Macrocyclic indole derivatives

Patent metadata

Field	Value
Publication number	US-11401278-B2
Application number	US-201816764672-A
Country	US
Kind code	B2
Filing date	Nov 15, 2018
Priority date	Nov 17, 2017
Publication date	Aug 2, 2022
Grant date	Aug 2, 2022

Abstract

The present invention relates to 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;

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 —S(O)—(C 1 -C 3 -alkyl) group, a —S(O) 2 —(C 1 -C 3 -alkyl) 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 C 1 -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 hydroxyl 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 3-6-membered cycloalkyl ring, or a 3-8-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, 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;
—R 6 -R 7 — is # —(CH 2 ) n —(B) t —(CH 2 ) p - ## , wherein any —CH 2 — group is unsubstituted or substituted with one or more substituents independently selected from a halogen atom, a hydroxyl 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 heterocycloalkyl group and a (heterocycloalkyl)-(C 1 -C 3 -alkylene)- group, and where a double bond in any alkenylene can be replaced by a 1,2-cyclopropyl group, and said 1,2-cyclopropyl group is unsubstituted or substituted one or two times with a halogen atom or a C 1 -C 2 -alkyl group, 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 or
—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 hydroxyl 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;

n is 1, 2, 3, 4, 5, 6, 7, or 8;
p is 1, 2, 3, 4, 5, 6, 7 or 8;
t is 1;
s is 0, 1 or 2;
where the integers selected for variables n, t, and p result in forming a 9-membered to 16-membered ring independent from the selection of variable A1 or A2;
B is independently selected from a —S(O)NR 15 - group, a —NR 15 S(O)— group, a —S(O) 2 NR 15 - group, and a —NR 15 S(O) 2 — group;
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 hydroxyl 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 20 R 21 group, and

a C 1 -C 3 -haloalkyl group, a C 3 -C 6 -cycloalkyl group, or a C 1 -C 6 -alkyl group in which one or two not directly adjacent carbon atoms are independently replaced by a heteroatom independently 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 -alkylene)- group,
a (C 1 -C 3 -haloalkyl)-(C 1 -C 3 -alkylene)-NH—(C 1 -C 3 -alkylene)- group,
a (C 1 -C 3 -haloalkyl)-NH—(C 1 -C 3 -alkylene)- group,
a (C 1 -C 3 -alkyl)-NH—C(O)—(C 1 -C 3 -alkylene)- group,
a (C 1 -C 3 -alkyl)-NR 15 —C(O)—(C 1 -C 3 -alkylene)- group,
a (C 1 -C 3 - alkyl)-C(O)—NH—(C 1 -C 3 -alkylene)- group,
a (C 1 -C 3 - alkyl)-C(O)—NR 15 —(C 1 -C 3 -alkylene)- group,
a

group, and a

group, where the phenyl ring is unsubstituted or substituted with a halogen atom, a hydroxyl group, or a C 1 -C 3 -alkoxy group and
the heterocycloalkyl group is unsubstitu

Assignees

• Broad Inst Inc
• Bayer Ag
• Bayer Pharma AG

Inventors

• Furst Laura
• Serrano-Wu Michael H
• Lemke Chris
• Mckinney David
• Fitzgerald Mark
• Nasveschuk Christopher
• Lazarski Kiel
• Ferrara Steven J
• Wei Guo
• Mccarren Patrick R
• 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

Classifications

• A61K31/4162

  condensed with heterocyclic ring systems · CPC title

• C07D513/14 Primary

  Ortho-condensed systems · CPC title

• 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

• A61P35/02

  specific for leukemia · CPC title