Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one compounds and derivatives as MDM2-p53 inhibitors

Patent metadata

Field	Value
Publication number	US-10246467-B2
Application number	US-201515503754-A
Country	US
Kind code	B2
Filing date	Aug 20, 2015
Priority date	Aug 21, 2014
Publication date	Apr 2, 2019
Grant date	Apr 2, 2019

Abstract

The present invention encompasses compounds of formula (I) wherein the groups R 1 to R 7 , A, V, W, X, Y, n, r and q are defined in claim 1 , 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 a group, optionally substituted by one or more, identical or different R b1 and/or R c1 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R b1 is independently selected from among —OR c1 , —NR c1 R c1 , halogen, —CN, —C(O)R c1 , —C(O)OR c1 , —C(O)NR c1 R c1 , —S(O) 2 R c1 , —S(O) 2 NR c1 R c1 , —NHC(O)R c1 and —N(C 1-4 alkyl)C(O)R c1 ;
each R c1 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R d1 and/or R e1 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R d1 is independently selected from among, —OR e1 , NR e1 R e1 halogen, —CN,

C(O)R e1 , —C(O)OR e1 , —C(O)NR e1 R e1 , S(O) 2 R e1 , —S(O) 2 NR e1 R e1 , —NHC(O)R e1 and —N(C 1-4 alkyl)C(O)R e1 ;
each R e1 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R f1 and/or R g1 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R f1 is independently selected from among —OR g1 , —NR g1 R g1 , halogen, —CN, —C(O)R g1 , —C(O)OR g1 , —C(O)NR g1 R g1 , —S(O) 2 R g1 , —S(O) 2 NR g1 R g1 , —NHC(O)R g1 and —N(C 1-4 alkyl)C(O)R g1 ;
each R g1 is independently selected from among hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

R 2 and R 3 , each independently, is selected from among hydrogen, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein this C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl is optionally substituted by one or more, identical or different R b2 and/or R c2 ;
each R b2 is independently selected from among —OR c2 , —NR c2 R c2 , halogen, —CN, —C(O)R c2 , —C(O)OR c2 , —C(O)NR c2 R c2 , —S(O) 2 R c2 , —S(O) 2 NR c2 R c2 , —NHC(O)R c2 and —N(C 1-4 alkyl)C(O)R c2 ;
each R c2 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R d2 and/or R e2 , selected from among 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 d2 is independently selected from among —OR e2 , —NR e2 R e2 , halogen, —CN, —C(O)R e2 , —C(O)OR e2 , —C(O)NR e2 R e2 , —S(O) 2 R e2 , —S(O) 2 NR e2 R e2 , —NHC(O)R e2 and —N(C 1-4 alkyl)C(O)R e2 ;
each R e2 independently of one another denotes hydrogen or a group selected from among 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;

A is selected from among phenyl and 5-6 membered heteroaryl;
each R 4 is independently selected from among R a4 and R b4 ;
each R a4 independently of one another is a group, optionally substituted by one or more, identical or different R b4 and/or R c4 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R b4 is independently selected from among —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 OR c4 , —S(O) 2 R c4 , —S(O) 2 NR c4 R c4 , —NHSO 2 R c4 , —N(C 1-4 alkyl)SO 2 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 among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R d4 is independently selected from among —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 among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R f4 is independently selected from among —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 among hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

r denotes the number 0, 1, 2 or 3
R 5 and R 6 , each independently, is selected from among hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
n denotes the number 0;
each R 7 is independently selected from among 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;
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 1 is a group, optionally substituted by one or more, identical or different R b1 and/or R c1 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl and C 3-7 cycloalkyl;
each R b1 is independently selected from among —OR c1 , —NR c1 R c1 , halogen, —CN, —C(O)R c1 , —C(O)OR c1 , —C(O)NR c1 R c1 , —S(O) 2 R c1 , —S(O) 2 NR c1 R c1 , —NHC(O)R c1 and —N(C 1-4 alkyl)C(O)R c1 ;
each R c1 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R d1 and/or R e1 , selected from among C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;
each R d1 is independently selected from among —OR e1 , —NR e1 R e1 , halogen, —CN, —C(O)R c1 , —C(O)OR c1 , —C(O)NR c1 R c1 , —S(O) 2 R c1 , —S(O) 2 NR c1 R c1 , —NHC(O)R c1 and —N(C 1-4 alkyl)C(O)R c1 ;
each R c1 independently of one another is selected from among hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

or a salt thereof.

4. The compound according claim 1 , wherein
one of R 2 and R 3 is hydrogen and the other is selected from among phenyl and 5-6 membered heteroaryl, wherein this phenyl and 5-6 membered heteroaryl is optionally substituted by one or more, identical or different R b2 and/or R c2 ;
each R b2 is independently selected from among —OR c2 , —NR c2 R c2 , halogen, —CN, —C(O)R c2 , —C(O)OR c2 , —C(O)NR c2 R c2 , —S(O) 2 NR c2 R c2 , —NHC(O)R c2 and —N(C 1-4 alkyl)C(O)R c2 ;
each R c2 independently of one another denotes hydrogen or a group selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 a

Assignees

• Boehringer Ingelheim Int

Inventors

• Ramharter Juergen
• Broeker Joachim
• Gille Annika
• Gollner Andreas
• Henry Manuel
• Kerres Nina
• Weinstabl Harald

Classifications

• A61P43/00

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · 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