Spirocyclic hetercycle compounds useful as hiv integrase inhibitors

Patent metadata

Field	Value
Publication number	US-2016317543-A1
Application number	US-201415105376-A
Country	US
Kind code	A1
Filing date	Dec 17, 2014
Priority date	Dec 20, 2013
Publication date	Nov 3, 2016
Grant date	—

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

1 . A compound having the formula:

or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
A is —NHC(O)— or 5 or 6-membered monocyclic heteroaryl;
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 —.

3 . The compound of claim 1 , wherein R 11 is H or —CH 2 OCH 3 .

4 . The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof,
wherein:
A is —NHC(O)— or:

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 )—.

6 . The compound of claim 1 , wherein A is —NH—C(O)—.

7 . The compound of claim 1 , wherein A is:

8 . The compound of claim 1 , wherein B is a 5 or 6-membered monocyclic heterocycloalkyl ring.

9 . The compound of claim 8 , wherein B is tetrahydrofuranyl or tetrahydropyranyl.

10 . The compound of claim 8 , wherein B is piperidinyl, optionally substituted on the ring nitrogen atom with —C(O)OR 5 , —C(O)R 5 , —S(O) 2 —(C 1 -C 6 alkyl) or —S(O) 2 NH—(C 1 -C 6 alkyl).

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

or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
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.

12 . The compound of claim 1 , wherein Y is —N(CH 3 )—.

13 . The compound of claim 1 , wherein R 1 is selected from methyl, ethyl, n-propyl and —CH 2 CH 2 OCH 3 .

14 . The compound of claim 1 , wherein R 2 represents two fluoro groups, in the ortho and para positions.

15 . A compound that is

Assignees

• 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
• 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

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/55

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

• C07D491/20

  Spiro-condensed systems · CPC title

• A61K31/499

  Spiro-condensed pyrazines or piperazines · CPC title

• A61P31/18

  for HIV · CPC title