Cis-morpholinone and other compounds as mdm2 inhibitors for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-2016002185-A1
Application number	US-201414768529-A
Country	US
Kind code	A1
Filing date	Feb 18, 2014
Priority date	Feb 19, 2013
Publication date	Jan 7, 2016
Grant date	—

Abstract

The present invention provides MDM2 inhibitor compounds of Formula (I), or the pharmaceutically acceptable salts thereof, wherein the variables are defined above, which compounds are useful as therapeutic agents, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor.

First claim

1 . A compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein,
X is O or —S(═O) 2 —;
R 1 is hydrogen, C 1-6 alkyl, —(CR e R e ) n C 6-8 aryl, —(CR e R e ) n C 3-8 cycloalkyl, —(CR e R e ) n 3-8membered heterocycloalkyl, —S(═O) 2 C 3-8 cycloalkyl, —C(═O)C 3-8 cycloalkyl, or

wherein any heteroaryl or heterocycloalkyl group has one or more heteroatoms independently selected from O, N or S, and wherein any cycloalkyl, heterocycloalkyl, heteroaryl or aryl group can be unsubstituted or substituted with from 1 to 3 substituents independently selected from C 1-6 alkyl, halo, —CN, —CF 3 , —SR e , —S(═O) 2 R e , —CHF 2 , —CH 2 F, —NR e R e , —OCF 3 , —OCHF 2 , —OCH 2 F, or —OR e ;
Q is —(CR e R e ) n C 6-8 aryl, —(CR e R e ) n 3-8membered heterocycloalkyl, —(CR e R e ) n 5-8membered heteroaryl, —(CR e R e ) n C 3-8 cycloalkyl, —CN, —(CR e R e )—OH, —C(═O)OH, —NR e R e , —(CR e R e ) n OR e , —C(═O)N(R e )S(═O) 2 R e , —C(═O)NR e R e , —C(═O)NR e (CR e R e ) n C(═O)OR e , —C(═O)NR e (CR e R e ) n C(═O)NR e R e , —N(R e )(CR e R e ) n C(═O)OR e , —OC(═O)NR e R e , —S(═O) 2 C 3-8 cycloalkyl, —C(═O)N(R e )(CR e R e ) n OH, —C(═O)N(R e )(CR e R e ) n 3-8membered heterocycloalkyl, —N(R e )C(═O)(CR e R e ) n OH, —N(R e )S(═O) 2 R e , —N(R e )C(═O)(CR e R e ) n C(═O)OR e , —C(═O)3-8membered heterocycloalkyl, —S(═O) 2 3-8membered heterocycloalkyl, —C(═O)N(R e )S(═O) 2 C 3-8 cycloalkyl, —O(CR e R e ) n C(═O)R e , —C(═O)N(R e )(CR e R e ) n 5-8membered heteroaryl, —N(R e )C(═O)(CR e R e ) n 5-8membered heteroaryl, —C(═O)3-8membered heterocycloalkyl(CR e R e ) n C(═O)OR e , or —C(═O)(CR e R e ) n C(═O)OR e , wherein any heteroaryl or heterocycloalkyl group has one or more heteroatoms independently selected from O, N or S, and wherein any cycloalkyl, heterocycloalkyl, heteroaryl or aryl group can be unsubstituted or substituted with from 1 to 3 substituents independently selected from C 1-6 alkyl, halo, —CN, —SR e , —C(═O)OR e , —CF 3 , —S(═O) 2 R e , —CHF 2 , —CH 2 F, —NR e R e , —OCF 3 , —OCHF 2 , —OCH 2 F, or —OR e ;
R 2 is hydrogen, C 1-6 alkyl, —(CR e R e ) n C(═O)OR e , —(CR e R e ) n NR e R e , —(CR e R e ) n C(═O)NR e R e , —(CR e R e ) n OH, —(CR e R e ) n C(═O)H, —(CR e R e ) n C 6-8 aryl, —(CR e R e ) n 3-8membered heterocycloalkyl, —(CR e R e ) n 5-8membered heteroaryl, —(CR e R e ) n CN, —(CR e R e ) n C(═O)5-8membered heterocycloalkyl, —(CR e R e ) n C(═O)N(R e )(CR e R e ) n 3-8membered heterocycloalkyl, —(CR e R e ) n— CH(OH)CH 2 OH, —CH═CH5-8membered heteroaryl, —(CR e R e ) n CH═CR e R e , —(CR e R e ) n OS(═O) 2 C 1-6 alkyl, —(CR e R e ) n OS(═O)OR e , or —(CR e R e ) n OC(═O)NR e R e , wherein any heteroaryl or heterocycloalkyl group has one or two heteroatoms independently selected from O, N or S, and wherein any cycloalkyl, heterocycloalkyl, heteroaryl or aryl group can be unsubstituted or substituted with from 1 to 3 substituents independently selected from C 1-6 alkyl, halo, —(CR e R e ) n halo, —OC 1-6 alkyl, —OCF 3 , —OCF 2 H, —OCFH 2 , —CN, —S(═O) 2 CF 3 , —C(═O)NR e R e , —C(═O)OR e , C 6-8 aryl, 5-8membered heteroaryl, —CF 3 , —SR e , —S(═O) 2 R e , —CHF 2 , —CH 2 F, —NR e R e , or —OR e ;
R 3 is hydrogen or C 1-6 alkyl;
R 4 is C 6-8 aryl or 5-9membered heteroaryl, wherein any heteroaryl group has one or more heteroatom independently selected from O, N or S, and wherein the aryl or heteroaryl group is substituted with from 1 to 3 substituents independently selected from C 1-6 alkyl, halo, —CF 3 , —CN, C 3-8 cycloalkyl, —SR e , —S(═O) 2 R e , —CHF 2 , —CH 2 F, —NR e R e , —OCF 3 , —OCHF 2 , —OCH 2 F, or —OR e ;
R 5 is C 6-8 aryl or 5-9membered heteroaryl, wherein any heteroaryl group has one or more heteroatom independently selected from O, N or S, and wherein the aryl or heteroaryl group is substituted with from 1 to 3 substituents independently selected from C 1-6 alkyl, halo, —CF 3 , —CN, C 3-8 cycloalkyl, —SR e , —S(═O) 2 R e , —CHF 2 , —CH 2 F, —NR e R e , —OCF 3 , —OCHF 2 , —OCH 2 F, or —OR e ;
R 6 is hydrogen or C 1-6 alkyl;
R 7 is hydrogen or C 1-6 alkyl;
each R a is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, —(CR e R e ) n C 3-8 cycloalkyl, or —(CR e R e ) n C 6-8 aryl, wherein any cycloalkyl or aryl group can be unsubstituted or substituted with from 1 to 3 substituents independently selected from C 1-6 alkyl, halo, —CN, —SR e , —C(═O)OR e —CF 3 , —S(═O) 2 R e , —CHF 2 , —CH 2 F, —NR e R e , —OCF 3 , —OCHF 2 , —OCH 2 F, or —OR e ;
each R e is independently hydrogen, C 1-6 alkyl, or —OH;
each R f is independently hydrogen, C 1-6 alkyl, or —OH;
each n is independently 0, 1, 2, 3 or 4; and
each m is independently 0, 1, 2, 3 or 4,
provided that R 2 and R 3 are not both hydrogen.

2 . The compound of claim 1 wherein X is O.

3 . The compound of claim 1 wherein X is —S(═O) 2 —.

4 . The compound of claim 1 wherein R 3 is hydrogen.

5 . The compound of claim 1 wherein R 3 is C 1-6 alkyl.

6 . The compound of claim 1 wherein R 3 is methyl.

7 . The compound of claim 1 wherein R 6 is hydrogen.

8 . The compound of claim 1 wherein R 6 is methyl.

9 . The compound of claim 1 wherein R 7 is hydrogen.

10 . The compound of claim 1 wherein R 7 is methyl.

11 . The compound of claim 1 wherein R 4 is substituted C 6-8 aryl.

12 . The compound of claim 1 wherein R 4 is substituted phenyl.

13 . The compound of claim 1 wherein R 4 is phenyl substituted with from 1 to 3 halo groups.

14 . The compound of claim 1 wherein R 4 is phenyl substituted with a fluorine.

15 . The compound of claim 1 wherein R 4 is phenyl substituted with a bromine.

16 . The compound of claim 1 wherein R 4 is 4-chlorophenyl or 4-bromophenyl.

17 . The compound of claim 1 wherein R 5 is substituted C 6-8 aryl.

18 . The compound of claim 1 wherein R 5 is substituted phenyl.

19 . The compound of claim 1 wherein R 5 is phenyl substituted with from 1 to 3 halo groups.

20 . The compound of claim 1 wherein R 5 is phenyl substituted with a fluorine.

21 . The compound of claim 1 wherein R 5 is phenyl substituted with a bromine.

22 . The compound of claim 1 wherein R 5 is 4-chlorophenyl or 4-bromophenyl.

23 . The compound of claim 1 wherein R 5 is 3-chlorophenyl or 3-bromophenyl.

24 . The compound of claim 1 wherein R 2 is hydrogen.

25 . The compound of claim 1 wherein R 2 is C 1-6 alkyl.

26 . The compound of claim 1 wherein R 2 is —CH 2 C(═O)OH.

27 . The compound of claim 1 wherein R 2 is —CH 2 phenyl.

28 . The compound of claim 1 wherein R 2 is —CH 2 phenyl substituted with from 1 to 3 substituents independently selected from C 1-6 alkyl, halo, —(CR e R e ) n halo, —OC 1-6 alkyl, —OCF 3 , —OCF 2 H, —OCFH 2 , —CN, —S(═O) 2 CF 3 , —C(═O)NR e R e , —C(═O)OR e , C 6-8 aryl, —CF 3 , —SR e , —S(═O) 2 R e , —CHF 2 , —CH 2 F, —NR e R e , or —OR e .

29 . The compound of claim 1 wherein R 2 is —CH 2 phenyl substituted with from 1 to 3 substituents independently selected from C 1-6 alkyl, halo, —OC 1-6 alkyl, —OCF 3 , —OCF 2 H, —OCF

Assignees

• Amgen Inc

Inventors

• Bartberger Michael D
• Beck Hilary Plake
• Degraffenreid Michael R
• Fox Brian M
• Gonzalez Lopez De Turiso Felix
• Julian Lisa D
• Kayser Frank
• Medina Julio C
• Olson Steven H
• Rew Yosup
• Roveto Philip M
• Sun Daqing
• Yan Xuelei

Classifications

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D265/32 Primary

  with oxygen atoms directly attached to ring carbon atoms · CPC title

• C07D279/12

  not condensed with other rings · CPC title

• A61P35/02

  specific for leukemia · CPC title