Methods of preparing macrocyclic indoles

Patent metadata

Field	Value
Publication number	US-12338250-B2
Application number	US-202017612019-A
Country	US
Kind code	B2
Filing date	May 15, 2020
Priority date	May 17, 2019
Publication date	Jun 24, 2025
Grant date	Jun 24, 2025

Abstract

The present invention relates to methods of preparing substituted indole derivatives of general formula (I):in which R1, R2, R3, R4, R5, R6, A and L are as defined herein, and intermediate compounds useful for preparing said compounds. These compounds are useful 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

We claim:

1. A method for preparing 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-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 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 each CH 2 group is independently 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 COO(C 1 -C 6 -alkyl) 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, and a —C(O)—NHS(O) 2 (aryl) group;
—R 6 -R 7 — is # —(CH 2 ) n —(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 each —CH 2 — group is independently 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;

n is 2, 3, 4, 5, or 6;
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 13-membered ring independently from the selection of variable A1 or A2;
B is —O—;
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 20 R 21 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—;

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)-C(O)—NH—(C 1 -C 3 -alkylene)- group,
a

group and a

group,
 where the phenyl ring is unsubstituted or substituted with a halogen atom, a hydroxy group or a C 1 -C 3 -alkoxy group and
 the heterocycloalkyl group is unsubstituted or substituted with an oxo (═O) group or is unsubstituted or substituted with one or more substituents independently selected from a halogen atom, a hydroxy group, a C 1 -C 3 -alkyl group and a C 1 -C 3 -alkoxy group,
or R 8 and R 9 together form a 5-membered or 6-membered ring optionally comprising one or two heteroatoms independently selected from —O— and —NR 14 —;
R 14 is a hydrogen atom or a C 1 -C 3 -alkyl group;
R 16 and R 17 are each independently selected from a hydrogen atom, a C 1 -C 6 -alkyl group, a C 1 -C 6 -haloalkyl group, a C 1 -C 6 -alkoxy group, a C 3 -C 5 -cycloalkyl group, a C 1 -C 3 -alkyl-C(O)— group, a C 1 -C 3 -alkylS(O) 2 — group and a C 1 -C 3 -alkyl-O—C(═O)— group;
R 18 is selected from a hydrogen atom, a hydroxy group, a cyano group, a C 1 -C 3 -alkyl group, a C 1 -C 6 -hydroxyalkyl group, a C 1 -C 3 -alkoxy group, a R 21 OC(O)—(C 1 -C 3 -alkylene)- group, a —C(O)OR 21 group, a —C(O)NR 20 R 21 group, a (C 1 -C 3 -alkyl)-O—(C 1 -C 3 -alkylene)-C(O)— group, a (C 1 -C 6 -alkyl)-C(O)— group and a C 3 -C 6 -cycloalkyl-C(O)— group;
R 19 is selected from a C 1

Assignees

• Broad Inst Inc
• Bayer Ag

Inventors

• Thede Kai
• Wittrock Sven
• Mengel Anne
• Mckinney David
• Lemke Christopher
• Ferrara Steven J
• Furst Laura
• Wei Guo
• Mccarren Patrick R

Classifications

• C07D403/04 Primary

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

• C07D498/16 Primary

  Peri-condensed systems · CPC title