Spirocyclic hetercycle compounds useful as HIV integrase inhibitors

Patent metadata

Field	Value
Publication number	US-9707234-B2
Application number	US-201415105376-A
Country	US
Kind code	B2
Filing date	Dec 17, 2014
Priority date	Dec 20, 2013
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

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 11 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 or prodrug thereof,
wherein:
A is —NHC(O)—;
B is a 3 to 8-membered heterocycloalkyl or an 8 to 14 membered bicyclic heterocycloalkyl, each of which can be optionally be substituted with one or more groups, each independently selected from R 7 ;
X is C 1 -C 3 alkylene;
Y is —C(R 3 ) 2 — or —N(R 4 )—;
R 1 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), —(C 1 -C 4 alkylene)-S—(C 1 -C 6 alkyl), —(C 1 -C 4 alkylene)-SO 2 —(C 1 -C 6 alkyl), —(C 1 -C 4 alkylene)-N—(C 1 -C 6 alkyl) 2 , —(C 1 -C 6 alkylene) p -P(O)(—OR 10 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, 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, C 1 -C 6 haloalkyl, —(C 1 -C 4 alkylene) p -(5 or 6-membered monocyclic heteroaryl), —(C 1 -C 4 alkylene) p -(phenyl), C 3 -C 7 cycloalkyl, —(C 1 -C 6 alkylene) p -P(O)(—OR 10 ) 2 , —(C 1 -C 4 alkylene)-S—(C 1 -C 6 alkyl), —(C 1 -C 4 alkylene)-SO 2 —(C 1 -C 6 alkyl), —N(R 6 )C(O)R 5 , —(C 1 -C 4 alkylene)-N—(C 1 -C 6 alkyl) 2 and 3 to 8-membered monocyclic heterocycloalkyl;
R 4 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —SO 2 R 5 , —C(O)R 5 , —(C 1 -C 6 alkylene) p -C(O)N(R 6 ) 2 , —(C 1 -C 6 alkylene) p -P(O)(—OR 10 ) 2 , —N(R 6 )C(O)R 5 , —(C 2 -C 4 alkylene)-O—(C 1 -C 6 alkyl), —(C 2 -C 4 alkylene)-S—(C 1 -C 6 alkyl), —(C 2 -C 4 alkylene)-SO 2 —(C 1 -C 6 alkyl), —(C 2 -C 4 alkylene)-N—(C 1 -C 6 alkyl) 2 , —(C 1 -C 6 alkylene) p -(C 3 -C 7 cycloalkyl), —(C 1 -C 4 alkylene) p -(5 or 6-membered monocyclic heteroaryl), —(C 1 -C 4 alkylene) p -(8 to 10-membered bicyclic heteroaryl), —(C 1 -C 4 alkylene) p -(phenyl) and 4 to 8-membered monocyclic heterocycloalkyl;
each occurrence of R 5 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 one or more groups, each independently selected from R 7 ;
each occurrence of R 6 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 6 alkylene)-N(R 8 ) 2 , C 1 -C 6 haloalkyl, —C(O)O(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene) p -R 9 and —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl);
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, 5 or 6-membered monocyclic heteroaryl, —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), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —OC(O)—(C 1 -C 6 haloalkyl), —C(O)O-benzyl, —(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 8 ) 2 , C 1 -C 6 hydroxyalkyl, —P(O)(OR 10 ) 2 , and —CN;
each occurrence of R 8 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, —C(O)O(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene) p -R 9 and —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl);
each occurrence of R 9 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 10 is independently selected from H and C 1 -C 6 alkyl;
R 11 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl and —(C 1 -C 4 alkylene)-O—(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 or prodrug thereof.

3. The compound of claim 1 , wherein R 11 is H or —CH 2 OCH 3 —, or a pharmaceutically acceptable salt or prodrug thereof.

4. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof,
wherein:
A is —NHC(O)—;
B is a 5 or 6-membered heterocycloalkyl;
Y is —CH 2 — or —N(CH 3 )—;
R 1 is selected from C 1 -C 6 alkyl and —(C 2 -C 4 alkylene)-O—(C 1 -C 6 alkyl); and
R 2 represents up to 3 optional substituents, each independently selected from halo.

5. The compound of claim 1 , wherein Y is —CH 2 — or —N(CH 3 ), or a pharmaceutically acceptable salt or prodrug thereof.

6. A compound
having the formula:

or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
A is

B is a 3 8-membered heterocycloalkyl or an 8 to 14 membered bicyclic heterocycloalkyl, each of which can be optionally be substituted with one or more groups, each independently selected from R 7 ;
X is C 1 -C 3 alkylene;
Y is —N(R 4 )—;
R 1 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), —(C 1 -C 4 alkylene)-S—(C 1 -C 6 alkyl), —(C 1 -C 4 alkylene)-SO 2 —(C 1 -C 6 alkyl), —C 1 -C 4 alkylene)-N—(C 1 -C 6 alkyl) 2 , —(C 1 -C 6 alkylene) p -P(O)(—OR 10 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, phenyl, 3 to 8-membered monocyclic heterocycloalkyl and 5 or 6-membered monocyclic heteroaryl;
R 2 respresents up to 3 optional subsitutents, each independetly selected from halo, C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl) and C 1 C 6 haloalkyl;
R 4 is selected from H, C 1 -C 6 alkly, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —SO 2 R 5 , —C(O)R 5 , —(C 1 -C 6 alkylene) p -C(O)N(R 6 ) 2 , —(C 1 -C 6 alkylene) p -P(O)(—OR 10 ) 2 , —N(R 6 )C(O)R 5 , —(C 2 -C 4 alkylene)-O—(C 1 -C 6 alkyl), —(C 2 -C 4 alkylene)-S—(C 1 -C 6 alkyl), —(C 2 C 4 alkylene)-SO 2 —(C 1 -C 6 alkyl), —(C 2 -C 4 alkylene)-N—(C 1 -C 6 alkyl) 2 , —(C 1 -C 6 alkylene) p —(C 3 -C 7 cycloalkyl), —(C 1 -C 4 alkylene) p -(5 or 6-membered monocyclic heteroaryl), —(C 1 -C 4 alkylene) p -(8 to 10-membered bicyclic heteroaryl), —(C 1 -C 4 alkylene) p -(phenyl) and 4 to 8 membered monocyclic heterocycloalkyl;
each occurrence of R 5 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 one or more groups, each independently selected from R 7 ;
each occurrence of R 6 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 6 alkylene)-N(R 8 ) 2 , C 1 -C 6 haloalkyl, —C(O)O

Assignees

• Merck Sharp & Dohme

Inventors

• Graham Thomas H
• Liu Wensheng
• Yu Tao
• Zhang Yonglian
• Waddell Sherman T
• Wai John S
• Coleman Paul J
• Sanders John M
• Embrey Mark W
• Walji Abbas M
• Ferguson Ii Ronald Dale
• Di Marco Christine Ng
• Steele Thomas G
• Hu Lihong
• Peng Xuanjia

Classifications

• C07D471/22

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

• C07D475/10

  with an aromatic or hetero-aromatic ring directly attached in position 2 · CPC title

• C07D495/10

  Spiro-condensed systems · CPC title

• A61K31/55

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

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title