Substituted nucleotide analogs

Patent metadata

Field	Value
Publication number	US-9278990-B2
Application number	US-201414519460-A
Country	US
Kind code	B2
Filing date	Oct 21, 2014
Priority date	Sep 22, 2010
Publication date	Mar 8, 2016
Grant date	Mar 8, 2016

Abstract

Disclosed herein are phosphorothioate nucleotide analogs, such as thiophosphoramidate prodrugs and thiohosphates (including α-thiomonophosphates, α-thiodiphosphates, and α-thiotriphosphates), methods of synthesizing phosphorothioate nucleotide analogs, such as thiophosphoramidate prodrugs and thiophosphates, and methods of treating viral infections such as HCV, with the phosphorothioate nucleotide analogs, such as thiophosphoramidate prodrugs and thiophosphates.

First claim

What is claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein:
B 1 is an optionally substituted pyrimidine base;
R 1 is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative;
R 2 is selected from the group consisting of an optionally substituted aryl and an optionally substituted monocyclic heteroaryl;
R 3a and R 3b are both hydrogen;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is selected from the group consisting of hydrogen, —OR 12 and —OC(═O)R 13 ;
R 7 is selected from the group consisting of hydrogen, —OR 14 and —OC(═O)R 15 ;
or R 6 and R 7 are both oxygen atoms and linked together by a carbonyl group;

R 8 is selected from the group consisting of azido, cyano, halogen, and unsubstituted C 1 -C 6 alkyl;
R 9 is hydrogen;
R 12 and R 14 are selected from the group consisting of hydrogen or an unsubstituted C 1-6 alkyl;
R 13 and R 15 are selected from the group consisting of an unsubstituted C 1-6 alkyl or an unsubstituted C 3-6 cycloalkyl; and
wherein when a substituent is substituted, the substituent is substituted with a group individually and independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, cycloalkenyl, C 6 -C 10 aryl, 4 to 14 atom heteroaryl, 3 to 18 atom heteroalicyclyl, (aryl)C 1-4 alkyl, (heteroaryl)C 1-4 alkyl, (heteroalicyclyl) C 1-4 alkyl, hydroxy, alkoxy, aryloxy, acyl, cyano, halogen, O-carbamyl, N-carbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfonyl, haloalkyl, haloalkoxy, an amino, a mono-substituted amino group and a di-substituted amino group.

2. The compound of claim 1 , wherein R 2 is optionally substituted aryl.

3. The compound of claim 2 , wherein R 2 is optionally substituted phenyl.

4. The compound of claim 3 , wherein R 2 is unsubstituted phenyl.

5. The compound of claim 4 , wherein R 1 is an optionally substituted N-linked α-amino acid.

6. The compound of claim 5 , wherein R 1 is selected from the group consisting of N-alaninyl, N-asparaginyl, N-aspartatyl, N-cysteinyl, N-glutamatyl, N-glutaminyl, N-glycinyl, N-prolinyl, N-serinyl, N-tyrosinyl, N-argininyl, N-histidinyl, N-isoleucinyl, N-leucinyl, N-lysinyl, N-methioninyl, N-phenylalaninyl, N-threoninyl, N-tryptophanyl, and N-valinyl.

7. The compound of claim 4 , wherein R 1 is an optionally substituted N-linked α-amino acid ester derivative.

8. The compound of claim 7 , wherein R 1 is an N-linked α-amino acid ester selected from the group consisting of N-alaninyl ester, N-asparaginyl ester, N-aspartatyl ester, N-cysteinyl ester, N-glutamatyl ester, N-glutaminyl ester, N-glycinyl ester, N-prolinyl ester, N-serinyl ester, N-tyrosinyl ester, N-argininyl ester, N-histidinyl ester, N-isoleucinyl ester, N-leucinyl ester, N-lysinyl ester, N-methioninyl ester, N-phenylalaninyl ester, N-threoninyl ester, N-tryptophanyl ester, and N-valinyl ester.

9. The compound of claim 8 , wherein R 1 is an N-linked α-amino acid ester, wherein the ester is selected from the group consisting of isopropyl ester, cyclopropyl ester, isobutyl ester, cyclobutyl ester, neopentyl ester, cyclopentyl ester, and cyclohexyl ester.

10. The compound of claim 9 , wherein R 1 is selected from the group consisting of N-alaninyl isopropyl ester, N-alaninyl cyclohexyl ester, N-alaninyl neopentyl ester, N-valinyl isopropyl ester, and N-leucinyl isopropyl ester.

11. The compound of claim 10 , wherein R 1 is N-alaninyl isopropyl ester.

12. The compound of claim 1 , wherein R 6 and R 7 are independently selected from the group consisting of —OH and —OC(═O)R 13 ; or R 6 and R 7 are both oxygen atoms and linked together by a carbonyl group.

13. The compound of claim 12 , wherein R 6 and R 7 are both —OH.

14. The compound of claim 13 , wherein R 8 is unsubstituted C 1 -C 6 alkyl.

15. The compound of claim 14 , wherein R 8 is methyl.

16. The compound of claim 1 , wherein B 1 is an unsubstituted pyrimidine base.

17. The compound of claim 16 , wherein B 1 is

18. A compound of Formula (I), or a 5′-thio-monophosphate thereof, or a pharmaceutically acceptable salt of the foregoing:

wherein:
B 1 is an optionally substituted pyrimidine base;
R 1 is O − or OH;
R 2 is

 wherein R 19 , R 20 and R 21 are independently absent or hydrogen, and n is 0 or 1;
R 3a and R 3b are both hydrogen;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is selected from the group consisting of —OR 12 and —OC(═O)R 13 ;
R 7 is selected from the group consisting of —OR 14 and —OC(═O)R 15 ;
or R 6 and R 7 are both oxygen atoms and linked together by a carbonyl group;

R 8 is selected from the group consisting of azido, cyano, halogen, and unsubstituted C 1 -C 6 alkyl;
R 9 is hydrogen;
R 8 is selected from the group consisting of halogen and unsubstituted C 1 -C 6 alkyl;
R 9 is hydrogen;
R 12 and R 14 are independently hydrogen or an unsubstituted C 1-6 alkyl; and
R 13 and R 15 are independently an unsubstituted C 1-6 alkyl or an unsubstituted C 3-6 cycloalkyl; and
wherein when a substituent is substituted, the substituent is substituted with a group individually and independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkynyl, C 3-8 cycloalkyl, cycloalkenyl, C 6 -C 10 aryl, 4 to 14 atom heteroaryl, 3 to 18 atom heteroalicyclyl, (aryl)C 1-4 alkyl, (heteroaryl)C 1-4 alkyl, (heteroalicyclyl) C 1-4 alkyl, hydroxy, alkoxy, aryloxy, acyl, cyano, halogen, O-carbamyl, N-carbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfonyl, haloalkyl, haloalkoxy, an amino, a mono-substituted amino group and a di-substituted amino group.

19. The compound of claim 18 , wherein n is 1.

20. The compound of claim 19 , wherein R 6 and R 7 are independently selected from the group consisting of —OH and —OC(═O)R 13 ; or R 6 and R 7 are both oxygen atoms and linked together by a carbonyl group.

21. The compound of claim 20 , wherein R 6 and R 7 are both —OH.

22. The compound of claim 21 , wherein R 8 is unsubstituted C 1 -C 6 alkyl.

23. The compound of claim 22 , wherein R 8 is methyl.

24. The compound of claim 18 , wherein B 1 is an unsubstituted pyrimidine base.

25. The compound of claim 24 , wherein B 1 is

26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

27. The pharmaceuti

Assignees

• Alios Biopharma Inc

Inventors

• Smith David Bernard
• Deval Jerome
• Dyatkina Natalia
• Beigelman Leonid
• Wang Guangyi

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61P31/18

  for HIV · CPC title

• A61P31/14

  for RNA viruses · CPC title