3′-substituted methyl or alkynyl nucleosides nucleotides for the treatment of HCV

• US 10,202,411 B2
• Filed: 04/16/2015
• Issued: 02/12/2019
• Est. Priority Date: 04/16/2014
• Status: Active Grant

• Current Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Inventors: Dukhan, David, Dousson, Cyril B., Gosselin, Gilles, Paparin, Jean-Laurent, Brandt, Guillaume, Rahali, Rachid, Salanson, Aurelien, Alexandre, Francois-Rene
• Primary Examiner(s): Lewis, Patrick T
• Application Number:
  US15/304,506
• Publication Number:
  US 20170044205A1
• Time in Patent Office: 1,398 Days
• Field of Search: None
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7064 containing condensed or non-condensed pyrimidines
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/11 containing cyclic phosphate
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents. In certain embodiments, the compounds are 3′-substituted methyl or alkynyl nucleosides of Formula I: (I); or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, wherein Base, PD, R^A, R^B1, R^B2, R^C and Z are as defined herein.

Claims

1. A compound according to Formula I:

2. The compound of claim 1 according to Formula I, wherein

the nucleobase is purine, pyrimidine, adenine, N⁶-alkylpurines, N⁶-acylpurines, N⁶-benzylpurine, N⁶-halopurine, N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkyl purine, N⁶-alkylaminopurine, N⁶-alkylthio purine, N²-alkylpurines, N²-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methyl cytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, benzyloxymethyluracil,

5-halouracil, 5-fluorouracil, C⁵-alkylpyrimidines, C⁵-benzylpyrimidines, C⁵-halopyrimidines, C⁵-vinylpyrimidine, C⁵-acetylenic pyrimidine, C⁵-acyl pyrimidine, C⁵-hydroxyalkyl purine, C⁵-amidopyrimidine, C⁵-cyanopyrimidine, C⁵-iodopyrimidine, C⁶-iodo-pyrimidine, C⁵—

Br-vinyl pyrimidine, C⁶—

Br-vinyl pyrimidine, C⁵-nitropyrimidine, C⁵-amino-pyrimidine, N²-alkylpurines, N²-alkyl-6-thiopurines, 5-azacytosine, 5-azauracil, triazolopyridine, imidazolopyridine, pyrrolopyrimidine, triazolopyrimidine, pyrazolopyrimidine, 8-azaguanine, guanine, hypoxanthine, 7-deazaguanine, 7-deazaadenine, 2-aminopurine, 6-aminopurine, 2,6-diaminopurine, 6-chloropurine, 7-fluoro-7-deazaguanine, 7-fluoro-7-deazaadenine, 2-amino-6-chloropurine, 6-methoxypurine, 6-ethoxypurine, 2-amino-6-hydroxypurine, 2-amino-6-methoxypurine, 2-amino-6-ethoxypurine, 2-amino-6-(n-propoxy)-purine, 2-amino-6-isopropoxypurine, 6-alkylthio-2-aminopurine, 4-azido-2-hydroxy-pyrimidine, or pyrrolotriazine;

where acyl is —

C(O)R and R is alkyl, aryl, alkylaryl, or arylalkyl;

R^A is hydroxyl, bromo, chloro, iodo, azido, —

NH₂, or alkyl-carbonyl-oxy;

R^B1 is hydrogen, C₂-C₆alkenyl, C₂-C₆alkynyl, fluoro, azido, —

NH₂, CN, or benzyloxycarbonyloxy;

R^B2 is hydrogen or methyl;

R^C is hydrogen, alkyl, alkenyl, alkynyl, or azido;

PD is

3. The compound of claim 1 wherein

R^A is hydroxyl, bromo, chloro, iodo, or alkylcarbonyloxy;

R^B1 is fluoro;

R^B2 is hydrogen or methyl;

R^C is hydrogen, azido, or methyl;

Base is a nucleobase;

PD is

4. The compound of claim 1 where PD is

5. The compound of claim 1 according to Formula:

6. The compound of claim 1 according to Formula V:

7. The compound of claim 1 according to Formula VI:

8. The compound of claim 1 according to any of Formulas VII or XLII:

9. The compound of claim 1 according to Formula VIII:

10. The compound of any of claim 9, wherein each Base is independently:

11. The compound of claim 10, wherein Base is

12. The compound of claim 1 according to any of Formulas IX-XII:

13. The compound of claim 1 according to any of Formulas XIII-XVIII:

14. The compound of claim 1 according to Formula XLIII or XLIV:

15. The compound of claim 1 where R^C is hydrogen.

16. The compound of claim 1 where X is N-linked amino acid residue or derivative thereof and Y is —

OR¹.

17. The compound of claim 16 where X is —

NR^X-G1(S_C1)—

C(O)-Q¹, where Q¹ is alkoxy, cycloalkyloxy, or aralkyloxy;

G1 is C₁ alkylene;

R^X is hydrogen; and

S_C1 is alkyl or arylalkyl; and

Y is —

OR¹.

18. The compound of claim 1, wherein R^A is acetyloxy or hydroxyl.

19. The compound of claim 1 according to any of Formulas 101-122:

20. The compound of claim 1 according to any of Formulas 301-329:

21. The compound of claim 1 according to any of Formulas 340, 330, 341, 331, 342, 332, 336, 123a to 125bii, 128a, 129a, 131a to 140, 142 to 164, 167 to 169, 172 to 186, 188, 190 to 190b, 191 to 193, 234 to 238, 240, 241, 242, 247, 249, 251 to 255, and 401-404, or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof and a pharmaceutically acceptable excipient, carrier, or diluent.

26. A method for the treatment of a human host infected with a virus, comprising administering to the host an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, solvate, or tautomeric form thereof.

27. The method of claim 26, wherein the virus is a hepatitis C virus.

28. The method of any of claim 27, further comprising administering a second anti-viral agent in combination or alternation with the compound or the composition, wherein the second anti-viral agent is an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, or a combination thereof.

29. The method of claim 28, wherein the compound is of Formula I:

22. A compound according to Formula 1001:

23. The compound of claim 22 where

R^A is hydroxyl, bromo, chloro, iodo, or alkylcarbonyloxy;

R^C is hydrogen, azido, or methyl;

Base is a nucleobase;

PD is hydrogen,

24. The compound of claim 22 where PD is