Fused tricyclic heterocyclic compounds useful for treating HIV infection

Patent metadata

Field	Value
Publication number	US-10233193-B2
Application number	US-201615575433-A
Country	US
Kind code	B2
Filing date	May 20, 2016
Priority date	May 25, 2015
Publication date	Mar 19, 2019
Grant date	Mar 19, 2019

Abstract

The present invention relates to Fused Tricyclic Heterocycle Derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, B, X, Y, m, R 1 , R 2 , R 3 , R 3 , R 3 , R 4 , R 5 and R 9 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 salt thereof,
wherein:
the group -A-B— is selected from —O—C(R 13 ) 2 —, —O—C(R 13 ) 2 —C(R 13 ) 2 —, —C(R 13 ) 2 —O—, —N(R 14 )—C(R 13 ) 2 —, —N(R 14 )—C(R 13 ) 2 —C(R 13 ) 2 — and —C(R 13 ) 2 —N(R 14 )—;
X is selected from a single bond, 5 or 6-membered monocyclic heteroaryl and —N(R 6 )C(O)—;
Y is a single bond or C 1 -C 3 alkylene;
R 1 is selected from C 6 -C 10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl, wherein said C 6 -C 10 aryl group, said 5 or 6-membered monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can each be optionally substituted with up to three R 8 groups;
R 2 is selected from H, C 1 -C 6 alkyl, —(C 1 -C 6 alkylene) m —Z—R 16 , —N(R 25 ) 2 , —N(R 11 ) 2 and —OR 7 ;
R 3 is selected from H, C 1 -C 6 alkyl, —(C 1 -C 6 alkylene) m —Z—R 16 , —N(R 25 ) 2 , —N(R 11 ) 2 and —OR 7 ;
R 4 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, —(C 1 -C 6 alkylene)—O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene) m —Z—R 16 , —N(R 25 ) 2 , —N(R 11 ) 2 and —OR 7 , or R 4 and R 5 and the common carbon atom to which they are attached, join to form an exocyclic olefin group having the formula:

R 5 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —(C 1 -C 6 alkylene)—O—(C 1 -C 6 alkyl), —N(R 11 ) 2 and —OR 7 ;
each occurrence of R 6 is independently selected from H, C 1 -C 6 alkyl, —(C 1 -C 6 alkylene) m —Z—R 16 and —N(R 25 ) 2 ;
each occurrence of R 7 is independently selected from H, C 1 -C 6 alkyl, —(C 1 -C 6 alkylene)—O—(C 1 -C 6 alkyl) and C 3 -C 7 cycloalkyl;
each occurrence of R 8 is independently selected from C 1 -C 6 alkyl, halo, —OR 15 , —SR 15 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 15 ) 2 , R 16 , —C(O)OR 7 , —C(O)N(R 7 ) 2 and —NHC(O)R 7 ;
R 9 is selected from H, C 1 -C 6 alkyl, —(C 1 -C 6 alkylene)—O—C 1 -C 6 alkyl, —(C 1 -C 6 alkylene)—N(R 15 )—C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 hydroxyalkyl;
each occurence of R 10 is independently selected from H and C 1 -C 6 alkyl;
each occurrence of R 11 is independently selected from H, C 1 -C 6 alkyl, —S(O) 2 R 12 and —C(O)R 12 ;
each occurrence of R 12 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered monocyclic heterocycloalkyl, 8 to 11-membered bicyclic heterocycloalkyl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl, wherein said C 3 -C 7 cycloalkyl group, said C 6 -C 10 aryl group, said 4 to 7-membered monocyclic heterocycloalkyl, said 8 to 11-membered bicyclic heterocycloalkyl group, said 5 or 6-membered monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can each be optionally substituted with up to three R 8 groups;
each occurrence of R 13 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, halo, C 1 -C 6 haloalkyl, —(C 1 -C 6 alkylene) m —Z—R 16 , —N(R 25 ) 2 , —C(O)R 15 , —C(O)N(R 15 ) 2 and —NHC(O)R 15 ;
each occurrence of R 14 is independently selected from H, C 1 -C 6 alkyl, —(C 1 -C 6 alkylene) m —Z—R 16 , C 3 -C 7 cycloalkyl and 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 15 , —C(O)OR 15 , —C(O)N(R 15 ) 2 , —NHC(O)R 15 and —S(O) 2 R 15 ;
each occurrence of R 15 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl and benzyl; and
each occurrence of R 16 is independently selected from —P(O)(—OR 24 ) 2 ,

each occurrence of R 17 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl and benzyl, wherein said C 1 -C 6 alkyl can be optionally substituted with a group selected from halo, —OR 21 , —SR 21 , guanidino, —N(R 21 ) 2 , —C(O)OR 21 , —C(O)N(R 21 ) 2 , —NHC(O)R 21 , 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl, and wherein said phenyl group and said benzyl group can be optionally substituted with up to 2 groups, each independently selected from C 1 -C 6 alkyl, halo and —OR 26 ;
each occurrence of R 18 is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl and benzyl, wherein said C 1 -C 6 alkyl can be optionally substituted with a group selected from halo, —OR 21 , —SR 21 , guanidino, —N(R 21 ) 2 , —C(O)OR 21 , —C(O)N(R 21 ) 2 , —NHC(O)R 21 , 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl, and wherein said phenyl group and said benzyl group can be optionally substituted with up to 2 groups, each independently selected from C 1 -C 6 alkyl, halo and —OR 21 ;
each occurrence of R 19 is independently selected from H, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, —(C 1 -C 3 alkylene) m —(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m —(C 6 -C 10 aryl) and —(C 1 -C 3 alkylene) m -adamantyl, wherein said C 1 -C 20 alkyl group, said C 2 -C 20 alkenyl group, said C 6 -C 10 aryl group and said adamantyl group can be optionally substituted with up to three groups, each independently selected from halo, —OR 21 , —C(O)OR 21 , —CN, —NO 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, —N(R 21 ) 2 , —C(O)N(R 21 ) 2 , —SR 21 , —S(O)R 21 , —S(O) 2 R 21 , —S(O) 2 N(R 21 ) 2 , —NHC(O)R 21 , —NHC(O)OR 21 and —NHC(O)N(R 21 ) 2 ;
each occurrence of R 20 is independently selected from H, C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl and 9- or 10-membered bicyclic heteroaryl, wherein said C 6 -C 10 aryl group, said 5- or 6-membered monocyclic heteroaryl group and said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with up to five R 22 groups;
each occurrence of R 21 is independently H, C 1 -C 10 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 3 alkylene) m —(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m —(C 6 -C 10 aryl), —(C 1 -C 3 alkylene) m —(4 to 7-membered heterocycloalkyl), —(C 1 -C 3 alkylene) m -(5- or 6-membered monocyclic heteroaryl) or —(C 1 -C 3 alkylene) m -(9- or 10-membered bicyclic heteroaryl), wherein said C 3 -C 7 cycloalkyl group, said C 6 -C 10 aryl group, said 4 to 7-membered heterocycloalkyl group, said -5- or 6-membered monocyclic heteroaryl group or said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with up to five R 22 groups;
each occurrence of R 22 is independently selected from C 1 -C 6 alkyl, halo, —OR 21 , —SR 21 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 21 ) 2 , —C(O)OR 21 , —C(O)N(R 21 ) 2 and —NHC(O)R 21 , or any two R 22 groups on adjacent ring carbon atoms can combine to form —O—R 23 —O—;
R 23 is —[C(R 10 ) 2 ] n —;
each occurence of R 24 is independently selected from H, C 1 -C 6 alkyl, C 6 -C 10 aryl, —(C 1 -C 6 alkylene)—O—(C 1 -C 20 alkyl), —(C 1 -C 6 alkylene)—O—C(O)—R 21 , and —(C 1 -C 6 alkylene)—O—C(O)O—R 21 ;
each occurence of R 25 is independently selected from H, C 1 -C 6 alkyl and —(C 1 -C 6 alkylene)—Z—R 16 ;
each occurr

Assignees

• Merck Sharp & Dohme
• Yu Tao
• Graham Thomas H
• Waddell Sherman T
• Mccauley John A
• Stamford Andrew W
• Sanders John M
• Hu Lihong
• Cai Jiaqiang
• Zhao Lianyun

Inventors

• Yu Tao
• Graham Thomas H
• Waddell Sherman T
• Mccauley John A
• Stamford Andrew W
• Sanders John M
• Hu Lihong
• Cai Jiaqiang
• Zhao Lianyun

Classifications

• A61K31/635

  having a heterocyclic ring, e.g. sulfadiazine · CPC title

• A61K31/505

  Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim · CPC title

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title

• A61K31/513

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

• A61K31/52

  Purines, e.g. adenine · CPC title