1,4-DISUBSTITUTED PYRIDAZINE ANALOGS THERE OF AND METHODS FOR TREATING SMN-DEFICIENCY-RELATED CONDITIONS

摘要

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.

主权项

1. A compound or salt thereof according to Formula (I) A is 2-hydroxy-phenyl which is substituted with 0, 1, 2, or 3 substituents independently selected from C1-C4alkyl, wherein 2 C1-C4alkyl 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, haloC1-C4alkyl, dihaloC1-C4alkyl, trihaloC1-C4alkyl, C1-C4alkoxy, C1-C4alkoxy-C3-C7cycloalkyl, haloC1-C4alkoxy, dihaloC1-C4alkoxy, trihaloC1-C4alkoxy, hydroxy, cyano, halogen, amino, mono- and di-C1-C4alkylamino, heteroaryl, C1-C4alkyl substituted with hydroxy, C1-C4alkoxy substituted with aryl, amino, —C(O)NH C1-C4alkyl-heteroaryl, —NHC(O)—C1-C4alkyl-heteroaryl, C1-C4alkyl C(O)NH— heteroaryl, C1-C4alkyl 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, C1-C4alkyl, C1-C4alkenyl, C1-C4alkoxy, C3-C7cycloalkyl, C1-C4alkyl-OH, trihaloC1-C4alkyl, mono- and di-C1-C4alkylamino, —C(O)NH2, —NH2, —NO2, hydroxyC1-C4alkylamino, hydroxyC1-C4alkyl, 4-7 member heterocycleC1-C4alkyl, aminoC1-C4alkyl and mono- and di-C1-C4alkylaminoC1-C4alkyl; or 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-C4alkylamino; 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-C4alkylamino and C1-C4alkyl, which alkyl is optionally substituted with hydroxy, amino or mono- and di-C1-C4alkylamino; R11 is hydrogen, C1-C4alkyl, amino or mono- and di-C1-C4alkylamino; 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.