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

Patent metadata

Field	Value
Publication number	US-9545404-B2
Application number	US-201414242282-A
Country	US
Kind code	B2
Filing date	Apr 1, 2014
Priority date	Aug 13, 2012
Publication date	Jan 17, 2017
Grant date	Jan 17, 2017

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-hydroxy-phenyl which is substituted with 1, 2, or 3 substituents independently selected from haloC 1 -C 4 alkyl, dihaloC 1 -C 4 alkyl, trihaloC 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy-C 3 -C 7 cycloalkyl, haloC 1 -C 4 alkoxy, dihaloC 1 -C 4 alkoxy, trihaloC 1 -C 4 alkoxy, hydroxy, cyano, halogen, amino, mono- and di-C 1 -C 4 alkylamino, heteroaryl, C 1 -C 4 alkyl substituted with hydroxy, C 1 -C 4 alkoxy substituted with aryl, amino, —C(O)NH C 1 -C 4 alkyl-heteroaryl, —NHC(O)—C 1 -C 4 alkyl-heteroaryl, C 1 -C 4 alkyl C(O)NH— heteroaryl, C 1 -C 4 alkyl NHC(O)-heteroaryl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl or 5, 6 or 9 membered heterocycle containing 1 or 2 heteroatoms, independently, selected from S, O and N, wherein heteroaryl has 5, 6 or 9 ring atoms, 1, 2 or 3 ring heteroatoms selected from N, O and S and substituted with 0, 1, or 2 substituents independently selected from oxo, hydroxy, nitro, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, C 1 -C 4 alkyl-OH, trihaloC 1 -C 4 alkyl, mono- and di-C 1 -C 4 alkylamino, —C(O)NH 2 , —NH 2 , —NO 2 , hydroxyC 1 -C 4 alkylamino, hydroxyC 1 -C 4 alkyl, 4-7 member heterocycleC 1 -C 4 alkyl, aminoC 1 -C 4 alkyl and mono-, di-C 1 -C 4 alkylaminoC 1 -C 4 alkyl; and C 1 -C 4 alkyl, wherein 2 C 1 -C 4 alkyl groups can combine with the atoms to which they are bound to form a 5-6 membered ring and is substituted with 0 or 1 substituents selected from oxo, oxime and hydroxy;
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 according to claim 1 , or a salt thereof, which compound is represented by Formula (III):

Wherein R 16 is a 5 member heteroaryl having one ring nitrogen atom and 0 or 1 additional ring heteroatom selected from N, O or S, wherein the heteroaryl is optionally substituted with C 1 -C 4 alkyl.

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

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

5. The compound, or salt thereof, according to claim 2 , wherein R 16 is:

6. A compound, or salt thereof, according to claim 1 , wherein the compound is of formula (IV):

wherein
X is —O— or

R′ is a 5-membered heteroaryl optionally substituted with 0, 1, or 2 groups selected from hydroxy, nitro, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, C1-C 4 alkyl-OH, trihaloC 1 -C 4 alkyl, mono- and di-C 1 -C 4 alkylamino, —C(O)NH 2 , —NH 2 , —NO 2 , hydroxyC 1 -C 4 alkylamino, hydroxyC 1 -C 4 alkyl, 4-7 member heterocycleC 1 -C 4 alkyl, aminoC 1 -C 4 alkyl and mono- and di-C 1 -C 4 alkylaminoC 1 -C 4 alkyl.

7. A compound, or salt thereof, selected from the group consisting of
2-(6-(2,2,6,6-tetramethylpiperidin-4-ylamino)-pyridazin-3-yl)phenol;
2-(6-(methyl-(2,2,6,6-tetra-methylpiperidin-4-yl)amino)-pyridazin-3-yl)phenol;
5-chloro-2-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;
5-chloro-2-(6-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyridazin-3-yl)phenol;
4-hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile;
2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-4-trifluoromethyl-phenol;
2-fluoro-6-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol;
3,5-dimethoxy-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol;
4,5-dimethoxy-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol;
5-methoxy-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol;
4,5-difluoro-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol;
5-fluoro-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol;
3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile;
N-allyl-3-hydroxy-4-(6-(methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzamide;
2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;
5-(5-methyl-oxazol-2-yl)-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol;
5-(4-hydroxymethyl)-1H-pyrazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;
5-(1H-imidazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethyl-piperidin-4-yl)amino)pyridazin-3-yl)phenol;
5-(4-amino-1H-pyrazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;
5-(4-amino-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol;
5-(3-amino-pyrazol-1-yl)-2-{6-[methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-phenol;
2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-(2-morpholino-ethyl)-1H-pyrazol-4-yl)phenol;
2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;
5-(5-amino-1H-pyrazol-1-yl)-2-(6-(methyl-(2,2,6,6-tetramethyl-piperidin-4-yl)amino)pyridazin-3-yl)phenol;
2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-1-yl)phenol;
2-{6-[(2-hydroxy-ethyl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-pyridazin-3-yl}-5-pyrazol-yl-phenol;
2-(6-(piperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;
2-(6-(((2S,4R,6R)-2,6-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;
2-(6-((-2,6-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;
2-(6-((-2,6-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;
5-(1H-pyrazol-1-yl)-2-(6-(pyrrolidin-3-yloxy)pyridazin-3-yl)phenol;
2-(6-((-2-methylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol;
(S)-5-(1H-Pyrazol-1-yl)-2-(6-(pyrrolidin-3-ylmethoxy)pyridazin-3-yl)phenol;
(R)-5-(1H-pyrazol-1-yl)-2-(6-(pyrrolidin-3-ylmethoxy)pyridazin-3-yl)phenol;
2-(6-((3-fluoropiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)-phenol;
2-[6-(1,2,2,6,6-pentamethyl-piperidin-4-yloxy)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;
5-pyrazol-1-yl-2-[6-(2,2,6,6-tetramethyl-piperidin-4-yloxy)-pyridazin-3-yl]-phenol;
2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol;
2-(6-piperazin-1-yl-pyridazin-3-yl)-5-pyrazol-1-yl-phenol;
2-[6-(azetidin-3-ylamino)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;
2-[6-(3,5-dimethyl-piperazin-1-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;
2-[6-(7-methyl-2,7-diaza-spiro[4.4]non-2-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;
2-(6-[1,4]diazepan-1-yl-pyridazin-3-yl)-5-pyrazol-1-yl-phenol;
2-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridazin-3-yl}-5-pyrazol-1-yl-phenol;
2-[6-(3,6-diaza-bicyclo[3.2.1]oct-3-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;
2-[6-(2,7-diaza-spiro[3.5]non-7-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phenol;
2-[6-(3-hydroxy-methyl-piperazin-1-yl)-pyridazin-3-yl]-5-pyrazol-1-yl-phen

Assignees

• Novartis Ag

Inventors

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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P21/00

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

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D237/20

  Nitrogen atoms (nitro radicals C07D237/12) · CPC title