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

Patent metadata

Field	Value
Publication number	US-10144739-B2
Application number	US-201615287958-A
Country	US
Kind code	B2
Filing date	Oct 7, 2016
Priority date	Oct 9, 2015
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

Abstract

The present invention encompasses compounds of formula (I)

wherein the groups R 1 to R 4 , R 7 , A, D, E, F, 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 , —N(C 1-4 alkyl)C(O)R c1 and the bivalent substituent ═O, while ═O may only be a substituent in non-aromatic ring systems;
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 , —N(C 1-4 alkyl)C(O)R e1 and the bivalent substituent ═O, while ═O may only be a substituent in non-aromatic ring systems;
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 Rg 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 , —N(C 1-4 alkyl)C(O)R g1 and the bivalent substituent ═O, while ═O may only be a substituent in non-aromatic ring systems;
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 said 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 , —N(C 1-4 alkyl)C(O)R c2 and the bivalent substituent ═O, while ═O may only be a substituent in non-aromatic ring systems;
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 , —N(C 1-4 alkyl)C(O)R e2 and the bivalent substituent ═O, while ═O may only be a substituent in non-aromatic ring systems;
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 if F is carbon or
A is 5-6 membered, nitrogen-containing heteroaryl if F is nitrogen;
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) 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 Rg 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;
n denotes the number 1, 2 or 3;
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 —CH═, wherein the hydrogen in each —CH═ may be replaced by a substituent R 7 ;
V is oxygen or sulfur;
D is nitrogen, E is carbon and F is carbon; or
D is carbon, E is nitrogen and F is carbon; or
D is carbon, E is carbon and F is nitrogen;
or a salt thereof.

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

or a salt thereof.

3. The compound according to claim 2 of formula (Ia*) or (Ib*) or (Ic*)

or a salt thereof.

4. 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 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

Assignees

• Boehringer Ingelheim Int

Inventors

• Gollner Andreas
• Broeker Joachim
• Kerres Nina
• Kofink Christiane
• Ramharter Juergen
• Weinstabl Harald

Classifications

• A61P43/00

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

• A61P37/00

  Drugs for immunological or allergic disorders · 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