Pyridinone derivatives and their use as selective ALK-2 inhibitors

Patent metadata

Field	Value
Publication number	US-11160797-B2
Application number	US-201716766114-A
Country	US
Kind code	B2
Filing date	Nov 24, 2017
Priority date	Nov 24, 2017
Publication date	Nov 2, 2021
Grant date	Nov 2, 2021

Abstract

The invention relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

First claim

The invention claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein
A represents

R 1 represents hydrogen, C 1-4 alkyl or C 1-4 alkoxy;
R 2 and R 3 independently represent hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 3-6 cycloalkyl or R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered ring which may contain one heteroatom;
X is N or —CH;
R 4 represents hydrogen or amino;
Y is N or —CR 5 ;
R 5 is hydrogen or fluorine;
Z is N or —CR 9 ;
n is 0, 1 or 2;
W is —C(═O)— or —S(O) 2 —;
R 6 and R 7 independently represent hydrogen, fluorine or C 1-4 alkyl;
R 8 represents hydrogen, C 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkyl, C 1-4 alkoxyC 1-6 alkyl or hydroxyC 1-6 alkyl;
R 9 represents hydrogen, halogen or C 1-4 alkyl; and
R 10 represents hydrogen or halogen.

2. A compound of formula (Ia) or a pharmaceutically acceptable salt thereof,

wherein
R 1 represents hydrogen, C 1-4 alkyl or C 1-4 alkoxy;
R 2 and R 3 independently represent hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 3-6 cycloalkyl or R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered ring which may contain one heteroatom;
R 4 represents hydrogen or amino;
R 5 is hydrogen or fluorine;
R 6 and R 7 independently represent hydrogen, fluorine or C 1-4 alkyl;
R 8 represents hydrogen, C 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkyl, C 1-4 alkoxyC 1-6 alkyl or hydroxyC 1-6 alkyl;
R 9 represents hydrogen, halogen or C 1-4 alkyl; and
R 10 represents hydrogen or halogen.

3. A compound of formula (Ib) or a pharmaceutically acceptable salt thereof,

wherein
R 1 represents hydrogen, C 1-4 alkyl or C 1-4 alkoxy;
R 2 and R 3 independently represent hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 3-6 cycloalkyl or R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 6-membered ring which may contain one heteroatom;
R 4 represents hydrogen or amino;
R 5 is hydrogen or fluorine;
R 6 and R 7 independently represent hydrogen, fluorine or C 1-4 alkyl;
R 8 represents hydrogen, C 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkyl, C 1-4 alkoxyC 1-6 alkyl or hydroxyC 1-6 alkyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1 is hydrogen.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein
R 2 and R 3 independently represent hydrogen or C 1-6 alkyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein
R 2 and R 3 are both methyl.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein
R 4 is hydrogen.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein
X is —CH.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein
R 6 and R 7 independently represent hydrogen or fluorine.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein
R 8 is hydrogen or C 1-6 alkyl.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein
Y is —CH.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein
W is —C(═O)—.

13. The compound of the formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
A represents

R 1 represents hydrogen;
R 2 and R 3 represent C 1-6 alkyl;
X is —CH;
R 4 represents hydrogen;
Y is —CR 5 ;
R 5 is hydrogen;
Z is —CR 9 ;
n is 0;
W is —C(═O)—;
R 6 and R 7 represent hydrogen;
R 8 represents C 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkyl or C 1-4 alkoxyC 1-6 alkyl;
R 9 represents hydrogen; and
R 10 represents hydrogen.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof which is selected from the group consisting of
5-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-3-yl)-1-methylindolin-2-one;
5-(1′-Isopropyl-5′-methoxy-6′-oxo-1,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
5-(5-(1-Isopropyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-3-yl)-1-methylindolin-2-one;
1-methyl-5-(6′-oxo-1′-(pentan-3-yl)-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)indolin-2-one;
5-(5′-Ethyl-1′-isopropyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
5-(1′-Cyclobutyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
5-(1′-(sec-butyl)-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
5-(1′-cyclopentyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
5-(1′-ethyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
5-(1′-cyclopropyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
5-(1′-(cyclobutylmethyl)-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
1-methyl-5-(6′-oxo-1′-(2,2,2-trifluoroethyl)-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)indolin-2-one;
5-(1′-(2-ethylbutyl)-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
5-(1′-isobutyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
5-(1′-(methoxymethyl)-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
1-methyl-5-(6′-oxo-1′-(3,3,3-trifluoropropyl)-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)indolin-2-one;
5-(1′-isopentyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
1-methyl-5-(6′-oxo-1′-(tetrahydro-2H-pyran-2-yl)-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)indolin-2-one;
1-methyl-5-(1′-methyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)indolin-2-one;
1-ethyl-5-(1′-isopropyl-6′-oxo-1,6′-dihydro-[3,3′-bipyridin]-5-yl)indolin-2-one;
1-Isopropyl-5-(1′-isopropyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)indolin-2-one;
3-Ethyl-5-(1′-isopropyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
3,3-Difluoro-5-(1′-isopropyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
1-Isobutyl-5-(1′-isopropyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)indolin-2-one;
5-(1′-Isopropyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-propylindolin-2-one;
6-(1′-Isopropyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methylindolin-2-one;
5-(1′-Isopropyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one;
6-(1′-Isopropyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one;
5-(1′-Isopropyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-(2-methoxyethyl)indolin-2-one;
5-(1′-isopropyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-1-(3-methoxypropyl)indolin-2-one;
5-(1′-Isopropyl-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin

Assignees

• Novartis Ag

Inventors

• Arista Luca
• Chamoin Sylvie
• D'ALESSANDRO Pier Luca
• Lindvall Mika
• Lizos Dimitrios
• Stiefl Nikolaus Johannes
• Teixeira-Fouchard Sylvie
• Ullrich Thomas
• Weiler Sven

Classifications

• A61P7/06

  Antianaemics · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P19/10

  for osteoporosis · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title