Substituted macrocyclic indole derivatives

Patent metadata

Field	Value
Publication number	US-11440923-B2
Application number	US-201816764668-A
Country	US
Kind code	B2
Filing date	Nov 15, 2018
Priority date	Nov 17, 2017
Publication date	Sep 13, 2022
Grant date	Sep 13, 2022

Abstract

The present invention relates to substituted macrocyclic indole derivatives of general formula (I):in which R1, R2, R3, R4, R5, R6, A and L are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

First claim

The invention claimed is:

1. A compound of general formula (I):

wherein
A is

wherein R 6 and R 7 , together with two carbon atoms of the pyrazole ring, two carbon atoms of the indole moiety and the nitrogen atom to which R 6 is attached, form a 9-membered to 16-membered ring and * is the point of attachment of these moieties to the indole carbon atom bearing the A substituent;

or
A is

wherein optionally one or two of the groups selected from CR 11 , CR 12 and CR 13 are replaced by a nitrogen atom,
wherein R 6 and R 10 , together with three carbon atoms of the phenyl ring, two carbon atoms of the indole moiety and the nitrogen atom to which R 6 is attached, form a 9-membered to 16-membered ring and * is the point of attachment of these moieties to the indole carbon atom bearing the A substituent;
R 1 and R 2 are each independently selected from a hydrogen atom, a halogen atom, a cyano group, a C 1 -C 3 -alkyl group and a C 1 -C 3 -alkoxy group;
R 3 is selected from a hydrogen atom, a halogen atom, a cyano group, a C 1 -C 3 -alkyl group, a C 1 -C 3 -haloalkyl group, a C 1 -C 3 -alkoxy group, a C 1 -C 3 -alkylthio group, a (C 1 -C 3 -alkyl)-S(O)— group, a (C 1 -C 3 -alkyl)-S(O) 2 — group, a C 1 -C 3 -haloalkoxy group, a C 1 -C 3 -haloalkylthio group and a C 3 -C 5 -cycloalkyl group;
R 4 is selected from an aryl group and a heteroaryl group, each of which is unsubstituted or substituted with one, two, three, four or five substituents and each substituent is independently selected from a halogen atom, a cyano group, a C 1 -C 3 -alkyl group, a C1-C 3 -haloalkyl group, a C 1 -C 3 -alkoxy group, a C 1 -C 3 -thioalkyl group, a C 1 -C 3 -haloalkoxy group, a (C 1 -C 3 )-haloalkyl-S— group and a C 3 -C 5 -cycloalkyl group;
L is a group —(CH 2 ) m -E- wherein any CH 2 group is unsubstituted or substituted with one or two substituents and each substituent is independently selected from a halogen atom, a cyano group, a hydroxy group, a C 1 -C 3 -alkyl group and a C 1 -C 3 -alkoxy group, or two substituents are optionally taken together with their intervening atoms to form a saturated or partially unsaturated 3-membered to 6-membered cycloalkyl ring, or a 3-membered to 8-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from an oxygen atom, a sulfur atom, a —S(O)— group, a —S(O) 2 — group and a —NR 14 — group;
E is a bond, an oxygen atom, a sulfur atom, a —S(O)— group, a —S(O) 2 — group or a —NR 14 — group and constitutes the connecting element to R 4 ;
m is 2, 3, or 4;
R 5 is selected from a COOH group, a

group, a —C(O)—NHS(O) 2 (C 1 -C 6 -alkyl) group, a —C(O)—NHS(O) 2 (C 3 -C 6 -cycloalkyl) group, a —C(O)—NHS(O) 2 (aryl) group, a —C(O)—NHS(O) 2 (CH 2 ) s NHCO(C 1 -C 6 -alkyl) group, a —C(O)—NHS(O) 2 (CH 2 ) s NHCO(C 3 -C 6 -cycloalkyl) group and a —C(O)—NHS(O) 2 (CH 2 ) s NHCO(aryl) group;
s is 0, 1 or 2;
—R 6 -R 7 — is # —(CH 2 ) n —(B) t —CR 22 R 23 — ## or # —(C 2 -C 9 -alkenylene)-(B) t —CR 22 R 23 — ## ,
wherein # is the point of attachment with the indole nitrogen atom and ## is the point of attachment with the pyrazole carbon atom bearing the R 7 substituent; and
wherein one or more —CH 2 — groups may be unsubstituted or substituted with one or more substituents independently selected from a halogen atom, a hydroxy group, a NR 16 R 17 group, a C 1 -C 3 -alkyl group, a C 1 -C 3 -haloalkyl group, a C 1 -C 3 -alkoxy group, a C 1 -C 3 -haloalkoxy group, a C 3 -C 6 -cycloalkyl group and a (heterocycloalkyl)-(C 1 -C 3 -alkylene)- group;

—R 6 -R 10 — is # —(CH 2 ) n —(B) t —CR 22 R 23 — ## or # —(C 2 -C 9 -alkenylene)-(B) t —CR 22 R 23 — ## , where one or more —CH 2 — groups are substituted with one or more substituents independently selected from a halogen atom, a hydroxy group, a NR 16 R 17 group, a C 1 -C 3 -alkyl group, a C 1 -C 3 -haloalkyl group, a C 1 -C 3 -alkoxy group and a C 1 -C 3 -haloalkoxy group, wherein # is the point of attachment with the indole nitrogen atom and ## is the point of attachment with the carbon atom of the aromatic moiety bearing the R 10 substituent;
n is 2, 3, 4, 5, 6, 7, 8, or 9, if B is selected from —O—, —S—, —S(O)—, —S(O) 2 — and —N(R 15 )— and
n is 1, 2, 3, 4, 5, 6, 7 or 8 if B is selected from —C(O)NR 15 — group and a —NR 15 C(O)— group and
n is 0, 1, 2, 3, 4, 5, 6, or 7 if B is selected from a —N(R 15 )—C(═O)—N(R 15 )— group, a —O—C(═O)—N(R 15 )— group and a —N(R 15 )—C(═O)—O— group;
t is 1;
where the integers selected for variables n and t, together with the methylene group CR 22 R 23 and the other non-variable atoms of the pyrazole and the indole moiety result in forming a 9-membered to 16-membered ring independently from the selection of variable A1, A2 or A3;
B is independently selected from a —C(O)NR 15 — group, a —NR 15 C(O)— group, a —N(R 15 )— group, a —N(R 15 )—C(═O)—N(R 15 )— group, a —O—C(═O)—N(R 15 )— group, a —N(R 15 )—C(═O)—O— group, —O—, —S—, —S(O)— and —S(O) 2 —;
R 8 is selected from a hydrogen atom,
a C 1 -C 6 -alkyl group, which is unsubstituted or substituted with one or more substituents independently selected from
a halogen atom, a hydroxy group, a C 1 -C 3 -alkoxy group, a C 1 -C 3 -haloalkoxy group,
a C 3 -C 6 -cycloalkyl group, a heterocycloalkyl group and a NR 21 R 22 group;

a C 1 -C 3 -haloalkyl group,
a C 3 -C 6 -cycloalkyl group and
a C 1 -C 6 -alkyl group in which one or two not directly adjacent carbon atoms are independently replaced by a heteroatom selected from —O— and —NH— and

R 9 is selected from a hydrogen atom,
a C 1 -C 4 -alkyl group,
a C 1 -C 3 -hydroxyalkyl group,
a C 1 -C 4 -haloalkyl group,
a C 1 -C 4 -haloalkyl-NH—C(O)—O—(C 1 -C 3 -alkylene)- group,
a C 2 -C 6 -haloalkenyl group,
a C 1 -C 6 -alkyl-O— group,
a C 1 -C 4 -haloalkoxy group,
a C 1 -C 6 -alkyl-O—(C 1 -C 3 -alkylene)- group,
a (C 3 -C 7 )-cycloalkyl group,
a (C 3 -C 7 )-cycloalkyl-O—(C 1 -C 3 -alkylene)- group,
a phenyl-O—(C 1 -C 3 -alkylene)- group,
a phenyl-(C 1 -C 3 -alkylene)-O—(C 1 -C 3 -alkylene)- group,
a R 18 -(phenylene)-(C 1 -C 3 -alkylene)-O—(C 1 -C 3 -alkylene)- group,
a R 18 -(phenylene)-O—(C 1 -C 3 -alkylene)- group,
a R 18 -(phenylene)-(heteroarylene)-O—(C 1 -C 3 -alkylene)- group,
a (R 18 )-(heterocycloalkylene)-(C 1 -C 3 -alkylene)- group,
a (R 18 )-(heterocycloalkylene)-(phenylene)-O—(C 1 -C 3 -alkylene)- group,
a (heterocycloalkenyl)-(phenylene)-O—(C 1 -C 3 -alkylene)- group,
a (R 18 )-(heteroarylene)-(C 1 -C 3 -alkylene)-O—(C 1 -C 3 -alkylene)- group,
a (R 18 )-(heteroarylene)-(phenylene)-O—(C 1 -C 3 -alkylene)- group,
a (R 19 )—S(O) 2 -(phenylene)-O—(C 1 -C 3 -alkylene)- group,
a (R 19 )—S(O) 2 —NH-(phenylene)-O—(C 1 -C 3 -alkylene)- group,
a (R 19 )—S(O) 2 —NH-(phenylene)-O—(C 1 -C 3 -alkylene)- group,
a (R 19 )—S(O) 2 —N(C 1 -C 6 -alkyl)-(phenylene)-O—(C 1 -C 3 -alkylene)- group,
a (R 19 )—S(O) 2 -(heterocycloalkylene)-(phenylene)-O—(C 1 -C 3 -alkylene)- group,
a (R 18 )-(heterocycloalkylene)-(heteroarylene)-O—(C 1 -C 3 -alkylene)- group,
a (R 19 )-(heteroarylene)-O—(C 1 -C 3 -alkylene)- group,
a (R 18 )-(heteroarylene)-O—(C 1 -C 3 -alkylene)- group,
a (R 19 )—S(O) 2 -(heteroarylene)-O—(C 1 -C 3 -alkylene)- group,
a (R 19 )—S(O) 2 -(heterocycloalkylene)-(heteroarylene)-O—(C 1 -C 3 -alkylene)- group,
a NR 20 R 21 —(C 1 -C 3 -alkylene)- group,
a (C 1 -C 3 -alkyl)-NH—(C 1 -C 3 -a

Assignees

• Bayer Ag
• Bayer Pharma AG
• Broad Inst Inc

Inventors

• Thede Kai
• Mengel Anne
• Christ Clara
• Kuhnke Joachim
• Johannes Sarah Anna Liesa
• Buchgraber Philipp
• Klar Ulrich
• Rauh Ulrike
• Kaulfuss Stefan
• Fernandez-Montalvan Amaury Ernesto
• Werbeck Nicolas
• Mönning Ursula
• Nowak-Reppel Katrin
• Wittrock Sven
• Mckinney David
• Serrano-Wu Michael H
• Lemke Chris
• Fitzgerald Mark
• Nasveschuk Christopher
• Lazarski Kiel
• Ferrara Steven J
• Furst Laura
• Wei Guo
• Mccarren Patrick R
• Harvey Rebecca Ann

Classifications

• A61K31/5377

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

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D487/14

  Ortho-condensed systems · CPC title

• C07D498/14 Primary

  Ortho-condensed systems · CPC title

• C07D471/22

  in which the condensed systems contains four or more hetero rings · CPC title