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

Abstract

The present invention provides a compound of formula IA or a pharmaceutically acceptable salt thereof; 5 (IA) 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.

What is claimed is: 
     
         1 . 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)NH 2 , —C(O)O—C 1 -C 4 alkyl, aryl, oxo, cyano, halogen, hydroxy, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, heterocyclyl, heteroaryl, heterocyclyl C 1 -C 4 alkyl, C 1 -C 4 alkyl aryl, C 1 -C 4 alkyl heterocyclyl, C 1 -C 4 alkyl heteroaryl, C 1 -C 4 alkoxy aryl, C 1 -C 4 alkoxy heterocyclyl, C 1 -C 4 alkoxy heteroaryl, C 1 -C 4 alkoxy substituted with hydroxy, C 1 -C 4 alkoxy, amino and mono- and di-C 1 -C 4 alkylamino; and 
         B is a group of the formula: 
       
       
         
           
           
               
               
           
         
         wherein 
         m, n and p are independently selected from 0 or 1; 
         R, R 1 , R 2 , R 3 , and R 4  are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, which alkyl is optionally substituted with hydroxy, amino or mono- and di-C 1 -C 4 akylamino; 
         R 5  and R 6  are independently selected from hydrogen and fluorine; or 
         R and R 3 , taken in combination form a fused 5 or 6 member heterocyclic ring having or 1 additional ring heteroatoms selected from N, O or S; 
         R 1  and R 3 , taken in combination form a C 1 -C 3 alkylene group; 
         R 1  and R 5 , taken in combination form a C 1 -C 3 alkylene group; 
         R 3  and R 4 , taken in combination with the carbon atom to which they attach, form a spirocyclicC 3 -C 6 cycloalkyl; 
         X is CR A R B , O, NR 7  or a bond; 
         R 7  is hydrogen, or C 1 -C 4 alkyl; 
         R A  and R B  are independently selected from hydrogen and C 1 -C 4 alkyl, or R A  and R B , taken in combination, form a divalent C 2 -C 5 alkylene group; 
         Z is CR 8  or N; when Z is N, X is a bond; 
         R 8  is hydrogen or taken in combination with R 6  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; 
         R 9  and R 13  are independently selected from hydrogen and C 1 -C 4 alkyl; 
         R 10  and R 14  are independently selected from hydrogen, amino, mono- and di-C 1 -C 4 akylamino and C 1 -C 4 alkyl, which alkyl is optionally substituted with hydroxy, amino or mono- and di-C 1 -C 4 akylamino; 
         R 11  is hydrogen, C 1 -C 4 alkyl, amino or mono- and di-C 1 -C 4 akylamino; 
         R 12  is hydrogen or C 1 -C 4 alkyl; or 
         R 9  and R 11 , taken in combination form a saturated azacycle having 4 to 7 ring atoms which is optionally substituted with 1-3 C 1 -C 4 alkyl groups; or 
       
       R 11  and R 12 , taken in combination form a saturated azacycle having 4 to 7 ring atoms which is optionally substituted with 1-3 C 1 -C 4 alkyl groups. 
     
     
         2 . The compound of  claim 1 , or salt thereof, wherein A is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein 
       u and v are each, independently, 0, 1, 2 or 3; and 
       each R a  and R b  are, independently, selected from, cyano, halogen, hydroxy, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, heterocyclyl, heteroaryl, heterocyclyl C 1 -C 4 alkyl, C 1 -C 4 alkyl aryl, C 1 -C 4 alkyl heterocyclyl, C 1 -C 4 alkyl heteroaryl, C 1 -C 4 alkoxy aryl, C 1 -C 4 alkoxy heterocyclyl, C 1 -C 4 alkoxy heteroaryl, and C 1 -C 4 alkoxy substituted with hydroxy, C 1 -C 4 alkoxy, amino and mono- and di-C 1 -C 4 alkylamino. 
     
     
         3 . A compound according to  claim 1 , or salt thereof, wherein A is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound, according to  claim 1 , or salt thereof, wherein the compound is of formula II: 
       
         
           
           
               
               
           
         
       
       wherein 
       R c  and R d  are each, independently, selected from hydrogen, cyano, halogen, hydroxy, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, heterocyclyl, heteroaryl, heterocyclyl C 1 -C 4 alkyl, C 1 -C 4 alkyl aryl, C 1 -C 4 alkyl heterocyclyl, C 1 -C 4 alkyl heteroaryl, C 1 -C 4 alkoxy aryl, C 1 -C 4 alkoxy heterocyclyl, C 1 -C 4 alkoxy heteroaryl, C 1 -C 4 alkoxy substituted with hydroxy, C 1 -C 4 alkoxy, amino and mono- and di-C 1 -C 4 alkylamino. 
     
     
         5 . A compound, or salt thereof, according to  claim 1 , wherein the compound is of formula III: 
       
         
           
           
               
               
           
         
       
       wherein 
       R c  and R d  are each, independently, selected from hydrogen, cyano, halogen, hydroxy, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, heterocyclyl, heteroaryl, heterocyclyl C 1 -C 4 alkyl, C 1 -C 4 alkyl aryl, C 1 -C 4 alkyl heterocyclyl, C 1 -C 4 alkyl heteroaryl, C 1 -C 4 alkoxy aryl, C 1 -C 4 alkoxy heterocyclyl, C 1 -C 4 alkoxy heteroaryl, C 1 -C 4 alkoxy substituted with hydroxy, C 1 -C 4 alkoxy, amino and mono- and di-C 1 -C 4 alkylamino. 
     
     
         6 . A compound, according to  claim 1 , or salt thereof, wherein the compound is of formula IV: 
       
         
           
           
               
               
           
         
       
       wherein 
       R c  and R d  are each, independently, selected from hydrogen, cyano, halogen, hydroxy, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, heterocyclyl, heteroaryl, heterocyclyl C 1 -C 4 alkyl, C 1 -C 4 alkyl aryl, C 1 -C 4 alkyl heterocyclyl, C 1 -C 4 alkyl heteroaryl, C 1 -C 4 alkoxy aryl, C 1 -C 4 alkoxy heterocyclyl, C 1 -C 4 alkoxy heteroaryl, C 1 -C 4 alkoxy substituted with hydroxy, C 1 -C 4 alkoxy, amino and mono- and di-C 1 -C 4 alkylamino. 
     
     
         7 . A compound, according to  claim 1 , or salt thereof, wherein the compound is of formula V: 
       
         
           
           
               
               
           
         
       
       wherein 
       R c  and R d  are each, independently, selected from hydrogen, cyano, halogen, hydroxy, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, heterocyclyl, heteroaryl, heterocyclyl C 1 -C 4 alkyl, C 1 -C 4 alkyl aryl, C 1 -C 4 alkyl heterocyclyl, C 1 -C 4 alkyl heteroaryl, C 1 -C 4 alkoxy aryl, C 1 -C 4 alkoxy heterocyclyl, C 1 -C 4 alkoxy heteroaryl, C 1 -C 4 alkoxy substituted with hydroxy, C 1 -C 4 alkoxy, amino and mono- and di-C 1 -C 4 alkylamino. 
     
     
         8 . A compound, according to  claim 1 , or salt thereof, wherein the compound is of formula VI: 
       
         
           
           
               
               
           
         
       
       wherein 
       R c  and R d  are each, independently, selected from hydrogen, cyano, halogen, hydroxy, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, heterocyclyl, heteroaryl, heterocyclyl C 1 -C 4 alkyl, C 1 -C 4 alkyl aryl, C 1 -C 4 alkyl heterocyclyl, C 1 -C 4 alkyl heteroaryl, C 1 -C 4 alkoxy aryl, C 1 -C 4 alkoxy heterocyclyl, C 1 -C 4 alkoxy heteroaryl, C 1 -C 4 alkoxy substituted with hydroxy, C 1 -C 4 alkoxy, amino and mono- and di-C 1 -C 4 alkylamino. 
     
     
         9 . A compound, according to  claim 1 , or salt thereof, wherein the compound is of formula VII: 
       
         
           
           
               
               
           
         
       
       wherein 
       R c  and R d  are each, independently, selected from hydrogen, cyano, halogen, hydroxy, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, heterocyclyl, heteroaryl, heterocyclyl C 1 -C 4 alkyl, C 1 -C 4 alkyl aryl, C 1 -C 4 alkyl heterocyclyl, C 1 -C 4 alkyl heteroaryl, C 1 -C 4 alkoxy aryl, C 1 -C 4 alkoxy heterocyclyl, C 1 -C 4 alkoxy heteroaryl, C 1 -C 4 alkoxy substituted with hydroxy, C 1 -C 4 alkoxy, amino and mono- and di-C 1 -C 4 alkylamino. 
     
     
         10 . A compound, according to  claim 1 , or salt thereof, wherein the compound is of formula VIII: 
       
         
           
           
               
               
           
         
       
       wherein 
       R c  and R d  are each, independently, selected from hydrogen, cyano, halogen, hydroxy, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkyl, heterocyclyl, heteroaryl, heterocyclyl C 1 -C 4 alkyl, C 1 -C 4 alkyl aryl, C 1 -C 4 alkyl heterocyclyl, C 1 -C 4 alkyl heteroaryl, C 1 -C 4 alkoxy aryl, C 1 -C 4 alkoxy heterocyclyl, C 1 -C 4 alkoxy heteroaryl, C 1 -C 4 alkoxy substituted with hydroxy, C 1 -C 4 alkoxy, amino and mono- and di-C 1 -C 4 alkylamino. 
     
     
         11 . The compound of  claim 1 , wherein B is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein X is O or N(Me) or NH; and 
         R 17  is hydrogen or methyl. 
       
     
     
         12 . 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-methylhexahydropyrrolo[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-(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;   
     
     
         13 . 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. 
     
     
         14 . A combination comprising a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof and one or more therapeutically active co-agents. 
     
     
         15 . A method to treat, prevent or ameliorate an SMN-deficiency-related condition, comprising administering to a subject in need thereof an effective amount of a compound or salt thereof of  claim 1 .