, in the presence of a suitable base in a suitable solvent. An example of a suitable base is triethylamine, and an example of suitable solvent is acetonitrile or dichloromethane. [0116] Further compounds of Formula (VI) wherein Z 1 represents –C(=O)– and n = 1, can be obtained by reacting a compound of Formula (XVII) with an acyl chloride of general formula R 1 -C(=O)-Cl in the presence of a base in a suitable solvent, including those bases and solvents described herein and/or known to those skilled in the art. Compounds of Formula (VI), wherein Z 1 represents –C(=O)– and n = 1, can be obtained by reacting compound of Formula (XVII) with a carboxylic acid of general formula R 1 -C(=O)-OH in the presence of an amide coupling agent (such as HATU) in a suitable solvent. Additional compounds of Formula (VI) can be prepared from a compound of Formula (XVII) using methods known in the art. Scheme 9 (XVIII) (XIX) (XX) [0117] An intermediate of Formula (VI) can be prepared from an intermediate of Formula (XVIII) following other conditions known in the art, similar to the conditions used to convert an intermediate of Formula (XVII) to an intermediate for Formula (VI). For example, intermediates of Formula (XIX) wherein Z 1 represents –C(=O)– and n = 1, can be obtained by reacting a compound of Formula (XVIII) with an acyl chloride of general formula R 1 -C(=O)- Cl in the presence of a base in a suitable solvent. Additional compounds of Formula (XIX), wherein Z 1 represents –C(=O)– and n = 1, can be obtained by reacting compound of Formula (XVIII) with a carboxylic acid of general formula R 1 -C(=O)-OH in the presence of an amide coupling agent (such as HATU) in a suitable solvent. Suitable solvents are known to those skilled in the art and/or described herein. [0118] Intermediates of Formula (XX) can be prepared from an intermediate of Formula (XI) in the presence of ammonium acetate, in a suitable solvent (such as ethanol). Intermediate of Formula (VI) can be prepared from an intermediate of Formula (XX) in the presence of a strong base (for example, NaH) in a suitable solvent (such as THF or 2- methylTHF) followed by the addition of an isothiocyanate of general formula R 9 -NCS. An intermediate of Formula (XX) can be treated with thiophosgene/NMM in a suitable solvent, such as dichloromethane, to afford an intermediate isothiocyanate, which can be converted to an intermediate of Formula (VI) by using an amine of general formula NH 2 -R 9 , in the presence of a base, such as triethylamine, in a suitable solvent (such as acetonitrile). Scheme 10 [0119] Intermediates of Formula (II) in which R 8 represents –NR 10A R 10B and the protecting group PG represents Boc, can be prepared from an intermediate of Formula (XXI) using a guanidine derivative of Formula (XXII), in the presence of a base, such as DBU, in a suitable solvent (such as acetonitrile) to afford an intermediate of Formula (XXIII). An intermediate of Formula (XXIII) can be converted in the intermediate of Formula (II) using methods known in the art. As an example, an intermediate of formula (XXIII) can be reacted with an aryl or heteroaryl boronic acid of general formula R 9 -B(OH) 2 , in the presence of TMEDA and Cu(OAc)2 to afford an intermediate of Formula (II) in which R 9 represents a substituted phenyl, a substituted monocyclic heteroaryl or a substituted fused-bicyclic heteroaryl. Scheme 11 [0120] Intermediates of Formula (XI) can be obtained from an intermediate of Formula (XV) using methods known in the art, for example by treating an intermediate of Formula (XV) with thiophosgene and NMM in a suitable solvent (such as dichloromethane). Treatment of an intermediate of Formula (XXIV) with an amine of general formula R 9 -NH 2 affords an intermediate of Formula (XI) in which PG represents a Boc group. Scheme 12 [0121] Intermediates of Formula (III) in which R 3 , R 4 , R 5 , R 6 and R 7 each represent hydrogen, and in which R 8 represents –NR 10A R 10B , can be prepared from a chloro-N-Boc- aminopyridinecarboxylic acid intermediate of Formula (I1) using a base (such as triethylamine) in the presence of 2-chloro-N-methylpyridinium iodide in a suitable solvent (for example, acetonitrile) to afford an intermediate of Formula (I2). An intermediate of Formula (I2) can be converted to an intermediate of Formula (XXV) using an amine of general formula R 9 -NH 2 , in a suitable solvent (for example, acetic acid). Reaction of an intermediate of Formula (XXV) with thiocarbonyldiimidazole in DMF can afford the thio intermediate of Formula (XXVI), which can be converted in an intermediate of Formula (XXVII) using thiophosgene in a suitable solvent (such as 1,4-dioxane). Treatment of an intermediate of Formula (XXVII) with an amine of general formula NR 10A R 10B can afford an intermediate of Formula (XXVIII). An intermediate of Formula (XXVIII) can be reacted with an organometallic derivative (such as a tin derivative of general formula R 2 -Sn(n-Bu) 3 ). A n intermediate of Formula (XXVIII) can be converted to an intermediate of Formula (III) in which R 3 , R 4 , R 5 , R 6 and R 7 each can be hydrogen, and in which R 8 represents –NR 10A R 10B , by hydrogenation using H 2 in the presence of a catalyst (such as Pt/C) in a mixture of solvents (for example, acetic acid/THF/ethanol). In the instance where R 2 can be an unsaturated group, such as an alkene, the R 2 can be converted to another R 2 group, such as an alkyl, by hydrogenation. Scheme 13 [0122] Intermediates of Formula (Va), in which R 8 represents –NR 10A R 10B , can be prepared from an intermediate of Formula (XXIX), in which LG represents a leaving group (such as sulfhydryl, methylsulfoxide or halo, in particular chloro of bromo). Intermediates of Formula (XXIX) can be reacted with an amine of general formula HNR 10A R 10B , in the presence of a base (for example, triethylamine) in a suitable solvent, such as acetonitrile, to afford an intermediate of Formula (XXX). The conversion of a bromo intermediate of Formula (XXX) to a boronic ester intermediate of Formula (Va) can be achieved using bis(pinacolato)diboron in the presence of a catalyst (such as Pd(dppf)Cl2) in the presence of a base, such as KOAc, in a suitable solvent (for example, 1,4-dioxane). Scheme 14 [0123] Intermediates of Formula (Vb) can be prepared from an intermediate of Formula (XXX) using bis(pinacolato)diboron, in the presence of a base (such as potassium acetate and 1,1’-bis(diphenylphosphino)ferrocene-palladium(II)dichlori de dichloromethane complex) in a suitable solvent, such as 1,4-dioxane, to obtain an intermediate of Formula (Vb). Scheme 15 ( XXXVI) (XXI) [0124] An alternative approach towards the chiral synthesis of compounds of Formula (XXI) is provided in Scheme 15. Oxidation of a chiral, boc-protected aminoalcohol of Formula (XXX), for example, via Swern oxidation, leads to aldehydes of Formula (XXXI). Subsequent formation of an unsaturated ester, for example, via the Wittig reaction (compounds of Formula (XXXII)), and then reduction of the resultant double bond (e.g., Pd/C) can afford compounds of Formula (XXXIII). Deprotection of the boc group and alkylation with ethyl 2- bromoacetate can provide compounds of Formula (XXXV). Boc protection of compounds of Formula (XXXV) followed by Dieckmann condensation can provide to compounds of Formula (XXI). Scheme 16 [0125] A compound of formula (I), where n is 1, Z 1 is –C(=O)– and R 14 is – OP(=O)(OH)2 can be synthetized according to Scheme 16 by reacting a compound of Formula (XXXVII) with a chloroformate ClCOOR 13a R 13b Cl, in presence of a base such as LiHMDS in a suitable solvent like THF. Subsequent reaction with a protected phosphate derivative, such as tetra-n-butylammonium di-tert-butylphosphate, followed by deprotection of the protecting group, using, for example, TFA in DCM to remove the tert-butyl group, can lead to a compound of Formula (I) (along with pharmaceutically acceptable salts thereof). Scheme 17 [0126] A compound of Formula (I) (including pharmaceutically acceptable salts thereof), where n is 1, Z 1 is –C(=O)– and R 14 is –O–(C=O)–CH=CH–C(=O)OH or an –O- linked D-amino acid can be prepared according to Scheme 17 by reacting a compound of Formula (XXXVII) with a carboxylic acid derivative, in presence of NaI and a base (such as Et 3 N), in a suitable solvent (such as acetone). In case of R 14 being –O–(C=O)–CH=CH– C(=O)OH, the carboxylic acid derivative can be (E)-4-(tert-Butoxy)-4-oxobut-2-enoic acid, which is then deprotected at the appropriate point of the synthesis using formic acid. In case of R 14 being an –O-linked D-amino acid, a N-protected amino acid can be reacted with a compound of Formula (XXXVII), and the N-protecting group can be removed in the final step to obtain a compound of Formula (I) (including pharmaceutically acceptable salts thereof). When the N-protecting group is Boc, the deprotection may occur in presence of HCl in dioxane, to provide a compound of Formula (I) as a HCl salt. Pharmaceutical Compositions [0127] 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. [0128] 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. [0129] 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. [0130] 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. [0131] 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. [0132] 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. [0133] 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 [0134] 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. [0135] 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. [0136] 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. [0137] In some embodiments, the HBV infection can be an acute HBV infection. In some embodiments, the HBV infection can be a chronic HBV infection. [0138] 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. [0139] 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). [0140] 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. [0141] 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, 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. [0142] 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. [0143] 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. [0144] 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. [0145] 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. A non-limiting list of potential advantages of compounds described herein (such as a compound of Formula (I), and pharmaceutically acceptable salts thereof) include improvement of one or more pharmacokinetic parameters (for example, Cmax, Tmax, AUC, half-life (t 1/2 ) and bioavailability (F)) improved stability, increased safety profile, increased efficacy, increased binding to the target and/or increased specificity for the target (for example, a cancer cell). [0146] Subjects who are clinically diagnosed with a HBV and/or HDV infection include “naïve” 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 log10 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. [0147] 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. [0148] Examples of agents that have been used to treat HBV and/or HDV include immunomodulating agents, and nucleosides/nucleotides. Examples of immunomodulating agents include interferons (such as IFN-D^and pegylated interferons that include PEG-IFN-D- 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 of any of the foregoing, 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. [0149] 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. Combination Therapies [0150] 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 including STOPS™ compounds), an entry inhibitor and/or a small molecule immunomodulator. Examples of additional agents include recombinant interferon alpha 2b, IFN-D, PEG-IFN-D-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide and tenofovir disoproxil. Examples of NAPs include, but are not limited to, REP 2139 and REP 2165. Exemplary siRNA’s that can be used in combination with a compound, or pharmaceutically acceptable salt thereof, provide herein include those described in WO 2021/178885, which is hereby incorporated by reference for the purpose of describing the siRNA compounds provided therein, such as a siRNA selected from SEQ. ID. NO.1-617 and SEQ. ID. NO. 618. [0151] 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 [0152] 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. Table of Abbreviations EXAMPLE 1 COMPOUND 1 [0153] To a solution of oxalyl dichloride (181 g, 1.43 mol) in CH2Cl2 (1.5L) at -65 °C was added DMSO (111 mL) in CH2Cl2 (500 mL). After stirring for 1 h, t-butyl (R)-(1- hydroxypropan-2-yl)carbamate (250 g, 1.43 mol) in CH2Cl2 (500 mL) was added dropwise. After stirring for 2 h, Et 3 N (144 g, 1.43 mol, 198 mL) was added dropwise. The mixture was gradually warmed to 25 °C and then stirred at 25 °C for 4 h. The reaction was quenched by the addition of NH4Cl (sat., aq., 2.5 L), and then extracted with CH2Cl2 (2 x 2.5 L). The combined organic layers were dried over Na2SO4, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to give the crude product as a colorless oil, t-butyl (R)-(1-oxopropan-2-yl)carbamate (450 g, 2.60 mol, 91% yield) which was used in the next step without further purification. [0154] To a solution of t-butyl (R)-(1-oxopropan-2-yl)carbamate (225 g, 1.30 mol) in CH 2 Cl 2 (2.25 L) was added (carbethoxymethylene)triphenylphosphorane (429 g, 1.23 mol). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give the crude product that was purified by silica gel column chromatography (PE:EA = 15:1 to 5:1) to afford ethyl (R)-4-((t-butoxycarbonyl)amino)pent-2-enoate (500 g, 2.06 mol, 79.1% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3^^į^^^^^^^GG^^J = 15.76, 4.88 Hz, 1 H) 5.89 (dd, J = 15.70, 1.56 Hz, 1 H) 4.58 (br s, 1 H) 4.39 (br s, 1 H) 4.18 (q, J = 7.13 Hz, 2 H) 1.44 (s, 9 H) 1.24-1.29 (m, 6 H). [0155] To a solution of ethyl (R)-4-((t-butoxycarbonyl)amino)pent-2-enoate (125 g, 513 mmol) in CH 3 OH (1.25 L) was added 10%Pd/C (6.00 g) and Pd(OH) 2 (6.06 g) under N 2 . The suspension was degassed under vacuum and purged with H 2 (1.04 g, 514 mmol) several times. The mixture was stirred under H2 (50 psi) at 50 °C for 12 h. The solids were removed by filtration under N2, and the filtrate was evaporated to dryness to afford ethyl (R)- 4-((t-butoxycarbonyl)amino)pentanoate (480 g, 1.96 mol, 95% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) į 4.29-4.45 (m, 1 H) 4.13 (q, J = 7.13 Hz, 2 H) 3.57-3.75 (m, 1 H) 2.35 (t, J = 7.69 Hz, 2 H) 1.66-1.84 (m, 3 H) 1.43 (s, 9 H) 1.25 (t, J = 7.13 Hz, 3 H) 1.14 (d, J = 6.50 Hz, 3 H). [0156] To a solution of ethyl (R)-4-((t-butoxycarbonyl)amino)pentanoate (480 g, 1.96 mol) in HCl/EA (4M, 2.5L). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give ethyl (R)-4-aminopentanoate HCl (450 g, crude) as a yellow oil that was used directly in the next step without purification. [0157] To mixture of ethyl (R)-4-aminopentanoate HCl (225 g, 1.24 mol) in THF (4L) and H2O (1L), was added K2CO3 (427 g, 3.10 mol) at 25 °C. After addition, the yellow solution was stirred at 25 °C for 30 min. A solution of ethyl 2-bromoacetate (206 g, 1.24 mol, 137 mL) dropwise at 25 °C over 30 min. The yellow solution was stirred at 25 °C for 11 h. The crude product, ethyl (R)-4-((2-ethoxy-2-oxoethyl)amino)pentanoate (400 g, 1.73 mol, 70% yield), was obtained as a colorless oil that used in the next step without work up or purification. [0158] A solution of (Boc)2O (189 g, 865 mmol, 199 mL) was added dropwise into ethyl (R)-4-((2-ethoxy-2-oxoethyl)amino)pentanoate (200 g, 865 mmol) over 30 min. The yellow solution was stirred for 6 h at 25 °C, and then pumped onto a filter. The filter cake was washed with EA (1L), and the filtrate was collected. To the filtrate was added H 2 O (3 L). The mixture was extracted with EA (2 x 5L). The combined organic layers were washed with brine (2 L) and dried over Na 2 SO 4 . The solids were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product, ethyl (R)-4-((t- butoxycarbonyl)(2-ethoxy-2-oxoethyl)amino)pentanoate (400 g, 1.21 mol, 70% yield), as a yellow oil, which used in the next step without purification. 1 H NMR (400 MHz, CDCl3) į 4.06-4.22 (m, 4 H) 3.54-3.93 (m, 2 H) 2.26-2.55 (m, 2 H) 1.71 (qd, J = 7.48, 3.69 Hz, 2 H) 1.45-1.55 (m, 6 H) 1.42 (s, 4 H) 1.22-1.35 (m, 6 H). [0159] To a mixture of ethyl (R)-4-((t-butoxycarbonyl)(2-ethoxy-2- oxoethyl)amino)pentanoate (200 g, 603 mmol) in THF (2 L) was added t-BuOK (135 g, 1.21 mol) at 0 °C under N 2 . The yellow mixture was stirred at 25 °C for 12 h under N 2 . The reaction was quenched by the addition of aq. citric acid (250 g in 3L of H2O) at below 10 °C. The mixture was extracted with EA (3 x 2.5 L). The combined organic layers were washed with brine (2L x 1) and dried over Na2SO4. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (PE:EA = 15:1 to 10:1) to afford 1-(t-butyl) 4-ethyl 5-oxo-2-(R)-methyl-3,6- dihydropyridine-1,4(2H)-dicarboxylate (210 g, 736 mmol, 61% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) į 12.06 (s, 1 H) 4.54 (br s, 1 H) 4.33 (br d, J = 19.39 Hz, 1 H) 4.23 (dtt, J = 10.62, 7.07, 7.07, 3.63, 3.63 Hz, 2 H) 3.64 (br d, J = 19.26 Hz, 1 H) 2.45-2.55 (m, 1 H) 2.18 (d, J = 15.63 Hz, 1 H) 1.47 (s, 9 H) 1.31 (t, J = 7.13 Hz, 3 H) 1.11 (d, J = 6.88 Hz, 3 H). [0160] To a solution of 1-(t-butyl) 4-ethyl 5-oxo-2-(R)-methyl-3,6- dihydropyridine-1,4(2H)-dicarboxylate (210 g, 736 mmol) in EA (1 L) was added a solution of HCl:EA (4 M, 2 L) dropwise at 25 °C. The mixture was stirred at 25 °C for 3 h, and then concentrated under reduced pressure. The crude product was triturated with EA (500 mL) at 25 °C for 30 min to afford ethyl (R)-5-hydroxy-2-methyl-1,2,3,6-tetrahydropyridine-4- carboxylate HCl (140 g, 631 mmol, 86% yield, 100% purity) as a white solid. (400 MHz, Methanol-d4) į 4.29 (q, J = 6.96 Hz, 2 H) 3.92-4.01 (m, 1 H) 3.77-3.87 (m, 1 H) 3.42- 3.54 (m, 1 H) 2.66-2.76 (m, 1 H) 2.23-2.39 (m, 1 H) 1.43 (d, J = 6.50 Hz, 3 H) 1.32 (t, J = 7.07 Hz, 3 H). [0161] A solution of ethyl (R)-5-hydroxy-2-methyl-1,2,3,6-tetrahydropyridine-4- carboxylate HCl (115 g, 519 mmol), in DMF (1 L) was cooled to 0 °C. DIPEA (268 g, 2.08 mol, 361 mL), and T 3 P (495 g, 778 mmol, 463 mL, 50% purity) were added. The mixture was stirred at 25 °C for 12 h. The reaction was quenched by the addition water 2 L at 25 °C. The mixture was diluted with EA (1.5 L) and extracted with EA (3 x 1 L). The combined organic layers were washed with brine 500 mL and dried over Na2SO4. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 10% EA:PE gradient) to afford ethyl (R)-1-(4-bromo-3- (trifluoromethyl)benzoyl)-5-hydroxy-2-methyl-1,2,3,6-tetrahy dropyridine-4-carboxylate (130 g, 259 mmol, 50% yield, 87% purity) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) į^^^^^^^^EU^ s, 1 H) 7.80 (d, J = 8.13 Hz, 1 H) 7.74 (d, J = 1.88 Hz, 1 H) 7.42 (dd, J = 8.13, 1.88 Hz, 1 H) 4.64-5.30 (m, 1 H) 4.19-4.34 (m, 2 H) 4.08-4.17 (m, 1 H) 3.81 (br dd, J = 12.13, 2.75 Hz, 1 H) 2.58 (br d, J = 14.76 Hz, 1 H) 2.24 (br d, J = 16.01 Hz, 1 H) 1.32 (t, J = 7.13 Hz, 3 H) 1.25 (br t, J = 3.13 Hz, 3 H). [0162] To a solution of ethyl (R)-1-(4-bromo-3-(trifluoromethyl)benzoyl)-5- hydroxy-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (90.0 g, 206 mmol) in ethanol (900 mL) was added NH 4 OAc (79.5 g, 1.03 mol). The mixture was stirred at 60 °C for 2 h. The mixture was concentrated under reduced pressure, diluted with water (200 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (200 mL) and dried over Na 2 SO 4 . The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 50% EA:PE gradient) to afford ethyl (R)-5-amino-1-(4-bromo-3- (trifluoromethyl)benzoyl)-2-methyl-1,2,3,6-tetrahydropyridin e-4-carboxylate (55.0 g, 125 mmol, 61% yield, 99% purity) as a yellow solid. 1 H-NMR (400 MHz, DMSO-d6) į 7.98 (d, J = 8.13 Hz, 1 H) 7.84 (d, J = 1.75 Hz, 1 H) 7.63 (dd, J = 8.19, 1.56 Hz, 1 H) 6.74-7.47 (m, 2 H) 4.63-4.91 (m, 1 H) 4.00-4.08 (m, 2 H) 3.80-3.95 (m, 1 H) 3.59-3.75 (m, 1 H) 2.45 (br d, J = 5.75 Hz, 1 H) 2.14 (br d, J = 1.25 Hz, 1 H) 1.06-1.20 (m, 6 H). [0163] To a solution of ethyl (R)-5-amino-1-(4-bromo-3- (trifluoromethyl)benzoyl)-2-methyl-1,2,3,6-tetrahydropyridin e-4-carboxylate (100 g, 230 mmol) and NMM (102 g, 1.01 mol, 111 mL) in CH2Cl2 (1 L) was added SCCl2 (55.5 g, 483 mmol, 37.0 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched by the addition ice-water (100 mL) at 0 °C. The mixture was diluted with CH 2 Cl 2 (150 mL) and extracted with CH 2 Cl 2 (3 x 500 mL). The combined organic layers were washed with brine (500 mL) and dried over Na 2 SO 4 . The solids were removed by filtration, and the solvent of the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 20% EA:PE gradient) to afford ethyl (R)-1-(4-bromo-3- (trifluoromethyl)benzoyl)-5-isothiocyanato-2-methyl-1,2,3,6- tetrahydropyridine-4- carboxylate (100 g, 163 mmol, 71% yield, 78% purity) as a yellow oil. 1 H-NMR (400 MHz, CDCl 3 ) į^^^^^^^G^^J = 8.13 Hz, 1 H) 7.66 (d, J = 1.75 Hz, 1 H) 7.34 (dd, J = 8.13, 2.00 Hz, 1 H) 4.55-5.18 (m, 1 H) 4.14-4.26 (m, 3 H) 3.67-3.85 (m, 2 H) 2.51-2.70 (m, 1 H) 2.31-2.47 (m, 1 H) 1.29 (t, J = 7.13 Hz, 3 H) 1.18 (dd, J = 7.00, 3.38 Hz, 4 H). [0164] To a solution of ethyl (R)-1-(4-bromo-3-(trifluoromethyl)benzoyl)-5- isothiocyanato-2-methyl-1,2,3,6-tetrahydropyridine-4-carboxy late (100 g, 210 mmol) in CH3CN (1L) were added 4-amino-N-methylbenzamide (31.5 g, 210 mmol) and Et3N (53.0 g, 524 mmol, 72.9 mL). The mixture was stirred at 95 °C for 12 h to obtain a yellow suspension. The mixture was concentrated under reduced pressure. The crude product was triturated with EA (500 mL) at 25 °C for 1 h to afford (R)-4-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-6- methyl-4-oxo-2-thioxo-1,4,5,6,7,8-hexahydropyrido[3,4-d]pyri midin-3(2H)-yl)-N- methylbenzamide (80.0 g, 119 mmol, 57% yield, 86% purity) as a white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) į 8.49-8.57 (m, 1 H) 8.02 (br d, J = 7.63 Hz, 1 H) 7.88 (m, 3 H) 7.69 (br d, J = 7.63 Hz, 1 H) 7.29 (br d, J = 8.88 Hz, 1 H) 7.25 (br s, 1 H) 5.08-5.27 (m, 1 H) 4.18-4.35 (m, 1 H) 4.05-4.14 (m, 1 H) 2.80 (d, J = 4.50 Hz, 3 H) 2.53-2.62 (m, 1 H) 2.17-2.36 (m, 1 H) 1.18-1.20 (m, 3 H). [0165] To a solution of (R)-4-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl- 4-oxo-2-thioxo-1,4,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-3 (2H)-yl)-N-methylbenzamide (80.0 g, 138 mmol) in dioxane (880 mL) was added SCCl 2 (31.6 g, 275 mmol, 21.1 mL). The mixture was stirred at 100 °C for 2 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 80% EA:PE gradient) to afford 4- [(6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-chloro-6-meth yl-4-oxo- 3H,4H,5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-3-yl]-N-methylbenza mide (49.0 g, 81.5 mmol, 59% yield, 97% purity) as an off-white solid. 1 H-NMR (400 MHz, CD3OD) į 7.94-8.03 (m, 3 H) 7.90 (d, J = 1.75 Hz, 1 H) 7.61-7.68 (m, 1 H) 7.42-7.54 (m, 2 H) 5.02-5.49 (m, 1 H) 4.13- 4.56 (m, 2 H) 2.95 (s, 3 H) 2.72-2.86 (m, 1 H) 2.56 (br d, J = 17.89 Hz, 1 H) 1.24-1.38 (m, 3 H). [0166] NEt 3 (0.83 mL, 6 mmol) was added to a solution of 4-[(6R)-7-[4-bromo-3- (trifluoromethyl)benzoyl]-2-chloro-6-methyl-4-oxo-3H,4H,5H,6 H,7H,8H-pyrido[3,4- d]pyrimidin-3-yl]-N-methylbenzamide (500 mg, 0.86 mmol) and (S)-but-3-en-2-amine (183 mg, 2.57 mmol) in anhydrous CH3CN (15 mL) under N2. The mixture was stirred at 110 °C for 30 h, at which point additional (S)-but-3-en-2-amine (183 mg, 2.57 mmol) and NEt3 (0.83 mL, 6 mmol) were added. The mixture was stirred at 110 °C for 18 h and then evaporated to dryness. The residue was dissolved in EA:isopropanol (85:15), washed with sat. aq. NH 4 Cl and brine and dried over Na 2 SO 4 . The solids were removed by filtration, and the filtrate was evaporated to dryness. The crude mixture was purified by chromatography on silica gel (0 to 10% CH3OH in CH2Cl2) to afford 4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but- 3-en-2-yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4 -d]pyrimidin-3(4H)-yl)-N- methylbenzamide (1). 1 H-NMR (600 MHz, DMSO-d6, 80 °C) į 1.14 (d, J = 7.0 Hz, 3H), 1.20 (d, J = 7.0 Hz, 3H), 2.35 (d, J = 16.6 Hz, 1H), 2.53-2.60 (m, 1H), 2.84 (d, J = 4.7 Hz, 3H), 4.03 (d, J = 18.7 Hz, 1H), 4.30-4.75 (m, 3H), 4.95-5.05 (m, 2H), 5.28 (d, J = 7.3 Hz, 1H), 5.79-5.87 (m, 1H), 7.36 (d, J = 7.6 Hz, 2H), 7.65-7.69 (m, 1H), 7.83-7.86 (m, 1H), 7.96-8.02 (m, 3H), 8.29-8.34 (m, 1H) ppm. LC-MS: (C 28 H 27 BrF 3 N 5 O 3 ) [M+H] + : 618/620.
EXAMPLE 2 COMPOUND 2 [0167] LiHMDS 1M in THF (2 eq., 3.23 mL, 3.23 mmol) was added to a solution of compound 1 (1 eq., 1 g, 1.62 mmol) in anhydrous THF (40 mL). The mixture was stirred at -40 °C for 10 min. Chloromethyl chloroformate (1.1 eq.,0.16 mL, 1.78 mmol) was added. The mixture was stirred at -40 °C for 1 h. The reaction was quenched with water and the mixture was extracted with in EA. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The crude mixture was purified by normal phase chromatography (from 0 to 100% of EA in CyH, then, from 0 to 10% of MeOH in DCM) to afford chloromethyl-(4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)- 2-(((S)-but-3-en-2- yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyri midin-3(4H)- yl)benzoyl)(methyl)carbamate (780 mg, 68%) as a yellow solid. 1 H-NMR (400 MHz, DMSO- d6, 80 °C) į 1.15 (d, J = 7.0 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 2.31-2.36 (m, 1H), 2.52-2.59 (m, 1H), 3.30 (s, 3H), 4.04-4.15 (m, 1H), 4.33-4.73 (m, 3H),4.92-5.04 (m, 2H), 5.08 (d, J = 7.9 Hz, 1H), 5.73-5.87 (m, 3H), 7.35-7.42 (m, 2H), 7.65 (dd, J = 8.1 Hz, 1.8 Hz, 1H), 7.71-7.77 (m, 2H), 7.83 (d, J = 1.9 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H) ppm. LCMS: C 30 H 28 BrClF 3 N 5 O 5 : 710/712 [M+H] + . [0168] Tetra-n-butylammonium di-tert-butylphosphate (3 eq., 952 mg, 2.11 mmol) was added to a solution of chloromethyl-(4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)- 2- (((S)-but-3-en-2-yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahydro pyrido[3,4-d]pyrimidin-3(4H)- yl)benzoyl)(methyl)carbamate (1 eq., 500 mg, 0.703 mmol) in THF (50 mL). The mixture was stirred at 40 °C for 16 h. The mixture was then evaporated to dryness and purified by reverse phase chromatography (from 5 to 100% of MeCN in water (+0.1% of formic acid)) to afford ((di-tert-butoxyphosphoryl)oxy)methyl (4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2- (((S)-but-3-en-2-yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahydro pyrido[3,4-d]pyrimidin-3(4H)- yl)benzoyl)(methyl)carbamate (450 mg) as a light-yellow solid. 1 H-NMR (400 MHz, DMSO- d6, 80 °C) į 1.16 (d, J = 6.8Hz, 3H), 1.21 (d, J = 6.7Hz, 3H), 1.43 (s, 18H), 2.32-2.38 (m, 1H), 2.52-2.60 (m, 1H), 3.32 (s, 3H), 3.98-4.10 (m, 1H), 4.33-4.72 (m, 3H), 4.93-5.05 (m, 2H), 5.14 (d, J = 8.0 Hz, 1H), 5.43-5.51 (m, 2H), 5.78-5.87 (m, 1H), 7.35-7.42 (m, 2H), 7.67 (dd, J = 8.1 Hz, 1.9 Hz, 1H), 7.70-7.75 (m, 2H), 7.85 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H) ppm. LCMS:C38H46BrF3N5O9P: 886 [M+H] + . [0169] TFA (20 eq.,0.76 mL, 10.17 mmol) was added to a solution of (4-((R)-7-(4- bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amin o)-6-methyl-4-oxo-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(methyl)ca rbamate (1 eq., 450 mg, 0.509 mmol) in DCM (35 mL) at 0 °C. The mixture was stirred at rt for 1 h. The mixture was evaporated to dryness and purified by reverse phase chromatography (from 5 to 100% of MeCN in water (+0.1% of formic acid)) to afford (phosphonooxy)methyl (4-((R)-7-(4-bromo- 3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amino)-6-m ethyl-4-oxo-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(methyl)ca rbamate (295 mg, 75%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6, 80 °C) į 1.17 (d, J = 6.9 Hz, 3H), 1.21 (d, J = 6.9 Hz, 3H), 2.31-2.38 (m, 1H), 2.52-2.60 (m, 1H), 3.31 (s, 3H), 4.00-4.10 (m, 1H), 4.33-4.72 (m, 3H), 4.93-5.08 (m, 2H), 5.28-5.36 (m, 1H), 5.39-5.51 (m, 2H), 5.78-5.90 (m, 1H), 7.30- 7.40 (m, 2H), 7.66 (dd, J= 8.0 Hz, 1.7Hz, 1H), 7.70-7.75 (m, 2H), 7.85 (d, J = 1.7 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H) ppm. EXAMPLE 3 COMPOUND 3 [0170] NaI (4 eq., 253 mg, 1.69 mmol), Et3N (4 eq., 0.23 mL, 1.69 mmol) and (E)- 4-(tert-Butoxy)-4-oxobut-2-enoic acid (3 eq., 217 mg, 1.27 mmol) were added to a solution of chloromethyl-(4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)- 2-(((S)-but-3-en-2-yl)amino)- 6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H )- yl)benzoyl)(methyl)carbamate (1 eq., 500 mg, 0.703 mmol) in acetone (50 mL). The mixture was stirred at 40 °C for 16 h. The mixture was evaporated to dryness and purified by reverse phase chromatography (from 5 to 100% of MeCN in water (+0.1% of formic acid)) to afford (((4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but -3-en-2-yl)amino)-6-methyl-4- oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)- yl)benzoyl)(methyl)carbamoyl)oxy)methyl tert-butyl fumarate (220 mg, 62%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6, 80 °C) į 1.16 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 1.45 (s, 9H), 2.31-2.40 (m, 1H), 2.52-2.60 (m, 1H), 3.29 (s, 3H), 4.05 (d, J = 18.4 Hz, 1H), 4.22-4.80 (m, 3H), 4.91-5.07 (m, 2H), 5.14 (d, J = 8.1 Hz, 1H), 5.66-5.76 (m, 2H), 5.77-5.89 (m, 1H), 6.56-6.76 (m, 2H), 7.35 (d, J = 7.8Hz, 2H), 7.66 (dd, J = 7.9Hz, 1.2 Hz, 1H), 7.69- 7.75 (m, 2H), 7.84 (d, J = 1.6Hz, 1H), 7.99 (d, J = 8.2Hz, 1H) ppm. LCMS:C38H39BrF3N5O9: 846/848 [M+H] + . [0171] A solution of (((4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)- but-3-en-2-yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido [3,4-d]pyrimidin-3(4H)- yl)benzoyl)(methyl)carbamoyl)oxy)methyl tert-butyl fumarate (1 eq., 180 mg, 0.21 mmol) in formic acid (9 mL) was stirred at rt for 20 h, evaporated to dryness and co-evaporated with Et 2 O to remove formic acid to afford (E)-4-((((4-((R)-7-(4-bromo-3- (trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amino)-6-met hyl-4-oxo-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(methyl)ca rbamoyl)oxy)methoxy)-4- oxobut-2-enoic acid (141 mg, 84%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6, 80 °C) į 1.16 (d, J = 6.7 Hz, 3H), 1.21 (d, J = 6.7 Hz, 3H), 2.31-2.39 (m, 1H), 2.52-2.62 (m, 1H), 3.30 (s, 3H), 4.05 (d, J = 18.2 Hz, 1H), 4.23-4.74 (m, 3H), 4.93-5.06 (m, 2H), 5.14 (d, J = 7.9 Hz, 1H), 5.71-5.78 (m, 2H), 5.78-5.90 (m, 1H), 6.59-6.70 (m, 1H), 6.70-6.79 (m, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.67 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.70-7.76 (m, 2H),7.85 (d, J = 1.3 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H) ppm. LCMS: C 34 H 31 BrF 3 N 5 O 9 : 790/792 [M+H] + .
EXAMPLE 4 COMPOUND 4 [0172] NaI (4 eq., 328 mg, 2.19 mmol), Et3N (4 eq., 0.31 mL, 2.19 mmol) and Boc- L-valine (3 eq., 357 mg, 1.65 mmol) were added to a solution of chloromethyl-(4-((R)-7-(4- bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amin o)-6-methyl-4-oxo-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(methyl)ca rbamate (1 eq., 390 mg, 0.55 mmol) in acetone (30 mL). The mixture was stirred at 40 °C for 16 h. The mixture was evaporated to dryness and purified by reverse phase chromatography (from 5 to 100% of MeCN in water (+0.1% of formic acid)) to afford (((4-((R)-7-(4-bromo-3- (trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amino)-6-met hyl-4-oxo-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(methyl)ca rbamoyl)oxy)methyl (tert- butoxycarbonyl)-L-valinate (305 mg, 62%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6, 80 °C) į 0.89 (dd, J = 6.9 Hz, 1.3 Hz, 6H), 1.16 (d, J = 6.5 Hz, 3H), 1.21 (d, J = 6.5 Hz, 3H), 1.39 (s, 9H), 1.96-2.06 (m, 1H), 2.31-2.39 (m, 1H), 2.53-2.62 (m, 1H), 3.28 (s, 3H), 3.85-3.92 (m, 1H), 3.99-4.11 (m, 1H), 4.27-4.76 (m, 3H), 4.95-5.06 (m, 2H), 5.08-5.13 (m, 1H), 5.62- 5.70 (m, 2H), 5.77-5.89 (m, 1H), 6.79-6.91 (m, 1H), 7.38 (d, J = 8.4Hz, 2H), 7.64-7.74 (m, 3H), 7.85 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H) ppm. LCMS: C40H46BrF3N6O9: 891/893 [M+H] + . [0173] HCl 4 N in dioxane (40 eq., 3.08 mL, 12.11 mmol) was added to (((4-((R)- 7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl )amino)-6-methyl-4-oxo- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(m ethyl)carbamoyl)oxy)methyl (tert-butoxycarbonyl)-L-valinate (1 eq., 270 mg, 0.303mmol). The mixture was stirred at rt for 1 h. The mixture was evaporated to dryness to afford the crude mixture which was triturated with Et 2 O to afford (((4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but -3-en-2- yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyri midin-3(4H)- yl)benzoyl)(methyl)carbamoyl)oxy)methyl L-valinate hydrochloride (225 mg, 90%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6, 80 °C) į 0.98 (dd, J = 9.3 Hz, 6.9 Hz, 6H), 1.16 (d, J = 6.8Hz, 3H), 1.22 (d, J = 6.6 Hz, 3H), 2.18-2.26 (m, 1H), 2.31-2.39 (m, 1H), 2.54-2.62 (m, 1H), 3.30 (s, 3H), 3.91 (d, J = 4.9 Hz, 1H), 4.01-4.12 (m, 1H), 4.28-4.73 (m, 3H), 4.93-5.05 (m, 2H), 5.15-5.23 (m, 1H), 5.73-5.87 (m, 3H), 7.39 (d, J = 7.9 Hz, 2H), 7.67 (dd, J = 8.3 Hz, 1.9 Hz, 1H), 7.72-7.77 (m, 2H), 7.84 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 8.53 (br.s., 3H) ppm. LCMS: C 35 H 39 BrClF 3 N 6 O 7 : 791/793 [M+H] + . EXAMPLE 5 COMPOUND 5 [0174] NaI (4 eq., 421.68 mg, 2.81 mmol), Et3N (4 eq., 0.39 mL, 2.81 mmol) and boc-D-Val-OH (3 eq., 458.41 mg, 2.11 mmol) were added to a solution of chloromethyl-(4- ((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en -2-yl)amino)-6-methyl-4-oxo- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(m ethyl)carbamate (1 eq., 500 mg, 0.703 mmol) in acetone (50 mL). The mixture was stirred at 60 °C for 3 h. The reaction was quenched with water and extracted with in EA. The combined organic layers were washed with sat. NaHCO3 and brine, dried over Na2SO4 and evaporated. The crude mixture was purified by reverse phase chromatography (from 5 to 100% of MeCN in water (+0.1% of formic acid)) to afford (((4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but -3-en-2- yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyri midin-3(4H)- yl)benzoyl)(methyl)carbamoyl)oxy)methyl (tert-butoxycarbonyl)-D-valinate (310 mg, 49%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6, 80 °C) į 0.89 (dd, J = 6.9 Hz, 1.3 Hz, 6H), 1.16 (d, J = 6.5 Hz, 3H), 1.21 (d, J = 6.5 Hz, 3H),1.39 (s, 9H), 1.96-2.06 (m, 1H), 2.31-2.39 (m, 1H), 2.53-2.62 (m, 1H), 3.27 (s, 3H), 3.85-3.92 (m, 1H), 3.99-4.11 (m, 1H), 4.27-4.76 (m, 3H), 4.95-5.06 (m, 2H), 5.08-5.13 (m, 1H), 5.62-5.70 (m, 2H), 5.76-5.88 (m, 1H), 6.75-6.96 (m, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.67 (dd, J = 8.5 Hz, 1.6Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 1.2 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H) ppm. LCMS: C40H46BrF3N6O9: 891/893 [M+H] + . [0175] HCl 4 N in dioxane (40 eq., 0.45 mL, 1.79 mmol) was added to (((4-((R)- 7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl )amino)-6-methyl-4-oxo- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(m ethyl)carbamoyl)oxy)methyl- (tert-butoxycarbonyl)-D-valinate (1 eq., 40 mg, 0.045 mmol). The mixture was stirred at rt for 1 h. The mixture was evaporated to dryness to afford the crude mixture which was triturated with Et 2 O to afford (((4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but -3-en-2- yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyri midin-3(4H)- yl)benzoyl)(methyl)carbamoyl)oxy)methyl D-valinate hydrochloride (33 mg, 89%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6, 80 °C) į 0.98 (d, J = 7.0Hz, 3H), 1.00 (d, J = 7.0Hz, 3H), 1.16 (d, J = 6.8Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H), 2.18-2.26 (m, 1H), 2.31-2.39 (m, 1H), 2.54-2.62 (m, 1H), 3.29 (s, 3H), 3.91 (d, J = 4.9 Hz, 1H), 4.01-4.10 (m, 1H), 4.30-4.72 (m, 3H), 4.93-5.05 (m, 2H), 5.15-5.23 (m, 1H), 5.71-5.89 (m, 3H), 7.39 (d, J = 7.9 Hz, 2H), 7.67 (dd, J = 8. 3Hz, 1.9 Hz, 1H), 7.72-7.77 (m, 2H), 7.84 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 8.53 (br.s., 3H) ppm. LCMS: C 35 H 39 BrClF 3 N 6 O 7 : 791/793 [M+H] + . EXAMPLE 6 COMPOUNDS 6 AND 7
[0176] LiHMDS 1M in THF (2 eq., 4.69 mL, 4.69 mmol) was added to a solution of 4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3- en-2-yl)amino)-6-methyl-4- oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N-met hylbenzamide (1 eq., 1.45 g, 2.34 mmol) in anhydrous THF (25 mL), and the mixture was stirred at -40 °C for 10 min. 1- chloroethyl chloroformate (1.1 eq., 0.28 mL, 2.58 mmol) was then added and the mixture was stirred at -40 °C for 1 h. The mixture was allowed to warm to rt and stirred for 16 h. The reaction was quenched with water and extracted with in EA. The combined organic layers were washed with brine, dried over Na 2 SO 4 and evaporated. The crude mixture was purified by normal phase chromatography (from 0 to 100% of EA in CyH, then, from 0 to 10% of MeOH in DCM) to afford 1-chloroethyl (4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2- (((S)-but-3-en-2-yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahydro pyrido[3,4-d]pyrimidin-3(4H)- yl)benzoyl)(methyl)carbamate (1.1 g, 65%) as a yellow solid. 1 H-NMR (400 MHz, DMSO-d6, 80 °C) į 1.14 (d, J = 6.7 Hz, 3H), 1.20 (d, J = 6.7 Hz, 3H), 1.47 (d, J = 5.8 Hz, 3H), 2.28-2.37 (m, 1H), 2.51-2.60 (m, 1H), 3.29 (s, 3H), 3.97-4.06 (m, 1H), 4.28-4.73 (m, 3H), 4.92-5.08 (m, 3H), 5.74-5.87 (m, 1H), 6.38-6.45 (m, 1H), 7.31-7.44 (m, 2H), 7.65 (dd, J = 8.0 Hz, 1.8 Hz, 1H), 7.70-7.75 (m, 2H), 7.83 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H) ppm. LCMS: C31H30BrClF3N5O5: 724/726 [M+H] + . [0177] NaI (4 eq., 700 mg, 4.69 mmol), Et3N (4 eq., 0.65 mL, 4.69 mmol) and Boc- L-valine (3 eq., 760 mg, 3.52 mmol) were added to a solution of 1-chloroethyl (4-((R)-7-(4- bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amin o)-6-methyl-4-oxo-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(methyl)ca rbamate (1 eq., 850 mg, 1.17 mmol) in acetone (60 mL) and the mixture was stirred at 80 °C for 16 h. The mixture was evaporated to dryness and purified by normal phase chromatography (from 0 to 100% of EA in CyH, then, from 0 to 10% of MeOH in DCM), then further purified by SFC (isocratic MeOH/CO 2 : 20:80) to obtain the two diastereoisomers (*S)-1-(((4-((R)-7-(4-bromo-3- (trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amino)-6-met hyl-4-oxo-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(methyl)ca rbamoyl)oxy)ethyl (tert- butoxycarbonyl)-L-valinate (6a, 301 mg, 28%) and (*R)-1-(((4-((R)-7-(4-bromo-3- (trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amino)-6-met hyl-4-oxo-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(methyl)ca rbamoyl)oxy)ethyl (tert- butoxycarbonyl)-L-valinate (7a, 290 mg, 27%) as white solids. [0178] Compound 6a: 1 H-NMR (400 MHz, DMSO-d 6 , 80 °C) į 0.86 (d, J = 6.6 Hz, 6H), 1.11-1.16 (m, 3H), 1.17-1.22 (m, 6H), 1.36 (s, 9H), 1.93-2.02 (m, 1H), 2.30-2.38 (m, 1H), 2.51-2.58 (m, 1H), 3.25 (s, 3H), 3.78-3.84 (m, 1H), 3.97-4.08 (m, 1H), 4.33-4.68 (m, 3H), 4.92-5.11 (m, 3H), 5.75-5.85 (m, 1H), 6.60-6.67 (m, 1H), 6.79 (br.s., 1H), 7.33-7.42 (m, 2H), 7.64 (dd, J = 8.1 Hz, 1.7 Hz, 1H), 7.69-7.74 (m, 2H), 7.82 (d, J = 1.7 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H) ppm. LCMS: C41H48 [0179] Compound 0.89 (m, 6H), 1.11-1.16 (m, 3H), 1.17-1.22 (m, 6H), 1.36 (s, 9H), 1.93-2.02 (m, 1H), 2.30-2.38 (m, 1H), 2.51-2.58 (m, 1H), 3.25 (s, 3H), 3.78-3.84 (m, 1H), 3.97-4.08 (m, 1H), 4.33-4.68 (m, 3H), 4.92-5.11 (m, 3H), 5.75-5.85 (m, 1H), 6.60-6.67 (m, 1H), 6.74 (br.s., 1H), 7.33-7.42 (m, 2H), 7.64 (dd, J = 8.1 Hz, 1.7 Hz, 1H), 7.66-7.72 (m, 2H), 7.83 (d, J = 1.7 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H) ppm. LCMS: C41H48BrF3N6O9: 905/907 [M+H] + . [0180] HCl 4 N in dioxane (40 eq., 2.87 mL, 11.48 mmol) was added to (*S)-1- (((4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but -3-en-2-yl)amino)-6-methyl-4- oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)- yl)benzoyl)(methyl)carbamoyl)oxy)ethyl (tert-butoxycarbonyl)-L-valinate (6a, 1 eq., 260 mg, 0.29 mmol) and the mixture was stirred at rt for 1 h. The mixture was evaporated to dryness to afford the crude mixture which was triturated with Et 2 O to afford (*S)-1-(((4-((R)-7-(4- bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amin o)-6-methyl-4-oxo-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(methyl)ca rbamoyl)oxy)ethyl L-valinate hydrochloride (6, 220 mg, 91%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6, 80 °C) į 0.97 (dd; J = 6.8 Hz, 5.3 Hz, 6H), 1.16 (d, J = 7.0 Hz, 3H), 1.21 (d, J = 7.0 Hz, 3H), 1.29 (d, J = 5.1 Hz, 3H), 2.15-2.26 (m, 1H), 2.30-2.39 (m, 1H), 2.52-2.61 (m, 1H), 3.30 (s, 3H), 3.87 (d, J = 4.4 Hz, 1H), 3.99-4.12 (m, 1H), 4.32-4.77 (m, 3H), 4.91-5.07 (m, 2H), 5.15-5.29 (m, 1H), 5.74-5.86 (m, 1H), 6.72-6.78 (m, 1H), 7.40 (d, J = 7.9 Hz, 2H), 7.67 (dd, J = 8.5 Hz, 1.6 Hz, 1H), 7.71-7.77 (m, 2H), 7.84 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 8.50 (s, 3H) ppm. LCMS: C36H41BrClF3N6O7: 805/807 [M+H] + . [0181] HCl 4 N in dioxane (40 eq., 2.09 mL, 8.39 mmol) was added to (*R)-1-(((4- ((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en -2-yl)amino)-6-methyl-4-oxo- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(m ethyl)carbamoyl)oxy)ethyl (tert-butoxycarbonyl)-L-valinate (7a, 1 eq., 190 mg, 0.21 mmol) and the mixture was stirred at rt for 1 h. The mixture was evaporated to dryness to afford the crude mixture which was triturated with Et 2 O to afford (*R)-1-(((4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2- (((S)-but-3-en-2-yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahydro pyrido[3,4-d]pyrimidin-3(4H)- yl)benzoyl)(methyl)carbamoyl)oxy)ethyl L-valinate hydrochloride (7, 150 mg, 85%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6, 80 °C) į 0.93-0.99 (m, 6H), 1.14 (d, J = 7.0 Hz, 3H), 1.20 (d, J = 7.0 Hz, 3H), 1.28 (d, J = 5.2 Hz, 3H), 2.12-2.23 (m, 1H), 2.27-2.39 (m, 1H), 2.52-2.59 (m, 1H), 3.28 (s, 3H), 3.81-3.88 (m, 1H), 3.99-4.09 (m, 1H), 4.32-4.77 (m, 3H), 4.91-5.04 (m, 2H), 5.12-5.21 (m, 1H), 5.74-5.86 (m, 1H), 6.67-6.74 (m, 1H), 7.38 (d, J = 7.1 Hz, 2H), 7.63-7.66 (m, 1H), 7.70-7.75 (m, 2H), 7.81-7.86 (m, 1H), 7.95-8.01 (m, 1H), 8.42 (s, 3H) ppm. LCMS: C 36 H 41 BrClF 3 N 6 O 7 : 805/807 [M+H] + . EXAMPLE 7 COMPOUND 8 [0182] Chlorotrimethylsilane (50 eq., 4.13 mL, 32.34 mmol) was added to a solution of 4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3- en-2-yl)amino)-6- methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)- yl)-N-methylbenzamide (1 eq., 400 mg, 0.65 mmol) and paraformaldehyde (1.67 eq., 32.34 mg, 1.08 mmol) in anhydrous THF (8 mL). The mixture was heated to 100 °C for 1 h. The mixture was poured into sat. aq. NaHCO 3 and diluted with EA:iPrOH (85:15). The layers were separated, and the organic layer was dried over Na 2 SO 4 . The solids were filtered and the filtrate was evaporated to dryness to give a yellow oil, which was purified by reverse phase chromatography (Water (0.5% FA):MeCN from 95:5 to 0:100) to give 4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2- (((S)-but-3-en-2-yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahydro pyrido[3,4-d]pyrimidin-3(4H)- yl)-N-(hydroxymethyl)-N-methylbenzamide (153 mg, 36%) as a white solid. 1 H-NMR (DMSO-d 6 , 400 MHz, 25 °C) į 1.03-1.27 (m, 6H), 2.16-2.40 (m, 1H), 2.47-2.59 (m, 1H), 3.00 (s, 3H), 3.80-4.38 (m, 2H), 4.53-5.25 (m, 6H), 5.71-5.92 (m, 2H), 5.95-6.32 (m, 1H), 7.23- 7.43 (m, 2H), 7.53-7.75 (m, 3H), 7.88 (s, 1H), 8.0 (d, J = 8.1 Hz, 1H) ppm. LCMS: C 29 H 29 BrF 3 N 5 O 4 : 648/650 [M+H] + . EXAMPLE 8 COMPOUND 9 [0183] p-TsOH (0.54 g, 3.13 mmol) was added to a mixture of L(-)-malic acid 1 (1 eq., 4.2 g, 31.32 mmol) and 2-methoxypropene (11.58 mL, 125.29 mmol) in acetone (80 mL) at 0 °C. After 5 min, the mixture was stirred at 35 °C for 18 h. The mixture was evaporated to dryness, dissolved in EA (50 mL), washed with brine:water (1:1, 4 x 20 mL) and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to afford a black oil, which was treated with cyclohexane to form a precipitate. The precipitate was isolated by filtration. The precipitate was solubilized in a minimum of hot EA (45 °C) and filtered. The filtrate was diluted with cyclohexane to form a precipitate, which was cooled in an ice bath for 1 h. The resulting solids were isolated by filtration and washed with cyclohexane to afford (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid 2 (2 g, 11.48 mmol, 36%) as a white solid. 1 H-NMR (DMSO-d6, 400 MHz) į 1.53 (d, J = 5.9 Hz, 6H), 2.67-2.81 (m, 2H), 4.79 (dd, J = 5.0 Hz, 4.4 Hz, 1H), 12.61 (s, 1H) ppm. [0184] NaI (531 mg, 3.54 mmol), Et 3 N (0.49 mL, 3.54 mmol) and (S)-2-(2,2- dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid 2 (462 mg, 2.66 mmol) were added to a solution of (4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3 -en-2-yl)amino)-6-methyl-4- oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoy l)(methyl)carbamate (1 eq., 630 mg, 0.89 mmol) in acetone (10 mL). The mixture was stirred at 65 °C for 16 h. The mixture was then evaporated to dryness and purified by normal phase chromatography (from 0 to 100% of EA in cyclohexane, then, from 0 to 10% CH 3 OH in DCM) to afford (((4-((R)-7- (4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)a mino)-6-methyl-4-oxo-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(methyl)ca rbamoyl)oxy)methyl 2-((S)- 2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (185 mg, 25%) as a white solid. 1 H-NMR (DMSO-d6, 400 MHz, 80 °C) į 1.14 (d, J = 6.6 Hz, 3H), 1.20 (d, J = 6.9 Hz, 3H), 1.49-1.56 (m, 6H), 2.29-2.37 (m, 1H), 2.52-2.60 (m, 1H), 2.82-2.98 (m, 2H), 3.27 (s, 3H), 3.99-4.09 (m, 1H), 4.24-4.70 (m, 3H), 4.78-4.85 (m, 1H), 4.93-5.04 (m, 2H), 5.08-5.15 (m, 1H), 5.60-5.70 (m, 2H), 5.75-5.89 (m, 1H), 7.32-7.41 (m, 2H), 7.61-7.73 (m, 3H), 7.83 (s, 1H), 7.94-7.99 (m, 1H) ppm. LC-MS: C 37 H 37 BrF 3 N 5 O 10 : 848/850 [M+H] + . [0185] A solution of (((4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)- but-3-en-2-yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido [3,4-d]pyrimidin-3(4H)- yl)benzoyl)(methyl)carbamoyl)oxy)methyl 2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4- yl)acetate (130 mg, 0.15 mmol) in formic acid (1.3 mL), CH3OH (1.3 mL) and water (1.3 mL) was stirred at rt for 20 h, and then evaporated to dryness. The residue purified by reverse phase chromatography (5 to 100% CH3CN in water (+ 0.1% of formic acid) to afford (S)-4-((((4- ((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en -2-yl)amino)-6-methyl-4-oxo- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)- yl)benzoyl)(methyl)carbamoyl)oxy)methoxy)-2-hydroxy-4-oxobut anoic acid (85 mg, 69%) as a white solid. 1 H-NMR (DMSO-d 6 , 400 MHz) į 1.06-1.32 (m, 6H), 2.22-2.39 (m, 1H), 2.54- 2.63 (m, 2H), 2.72-2.84 (m, 1H), 3.26 (s, 3H), 3.75-4.44 (m, 3H), 4.50-5.25 (m, 4H), 5.42-5.96 (m, 4H), 7.25-7.46 (m, 2H), 7.64-7.75 (m, 3H), 7.89 (s, 1H), 7.95-8.03 (m, 1H) ppm. LC-MS: C34H33BrF3N5O10: 808/810 [M+H] + . EXAMPLE 9 COMPOUNDS 10 AND 11 [0186] Compounds 10 and 11 were synthetized following the procedure reported for the synthesis of Compounds 6 and 7, using 1-chloro-2-methylpropyl chloroformate in place of 1-chloroethyl chloroformate in the first step. [0187] Compound 10: (*S)-1-(((4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)- 2-(((S)-but-3-en-2-yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahyd ropyrido[3,4-d]pyrimidin- 3(4H)-yl)benzoyl)(methyl)carbamoyl)oxy)-2-methylpropyl L-valinate hydrochloride (150 mg, 80%) as a white solid. 1 H-NMR (DMSO-d 6 , 400 MHz, 80 °C) į 0.82 (dd, J = 6.9 Hz, 2.4 Hz, 6H), 0.99 (dd, J = 7.0 Hz, 3.3 Hz, 6H), 1.16 (d, J = 6.7 Hz, 3H), 1.22 (d, J = 6.7 Hz, 3H), 1.88-1.97 (m, 1H), 2.19-2.28 (m, 1H), 2.31-2.39 (m, 1H), 2.53-2.62 (m, 1H), 3.30 (s, 3H), 3.94 (d, J = 3.8 Hz, 1H), 4.01-4.11 (m, 1H), 4.29-4.74 (m, 3H), 4.95-5.06 (m, 2H), 5.13-5.20 (m, 1H), 5.76-5.87 (m, 1H), 6.58 (d, J = 4.2 Hz, 1H), 7.41 (d, J = 7.7 Hz, 2H), 7.67 (dd, J = 8.0 Hz, 1.8 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 8.47 (br.s., 3H) ppm. LCMS: C 38 H 45 BrClF 3 N 6 O 7 : 833/835 [M+H] + . [0188] Compound 11: (*R)-1-(((4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)- 2-(((S)-but-3-en-2-yl)amino)-6-methyl-4-oxo-5,6,7,8-tetrahyd ropyrido[3,4-d]pyrimidin- 3(4H)-yl)benzoyl)(methyl)carbamoyl)oxy)-2-methylpropyl L-valinate hydrochloride (210 mg, 90%) as a white solid. 1 H-NMR (DMSO-d 6 , 400 MHz, 80 °C) į 0.82 (dd, J = 6.7 Hz, 2.4 Hz, 6H), 0.99 (dd, J = 7.3 Hz, 6.9 Hz, 6H), 1.14 (d, J = 6.7 Hz, 3H), 1.20 (d, J = 6.7 Hz, 3H), 1.88-1.97 (m, 1H), 2.19-2.28 (m, 1H), 2.31-2.38 (m, 1H), 2.53-2.61 (m, 1H), 3.29 (s, 3H), 3.84-3.92 (m, 1H), 4.01-4.10 (m, 1H), 4.29-4.71 (m, 3H), 4.95-5.13 (m, 3H), 5.76-5.87 (m, 1H), 6.56 (d, J = 4.4 Hz, 1H), 7.38-7.44 (m, 2H), 7.67 (dd, J = 8.2 Hz, 1.6 Hz, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 8.52 (br.s., 3H) ppm. LCMS: C 38 H 45 BrClF 3 N 6 O 7 : 833/835 [M+H] + . EXAMPLE 10 COMPOUND 12 [0189] DIPEA (38 mL, 218.1 mmol) was added to a solution of 1-(t- butoxycarbonyl)piperidine-4-carboxylic acid (10 g, 43.62 mmol) and HATU (21.56 g, 56.7 mmol) in anhydrous DMF (160 mL). The mixture was stirred at rt for 1 h and then cooled to 0 °C. Methylammonium chloride (3.83 g, 56.7 mmol) was added. The mixture warmed to rt and stirred for 20 h, diluted with EA and washed with 0.25 M HCl, sat. aq. NaHCO 3 , water and brine. The organic layer was dried over Na2SO4. The solids were filtered and the filtrate was evaporated to dryness to give t-butyl 4-(methylcarbamoyl)piperidine-1-carboxylate (5.66 g, 54%) as a red solid, which was used in the next step without further purification. 1 H-NMR (DMSO-d6, 400 MHz, 25 °C) į 1.29-1.44 (m, 11H), 1.56-1.66 (m, 2H), 2.23 (tt, J = 11.5 Hz, 3.7 Hz, 1H), 2.55 (d, J = 4.6 Hz, 3H), 2.63-2.79 (m, 2H), 3.85-3.99 (m, 2H), 7.65-7.76 (m, 1H) ppm. LC-MS: C 12 H 22 N 2 O 3 : 243 [M+H] + . [0190] 4-nitrobenzoyl chloride (5.201 g, 28.029 mmol) was added to a solution of t-butyl 4-(methylcarbamoyl)piperidine-1-carboxylate (5.66 g, 23.36 mmol), NEt 3 (4.22 mL, 30.36 mmol) and DMAP (0.29 g, 2.34 mmol) in anhydrous DCM (250 mL) cooled to -78 °C. The mixture slowly warmed to rt, then stirred at rt for 20 h. The mixture was diluted with DCM and the reaction was quenched with sat. aq. NaHCO 3 . The layers were separated, and the organic layer was washed with brine and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give t-butyl 4-(methyl(4- nitrobenzoyl)carbamoyl)piperidine-1-carboxylate (9.51 g, crude) as a reddish oil, which was used in the next step without further purification. [0191] Pd/C (0.52 g, 0.49 mmol) was added to a solution of t-butyl 4-(methyl(4- nitrobenzoyl)carbamoyl)piperidine-1-carboxylate (9.51 g, 24.3 mmol) in EA (150 mL) at rt. H 2 was bubbled through the mixture, and the mixture was stirred under H 2 atmosphere for 4 days. The mixture was filtered through packed celite. The filtrate was evaporated to dryness to give a yellow oil, which was purified by chromatography on silica gel (cyclohexane:EA from 100:0 to 50:50) to give a yellow oil. The yellow oil was dissolved in EA and washed with sat. aq. NaHCO3 and brine. The organic layer was dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to afford t-butyl 4-((4- aminobenzoyl)(methyl)carbamoyl)piperidine-1-carboxylate (4.87 g, 55%) as a yellow oil. 1 H- NMR (DMSO-d 6 , 400 MHz, 25 °C) į 1.32-1.49 (m, 11H), 1.62-1.74 (m, 2H), 2.53-2.72 (m, 2H), 2.76-2.88 (m, 1H), 3.04 (s, 3H), 3.81-3.94 (m, 2H), 6.20 (s, 2H), 6.56-6.91 (m, 2H), 7.43- 7.48 (m, 2H) ppm. LC-MS: C 19 H 27 N 3 O 4 : 360 [M-H]-. [0192] NEt3 (2.31 mL, 16.6 mmol) was added to a solution of ethyl (R)-1-(4- bromo-3-(trifluoromethyl)benzoyl)-5-isothiocyanato-2-methyl- 1,2,3,6-tetrahydropyridine-4- carboxylate (2.64 g, 5.53 mmol) and t-butyl 4-((4- aminobenzoyl)(methyl)carbamoyl)piperidine-1-carboxylate (2 g, 5.53 mmol) in anhydrous MeCN (30 mL). The mixture was stirred at 100 °C for 20 h, cooled to rt and evaporated to dryness to give a solid. The solid was purified by flash chromatography on silica gel (DCM:acetone from 100:0 to 75:25) to afford t-butyl (R)-4-((4-(7-(4-bromo-3- (trifluoromethyl)benzoyl)-6-methyl-4-oxo-2-thioxo-1,4,5,6,7, 8-hexahydropyrido[3,4- d]pyrimidin-3(2H)-yl)benzoyl)(methyl)carbamoyl)piperidine-1- carboxylate (2.03 g, 46%) as a yellow solid. 1 H-NMR (DMSO-d6, 400 MHz, 25 °C) į 1.08-1.29 (m, 3H), 1.32-1.49 (m, 11H), 1.70-1.81 (m, 2H), 2.19-2.37 (m, 1H), 2.54-2.74 (m, 3H), 2.88-3.00 (m, 1H), 3.15 (s, 3H), 3.80-4.33 (m, 4H), 5.00-5.23 (m, 1H), 7.25-7.42 (m, 2H), 7.65-7.71 (m, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.85-7.94 (m, 1H), 7.98-8.06 (m, 1H), 12.33-13.03 (m, 1H) ppm. LC-MS: C 35 H 37 BrF 3 N 5 O 6 S: 792/794 [M+H] + . [0193] MeI (0.18 mL, 2.82 mmol) and DBU (0.46 mL, 3.073 mmol) were added to a solution of t-butyl (R)-4-((4-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-4 -oxo-2- thioxo-1,4,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-3(2H)- yl)benzoyl)(methyl)carbamoyl)piperidine-1-carboxylate (2.03 g, 2.56 mmol) in anhydrous DMF (20 mL) cooled at 0 °C. The mixture was stirred at 0 °C for 1 h. Water was added and a white precipitate was formed. The suspension was filtered and the solid was washed with water to give t-butyl (R)-4-((4-(7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-2 - (methylthio)-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin- 3(4H)- yl)benzoyl)(methyl)carbamoyl)piperidine-1-carboxylate (2.08 g, 99%, crude) as a yellow solid, which was used as such in the next step without further purification. LC-MS: C 36 H 39 BrF 3 N 5 O 6 S: 804/806 [M-H]-. [0194] m-CPBA (0.7 g, 2.84 mmol) was added to a solution of t-butyl (R)-4-((4- (7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-2-(methylth io)-4-oxo-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(methyl)ca rbamoyl)piperidine-1- carboxylate (2.08 g, 2.58 mmol) in anhydrous DCM (60 mL) at cooled to 0 °C. The mixture warmed to rt and stirred for 2 h . The reaction was quenched with sat. aq. Na2S2O3 and diluted with DCM . The layers were separated, and the organic layer was washed with sat. aq. NaHCO3 and brine, and dried over Na2SO4. The solids were removed by filtration and the filtrate was evaporated to dryness to give t-butyl 4-((4-((6R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-6- methyl-2-(methylsulfinyl)-4-oxo-5,6,7,8-tetrahydropyrido[3,4 -d]pyrimidin-3(4H)- yl)benzoyl)(methyl)carbamoyl)piperidine-1-carboxylate (2.31 g, 99%, crude) as a yellow solid, which was used in next step without further purification. LC-MS: C 36 H 39 BrF 3 N 5 O 7 S: 820/822 [M-H]-. [0195] DIPEA (2.29 mL, 13.87 mmol) was added to a solution of t-butyl 4-((4- ((6R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-6-methyl-2-(met hylsulfinyl)-4-oxo-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(methyl)ca rbamoyl)piperidine-1- carboxylate (1.63 g, 1.98 mmol) and (S)-but-3-en-2-amine hydrochloride (0.64 g, 5.94 mmol) in anhydrous MeCN (10 mL) under N 2 . The mixture was stirred at 50 °C for 18 h and then evaporated to dryness to give a dark red solid. The crude mixture was purified by flash chromatography on silica gel (DCM:acetone from 100:0 to 50:50) and then by reverse phase chromatography (Water (0.1% FA):MeCN from 95:5 to 0:100). The collected fractions were combined, extracted with DCM, washed with a mixture of sat. aq. NaHCO3 and brine, dried over Na2SO4 and evaporated to dryness at 30°C to give t-butyl 4-((4-((R)-7-(4-bromo-3- (trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amino)-6-met hyl-4-oxo-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(methyl)ca rbamoyl)piperidine-1- carboxylate (270 mg, 16%) as a white solid. 1 H-NMR (DMSO-d 6 , 400 MHz, 80 °C) į 1.17 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 7.0 Hz, 3H), 1.41 (s, 9H), 1.42-1.60 (m, 2H), 1.81 (d, J = 12.6 Hz, 2H), 2.29-2.38 (m, 1H), 2.51-2.61 (m, 1H), 2.64-2.77 (m, 2H), 3.00-3.09 (m, 1H), 3.19 (s, 3H), 3.86-3.97 (m, 2H), 3.99-4.11 (m, 1H), 4.28-4.72 (m, 3H), 4.94-5.05 (m, 2H), 5.34 (d, J = 8.3 Hz, 1H), 5.77-5.90 (m, 1H), 7.44 (d, J = 7.5 Hz, 2H), 7.61-7.70 (m, 1H), 7.77-7.86 (m, 3H), 7.98 (d, J = 8.3 Hz, 1H) ppm. LC-MS: C39H44BrF3N6O6: 829/831 [M+H] + . [0196] HCl 4N in dioxane (2.47 mL, 9.88 mmol) was added to t-butyl 4-((4-((R)- 7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl )amino)-6-methyl-4-oxo- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)(m ethyl)carbamoyl)piperidine-1- carboxylate (82 mg, 0.099 mmol) at 0 °C. The mixture warmed to rt and stirred for 1 h. The crude mixture was cooled to 0 °C. Ether was added and a white precipitate was formed. The precipitate was isolated by filtration, and the resulting solid was washed with ether to give a white solid. The solid was triturated ether (2x), DCM (2x) and a mixture of MeCN and ether (2x), and then dried under high vacuum to give N-(4-((R)-7-(4-bromo-3- (trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amino)-6-met hyl-4-oxo-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)benzoyl)-N-methylp iperidine-4-carboxamide hydrochloride (56 mg, 74%) as a white solid. 1 H-NMR (DMSO-d 6 , 400 MHz, 80 °C) į 1.16 (d, J = 7.0 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 1.78-1.92 (m, 2H), 1.94-2.03 (m, 2H), 2.29-2.38 (m, 1H), 2.50-2.58 (m, 1H), 2.80-2.90 (m, 2H), 3.19 (s, 3H), 3.15-3.33 (m, 3H), 3.97-4.07 (m, 1H), 4.25-4.73 (m, 3H), 4.92-5.05 (m, 2H), 5.36 (d, J = 8.0 Hz, 1H), 5.76-5.88 (m, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.65 (dd, J = 8.0 Hz, 1.3 Hz, 1H), 7.79-7.86 (m, 3H), 7.97 (d, J = 8.6 Hz, 1H), 8.46-8.86 (m, 2H) ppm. LC-MS: C34H37BrClF3N6O4: 729/731 [M+H] + . EXAMPLE 15 ADDITIONAL COMPOUNDS [0197] Additional compounds shown below and including those described herein, can be prepared using similar materials and methods described herein, such as those described herein. , , ,
acceptable salts of any of the foregoing). EXAMPLE A SINGLE DOSE PHARMACOKINETICS [0198] Pharmacokinetics parameters were measured after oral dosing in rat. The term 100 a refers to an equivalent dose of the parent compound and corresponds to a dose of 128 mg/kg of compound 4. Compound 1 was dosed as a suspension in PEG400/copovidone 95/5 and compound 4 as a suspension in CMC at pH 3. When administered to a subject, the test compounds are absorbed intact and then converted to the parent compound, Compound 1. The results of the single dose pharmacokinetics studies are provided in Table 1. As shown by the results in Table 1, compounds of Formula (I) (including pharmaceutically acceptable salts thereof) have increased concentration in the blood and more reaches systemic circulation compared to the parent compound. Thus, compounds of Formula (I) (including pharmaceutically acceptable salts thereof) have increased oral bioavailability. Table 1 EXAMPLE B HBV-DNA ANTIVIRAL ASSAY USING HEPG2.117 CELLS [0199] 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 CellTiter-Glo 2.0 (Promega). [0200] 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 μg/mL) are 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 are incubated at 37 qC and 5% CO2. [0201] On day 1, medium is removed from each well, the test articles are diluted in culture medium without doxcycyline and 100 μL was added to cell culture wells (9 concentrations, 4-fold dilution). For each plate, 6 untreated (merely DMSO) wells are included. The final concentration of DMSO in the culture medium is 2%. Each plate is prepared in duplicate (one for HBV DNA extraction, one for CellTiter-Glo 2.0 measurement). The cells are incubated at 37 °C and 5% CO 2 for 3 days. [0202] On day 4, cell viability is assessed using CellTiter-Glo 2.0 and cell lysates are prepared for HBV DNA extraction and subsequent quantification by qPCR. HBV DNA quantification by qPCR [0203] Medium is removed from each well and 100 μL of 0.33% NP-40 in H2O was added to each well. Plates are sealed, incubated at 4 °C for 5 mins, vortexed extensively and centrifuged briefly. Next, 35 μL of lysate is added to 65 μL QuickExtract DNA Extraction Solution (Epicentre) in a PCR plate for each well. PCR plate is incubated at 65 °C for 6 mins, 98 °C for 2 mins and finally cooled to 4 °C. HBV DNA is then quantified by qPCR with HBV- specific primers and probes as specified in Table 2 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 2: HBV DNA Primers and Probe for HepG2.117 assay [0204] A DNA standard is 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 μL) and used to generate a standard curve by plotting Cq values vs. HBV DNA standard concentration. The quantity of HBV DNA in each sample is determined by interpolating from the standard curve. Cell viability [0205] Using the other plates, the cell viability is quantified by CellTiter-Glo 2.0 according to the manufacturer’s manual. ,Q^EULHI^^^^^^^/^RI^UHDJHQW^VROXWLRQ^LV^DGGHG^WR^WKH^ culture plates and shaken for 2’. The plates are incubated at rt for 10 min and luminescence signal is subsequently measured on a VarioSkan Lux (ThermoFisher) plate reader. Data analysis [0206] Cell viability is 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 is required due to the excellent dynamic window of this assay. The CC50, EC50 and EC90 values were determined by dose-response curves fitted using non-linear regression. [0207] As shown in Table 3, compounds of Formula (I) are active against HBV, where ‘A’ indicates an EC 50 ^^^^^Q0^^ µ%¶^ LQGLFDWHV^DQ^(& 50 !^^^^Q0^DQG^^^^^^^Q0^^ µ&¶^ indicates an EC 50 !^^^^^Q0^DQG^^^^^^^^Q0^^DQG^ µ'¶^ LQGLFDWHV^DQ^(& 50 > 5000 nM. Cell viability assessments indicated a large window between effective antiviral concentrations and cytotoxic compound concentrations. Table 3 [0208] 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 present disclosure.
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