US 2019/0160062 A1Published application

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

AssigneeNovartis AG

InventorsAtwood Kim CHEUNG, Natalie DALES, Timothy Brian HURLEY

Life of this patent

Estimating the term…

Abstract

The present invention provides a compound of formula IA 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.

Claims15

Dependent claims

A compound or salt thereof according to Formula (I)

wherein
A is bicyclic heteroaryl or heterocyle having 9 or 10 ring atoms and 1 or 2 ring N atoms and 0 or 1 O atoms, which bicyclic heteroaryl or heterocycle is substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from —C(O)NH2, —C(O)O—C1-C4alkyl, aryl, oxo, cyano, halogen, hydroxy, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C3-C7cycloalkyl, heterocyclyl, heteroaryl, heterocyclyl C1-C4alkyl, C1-C4alkyl aryl, C1-C4alkyl heterocyclyl, C1-C4alkyl heteroaryl, C1-C4alkoxy aryl, C1-C4alkoxy heterocyclyl, C1-C4alkoxy heteroaryl, C1-C4alkoxy substituted with hydroxy, C1-C4alkoxy, amino and mono- and di-C1-C4alkylamino;
and
B is a group of the formula:
wherein
m, n and p are independently selected from 0 or 1;
R, R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, C1-C4alkyl, which alkyl is optionally substituted with hydroxy, amino or mono- and di-C1-C4akylamino;
R5 and R6 are independently selected from hydrogen and fluorine;
or
R and R3, taken in combination form a fused 5 or 6 member heterocyclic ring having 0 or 1 additional ring heteroatoms selected from N, O or S;
R1 and R3, taken in combination form a C1-C3alkylene group;
R1 and R5, taken in combination form a C1-C3alkylene group;
R3 and R4, taken in combination with the carbon atom to which they attach, form a spirocyclicC3-C6cycloalkyl;
X is CRARB, O, NR7 or a bond;
R7 is hydrogen, or C1-C4alkyl;
RA and RB are independently selected from hydrogen and C1-C4alkyl, or RA and RB, taken in combination, form a divalent C2-C5alkylene group;
Z is CR8 or N;
when Z is N, X is a bond;
R8 is hydrogen or taken in combination with R6 form a double bond;
or
B is a group of the formula:
wherein
p and q are independently selected from the group consisting of 0, 1, and 2;
R9 and R13 are independently selected from hydrogen and C1-C4alkyl;
R10 and R14 are independently selected from hydrogen, amino, mono- and di-C1-C4akylamino and C1-C4alkyl, which alkyl is optionally substituted with hydroxy, amino or mono- and di-C1-C4akylamino;
R11 is hydrogen, C1-C4alkyl, amino or mono- and di-C1-C4akylamino;
R12 is hydrogen or C1-C4alkyl;
or
R9 and R11, taken in combination form a saturated azacycle having 4 to 7 ring atoms which is optionally substituted with 1-3 C1-C4alkyl groups;
or
R11 and R12, taken in combination form a saturated azacycle having 4 to 7 ring atoms which is optionally substituted with 1-3 C1-C4alkyl groups.

28 more elements

A compound, or salt thereof, selected from the group consisting of

7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-2(1H)-one;
6-(6-((3aR,6aS)-5-methyl hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)quinolin-7-ol;
7-hydroxy-1-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-2(1H)-one;
6-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-morpholinoquinolin-7-ol;
4-chloro-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
3-bromo-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
3-ethyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
3-(1H-imidazol-1-yl)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(1-methyl-1H-imidazol-4-yl)quinolin-7-ol;
3-isopropyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoline-3,7-diol;
7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoline-3-carbonitrile;
6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
4-(dimethylamino)-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
3-chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
4-methoxy-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
6-(3-(benzyloxy)isoquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;
8-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinoline-1,6-diol;
7-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-6-ol;
1-cyclopropyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-6-ol;
7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-6-ol;
6-(1-(benzyloxy)isoquinolin-7-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine;
7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-6-ol;
2-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-6-ol;
2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)quinolin-7-ol;
2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
4-ethoxy-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
4-chloro-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-6-ol;
6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)quinolin-7-ol;
3-chloro-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-6-ol;
3-bromo-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-6-ol;
3-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-6-ol;
5-bromo-3-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-6-ol;
6-hydroxy-1-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-4(1H)-one;
2,3-dimethyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoxalin-6-ol;
2-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoxalin-6-ol;
3-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoxalin-6-ol;
4-methoxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
4-(azetidin-1-yl)-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
7-hydroxy-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoline-4-carbonitrile;
4-cyclopropyl-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
4-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)quinolin-7-ol;
2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(oxetan-3-yl)quinolin-7-ol;
4-(dimethylamino)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol;
7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinazolin-4(1H)-one;
6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinazolin-7-ol;
7-hydroxy-1-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3,4-dihydroquinolin-2(1H)-one;
7-hydroxy-1-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3,4-dihydroquinolin-2(1H)-one;
7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinoline-1-carbonitrile;
7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoline-2-carbonitrile;
6-hydroxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoline-2-carbonitrile;
6-hydroxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinoline-1-carboxamide;
7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoline-2-carboxamide;
6-hydroxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoline-2-carboxamide;
methyl 6-hydroxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoline-2-carboxylate;
6-hydroxy-7-(6-(piperazin-1-yl)pyridazin-3-yl)quinoline-2-carbonitrile;
7-hydroxy-6-(6-(piperazin-1-yl)pyridazin-3-yl)quinoline-2-carbonitrile;
7-(6-(piperazin-1-yl)pyridazin-3-yl)isoquinolin-6-ol;
7-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)quinolin-6-ol;
1-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-7-ol;
1-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-6-ol;
1,3-dimethyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-6-ol;
7-hydroxy-3-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinoline-1-carbonitrile;
1-amino-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-6-ol;
7-hydroxy-1,3-dimethyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinazoline-2,4(1H,3H)-dione;
6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzo[d]oxazol-2(3H)-one;
2-methyl-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2H-indazol-6-ol;
1-methyl-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1H-indazol-6-ol;
6-hydroxy-2-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-1(2H)-one;
2-ethyl-6-hydroxy-7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoquinolin-1(2H)-one;
1-ethoxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-6-ol;
7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoquinoline-1,6-diol;
7-(6-(methyl(2,2,6,6-tetramethyl-piperidin-4-yl)amino)-pyridazin-3-yl)-3-phenylisoquinolin-6-ol;
3-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-6-ol;
3-cyclopropyl-7-(6-(methyl(2,2,6,6-tetramethyl-piperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-6-ol;
3-isopropyl-7-(6-(methyl(2,2,6,6-tetramethyl-piperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-6-ol;
3-propyl-7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)-pyridazin-3-yl)isoquinolin-6-ol;
3-isopropyl-7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)-pyridazin-3-yl)isoquinolin-6-ol;
and
3-methyl-7-(6-(piperazin-1-yl)pyridazin-3-yl)isoquinolin-6-ol;

80 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/259,441Filed 28 Jan 2019
Priority: 31 Jul 2013
Published: 30 May 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

A61K 31/501
Pyridazines; Hydrogenated pyridazines: not condensed and containing further heterocyclic rings
A61K 31/502
Pyridazines; Hydrogenated pyridazines: ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
A61K 31/517
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol

Family

Application61/860,388Us provisional application · filed 31 Jul 2013
Application14/909,052Continuation · filed 29 Jan 2016
Application16/030,139Continuation · filed 9 Jul 2018
Application16/259,441Continuation
US 11,672,799 B2Related patent
US 2016/0184305 A1Published application
US 2019/0160062 A1This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound or salt thereof according to Formula (I)

wherein
A is bicyclic heteroaryl or heterocyle having 9 or 10 ring atoms and 1 or 2 ring N atoms and 0 or 1 O atoms, which bicyclic heteroaryl or heterocycle is substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from —C(O)NH2, —C(O)O—C1-C4alkyl, aryl, oxo, cyano, halogen, hydroxy, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkoxy, C3-C7cycloalkyl, heterocyclyl, heteroaryl, heterocyclyl C1-C4alkyl, C1-C4alkyl aryl, C1-C4alkyl heterocyclyl, C1-C4alkyl heteroaryl, C1-C4alkoxy aryl, C1-C4alkoxy heterocyclyl, C1-C4alkoxy heteroaryl, C1-C4alkoxy substituted with hydroxy, C1-C4alkoxy, amino and mono- and di-C1-C4alkylamino;
and
B is a group of the formula:
wherein
m, n and p are independently selected from 0 or 1;
R, R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, C1-C4alkyl, which alkyl is optionally substituted with hydroxy, amino or mono- and di-C1-C4akylamino;
R5 and R6 are independently selected from hydrogen and fluorine;
or
R and R3, taken in combination form a fused 5 or 6 member heterocyclic ring having 0 or 1 additional ring heteroatoms selected from N, O or S;
R1 and R3, taken in combination form a C1-C3alkylene group;
R1 and R5, taken in combination form a C1-C3alkylene group;
R3 and R4, taken in combination with the carbon atom to which they attach, form a spirocyclicC3-C6cycloalkyl;
X is CRARB, O, NR7 or a bond;
R7 is hydrogen, or C1-C4alkyl;
RA and RB are independently selected from hydrogen and C1-C4alkyl, or RA and RB, taken in combination, form a divalent C2-C5alkylene group;
Z is CR8 or N;
when Z is N, X is a bond;
R8 is hydrogen or taken in combination with R6 form a double bond;
or
B is a group of the formula:
wherein
p and q are independently selected from the group consisting of 0, 1, and 2;
R9 and R13 are independently selected from hydrogen and C1-C4alkyl;
R10 and R14 are independently selected from hydrogen, amino, mono- and di-C1-C4akylamino and C1-C4alkyl, which alkyl is optionally substituted with hydroxy, amino or mono- and di-C1-C4akylamino;
R11 is hydrogen, C1-C4alkyl, amino or mono- and di-C1-C4akylamino;
R12 is hydrogen or C1-C4alkyl;
or
R9 and R11, taken in combination form a saturated azacycle having 4 to 7 ring atoms which is optionally substituted with 1-3 C1-C4alkyl groups;
or
R11 and R12, taken in combination form a saturated azacycle having 4 to 7 ring atoms which is optionally substituted with 1-3 C1-C4alkyl groups.

28 more elements

Facts

Application

16/259,441Filed 28 Jan 2019

Priority

31 Jul 2013

Published

30 May 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification16 codes

A61K 31/501
Pyridazines; Hydrogenated pyridazines: not condensed and containing further heterocyclic rings
A61K 31/502
Pyridazines; Hydrogenated pyridazines: ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
A61K 31/517
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol

Family

Application61/860,388Us provisional application · filed 31 Jul 2013

Application14/909,052Continuation · filed 29 Jan 2016

Application16/030,139Continuation · filed 9 Jul 2018

Application16/259,441Continuation

US 11,672,799 B2Related patent

US 2016/0184305 A1Published application

US 2019/0160062 A1This patent

From the US filing history. Foreign family members aren’t listed.