Imidazolonylquinolines and the use thereof as ATM kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10975075-B2
Application number	US-202016910438-A
Country	US
Kind code	B2
Filing date	Jun 24, 2020
Priority date	Apr 2, 2015
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

Abstract

The compounds are imidazolonylquinoline compounds of the following formula

and are useful in the inhibition, regulation and/or modulation of signal transduction by kinases, in particular ATM kinase, furthermore for the treatment of diseases which relate to ATM kinase, in particular cancer, and which compounds can be supplied in pharmaceutical compositions and kits.

First claim

The invention claimed is:

1. A compound of formula (I)

where
R1 is methyl,
R3 denotes unbranched or branched alkyl having 1, 2 or 3 C atoms, where, independently of one another, 1, 2, 3, 4 or 5 H atoms may be replaced by Hal,
Het 1 is selected from the group consisting of pyrazolyl, triazolyl and imidazolyl and is unsubstituted or substituted by one or two substituents selected, independently of one another, from the group consisting of azetidinvl, —OY, —NYY, Hal, and A, which may be unsubstituted or mono- or polysubstituted by Hal,
Het 2 denotes a monocyclic saturated heterocycle having 2, 3, 4, 5, 6 or 7 C atoms and 1, 2, 3 or 4 N, O and/or S atoms, which may be unsubstituted or monosubstituted by A,
HET denotes a 5- -membered aromatic heterocycle, which is linked to the N atom of the skeleton via the ring C atom, and is selected from the group consisting of pyrazolyl, thiazolyl and imidazolyl, where this heterocycle may be unsubstituted or substituted by one, two or three substituents, which are selected, independently of one another, from the group consisting of: Hal, A and Het 2 ,
A in each case independently denotes unbranched or branched alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, where, independently of one another, 1, 2, 3, 4, 5, 6 or 7 H atoms may be replaced by Hal,
Y denotes H or A, and
Hal denotes F, Cl, Br or I, or a pharmaceutically acceptable salt thereof.

2. The compound of the formula (I) according to claim 1 , where the aromatic heterocycles HET may be substituted by one, two, three or more substituents which are selected, independently of one another, from the group consisting of: F, CI, methyl, ethyl, propyl, isopropyl, piperazinyl and tetrahydropyranyl, or a pharmaceutically acceptable salt thereof.

3. The compound of the formula (I) according to claim 1 , where HET is selected from the group consisting of 1 H-pyrazol-4-yl, 1-ethyl-3-methyl-1 H-pyrazol-4-yl, 1,2-dimethyl-1 H-pyrazol-4-yl, 1,3-dimethyl-1 H-pyrazol-4-yl, 1-methyl-1 H-pyrazol-4-yl, 1-(tetrahydropyran-4-yl)-1 H-pyrazol-4-yl, 2-methyl-2H-pyrazol-3-yl, 3-methyl-1 H-pyrazol-4-yl, 2-methylthiazol-4-yl, 3,5-dimethyl-1 H-pyrazol-4-yl, 3-fluoro-1-methylpyrazol-4-yl, thiazol-2-yl, and 1-methyl-1 H-imidazolyl,
or a pharmaceutically acceptable salt thereof.

4. The compound of the formula (I) according to claim 1 , where Het 1 is pyrazolyl, which may be unsubstituted or substituted by one or two substituents selected, independently of one another, from the group consisting of —OY, —NYY, Hal, and A, which may be unsubstituted or mono- or polysubstituted by Hal,
or a pharmaceutically acceptable salt thereof.

5. The compound of the formula (I) according to claim 1 , where Het 1 is triazolyl, which may be unsubstituted or substituted by one or two substituents selected, independently of one another, from the group consisting of —OY, —NYY, Hal, and A, which may be unsubstituted or mono- or polysubstituted by Hal,
or a pharmaceutically acceptable salt thereof.

6. The compound of the formula (I) according to claim 1 , where Het 1 is unsubstituted or substituted by one or two substituents selected, independently of one another, from the group consisting of methyl, ethyl, amino, methoxy, fluoromethyl, difluoromethyl, fluorine and azetidinyl,
or a pharmaceutically acceptable salt thereof.

7. The compound of the formula (I) according to claim 1 , where Het 1 is selected from the group consisting of 1 H-pyrazol-4-yl, 2H-pyrazol-3-yl, 1 H-pyrazol-3-yl, 1-methyl-1 H-pyrazol-4-yl, 3-methyl-1 H-pyrazol-4-yl, 5-methyl-1 H-pyrazol-3-yl, 4-methyl-1H-pyrazol-3-yl, 1-fluoromethyl-1 H-pyrazol-4-yl, 1-difluoromethyl-1 H-pyrazol-4-yl, 1,3-dimethyl-1 H-pyrazol-4-yl, 1-ethyl-1 H-pyrazol-4-yl, 1-ethyl-3-methyl-1 H-pyrazolyl, 3-fluoro-1 -methyl-1 H-pyrazol-4-yl, 3-amino-1 H-pyrazol-5-yl, 2H-1,2,3-triazol-4-yl, 3H-1,2,3-triazol-4-yl-, 1-methyl-1 H-1,2,3-triazol-4-yl, 2-methyl-2H-1,2,3-triazol-4-yl, 2-amino-1 H-imidazol-4-yl, 6-methoxypyridin-3-yl, and 1-(azetidin-3-yl)-3-methyl-1 H-pyrazol-4-yl,
or a pharmaceutically acceptable salt thereof.

8. The compound of the formula (I) according to claim 1 , where R3 denotes methyl,
or a pharmaceutically acceptable salt thereof.

9. A compound, which is one of the following compounds

1-(1,3-Dimethyl-1H-pyrazol-4-yl)-7-methoxy-3- methyl-8-(1H-pyrazol-4-yl)-1,3-dihydro- imidazo[4,5-c]quinolin-2-one

1-(1,3-Dimethyl-1H-pyrazol-4-yl)-7-methoxy-3- methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,3- dihydroimidazo[4,5-c]quinolin-2-one

1,8-Bis-(1,3-dimethyl-1H-pyrazol-4-yl)-7-methoxy- 3-methyl-1,3-dihydroimidazo[4,5-c]-quinolin-2-one

7-Methoxy-3-methyl-1-(1-methyl-1H-pyrazol-4-yl)- 8-(1H-pyrazol-4-yl)-1,3-dihydroimidazo-[4,5-c] quinolin-2-one

1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(1-ethyl-1H- pyrazol-4-yl)-7-methoxy-3-methyl-1,3- dihydroimidazo[4,5-c]quinolin-2-one

7-Methoxy-3-methyl-1,8-bis-(1-methyl-1H-pyrazol- 4-yl)-1,3-dihydroimidazo[4,5-c]-quinolin-2-one

7-Methoxy-3-methyl-1-(2-methylthiazol-4-yl)-8- (1H-pyrazol-4-yl)-1,3-dihydroimidazo-[4,5-c] quinolin-2-one

7-Methoxy-3-methyl-8-(1H-pyrazol-4-yl)-1-[1- (tetrahydropyran-4-yl)-1H-pyrazol-4-yl]-1,3- dihydroimidazo[4,5-c]quinolin-2-one

Assignees

• Merck Patent Gmbh

Inventors

• Fuchss Thomas
• Schiemann Kai

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• A61K31/4375 Primary

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title