Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one compounds and derivatives as MDM2-P53 inhibitors

Patent metadata

Field	Value
Publication number	US-10138251-B2
Application number	US-201514683173-A
Country	US
Kind code	B2
Filing date	Apr 10, 2015
Priority date	Apr 11, 2014
Publication date	Nov 27, 2018
Grant date	Nov 27, 2018

Abstract

The present invention encompasses compounds of formula (I)

wherein the groups R 1 to R 7 , V, W, X, Y, n and q are defined herein, their use as inhibitors of MDM2-p53 interaction, pharmaceutical compositions which contain compounds of this kind, their use as medicaments, especially as agents for treatment and/or prevention of oncological diseases and synthetic intermediates.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 is C 1-6 alkyl, optionally substituted by a group selected from the group consisting of C 3-6 cycloalkyl, phenyl and 5-6 membered heteroaryl, wherein this C 3-6 cycloalkyl, phenyl and 5-6 membered heteroaryl is optionally substituted by one or more, identical or different substituents selected from the group consisting of —OC 1-6 alkyl, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
one of R 2 and R 3 is hydrogen and the other is selected from the group consisting of phenyl and 5-6 membered heteroaryl, wherein this phenyl and 5-6 membered heteroaryl is optionally substituted by one or more, identical or different halogen(s);
R 4 is hydrogen or a group, optionally substituted by one or more, identical or different R b3 and/or R c3 , selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl; or
R 4 is selected from the group consisting of —CN, —C(O)R c3 , —C(O)OR c3 , —C(O)NR c3 R c3 , —S(O) 2 R c3 and —S(O) 2 NR c3 R c3 ;
each R b3 is independently selected from the group consisting of —OR c3 , —NR c3 R c3 , halogen, —CN, —C(O)R c3 , —C(O)OR c3 , —C(O)NR c3 R c3 , —C(O)NR g3 OR c3 , —S(O) 2 R c3 , —S(O) 2 NR c3 R c3 , —NHC(O)R c3 and —N(C 1-4 alkyl)C(O)R c3 ;
each R c3 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R d3 and/or R e3 , selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R d3 is independently selected from the group consisting of —OR e3 , —NR e3 , halogen, —CN, —C(O)R e3 , —C(O)OR e3 , —C(O)NR e3 R e3 , —C(O)NR g3 OR e3 , —S(O) 2 R e3 , —S(O) 2 NR e3 R e3 , —NHC(O)R e3 and —N(C 1-4 alkyl)C(O)R e3 ;
each R e3 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R f3 and/or R g3 , selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R f3 is independently selected from the group consisting of —OR g3 , —NR g3 R g3 , halogen, —CN, —C(O)R g3 , —C(O)OR g3 , —C(O)NR g3 R g3 , —C(O)NR g3 OR g3 , —S(O) 2 R g3 , —S(O) 2 NR g3 R g3 , —NHC(O)R g3 and —N(C 1-4 alkyl)C(O)R g3 ;
each R g3 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

R 5 and R 6 , each independently, is hydrogen or a group, optionally substituted by one or more, identical or different R b4 and/or R c4 , selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R b4 is independently selected from the group consisting of —OR c4 , —NR c4 R c4 , halogen, —CN, —C(O)R c4 , —C(O)OR c4 , —C(O)NR c4 R c4 , —C(O)NR g4 R c4 , —S(O) 2 R c4 , —S(O) 2 NR c4 R c4 , —NHC(O)R c4 and —N(C 1-4 alkyl)C(O)R c4 ;
each R c4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R d4 and/or R e4 , selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R d4 is independently selected from the group consisting of —OR e4 , —NR e4 R e4 , halogen, —CN, —C(O)R e4 , —C(O)OR e4 , —C(O)NR e4 R e4 , —C(O)NR g4 OR e4 , —S(O) 2 R e4 , —S(O) 2 NR e4 R e4 , —NHC(O)R e4 and —N(C 1-4 alkyl)C(O)R e4 ;
each R e4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R f4 and/or R g4 , selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R f4 is independently selected from the group consisting of —OR g4 , —NR g4 R g4 , halogen, —CN, —C(O)R g4 , —C(O)OR g4 , —C(O)NR g4 R g4 , —C(O)NR g4 OR g4 , —S(O) 2 R g4 , —S(O) 2 NR g4 R g4 , —NHC(O)R g4 and —N(C 1-4 alkyl)C(O)R g4 ;
each R g4 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R 7 is independently selected from the group consisting of halogen, C 1-4 alkyl, —CN, C 1-4 haloalkyl, —OC 1-4 alkyl and —OC 1-4 haloalkyl;
q denotes the number 0, 1, 2 or 3;
W, X and Y is each independently selected from —N═ and —CH═
with the proviso that the hydrogen in each —CH═ may be replaced by a substituent R 7 if present and that a maximum of two of W, X and Y can be —N═;
V is oxygen or sulfur;
n denotes the number 1, 2 or 3;
or a salt thereof.

2. The compound according to claim 1 of formula (Ia)

or a salt thereof.

3. The compound according to claim 1 , wherein R 3 is hydrogen;
or a salt thereof.

4. The compound according to claim 1 , wherein R 4 is hydrogen or a group, optionally substituted by one or more, identical or different R b3 and/or R c3 , selected from the group consisting of C 1-6 alkyl, C 6-10 aryl and 5-10 membered heteroaryl; or
R 4 is selected from the group consisting of —C(O)R c3 and —S(O) 2 R c3 ;
each R b3 is independently selected from the group consisting of —OR c3 , —NR c3 R c3 halogen, —CN, —C(O)R c3 , —C(O)OR c3 , —C(O)NR c3 R c3 , —C(O)NR c3 OR 3 , —S(O) 2 R c3 , —S(O) 2 NR c3 R c3 , —NHC(O)R c3 and —N(C 1-4 alkyl)C(O)R c3 ;
each R c3 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R d3 and/or R e3 , selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R d3 is independently selected from the group consisting of —OR e3 , —NR e3 R e3 halogen, —CN, —C(O)R e3 , —C(O)OR e3 , —C(O)NR e3 R e3 , —C(O)NR e3 OR e3 , —S(O) 2 R e3 , —S(O) 2 NR e3 R e3 , —NHC(O)R e3 and —N(C 1-4 alkyl)C(O)R e3 ;
each R e3 independently of one another is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

or a salt thereof.

5. The compound according to claim 4 , wherein R 4 is hydrogen;
or a salt thereof.

6. The compound according to claim 1 , wherein one of R 5 and R 6 is hydrogen and the other is hydrogen or a group, optionally substituted by one or more, identical or different R b4 and/or R e4 , selected from the group consisting of C 1-6 alkyl, C 6-10 aryl and 5-10 membered heteroaryl;
each R b4 is independently selected from the group consisting of —OR c4 , —NR c4 R c4 , halogen, —CN, —C(O)R c4 , —C(O)OR, —C(O)NR c4 R c4 , —C(O)NR c4 OR c4 , —S(O) 2 R c4 , —S(O) 2 NR c4 R c4 , —NHC(O)R 4 and —N(C 1-4 alkyl)C(O)R c4 ;
each R c4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R d4 and/or R e4

Assignees

• Boehringer Ingelheim Int

Inventors

• Gollner Andreas
• Kofink Christiane
• Ramharter Juergen
• Weinstabl Harald
• Wunberg Tobias

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title