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

Patent metadata

Field	Value
Publication number	US-RE50594-E
Application number	US-202318093145-A
Country	US
Kind code	E1
Filing date	Jan 4, 2023
Priority date	Oct 9, 2015
Publication date	Sep 23, 2025
Grant date	Sep 23, 2025

Abstract

The present invention encompasses intermediates for preparing 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. Intermediate of formula B-20

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;
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;
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;
V is oxygen or sulfur; and
wherein W, X and Y is each independently selected from —N═ and —CH═, wherein the hydrogen in each —CH═ may be replaced by a substituent R 7 if present and wherein a maximum of two of W, X and Y can be —N═,
or a salt thereof.

2. A method for synthesizing an intermediate of formula B-20

comprising reacting a compound B-2

with an imine B-19

wherein R 2 , R 3 , R 4 , R 7 , A, V, r and q are as defined in claim 1 , and wherein W, X and Y is each independently selected from —N═ and —CH═, wherein the hydrogen in each —CH═ may be replaced by a substituent R 7 if present and wherein a maximum of two of W, X and Y can be —N═.

3. 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 and C 1-6 haloalkyl;
each R b1 is independently selected from among —OR c1 and —S(O) 2 R c1 ;
each R c1 independently of one another is 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 and phenyl;
each R d1 is independently selected from among —OR e1 , —CN and halogen;
each R e1 independently of one another is C 1-6 alkyl or C 1-6 alkyl-O—C 1-6 alkyl;

one of R 2 and R 3 is hydrogen and the other is selected from among phenyl, thienyl and pyridyl, wherein said phenyl, thienyl and pyridyl is optionally substituted by one or more, identical or different substituents selected from among —OC 1-6 alkyl, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
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 1-6 haloalkyl, C 3-7 cycloalkyl and 3-10 membered heterocyclyl;
each R b4 is independently selected from among —OR c4 , —NR c4 R c4 , halogen, —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 , and —NHC(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 1-6 haloalkyl, C 3-7 cycloalkyl and 3-10 membered heterocyclyl;
each R d4 is independently selected from among —OR e4 , —NR e4 R e4 and —S(O) 2 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 3-7 cycloalkyl and 3-10 membered heterocyclyl;
each R f4 is independently —OR g4 ;
each R g4 is independently selected from among hydrogen and C 1-6 alkyl;

r denotes the number 0, 1, 2 or 3;
n denotes the number 1 or 2;
each R 7 is independently halogen or —CN;
q denotes the number 1 or 2;
W, X and Y is each —CH═, wherein the hydrogen in each —CH═ may be replaced by a substituent R 7 ;
V is oxygen;
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.

4. The compound according

Assignees

• Boehringer Ingelheim Int

Inventors

• Gollner Andreas
• Broeker Joachim
• Kerres Nina
• Kofink Christiane
• Ramharter Juergen
• Weinstabl Harald
• Gille Annika
• Goepper Stefan
• Henry Manuel
• Huchler Guenther

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/4162

  condensed with heterocyclic ring systems · CPC title