1,4-disubstituted pyridazine analogs thereof and methods for treating SMN-deficiency-related conditions

Patent metadata

Field	Value
Publication number	US-11229648-B2
Application number	US-202016934787-A
Country	US
Kind code	B2
Filing date	Jul 21, 2020
Priority date	Aug 13, 2012
Publication date	Jan 25, 2022
Grant date	Jan 25, 2022

Abstract

The present invention provides 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

What is claimed is:

1. A method to treat spinal muscular atrophy Type I, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt thereof according to Formula (I)

or a pharmaceutically acceptable salt thereof, wherein
A is 2-naphthyl optionally substituted at the 3 position with hydroxy and additionally substituted with 0, 1, or 2 substituents selected from hydroxy, cyano, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 5 alkoxy, wherein the alkoxy is unsubstituted or substituted with hydroxy, C 1 -C 4 alkoxy, amino, N(H)C(O)C 1 -C 4 alkyl, N(H)C(O) 2 C 1 -C 4 alkyl, alkylene 4 to 7 member heterocycle, 4 to 7 member heterocycle and mono- and di-C 1 -C 4 alkylamino, and
B is selected from the group consisting of

wherein X is 0 or N(Me); and
R 17 is hydrogen or methyl.

2. The method according to claim 1 comprising administering to the subject in need thereof an effective amount of the compound according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein A is 2-naphthyl optionally substituted at the 3 position with hydroxy and additionally substituted with 0, 1, or 2 substituents selected from hydroxy, cyano, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, wherein the alkoxy is unsubstituted or substituted with hydroxy, C 1 -C 4 alkoxy, amino, N(H)C(O)C 1 -C 4 alkyl, N(H)C(O) 2 C 1 -C 4 alkyl, 4 to 7 member heterocycle and mono- and di-C 1 -C 4 alkylamino.

3. The method according to claim 1 comprising administering to the subject in need thereof an effective amount of the compound according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein X is —O—.

4. The method according to claim 1 comprising administering to the subject in need thereof an effective amount of the compound according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein X is N(Me).

5. The method according to claim 1 comprising administering to the subject in need thereof an effective amount of the compound according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein B is:

6. The method according to claim 1 , wherein the compound of Formula (I) is represented by Formula (II):

or a pharmaceutically acceptable salt thereof,
wherein R 15 is hydrogen, hydroxyl, C 1 -C 4 alkoxy, which alkoxy is optionally substituted with hydroxy, methoxy, amino, mono- and di-methylamino or morpholine.

7. A method to treat spinal muscular atrophy Type II, comprising administering to a subject in need thereof an effective amount of a compound according to Formula (I)

or a pharmaceutically acceptable salt thereof, wherein
A is 2-naphthyl optionally substituted at the 3 position with hydroxy and additionally substituted with 0, 1, or 2 substituents selected from hydroxy, cyano, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 5 alkoxy, wherein the alkoxy is unsubstituted or substituted with hydroxy, C 1 -C 4 alkoxy, amino, N(H)C(O)C 1 -C 4 alkyl, N(H)C(O) 2 C 1 -C 4 alkyl, alkylene 4 to 7 member heterocycle, 4 to 7 member heterocycle and mono- and di-C 1 -C 4 alkylamino; and
B is selected from the group consisting of

wherein X is O or N(Me); and
R 17 is hydrogen or methyl.

8. The method according to claim 7 comprising administering to the subject in need thereof an effective amount of the compound according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein A is 2-naphthyl optionally substituted at the 3 position with hydroxy and additionally substituted with 0, 1, or 2 substituents selected from hydroxy, cyano, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, wherein the alkoxy is unsubstituted or substituted with hydroxy, C 1 -C 4 alkoxy, amino, N(H)C(O)C 1 -C 4 alkyl, N(H)C(O) 2 C 1 -C 4 alkyl, 4 to 7 member heterocycle and mono- and di-C 1 -C 4 alkylamino.

9. The method according to claim 7 comprising administering to the subject in need thereof an effective amount of the compound according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein X is —O—.

10. The method according to claim 7 comprising administering to the subject in need thereof an effective amount of the compound according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein X is N(Me).

11. The method according to claim 7 comprising administering to the subject in need thereof an effective amount of the compound according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein B is:

12. The method according to claim 7 , wherein the compound of Formula (I) is represented by Formula (II):

or a pharmaceutically acceptable salt thereof,
wherein R 15 is hydrogen, hydroxyl, C 1 -C 4 alkoxy, which alkoxy is optionally substituted with hydroxy, methoxy, amino, mono- and di-methylamino or morpholine.

13. A method to treat spinal muscular atrophy Type III, comprising administering to a subject in need thereof an effective amount of a compound according to Formula (I)

or a pharmaceutically acceptable salt thereof, wherein
A is 2-naphthyl optionally substituted at the 3 position with hydroxy and additionally substituted with 0, 1, or 2 substituents selected from hydroxy, cyano, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 5 alkoxy, wherein the alkoxy is unsubstituted or substituted with hydroxy, C 1 -C 4 alkoxy, amino, N(H)C(O)C 1 -C 4 alkyl, N(H)C(O) 2 C 1 -C 4 alkyl, alkylene 4 to 7 member heterocycle, 4 to 7 member heterocycle and mono- and di-C 1 -C 4 alkylamino; and
B is selected from the group consisting of

wherein X is O or N(Me); and
R 17 is hydrogen or methyl.

14. The method according to claim 13 comprising administering to the subject in need thereof an effective amount of the compound according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein A is 2-naphthyl optionally substituted at the 3 position with hydroxy and additionally substituted with 0, 1, or 2 substituents selected from hydroxy, cyano, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, wherein the alkoxy is unsubstituted or substituted with hydroxy, C 1 -C 4 alkoxy, amino, N(H)C(O)C 1 -C 4 alkyl, N(H)C(O) 2 C 1 -C 4 alkyl, 4 to 7 member heterocycle and mono- and di-C 1 -C 4 alkylamino.

15. The method according to claim 13 comprising administering to the subject in need thereof an effective amount of the compound according to Formula (I) or a pharmaceutically acceptable salt thereof, wherein X is —O—.

16. The method according to claim 13

Assignees

• Novartis Ag

Inventors

• Cheung Atwood Kim
• Chin Donovan Noel
• Dales Natalie
• Fazal Aleem
• Hurley Timothy Brian
• Kerrigan John
• O'Brien Gary
• Shu Lei
• Sun Robert
• Sung Moo Je

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61K31/41 Primary

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title