Fused tricyclic heterocyclic compounds as HIV integrase inhibitors

Patent metadata

Field	Value
Publication number	US-9951079-B2
Application number	US-201414895613-A
Country	US
Kind code	B2
Filing date	Jun 9, 2014
Priority date	Jun 13, 2013
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

The present invention relates to Fused Tricyclic Heterocycle Derivatives of Formula (I): (I) and pharmaceutically acceptable salts thereof, wherein A, X, Y, m, R1, R5, Ra and Rb are as defined herein. The present invention also relates to compositions comprising at least one Fused Tricyclic Heterocycle Derivative, and methods of using the Fused Tricyclic Heterocycle Derivatives 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 salts thereof,
wherein:
A is C 1 -C 4 alkylene, C 2 -C 4 alkenylene, C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heteroaryl, 4 to 7-membered heterocycloalkyl, arylene, —O—, —NH—C(O)—, —C(O)NH— or —C(O)—;
the group —X—Y— is selected from —O—C(R 2 ) 2 —, —O—C(R 2 ) 2 —C(R 2 ) 2 —, —C(R 2 ) 2 —O—, —N(R 4 )—C(R 2 ) 2 —, —N(R 4 )—C(R 2 ) 2 —C(R 2 ) 2 — and —C(R 2 ) 2 —N(R 4 )—;
m is 1 or 2;
each occurrence of n is independently 0 or 1;
R a is H or C 1 -C 6 alkyl;
R b is H or C 1 -C 6 alkyl;
R 1 is H or C 1 -C 6 alkyl, which is optionally substituted with up to three R 3 groups;
each occurrence of R 2 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, halo, C 1 -C 6 haloalkyl, —C(O)R 6 , —C(O)N(R 6 ) 2 and —NHC(O)R 6 ;
each occurrence of R 3 is independently selected from C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocycloalkyl, C 6 -C 10 aryl, halo, C 1 -C 6 haloalkyl, —OR 6 , —N(R 6 ) 2 , —C(O)R 6 , —C(O)N(R 6 ) 2 , —NHC(O)R 6 and —SR 6 , wherein said C 3 -C 7 cycloalkyl group, said 5 or 6-membered monocyclic heteroaryl group, said 4 to 6-membered monocyclic heterocycloalkyl group and said C 6 -C 10 aryl group can each be optionally and independently substituted with one or more groups, each independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocycloalkyl, C 6 -C 10 aryl, halo, C 1 -C 6 haloalkyl, —OR 6 , —N(R 6 ) 2 , —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —NHC(O)R 6 and —SR 6 ;
R 4 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 6 -C 10 aryl, wherein said C 3 -C 7 cycloalkyl group and said C 6 -C 10 aryl group can be optionally substituted with one or more groups, each independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, halo, C 1 -C 6 haloalkyl, —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —NHC(O)R 6 and —S(O) 2 R 6 ;
R 5 is selected from C 1 -C 6 alkyl, —(C 1 -C 3 alkylene) n -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) n -(5 or 6-membered monocyclic heteroaryl), —(C 1 -C 3 alkylene) n -(4 to 6-membered monocyclic heterocycloalkyl) and —(C 1 -C 3 alkylene) n -(C 6 -C 10 aryl), wherein said C 3 -C 7 cycloalkyl group, said 5 or 6-membered monocyclic heteroaryl group, said 4 to 6-membered monocyclic heterocycloalkyl group and said C 6 -C 10 aryl group can each be optionally and independently substituted with one or more groups, each independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocycloalkyl, C 6 -C 10 aryl, halo, C 1 -C 6 haloalkyl, —OR 6 , —N(R 6 ) 2 , —C(O)R 6 , —C(O)N(R 6 ) 2 , —NHC(O)R 6 , —S(O) 2 R 6 and —SR 6 ; and
each occurrence of R 6 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl and benzyl.

2. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl or (C 1 -C 3 alkylene)-O—(C 1 -C 6 alkyl), or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein R 5 is —(C 1 -C 3 alkylene) n -(C 6 -C 10 aryl), and wherein the C 6 -C 10 aryl moiety of said —(C 1 -C 3 alkylene) n (C 6 -C 10 aryl) group can be can be optionally and independently substituted with up to 3 groups, each independently selected from C 1 -C 6 alkyl and halo, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the group —X—Y— is selected from —O—CH 2 —, —O—CH 2 —CH 2 — and —CH 2 —O—, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein A is 5 or 6-membered monocyclic heteroaryl or —NH—C(O)—, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein each occurrence of R 2 is H, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , having the formula (Ia):

or a pharmaceutically acceptable salts thereof,
wherein:
A is —NH—C(O)— or 5-membered heteroaryl;
the group —X—Y— is selected from —O—CH 2 —, —O—CH 2 —CH 2 — and —CH 2 —O—;
m is 1 or 2;
R 1 is H, C 1 -C 6 alkyl or —(C 1 -C 3 alkylene)-O—(C 1 -C 6 alkyl);
R 7 represents up to 2 phenyl group substituents, each independently selected from halo; and
R c is H or C 1 -C 6 alkyl.

8. The compound of claim 7 , wherein m is 1 and the group —X—Y— is —O—CH 2 —, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 7 , wherein R 1 is H, ethyl, isopropyl, n-propyl or —CH 2 CH 2 OCH 3 , or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein A is —NHC(O)—, thiadiazolyl or trizolyl, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 7 , wherein each occurrence of R 7 is F, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 7 , wherein R 7 represents two F substitutents, located at the ortho and para positions on the phenyl group to which they are attached, or a pharmaceutically acceptable salt thereof.

13. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

14. 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.

15. 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.

16. A method for the treatment of infection by HIV or for the treatment, or delay in the onset or progression 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.

17. The pharmaceutical composition of claim 14 , further comprising one or more additional therapeutic agents selected from lamivudine, abacavir, darunavir, ritonavir, azanavir, emtricitabine, tenofovir, rilpivirine and lopinavir.

18. A method for the treatment of infection by HIV or for the treatment, or delay in the onset or progression 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, and one or more additional therapeutic agents selected from: lamivudine, darunavir, abacavir, ritonavir, azanavir, emtricitabine, tenofovir, 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.

Assignees

• Merck Sharp & Dohme

Inventors

• Embrey Mark W
• Babaoglu Kerim
• Walji Abbas
• Wai John S
• Coleman Paul J

Classifications

• C07D498/14

  Ortho-condensed systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/5383

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

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• A61K31/4985

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