4-pyridinonetriazine derivatives as HIV integrase inhibitors

Patent metadata

Field	Value
Publication number	US-9714243-B2
Application number	US-201314652580-A
Country	US
Kind code	B2
Filing date	Dec 12, 2013
Priority date	Dec 17, 2012
Publication date	Jul 25, 2017
Grant date	Jul 25, 2017

Abstract

The present invention relates to 4-Pyridinonetriazine Derivatives of Formula (I); and pharmaceutically acceptable salts thereof, wherein A, X, Y, R 1 , R 2 , R 3 and R 5 are as defined herein. The present invention also relates to compositions comprising at least one 4-Pyridinonetriazine Derivative, and methods of using the 4-Pyridinonetriazine 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 salt thereof,
wherein:
A is —NHC(O)— or 5 or 6-membered monocyclic heteroaryl;
X is C 1 - C 3 alkylene;
Y is O, —C(R 8 ) 2 — or —N(R 4 )—;
R 1 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl);
R 2 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 6 alkylene) p -C(O)OR 6 , —(C 1 -C 6 alkylene) p -C(O)R 6 , —(C 1 -C 6 alkylene) p -C(O)N(R 9 ) 2 , C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heterocycloalkyl, 5 or 6-membered monocyclic heteroaryl and —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl), wherein said C 3 -C 7 cycloalkyl group, said 5 or 6-membered monocyclic heteroaryl group and said 5 or 6-membered monocyclic heterocycloalkyl group can be optionally substituted with R 7 ;
R 3 is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heterocycloalkyl and —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl), wherein said C 3 -C 7 cycloalkyl group and said 5 or 6-membered monocyclic heterocycloalkyl group can be optionally substituted with one or more groups selected from R 7 , or R 2 and R 3 , together with the common carbon atom to which they are both attached, can optionally join to form a spirocyclic C 3 -C 7 cycloalkyl group or a spirocyclic C 3 -C 7 cycloalkenyl group, wherein said spirocyclic C 3 -C 7 cycloalkyl group and said spirocyclic C 3 -C 7 cycloalkenyl group can be optionally substituted with one or more groups selected from R 7 , and wherein said spirocyclic C 3 -C 7 cycloalkyl group can be fused to another ring, selected from C 3 -C 7 cycloalkyl, 3 to 8-membered monocyclic heterocycloalkyl and 5 or 6-membered monocyclic heteroaryl, and wherein said spirocyclic C 3 -C 7 cycloalkyl group can form a spirocyclic ring system with a C 3 -C 7 cycloalkyl group or a 3 to 8-membered monocyclic heterocycloalkyl group, or R 1 and R 3 , together with the carbon atoms to which they are attached, can optionally join to form a 3 to 8-membered monocyclic heterocycloalkyl group, which can be optionally substituted with one or more groups selected from R 7 ;
R 4 is selected from H, C 1 -C 6 alkyl, —SO 2 R 6 , —C(O)R 6 , —(C 1 -C 6 alkylene) p -C(O)N(R 9 ) 2 , and —(C 2 -C 4 alkylene)-O—(C 1 -C 6 alkyl);
R 5 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; and
each occurrence of R 6 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, phenyl, 3 to 8-membered monocyclic heterocycloalkyl or 6-membered monocyclic heteroaryl and 8 to 10-membered bicyclic heteroaryl, wherein said C 3 -C 7 cycloalkyl group, said phenyl group, said 5 or 6-membered monocyclic heteroaryl group and said 8 to 10-membered bicyclic heteroaryl group can be optionally substituted with R 7 ;
each occurrence of R 7 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), —OC(O)—(C 1 -C 6 haloalkyl), —(C 1 -C 6 alkylene) p -C(O)OR 6 , —(C 1 -C 6 alkylene) p -C(O)R 6 , —(C 1 -C 6 alkylene) p -C(O)N(R 9 ) 2 , C 1 -C 6 hydroxyalkyl, —P(O)(OR 11 ) 2 , and —CN;
each occurrence of R 8 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 3 to 8-membered monocyclic heterocycloalkyl and 5 or 6-membered monocyclic heteroaryl;
each occurrence of R 9 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 6 alkylene)-N(R 9 ) 2 , C 1 -C 6 haloalkyl, —C(O)O(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene) p -R 10 and —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl);
each occurrence of R 10 is independently selected from H, 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 1 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 Y is O, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein Y is —CHR 8 — or —N(R 4 )—; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein A is —NH—C(O)—, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein A is 5 or 6-membered monocyclic heteroaryl, or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof,
wherein:
A is —NHC(O)— or 5-membered heteroaryl;
Y is selected from O, —NHR 4 , —CH 2 — or —CH(CH 3 )—;
R 1 is C 1 -C 6 alkyl or —CH 2 CH 2 OCH 3 ;
R 2 is selected from H, C 1 -C 6 alkyl, and —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl);
R 3 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heterocycloalkyl and —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl), or R 2 and R 3 , together with the common carbon atom to which they are both attached, join to form a spirocyclic C 3 -C 7 cycloalkyl group which can be optionally substituted as set forth in claim 1 , or R 1 and R 3 , together with the atoms o which they are attached, join to form a 3 to 8-membered heterocycloalkyl group, which can be optionally substituted as set forth above for the compounds of formula (I);
R 4 is selected from H, C 1 -C 6 alkyl and —(C 2 -C 4 alkylene)-O—(C 1 -C 6 alkyl);
R 5 represents up to 2 optional substitutents, each independently selected from halo; and
R 11 is H or methyl.

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

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is C 1 -C 6 alkyl;
R 2 is selected from H, C 1 -C 6 alkyl, and —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl);
R 3 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 5 or 6-membered monocyclic heterocycloalkyl and —(C 1 -C 4 alkylene)-O—(C 1 -C 6 alkyl), or R 2 and R 3 , together with the common carbon atom to which they are both attached, join to form a spirocyclic C 3 -C 7 cycloalkyl group which can be optionally substituted as set forth in claim 1 ;
R 4 is selected from H, C 1 -C 6 alkyl and —(C 2 -C 4 alkylene)-O—(C 1 -C 6 alkyl);
R 5 represents up to 2 optional substitutents, each being fluoro; and
R 11 is H or methyl.

8. The compound of claim 1 , wherein R 2 is H, methyl or —CH 2 CH 2 OCH 3 , or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein R 3 is methyl, cyclopropyl, —CH 2 CH 2 OCH 3 or tetrahyrdopyranyl, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein R 2 and R 3 , together with the common carbon atom to which they are both attached, join to form a spirocyclic C 3 -C 7 cycloalkyl group that is optionally substituted as set forth in claim 1 , or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein R 1 and R 3 , together with the atoms to which they are both attached, join to form a 3 to 8-memb

Assignees

• Merck Sharp & Dohme

Inventors

• Embrey Mark W
• Graham Thomas H
• Walji Abbas
• Waddell Sherman T
• Yu Tao
• Zhang Yonglian
• Liu Wensheng
• Coleman Paul J
• Wai John
• Steele Thomas
• Di Marco Christina

Classifications

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• C07D498/14

  Ortho-condensed systems · CPC title

• A61K45/06

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

• C07D471/14

  Ortho-condensed systems · CPC title

• A61K31/53

  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