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

Patent metadata

Field	Value
Publication number	US-10758533-B2
Application number	US-201916237907-A
Country	US
Kind code	B2
Filing date	Jan 2, 2019
Priority date	Aug 13, 2012
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

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 compound or salt thereof according to Formula (I)

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;
B is selected from the group consisting of

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

2. A compound of claim 1 , or a 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. A compound according to claim 1 , or a salt thereof, which compound is represented by Formula (II):

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.

4. A compound, or salt thereof, according to claim 1 , wherein X is —O—.

5. A compound, or salt thereof, according to claim 1 , wherein B is:

6. A compound or salt thereof selected from the group consisting of
6-(naphthalen-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;
3-(6-(1,2,3,6-tetra-hydropyridin-4-yl)pyridazin-3-yl)naphthalen-2-ol;
3-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol;
3-(6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol;
3-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol;
3-(6-(piperidin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol;
3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalene-2,7-diol;
3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol;
3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol;
[3-(7-hydroxy-6-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-naphthalen-2-yloxy)-propyl]-carbamic acid tert-butyl ester;
7-(3-amino-propoxy)-3-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-naphthalen-2-ol;
N-[3-(7-hydroxy-6-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-naphthalen-2-yloxy)-propyl]-acetamide;
7-(3-hydroxypropoxy)-3-{6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)-amino)pyridazin-3-yl}naphthalen-2-ol;
7-(3-methoxypropoxy)-3-{6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl}-naphthalen-2-ol;
7-(2-morpholinoethoxy)-3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalen-2-ol;
3-(6-(piperidin-4-ylmethyl)pyridazin-3-yl)naphthalen-2-ol;
7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2-naphthonitrile;
3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(piperidin-1-ylmethyl)naphthalen-2-ol;
3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(pyrrolidin-1-ylmethyl)naphthalen-2-ol;
1-bromo-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol;
1-chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol;
7-methoxy-3-(6-(methyl(2,2,6,6-tetramethyl piperidin-4-yl)amino) pyridazin-3-yl)naphthalen-2-ol;
7-methoxy-3-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol;
7-(3,6-dihydro-2H-pyran-4-yl)-3-(6-(methyl(2,2,6,6-tetramethyl piperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol;
3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)naphthalen-2-ol;
7-(difluoromethyl)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol;
7-((4-hydroxy-2-methylbutan-2-yl)oxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol; and
7-(3-hydroxy-3-methylbutoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

8. A method to treat Spinal Muscular Atrophy Type I comprising administering to a subject in need thereof an effective amount of a compound or salt thereof of claim 1 .

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

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title