Macrocyclic fluorine substituted indole derivatives

Patent metadata

Field	Value
Publication number	US-11286263-B2
Application number	US-201816764563-A
Country	US
Kind code	B2
Filing date	Nov 15, 2018
Priority date	Nov 17, 2017
Publication date	Mar 29, 2022
Grant date	Mar 29, 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 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- 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- to 16-membered ring and * is the point of attachment of these moieties to the indole carbon atom bearing the A substituent;

R 1 is a fluorine atom,
R 2 and R 3 are each a hydrogen atom;
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 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;
—R 6 -R 7 — is selected from # —(CH 2 ) n —(B) t —(CH 2 ) p —X— ## , # (C 2 -C 6 -alkenylene)-(B) t —(CH 2 ) p —X— ## , # —(CH 2 ) n —(B) t —(C 2 -C 5 -alkenylene)—X— ## , and # —(CH 2 ) q —(B)—(CH 2 ) r —(B)—(CH 2 ) v X— ## ,
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, and
where a —CH═CH— group in any alkenylene can be replaced by a 1,2-(C 3 -C 5 )cycloalkylene group which is unsubstituted or substituted one or two times with a halogen atom or a C 1 -C 2 -alkyl group; and
where X is an unsubstituted —CH 2 — group;

—R 6 -R 10 — is selected from # —(CH 2 ) n —(B) t —(CH 2 ) p —X— ## , # (C 2 -C 6 -alkenylene)-(B) t —(CH 2 ) p —X— ## , # —(CH 2 ) n —(B) t —(C 2 -C 5 -alkenylene)-X— ## , and # —(CH 2 ) q —(B)—(CH 2 ) r —(B)—(CH 2 ) v —X— ## ,
wherein # is the point of attachment with the indole nitrogen atom and ## is the point of attachment with the carbon atom of the phenyl moiety bearing the R 10 substituent,
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,
where a —CH═CH— group in any alkenylene can be replaced by a 1,2-(C 1 -C 6 )cycloalkylene group which is unsubstituted or substituted one or two times with a halogen atom or a C 1 -C 2 -alkyl group, and
where X is an unsubstituted —CH 2 — group;

n is 2, 3, 4, 5, 6, 7, 8, or 9;
t is 0 or 1;
p is 0, 1, 2, 3, 4, or 5;
q is 2, 3, 4, 5, or 6;
r is 2, 3, 4, 5, or 6;
v is 0 or 1;
s is 0, 1, 2, or 3;
where the integers selected for variables n, t, p, q, r, and v result in forming a 9- 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(CH 3 ) 2 ] + — 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 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 3 -C 6 -cycloalkyl group,

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)-

Assignees

• Broad Inst Inc
• Bayer Ag
• Bayer Pharma AG

Inventors

• Ferrara Steven James
• Serrano-Wu Michael H
• Lemke Chris
• Mckinney David
• Fitzgerald Mark
• Nasveschuk Christopher
• Lazarski Kiel
• Furst Laura
• Wei Guo
• Mccarren Patrick Ryan
• Thede Kai
• Mengel Anne
• Christ Clara
• Kuhnke Joachim
• Johannes Sarah Anna Liesa
• Buchgraber Philipp
• Klar Ulrich
• Sack Ulrike
• Kaulfuss Stefan
• Fernandez-Montalvan Amaury Ernesto
• Werbeck Nicolas
• Mönning Ursula

Classifications

• C07D498/14 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

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

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D487/14

  Ortho-condensed systems · CPC title