Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use

Patent metadata

Field	Value
Publication number	US-11548902-B1
Application number	US-202117361758-A
Country	US
Kind code	B1
Filing date	Jun 29, 2021
Priority date	Mar 22, 2019
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

Abstract

Compounds for use in treating or preventing human immunodeficiency virus (HIV) infection are disclosed. The compounds have the following formula (I):

including stereoisomers and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , L, W 1 , W 2 , X, Y, and Z are as defined herein. Methods associated with the preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

First claim

We claim:

1. A compound of formula:

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound of claim 1 , or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

3. A method of treating an HIV infection in a human having the HIV infection, the method comprising administering to the human a therapeutically effective amount of the compound of claim 1 , or the pharmaceutically acceptable salt thereof.

4. The method of claim 3 , further comprising administering to the human a therapeutically effective amount of one, two, three, or four additional therapeutic agents, wherein the additional therapeutic agent or agents are anti-HIV agents.

5. The method of claim 4 , the additional therapeutic agent or agents are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

6. The method of claim 4 , wherein the additional therapeutic agent or agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, N—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharmaceutically acceptable salt thereof.

7. A compound of formula:

8. A pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically acceptable excipient.

9. A method of treating an HIV infection in a human having the HIV infection, the method comprising administering to the human a therapeutically acceptable amount of the compound of claim 7 .

10. The method of claim 9 , further comprising administering to the human a therapeutically effective amount of one, two, three, or four additional therapeutic agents, wherein the additional therapeutic agent or agents are anti-HIV agents.

11. The method of claim 10 , the additional therapeutic agent or agents are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

12. The method of claim 10 , wherein the additional therapeutic agent or agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, N—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharmaceutically acceptable salt thereof.

13. A compound of formula:

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising ah the compound of claim 13 , or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. A method of treating an HIV infection in a human having the HIV infection, the method comprising administering to the human a therapeutically acceptable amount of the compound of claim 13 , or the pharmaceutically acceptable salt thereof.

16. The method of claim 15 , further comprising administering to the human a therapeutically effective amount of one, two, three, or four additional therapeutic agents, wherein the additional therapeutic agent or agents are anti-HIV agents.

17. The method of claim 16 , the additional therapeutic agent or agents are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

18. The method of claim 16 , wherein the additional therapeutic agent or agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, N—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharmaceutically acceptable salt thereof.

19. A compound of formula:

20. A pharmaceutical composition comprising the compound of claim 19 and a pharmaceutically acceptable excipient.

21. A method of treating an HIV infection in a human having the HIV infection, the method comprising administering to the human a therapeutically acceptable amount of the compound of claim 19 .

22. The method of claim 21 , further comprising administering to the human a therapeutically effective amount of one, two, three, or four additional therapeutic agents, wherein the additional therapeutic agent or agents are anti-HIV agents.

23. The method of claim 22 , the additional therapeutic agent or agents are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

24. The method of claim 22 , wherein the additional therapeutic agent or agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, N—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharmaceutically acceptable salt thereof.

25. A compound of formula:

or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising the compound of claim 25 , or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

27. A method of treating an HIV infection in a human having the HIV infection, the method comprising administerin

Assignees

• Gilead Sciences Inc

Inventors

• Chu Hang
• Gonzalez Buenrostro Ana Z
• Guo Hongyan
• Han Xiaochun
• Jiang Lan
• Li Jiayao
• Mitchell Michael L
• Pyun Hyung-Jung
• Schroeder Scott D
• Schwarzwälder Gregg M
• Shapiro Nathan D
• Shivakumar Devleena M
• Wu Qiaoyin
• Yang Hong
• Zhang Jennifer R

Classifications

• C07D498/18 Primary

  Bridged systems · CPC title

• C07D498/22

  in which the condensed system contains four or more hetero rings · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D491/06

  Peri-condensed systems · CPC title

• C07D513/18

  Bridged systems · CPC title