Inhibitors of TRPC6

Abstract

The invention related to compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein R 1 to R 2 , A, Y and L are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

What is claimed is: 
     
       1. A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         L is absent or is methylene or ethylene; 
         Y is CH or N; 
         A is CH or N; 
         R 1  is selected from the group consisting of: 
         C 1-6 alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, C 3-6 cycloalkyl and OC 3-6 cycloalkyl; 
         phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of CF 3 , halo, C 3-6 cycloalkyl, OC 3-6 cycloalkyl, and OC 1-6 alkyl; wherein said OC 1-6 alkyl may be optionally substituted with one to three halo; and 
         C 3-6 cycloalkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halo and C 1-6 alkyl optionally substituted with 1 to 3 halo; 
         R 2  is selected from the group consisting of H, C 1-6 alkyl, OCF 3 , C 3-6 cycloalkyl, OC 3-6 alkyl, and OC 3-6 cycloalkyl; 
         R 3  is selected from the group consisting of H; C_alkyl, C 3-6 cycloalkyl, and OC 3-6 cycloalkyl; wherein each of the C 1-6 alkyl, C 3-6 cycloalkyl, or OC 3-6 cycltoalkyl of the R 3  group may independently be optionally substituted with one to three groups each independently selected from the group consisting of halo, OH, OC 1-6 alkyl, SC 1-6 alkyl, and N(C 1-6 alky) 2 ; and wherein one to three carbon atoms of the C 1-6 alkyl of the R 3  group may optionally be replaced one or two moieties selected from the group consisting of NH, N(C 1-6 alkyl), O, and S; 
         R 4  and R 5  are each independently selected from the group consisting of H and C 1-6 ,alkyl; or 
         R 3  and R 4  together with the atom to which they are attached may join to form a 3-membered carbocyclyl ring; or 
         R 3  and R 5  together with the atoms to which they are attached may join to form a 3- to 9-membered bicyclic ring, wherein said 3- to 9-membered bicyclic ring may optionally contain one to three heteroatoms selected from the group consisting of N, O, and S; 
         R 6  is selected from the group consisting of H, C 1-6 alkyl, CN, CF 3 , OCF 3 , C 3-6 cycloalkyl, OC 1-6 alkyl, and OC 3-6 cycloalkyl; 
         R 7  is selected from the group consisting of H and OC 1-6 alkyl; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       2. The compound according to  claim 1 , wherein
 R 1  is selected from the group consisting of: 
 C 1-6 alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halo and C 3-6 cycloalkyl; 
 phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of CF 3 , halo, OC 3-6 cycloalkyl, and OC 1-6 alkyl; wherein said OC 1-6 alkyl may be optionally substituted with one to three halo; and 
 C 3-6 cycloalkyl optionally substituted with 1 to 3 halo groups; 
 R 2  is OC 1-6 alkyl; 
 R 3  is selected from the group consisting of H and C 1-6 alkyl, optionally substituted with OH or OC 1-6 alkyl; 
 R 4 is H; 
 R 5  is H; or 
 R 3  and R 4  together with the atom to which they are attached may join to form a 3-membered carbocyclyl ring; and R 
 R 3  and R 5  together with the atoms to which they are attached may join to form a 3- to 9-membered bicyclic ring, wherein said 3- to 9-membered bicyclic ring may optionally contain one to three heteroatoms selected from the group consisting of N and O; 
 R 6  is selected from the group consisting of H; C 1-6 alkyl, OC 1-6 alkyl, and OC 3-6 cycloalkyl; and 
 R 7  is selected from the group consisting of H and OC 1-6 alkyl; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       3. The compound according to  claim 1 , wherein
 A is CH and Y is N; or 
 A is CH and Y is CH; or 
 A is N and Y is CH; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       4. The compound according to  claim 1 , wherein
   1  is phenyl optionally substituted with a group selected from the group consisting of CF 3 , halo, OC 3-6 cycloalkyl, and OC 1-6 alkyl; wherein the OC 3-6  alkyl may be optionally substituted with one to three halo; 
 R 2  is OC 1-6 alkyl; 
 R 3  is selected from the group consisting of H and C 1-6 alkyl optionally substituted with OH or OC 1-6 alkyl; 
 R 4  is H; 
 R 5  is H; or 
 R 3  and R 4  can together with the atom to which they are attached may join to form a 3-membered carbocyclyl ring; or 
 R 3  and R 5  together with the atoms to which they are attached may join to form a 3- to 9-membered bicyclic ring, wherein said 3- to 9-membered bicyclic ring may optionally contain one to three heteroatoms selected from the group consisting of N and O; 
 R 6  is selected from the group consisting of H, C 1-6 alky, OC 1-6 alkyl, and OC 3-6 cycloalkyl; 
 R 7  is selected from the group consisting of H and OC 1-6 alkyl; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       5. The compound according to  claim 1 , wherein
 R 1  is phenyl optionally substituted with a group selected from the group consisting of CF 3 , OCF 3 , F, and methoxy; 
 R 2  is selected from the group consisting of methoxy or ethoxy; 
 R 3  is selected from the group consisting of H, C 1-6 alkyl, 2-hydroxymethyl, methoxymethyl, and 1-hydroxyethyl; 
 R 4  is H; 
 R 5  is H; or 
 R 3  and R 4  together with the atom to which they are attached may join to form a 3-membered carbocyclyl ring; or 
 R 3  and R 5  together with the atoms to which they are attached may join to form a 3- to 9-membered bicyclic ring, wherein said 3- to 9-membered bicyclic ring may optionally contain one to three heteroatoms selected from the group consisting of N, O, and S; 
 R 6  is selected from the group consisting of H, methyl, methoxy, ethoxy, propoxy, and cyclopropyloxy; and 
 R 7  is selected from the group consisting of H and methoxy; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       6. The compound according to  claim 1 , wherein
 R 1  together with L represent a group selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethyiphenyl, 4-difluoromethoxyphenyl 4-cyclopropyloxyphenyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, 2-fluorobenzyl, and phenylethyl; and 
 R 2  is methoxy or ethoxy; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       7. The compound according to  claim 1 , wherein
 Y is CH and A is N; 
 R 1  together with L represent a group selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4difluoromethoxyphenyl, 4-cyclopropoxyphenyl, benzyl, 2-fluorobenzyl, and phenylethyl; 
 R 2  is methoxy or ethoxy; 
 R 3 , R 4  and R 5  are each H; 
 R 6  is H, methyl, methoxy, or ethoxy; and 
 R 7  is H; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       8. The compound according to  claim 1 , wherein
 Y is CH and A is CH; 
 R 1  together with L represent a group selected from the group consisting of phenyl, 4-chlorophenyi, 4-fluorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, cyclopentyl, cyclohexyl, benzyl, 2-fluorobenzyl, and phenylethyl; 
 R 2  is methoxy or ethoxy; 
 R 3 , R 4  and R 5  are each H; 
 R 6  is H, methyl, methoxy or ethoxy; and 
 R 7  is H; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       9. The compound according to  claim 1 , wherein
 Y is N and A is CH; 
 R 1  together with L represent a group selected from the group consisting of phenyl, and 4-fluorophenyl; 
 R 2  is methoxy; 
 R 3  is selected from the group consisting of H, 2-hydroxymethyl, and hydroxyethyl; 
 R 4  is H; 
 R 5  is H; or 
 R 3  and R 4  together with the atom to which they are attached may join to form a 3-membered carbocyclyl ring; or 
 R 3  and R 5  together with the atoms to which they are attached may join to form a 3- to 9-membered bicyclic ring, wherein said 3- to 9-membered bicyclic ring may optionally contain one to three heteroatoms selected from the group consisting of N, O, and S; 
 R 6  is selected from the group consisting of H and methoxy; and 
 R 7  is H; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       10. The compound according to  claim 1 , wherein
 R 1  is C 1-6 alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halo and C 3-6 cycloalkyl; 
 R 2  is OC 1-6 alkyl; 
 R 3 , R 4  and R 5  are each H; 
 R 6  is selected from the group consisting of H, C 1-6 alkyl, and OC 1-6 alkyl; and 
 R 7  is H; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       11. The compound according to  claim 1 , wherein
 R 1  together with L represent a group selected from the group consisting ethyl, propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobulylmethyl, 2,2-dimethylpropyl, 1-methylcyclopropylmethyl, 1-fluoromethylcyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclopentyl, cyclohexyl, 2,2difluorocyclobutylmethyl, 3,3difluorocyclobutylmethyl, 3-(trifluoromethyl)cyclobutylmethyl, and 3,3,3-trifluoro-2-methyl-propyl; 
 R 2  is methoxy; 
 R 3 , R 4  and R 5  are each H; 
 R 6  is selected from the group consisting of H, methyl, and methoxy; and 
 R 7  is H; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       12. The compound according to  claim 1 , wherein
 Y is CH and A is N; 
 R 1  together with L represent a group selected from the group consisting propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 2,2-dimethylpropyl, 1-cyclopropylethyl, and 2-cyclopropylethyl; 
 R 2  is methoxy; 
 R 3 , R 4  and R 5  are each H; 
 R 6  is selected from the group consisting of H, methyl, and methoxy; and 
 R 7  is H; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       13. The compound according to  claim 1 , wherein
 Y is CH and A is CH; 
 R 1  together with L represent a group selected from the group consisting ethyl, propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 2,2-dimethylpropyl, 1-methylcyclopropylmethyl, 1-fluoromethylcyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclobutylmethyl, 3,3-difluorocyclobutylmethyl, 3-(trifluoromethyl)cyclobutylmethyl, and 3,3,3-trifluoro-2-methyl-propyl; 
 R 2  is methoxy; 
 R 3 , R 4  and R 5  are each H; 
 R 6  is selected from the group consisting of H, methyl, and methoxy; and 
 R 7  is H; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       14. The compound according to  claim 1 , wherein
 R 3  and R 4  together with the atom to which they are attached join to form a 3-membered carbocyclyl ring, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       15. The compound according to  claim 1 , wherein
 R 3  and R 5  together with the atoms to which they are attached join to form a 3- to 9-membered bicyclic ring, wherein said 3- to 9-membered bicyclic ring may optionally contain one to two heteroatoms independently selected from the group consisting of N and O, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       16. The compound according to  claim 1 , selected from the group consisting of
 [4-(6-Amino-4-methoxy-pyridin-3-yl)-piperazin-1-yl][5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]methanone, 
 (6-Amino-4-methyl-3′,4′,5′, 6′-tetrahydro-2′H-[3,4′]-bipyridinyi-1′-yl)[5-(4-fluoro-phenoxy)-4-methoxypyridin-2-yl]-methanone, 
 (6-Amino-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′yl)-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-l1′-yl)[5-(4-fluoro-phenoxy)-4-methoxypyridin-2-yl]-methanone, 
 
       [4-(6-Amino-4-methoxy-pyridin-3-yl)-piperazin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone, 
       [4-(6-Amino-pyridazin-3-yl)-piperidin-1yl]-[5-(4-isopropoxy-phenoxy)-4-methoxy-pyridin-2yl]-methanone, 
       [(R)-4-(6-Amino-4-methyl-pyridin-3-yl)-2-hydroxymethyl-piperazin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone,
 [7-(6-Amino-4 -methoxy-pyridin-3 -yl)-4,7-diaza-spiro [2.5]oct-4yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)methanone, 
 [7-(6-Amino-4-methoxy-pyridin-3-yl)-4,7-diaza-spiro [2.5]oct-4-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 (6-Amino-4-methyl-3′,4′,5′,6′-tetrahydro-2′H-[3,4]bipyridinyl-1′-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl)methanone, 
 [4-(6-Amino-5 -methoxy-pyridazin-3-yl)-piperidin-1yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 [4-(6-Amino-pyridin-3-yl)-piperazin-1 -yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone, 
 [4-(6-Amino-pyridin-3-yl)-piperazin-1-yl]-[5-(4-fuorophenoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 (6-Amino-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]pyridinyl-1′yl)-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]methanone, 
 [4-(6-Amino-pyridin-3-yl)-piperazin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 [(R)-4-(6-Amino-4-methyl-pyridin-3-yl)-2-hydroxymethyl-piperazin-1-yl]-(4-methoxy-5 -phenoxy-pyridin-2-yl)-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(2-fluoro-benzyloxy)-4-methoxypyridin-2-yl]-methanone, 
 [(R)-4-(6-Amino-pyridin-3-yl)-2-hydroxymethyl-piperazin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 [4-(6-Amino-5-methoxy-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone, 
 (6-Amino-3′,4′,5′,6′-tetrahydro-2′H-[3,4′-]bipyridinyl-1′-yl)-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2-yl]-methanone, 45 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(5-cyclobutylmethoxy-4-methoxy-pyridin-2-yl)-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[4-methoxy-5-(1-methyl-cyclopropylmethoxy)-pyridin-2-yl]-methanone, 
 [(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2-methoxymethyl-piperazin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[4-methoxy-5-(4-methoxy-phenoxy)pyridin-2yl]-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(5-cyclohexyloxy-4-methoxy-pyridin-2-yl)-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydrp-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(4-fluoro-benzyloxy)-4-methoxypyridin-2-yl]-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2-yl]-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4chloro-phenoxy)-4 -methoxy-pyridin-2-yl]-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridiny 1′-yl)-(5-cyclopentyloxy4-methoxy-pyridin-2-yl)-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(5-isobutoxy-4-methoxy-pyridin-2-yl)-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(5-cyclopropylmethoxy-4-methoxypyridin-2-yl)-methanone, 
 [3-(6-Amino-4-methoxy-pyridin-3-yl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-[5-(4-fluoro-phenoxy)-4-methoxypyridin-2-yl]-methanone, 
 (6-Amino 4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(5-isobutoxy-4-methoxy-pyridin-2-yl)-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-cyclopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 [4-(6-Amino-pyridazin-3 -yl)-piperidin-1-yl]-[5-(4-fluoro-benzyloxy)-4-methoxy-pyridin-2-yl]-methanone, 
 [(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2-hydroxymethyl-piperazin-1-yl]-[5 -(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(5-benzyloxy-4-methoxy-pyridin-2-yl)-methanone, 
 [4-(6-Amino-pyridazin-3 -yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone, 
 (6-Amino-4-metboxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(3,3-difluoro-cyclobutylmethoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(4-methoxy-5-propoxy-pyridin-2-yl)-methanone, 
 [4-(6-Amino-4-methoxy-pyridazin-3 -yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(2-cyclopropyl-ethoxy)-4-methoxypyridin-2yl]-methanone, 
 (1R)-1-[(2R)-4-(6-amino-4-methoxypyridin-3-yl)-1-(5-phenoxypyridine-2-carbonyl)piperazin-2-yl]ethan-1-ol, 
 [3-(6-Amino-4-methoxy-pyridin-3-yl)-3,8-diaza-bicylo[3.2.1]oct-8-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(4-methoxy-5-phenethyloxy-pyridin-2-yl)-methanone, 
 (6-Amino-4- methoxy-3′,4′,5′,6′-tetrabydro-2′H-[3,4′]bipyridinyl-1′-yl)-(5-cyclobutylmethoxy-4-methoxypyridin-2-yl)-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5(4-difluoromethoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 [(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2methoxymethyl-piperazin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(2-fluoro-benzyloxy)-4-methoxy-pyridin-2-yl]-methanone, 
 (1S)-1-[(2R)-4-(6-amino-4-methoxypyridin-3-yl)-1-(5-phenoxypyridine-2 -carbonyl)piperazin-2-yl]ethan-1-ol, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(2,2-dimethyl-propoxy)-4-methoxy-pyridin-2yl]methanone, 
 [4-(6-Amino-5-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone, 
 [4-(6-Amino-4-methoxy-pyridin-3-yl)-piperazin-1-yl]-(5-cyclopropylmethoxy-4-methoxy-pyridin-2-yl)-methanone, [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(5-cyclohexyloxy-4-methoxy-pyridin-2-yl)-methanone, 
 [(S)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2-hydroxymethyl-piperazin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6″-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(1-fluoromethyl-cyclopropylmethoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(5-ethoxy-4-methoxy-pyridin-2-yl)-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(2-cyclopropyl-ethoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 [7-(6-Amino-4-methoxy-pyridin-3-yl)-3-oxa-9aza-bicyclo[3.3.1]non-9-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone, 
 [(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2-hydroxymethyl-piperazin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-((S)-1-cyclopropyl-ethoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 [(S)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2-hydroxymethyl-piperazin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-(5-isopropoxy-4-methoxy-pyridin-2-yl)-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenethyloxy-pyridin-2-yl)-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(2,2-dimethyl-propoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(1-methyl-cyclopropylmethoxy)-pyridin-2-yl]-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-propoxy-pyridin-2-yl)-methanone, 
 (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-((R)-1-cyclopropyl-ethoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 [4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-(5-cyclopropylmethoxy-4-methoxy-pyridin-2-yl)-methanone, 
 [4-(6-Amino-pyridazin-3 -yl)-piperidin-1-yl]-[5-((S)-1-cyclopropyl-ethoxy)-4 -methoxy-pyridin-2-yl]-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethoxy-phenoxy)-pyridin-2yl]-methanone, 
 [(R)-4-(6-Amino-pyridin-3-yl)-2-hydroxymethyl-piperazin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone, 
 [(R)-4-(6-Amino-pyridin-3-yl)-2-hydroxymethyl-piperazin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2yl]-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1yl]-[5-(phenoxy)-4-ethoxy-pyridin-2yl]-methanone, 
 (6-Amino-4-cyclopropoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]biphyidinyl-1′-yl)-[5-(phenoxy)-4-methoxy-pyridin-2yl]-methanone, 
 (6-Amino-4-propoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5-(phenoxy)-4-methoxy-pyridin-2-yl]-methanone, 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-ethoxy-pyridin-2-yl]-methanone, 
 [3-(6-Amino-pyridazin-3-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-[4-ethoxy-5-(4-fluoro-phenoxy)-pyridin-2-yl]-methanone, 
 5-Methoxy-6-(1-{5-[4-(trifluoromethyl)-phenoxy]-pyridine-2-carbonyl}piperidin-4-yl)-pyridazin-3-amine, 
 4-Methoxy-5-[1-(4-methoxy-5-{[trans-3-(trifluoromethyl)cyclobutyl]-methoxy}pyridine-2-carbonyl)-piperidin-4-yl]pyridin-2-amine, 
 4-Methoxy-5-[1-(4-methoxy-5-{[(cis-3-(trifluoromethyl)-cyclobutyl]methoxy}-pyridine-2-carbonyl)piperidin-4-yl]pyridin-2-amine, 
 4-Methoxy-5-(1-{4-methoxy-5-[(2)-3,3,3-trifluoro-2-methylpropoxy]-pyridine-2-carbonyl}peridin-4-yl)pyridin-2-amine, and 
 5-(1-{5-[(2,2-Difluorocyclobutyl)-methoxy]-4-methoxypyridine-2-carbonyl}-piperidin-4-yl)-4-methoxypyridin-2-amine, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       17. A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. 
     
     
       18. A method for treating a disease or disorder that can be alleviated by TRPC6 inhibition the method comprising:
 administering a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, to patient in need thereof, 
 wherein the disease or disorder is selected from the group consisting of cardiac hypertrophy, ischemia, ischemic reperfusion injury, hypertension, pulmonary arterial hypertension, idiopathic pulmonary arterial hypertension, restenosis, chronic obstructive pulmonary disease, cystic fibrosis, kizheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), trauma induced brain disorders, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, multiple sclerosis, mus c -ular dystrophy. Duchenne's muscular dystrophy, preeclampsia and pregnancy-induced hypertension, non-alcoholic steatohepatitis, minimal change disease, focal segmental glomerulosclerosis (FSGS), nephrotic syndrome, diabetic nephropathy or diabetic kidney disease (DKD), chronic kidney disease, renal insufficiency, end stage renal disease, ischemia or an ischemic reperfusion injury, idiopathic pulmonary fibrosis (IPF), acute respiratory disease syndrome (ARDS), emphysema and diabetes. 
 
     
     
       19. The compound according to  claim 1 , selected from the group consisting of:
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-isopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-chloro-phenoxy)-4-methoxy-pyridin-2-yl]--methanone; 
 [4-(6-Amino-pyiidazin-3-yl)-piperidin-1-yl]-[5-(4-cyclopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-fluoro-benzyloxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-difluoromethoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3 -yl)-pipenridin-1-yl]-[5-(2-fluoro-benzyloxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethoxy-phenoxy)-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(phenoxy)-4-ethoxy-pyridin-2-yl]-methanone; and 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-ethoxy-pyridin-2-yl]-methanone; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       20. A pharmaceutically acceptable salt of the compound according to  claim 19 , selected from the group consisting of:
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-isopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridine-2-yl)-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-chloro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-cyclopropoxy -phenoxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-benzyloxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1yl]-[5-(4-difluoromethoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(2-fluoro-benzyloxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethoxy-phenoxy)-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(phenoxy)-4-ethoxy-pyridin-2-yl]-methanone; and 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-ethoxy-pyridin-2-yl]-methanone. 
 
     
     
       21. The compound according to  claim 19 , selected from the group consisting of:
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-isopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4 -(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-chloro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-cyclopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-benzyloxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-difluoromethoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(2-fluoro-benzyloxy)-4-methoxy-pyridin-2-yl]-methanone; 
 [4 -(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethoxy-phenoxy)-pyridin-2-yl]-mthanone; 
 [4-(6- Amino-pyridazin-3-yl)-piperidin-1yl]-[5-(phenoxy)-4-ethoxy-pyridin-2-yl]-methanone; and 
 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-ethoxy-pyridin-2-yl]-methanone. 
 
     
     
       22. A compound, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-isopropoxy-phenoxy)-4-methoxypyridin-2-yl]-methanone. 
     
     
       23. A compound, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone. 
     
     
       24. A compound, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone. 
     
     
       25. A compound, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-difluoromethoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone. 
     
     
       26. A compound, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethoxy-phenoxy)-pyridin-2-yl]-methanone. 
     
     
       27. A compound, which is [4-(6-Amino-pyridazin-3-yl)-piperidni-1-yl]-[5-(phenoxy)-4-ethoxy-pyridin-2-yl]-methanone. 
     
     
       28. The compound of  claim 4 , wherein R 1  is phenyl optionally substituted with OCF 3 . 
     
     
       29. The compound of claim 19, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-isopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone, or a pharmaceutically acceptable salt thereof.  
     
     
       30. The compound of claim 19, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone, or a pharmaceutically acceptable salt thereof.  
     
     
       31. The compound of claim 19, which is [4-(6-Amino-pyridazin-3-yl)-piperidin1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone, or a pharmaceutically acceptable salt thereof.  
     
     
       32. The compound of claim 19, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-difluoromethoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone, or a pharmaceutically acceptable salt thereof.  
     
     
       33. The compound of claim 19, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethoxy-phenoxy)-pyridin-2-yl]-methanone, or a pharmaceutically acceptable salt thereof.  
     
     
       34. The compound of claim 19, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(phenoxy)-4-ethoxy-pyridin-2-yl]-methanone, or a pharmaceutically acceptable salt thereof.  
     
     
       35. The pharmaceutically acceptable salt form of the compound of claim 19, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-isopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone.  
     
     
       36. The pharmaceutically acceptable salt form of the compound claim 19, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone.  
     
     
       37. The pharmaceutically acceptable salt form of the compound of claim 19, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone.  
     
     
       38. The pharmaceutically acceptable salt form of the compound of claim 19, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-difluoromethoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone.  
     
     
       39. The pharmaceutically acceptable salt form of the compound of claim 19, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethoxy-phenoxy)-pyridin-2-yl]-methanone.  
     
     
       40. The pharmaceutically acceptable salt form of the compound of claim 19, which is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(phenoxy)-4-ethoxy-pyridin-2-yl]-methanone.