Spirocyclic heterocyclic compounds useful as HIV integrase inhibitors

Patent metadata

Field	Value
Publication number	US-10221186-B2
Application number	US-201515533169-A
Country	US
Kind code	B2
Filing date	Dec 4, 2015
Priority date	Dec 9, 2014
Publication date	Mar 5, 2019
Grant date	Mar 5, 2019

Abstract

The present invention relates to Spirocyclic Heterocycle Compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, B, X, Y, R 1 , R 2 and R 4 are as defined herein. The present invention also relates to compositions comprising at least one Spirocyclic Heterocycle Compound, and methods of using the Spirocyclic Heterocycle Compounds for treating or preventing HIV infection in a subject.

First claim

What is claimed is:

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof,
wherein:
A is —NHC(O)—;
B is a 3 to 8-membered heterocycloalkyl, which can be optionally substituted with one or more groups, each independently selected from R 5 ;
X is C 1 -C 4 alkylene;
R 1 is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl), —(C 1 -C 4 alkylene)-S—(C 1 -C 6 alkyl), —(C 1 -C 4 alkylene)-SO 2 —(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —(C 1 -C 4 alkylene)-N(C 1 -C 6 alkyl) 2 , —(C 1 -C 4 alkylene)-P(O)(—O—C 1 -C 6 alkyl) 2 , —(C 1 -C 4 alkylene)-P(O)(OH) 2 , phenyl, 3 to 8-membered monocyclic heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl;
R 2 represents up to 3 optional substitutents, each independently selected from halo, C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl) and C 1 -C 6 haloalkyl;
each occurrence of R 3 is independently selected from H, C 1 -C 6 alkyl, —OH, —O —(C 1 -C 6 alkyl), C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, —S—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl) and —N(C 1 -C 6 alkyl) 2 ;
R 4 is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl) and C 1 -C 6 haloalkyl;
each occurrence of R 5 is independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3 to 8-membered monocyclic heterocycloalkyl, 6 to 10-membered bicyclic heterocycloalkyl, —O—(C 1 -C 6 alkyl), —O—(C 6 -C 10 aryl), —O—(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —S(O) 2 (C 1 -C 6 alkyl), —NHS(O) 2 -(C 1 -C 6 alkyl), —S(O) 2 NH—(C 1 -C 6 alkyl), —OC(O)—(C 1 -C 6 haloalkyl), —(C 1 -C 6 alkylene) p —C(O)O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene) p —C(O)—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene) p —C(O)N(R 6 ) 2 , C 1 -C 6 hydroxyalkyl, —P(O)(OR 8 ) 2 , and —CN;
each occurrence of R 6 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl and —(C 1 -C 6 alkylene) p -R 7 ;
each occurrence of R 7 is independently selected from H, C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl and 3 to 8-membered monocyclic heterocycloalkyl;
each occurrence of R 8 is independently selected from H and C 1 -C 6 alkyl; and
each occurrence of p is independently 0 or 1.

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

3. The compound of claim 1 , having the formula:

or a pharmaceutically acceptable salt thereof,
wherein:
A is: —NHC(O)—;
B is 4 to 7-membered monocyclic heterocycloalkyl;
R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl);
R 2 represents up to 2 optional substituents, each independently selected from halo; and
each occurrence of R 3 is independently H or C 1 -C 6 alkoxy.

4. The compound of claim 1 , wherein B is selected from:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein R 2 represents up to 3 substituent groups, each independently selected from F and Cl, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , wherein R 2 and the phenyl group to which R 2 is attached is:

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein 1 is selected from methyl, ethyl, —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH 2 CH 2 OCH 3 and —CH 2 CH 2 OCH 2 CH 3 , or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein one occurrence of R 3 is H and the other occurrence of R 3 is H or methoxy, or a pharmaceutically acceptable salt thereof.

9. A compound selected from

or a pharmaceutically acceptable salt thereof.

10. 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.

11. 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 claim 1 , or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition of claim 10 , further comprising one or more additional therapeutic agents selected from raltegravir, lamivudine, abacavir, ritonavir, dolutegravir, arunavir, atazanavir, emtricitabine, tenofovir, elvitegravir, rilpivirine and lopinavir.

13. The method of claim 11 , further comprising administering to the subject one or more additional therapeutic agents selected from raltegravir, abacavir, lamivudine, ritonavir 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 AIDS.

Assignees

• Merck Sharp & Dohme

Inventors

• Embrey Mark W
• Graham Thomas H
• Raheem Izzat T
• Schreier John D
• Waddell Sherman T
• Wai John S
• Hu Lihong
• Peng Xuanjia

Classifications

• C07D487/20

  Spiro-condensed systems · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K31/683

  Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols · CPC title

• C07D491/20 Primary

  Spiro-condensed systems · CPC title