Thiadiazole analogs thereof and methods for treating smn-deficiency-related-conditions

Abstract

The present invention provides a compound of Formula (X) 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.

What is claimed is: 
     
         1 . A compound, or salt thereof, which compound is represented by Formula (X) 
       
         
           
           
               
               
           
         
         wherein 
         A′ is phenyl which is substituted with 1, 2, or 3 substituents independently selected from 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 substituent selected from oxo, oxime and hydroxy, 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-C 1 -C 4 alkylamino, di-C 1 -C 4 alkylamino, heteroaryl, C 1 -C 4 alkyl substituted with hydroxy, C 1 -C 4 alkoxy substituted with aryl, —C(O)NHC 1 -C 4 alkyl-heteroaryl, —NHC(O)—C 1 -C 4 alkyl-heteroaryl, C 1 -C 4 alkylC(O)NH-heteroaryl, C 1 -C 4 alkylNHC(O)-heteroaryl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl and 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-C 1 -C 4 alkylamino, di-C 1 -C 4 alkylamino, —C(O)NH 2 , —NH 2 , —NO 2 , hydroxyC1-C 4 alkylamino, hydroxyC 1 -C 4 alkyl, 4-7member heterocycleC 1 -C 4 alkyl, aminoC 1 -C 4 alkyl, mono-C 1 -C 4 alkylaminoC 1 -C 4 alkyl and di-C 1 -C 4 alkylaminoC 1 -C 4 alkyl; or 
         A′ is 6 member heteroaryl having 1-3 ring nitrogen atoms, which 6 member heteroaryl is substituted by phenyl or a heteroaryl having 5 or 6 ring atoms, 1 or 2 ring heteroatoms independently selected from N, O and S, and substituted with 0, 1, or 2 substituents independently selected from C 1 -C 4 alkyl, mono-C 1 -C 4 alkylamino, di-C 1 -C 4 alkylamino, hydroxyC 1 -C 4 alkylamino, hydroxyC 1 -C 4 alkyl, aminoC 1 -C 4 alkyl, mono-C 1 -C 4 alkylaminoC 1 -C 4 alkyl and di-C 1 -C 4 alkylaminoC 1 -C 4 alkyl; or 
         A′ is bicyclic heteroaryl having 9 to 10 ring atoms and 1, 2, or 3 ring heteroatoms independently selected from N, O or S, which bicyclic heteroaryl is substituted with 0, 1, or 2 substituents independently selected from 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 1 -C 4 alkoxy substituted with hydroxy, C 1 -C 4 alkoxy, amino, mono-C 1 -C 4 alkylamino and di-C 1 -C 4 alkylamino; 
         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 0 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, 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′ , 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 
         Y is C or O and when Y is O R 11  and R 12  are both absent; 
         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 . A compound, or salt thereof, according to  claim 1 , wherein A′ is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . A compound, or a salt thereof, according to  claim 1 , which compound is represented by Formula (XX): 
       
         
           
           
               
               
           
         
         wherein 
         R b  is hydrogen or hydroxy; 
         R c  is hydrogen or halogen; and 
         R d  is halogen. 
       
     
     
         4 . A compound, or salt thereof, according to  claim 1 , wherein B is selected from 
       
         
           
           
               
               
           
         
         wherein Z is NH or N(Me). 
       
     
     
         5 . A compound, or salt thereof, according to  claim 4 , wherein B is 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound, or salt thereof, according to  claim 1 , wherein B is selected from 
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound, or salt thereof, according to  claim 6  wherein B is 
       
         
           
           
               
               
           
         
       
     
     
         8 . 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. 
     
     
         9 . 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. 
     
     
         10 . A method to treat 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 . 
     
     
         11 . The method of  claim 15 , wherein said SMN-deficiency-related condition is Spinal Muscular Atrophy. 
     
     
         12 . A compound, or salt thereof, which compound is represented by Formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         Y is N or C—R a ; 
         R a  is hydrogen or C 1 -C 4 alkyl; 
         R b  is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, cyano, halogen, trihalo C 1 -C 4 alkyl or trihalo C 1 -C 4 alkoxy; 
         R c  and R d  are each, independently, hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, trihalo C 1 -C 4 alkyl, trihalo C 1 -C 4 alkoxy or heteroaryl; 
         A is 6 member heteroaryl having 1-3 ring nitrogen atoms, which 6 member heteroaryl is substituted with 0, 1, or 2 substituents independently selected from oxo, C 1 -C 4 alkyl, mono- and di-C 1 -C 4 alkylamino, hydroxyC 1 -C 4 alkylamino, hydroxyC 1 -C 4 alkyl, aminoC 1 -C 4 alkyl and mono- and di-C 1 -C 4 alkylaminoC 1 -C 4 alkyl; or 
         A is 5 member heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S and substituted with 0, 1, or 2 substituents independently selected from C 1 -C 4 alkyl, hydroxyl, mono- and di-C 1 -C 4 alkylamino, hydroxyC 1 -C 4 alkylamino, hydroxyC 1 -C 4 alkyl, aminoC 1 -C 4 alkyl and mono- and di-C 1 -C 4 alkylaminoC 1 -C 4 alkyl; or 
         A and R c , together with the atoms to which they are bound, form a 6 member aryl with 1, or 2 substituents 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 and C 1 -C 4 alkoxy substituted with hydroxy, C 1 -C 4 alkoxy, amino and mono- and di-C 1 -C 4 alkylamino; 
         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 0 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′ , 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. 
       
     
     
         13 . A compound, or a salt thereof, according to  claim 3 , wherein A is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound, or salt thereof, according to  claim 12 , wherein B is selected from 
       
         
           
           
               
               
           
         
         wherein Z is NH or N(Me). 
       
     
     
         15 . A compound, or salt thereof, according to  claim 14 , wherein B is 
       
         
           
           
               
               
           
         
       
     
     
         16 . A compound, or salt thereof, according to  claim 12 , wherein B is selected from 
       
         
           
           
               
               
           
         
       
     
     
         17 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 12 , or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. 
     
     
         18 . A combination comprising a therapeutically effective amount of a compound according to  claim 12  or a pharmaceutically acceptable salt thereof and one or more therapeutically active co-agents. 
     
     
         19 . A method to treat 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 12 . 
     
     
         20 . The method of  claim 19 , wherein said SMN-deficiency-related condition is Spinal Muscular Atrophy.