US 2026/0258043 A1 · PROCESS FOR THE PREPARATION OF (6S,9R)-3-OXO-3,5,6,7,8,9-HEXAHYDRO-2H-6,9-EPIMINOCYCLOHEPTA[C]PYRIDAZINE-10-CARBOXAMIDE DERIVATIVES

Abstract

The present invention relates to a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: ring B is a monocyclic aromatic group which is optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, NHCO-aryl, —(CH2)q—O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and CO2-alkyl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, NHCO-aryl, —(CH2)q—O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, haloalkyl, alkoxy, NHCO-alkyl, NR13R13′, SO2-alkyl, CN, hydroxyalkyl, CONR14R14′, alkyl-NR15R15′, heterocy-cloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2)m-NHSO2-alkyl, CO2R16, alkoxy-alkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy, and O—(CH2)p-cycloalkyl, where in the latter group, said cycloalkyl is optionally further substituted by one or more halo, haloalkyl, alkyl or alkoxy groups; m is an integer from 0 to 3; p and q are each independently 0 to 3; Y is CR10R10′, wherein R10 and R10′ are each independently selected from H, F, alkyl, and haloalkyl; Ra and Rb are each independently selected from H and alkyl; R6 is selected from H, alkyl, cycloalkyl and hydroxyalkyl; and R13, R13′, R14, R14′, R15, R15′, and R16 are each independently selected from H, alkyl, haloalkyl and alkoxyalkyl; said process comprising the steps of: (i) treating a compound of formula (IV), where B is defined as above, with a compound of formula (V), where R21 is phenyl optionally substituted with 1 to 5 fluorine atoms, to form a compound of formula (III); and (ii) treating said compound of formula (III) with a compound of formula (II), or a pharmaceutically acceptable salt thereof, where Y, Ra, Rb and R6 are as described above, to form a compound of formula (I). Further aspects relate to intermediates useful in the claimed process.

Claims48

Dependent claims

A process for preparing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof,

wherein:
ring B is a monocyclic aromatic group which is optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, NHCO-aryl, —(CH2)q—O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and CO2-alkyl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, NHCO-aryl, —(CH2)q—O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, haloalkyl, alkoxy, NHCO-alkyl, NR13R13′, SO2-alkyl, CN, hydroxyalkyl, CONR14R14′, alkyl-NR15R15′, heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2)m—NHSO2-alkyl, CO2R16, alkoxy-alkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy, and O—(CH2)p-cycloalkyl, where in the latter group, said cycloalkyl is optionally further substituted by one or more halo, haloalkyl, alkyl or alkoxy groups;
m is an integer from 0 to 3;
p and q are each independently 0 to 3;
Y is CR10R10′, wherein R10 and R10′ are each independently selected from H, F, alkyl, and haloalkyl;
Ra and Rb are each independently selected from H and alkyl;
R6 is selected from H, alkyl, cycloalkyl and hydroxyalkyl;
R13, R13′, R14, R14′, R15, R15′, and R16 are each independently selected from H, alkyl, haloalkyl and alkoxyalkyl;
said process comprising the steps of:
(i) treating a compound of formula (IV), where B is defined as above, with a compound of formula (V), where R21 is phenyl optionally substituted with 1 to 5 fluorine atoms, to form a compound of formula (III);
and
(ii) treating said compound of formula (III) with a compound of formula (II), or a pharmaceutically acceptable salt thereof, where Y, Ra, Rb and R6 are as described above, to form a compound of formula (I);

9 more elements

A process according to any preceding claim, wherein Ring B is:

wherein:
R1, R4, and R5 are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, and halo;
R2 and R3 are each independently selected from H, OH, halo, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl, NHCO-aryl, —(CH2)q—O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and CO2-alkyl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, NHCO-aryl, —(CH2)q—O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, NR13R13′, SO2-alkyl, CN, hydroxyalkyl, CONR14R14′, alkyl-NR15R15′, heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2)m—NHSO2-alkyl, CO2R16, alkoxy-alkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy, and O—(CH2)p-cycloalkyl, where in the latter group, said cycloalkyl is optionally further substituted by one or more halo, haloalkyl, alkyl or alkoxy groups.

A compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof:

wherein:
ring B is a monocyclic aromatic group which is optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, NHCO-aryl, —(CH2)q—O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and CO2-alkyl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, NHCO-aryl, —(CH2)q—O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, haloalkyl, alkoxy, NHCO-alkyl, NR13R13′, SO2-alkyl, CN, hydroxyalkyl, CONR14R14′, alkyl-NR15R15′, heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH2)m—NHSO2-alkyl, CO2R16, alkoxy-alkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy, and O—(CH2)p-cycloalkyl, where in the latter group, said cycloalkyl is optionally further substituted by one or more halo, haloalkyl, alkyl or alkoxy groups;
m is an integer from 0 to 3;
p and q are each independently 0 to 3;
R13, R13′, R14, R14′, R15, R15′, and R16 are each independently selected from H, alkyl, haloalkyl and alkoxyalkyl;
and
R21 is phenyl optionally substituted with 1 to 5 fluorine atoms.

4 more elements

Dependencies are inferred from the claim text.

Process for the preparation of (6s,9r)-3-oxo-3,5,6,7,8,9-hexahydro-2h-6,9-epiminocyclohepta[c]pyridazine-10-carboxamide derivatives

Life of this patent

Process for the preparation of (6s,9r)-3-oxo-3,5,6,7,8,9-hexahydro-2h-6,9-epiminocyclohepta[c]pyridazine-10-carboxamide derivatives

Life of this patent

Abstract

Claims48