Tricyclic heterocycle compounds useful as HIV integrase inhibitors

Patent metadata

Field	Value
Publication number	US-11413292-B2
Application number	US-201916966961-A
Country	US
Kind code	B2
Filing date	Feb 11, 2019
Priority date	Feb 15, 2018
Publication date	Aug 16, 2022
Grant date	Aug 16, 2022

Abstract

The present invention relates to Tricyclic Heterocycle Compounds of Formula (I): and pharmaceutically acceptable salts or prodrug thereof, wherein X, Y, Z, R1 and n are as defined herein. The present invention also relates to compositions comprising at least one Tricyclic Heterocycle Compound, and methods of using the Tricyclic Heterocycle Compounds for treating or preventing HIV infection in a subject.

First claim

What is claimed is:

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof,
wherein:
X is —CR 2 R 3 , —O— or —NR 4 ;
Y is —CHR 4 —CR 2 R 3 , —CR 2 R 3 , —O— or —NR 4 ;
Z is —CR 2 R 3 —CHR 4 , —CR 2 R 3 ;
each occurrence of R 1 is independently selected from the group consisting of halo, hydroxyl, C 1 -6 alkyl and —O—(C 1 -C6 alkyl);
each occurrence of R 2 is independently selected from the group consisting of hydrogen, halo, hydroxyl, C 1 -6 alkyl and —O—(C 1 -C6 alkyl);
each occurrence of R 3 is independently selected from the group consisting of hydrogen, halo, hydroxyl, C 1 -6 alkyl and —O—(C 1 -C6 alkyl);
each occurrence of R 4 is independently selected from the group consisting of hydrogen or C 1 -6 alkyl;
n is an integer between zero and three.

2. The compound of claim 1 wherein X is —CR 2 R 3 , or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein Y is —CHR 4 —CR 2 R 3 , or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein Y is —CR 2 R 3 , or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein Y is —O—, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein Y is —NR 4 , or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein Z is —CR 2 R 3 —CHR 4 , or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 wherein Z is —CR 2 R 3 , or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 wherein each occurrence of R 2 is independently selected from the group consisting of hydrogen, hydroxyl, and —OCH 3 , or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 wherein R 4 is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 wherein n is two or three, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 selected from:

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. A method for the inhibition of HIV integrase in a subject in need thereof which comprises administering to the subject an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

15. A method for the treatment of infection by HIV or for the treatment of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound according to of claim 1 , or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition of claim 13 , further comprising one or more additional therapeutic agents selected from, raltegravir, lamivudine, abacavir, ritonavir, dolutegravir, arunavir, atazanavir, emtricitabine, tenofovir, elvitegravir, rilpivirine and lopinavir.

17. The method of claim 15 , further comprising administering to the subject one or more additional therapeutic agents selected from raltegravir, lamivudine, abacavir, ritonavir, dolutegravir, arunavir, atazanavir, emtricitabine, tenofovir, elvitegravir, rilpivirine and lopinavir, wherein the amounts administered of the compound of claim 1 and the one or more additional therapeutic agents, are together effective to treat infection by HIV or to treat, prevent or delay the onset or progression of AIDS.

18. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for the inhibition of HIV integrase, for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in a subject in need thereof.

Assignees

• Merck Sharp & Dohme
• Merck Sharp & Dohme Llc

Inventors

• Embrey Mark W
• Hartingh Timothy John
• Labroli Marc
• Raheem Izzat T

Classifications

• A61K31/5365

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/53 Primary

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61K31/4418

  having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title

• C07D471/08

  Bridged systems · CPC title