New spiro[3h-indole-3,2'-pyrrolidin]-2(1h)-one compounds and derivatives as mdm2-p53 inhibitors

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.

1 .- 11 . (canceled) 
     
     
         12 . A compound of formula A-4 
       
         
           
           
               
               
           
         
         R 2  and R 3 , each independently, are each selected from the group consisting of hydrogen, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein this C 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 the group consisting of —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 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 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; 
         and R is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted phenyl and optionally substituted benzyl; 
         or a salt thereof. 
       
     
     
         13 . A compound of formula A-7 
       
         
           
           
               
               
           
         
       
       wherein
 R 2  and R 3  are each independently selected from the group consisting of 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 the group consisting of —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 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; 
 
 R 5  and R 6  are each independently 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 OR 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. 
 
     
     
         14 .- 18 . (canceled) 
     
     
         19 . A compound of formula A-14 
       
         
           
           
               
               
           
         
       
       wherein
 R 2 , R 3 , R 5  to R 7 , V, W, X, Y, n and q is defined as in  claim 12 ; 
 R 2  and R 3  are each independently selected from the group consisting of 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 the group consisting of —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 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; 
 
 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 OR 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. 
 
     
     
         20 . The compound according to  claim 19 , wherein
 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 R b2  and/or R c2 ;
 each R b2  is independently selected from the group consisting of —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 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, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocyclyl; 
   or a salt thereof.   
     
     
         21 . The compound according to  claim 19 , wherein
 one of R 2  and R 3  is hydrogen and the other is phenyl 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;   or a salt thereof.   
     
     
         22 . The compound according to  claim 19 , wherein
 R 3  is hydrogen;   or a salt thereof.   
     
     
         23 . The compound according to  claim 19 , 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 c4 , 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 c4 , —C(O)NR c4 R c4 , —C(O)NR e4 OR 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 3-6 cycloalkyl, 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 e4 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 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.   
     
     
         24 . The compound according to  claim 19 , wherein
 R 5  is hydrogen and R is not hydrogen;   or a salt thereof.   
     
     
         25 . The compound according to  claim 19 , wherein
 R 5  and R 6  is hydrogen;   or a salt thereof.   
     
     
         26 . The compound according to  claim 19 , wherein
 each R 7  independently is halogen and q is 1 or 2;   or a salt thereof.   
     
     
         27 . The compound according to  claim 19 , wherein
 W, X and Y are —CH═   with the proviso that the hydrogen in each —CH═ may be replaced by a substituent R 7  if present;   or a salt thereof.   
     
     
         28 . The compound according to  claim 19 , wherein
 V is oxygen;   or a salt thereof.