US2021163449A1PendingUtilityA1

Inhibitors of trpc6

Assignee: BOEHRINGER INGELHEIM INTPriority: Oct 27, 2017Filed: Dec 8, 2020Published: Jun 3, 2021
Est. expiryOct 27, 2037(~11.2 yrs left)· nominal 20-yr term from priority
A61P 25/28A61P 13/12A61P 3/10A61P 11/00A61P 9/00A61K 31/501C07D 213/04C07D 498/08C07D 487/08C07D 401/12C07D 451/02C07D 401/14A61K 31/45A61K 31/496
68
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Claims

Abstract

The invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 to R 7 , 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.

Claims

exact text as granted — not AI-modified
1 - 12 . (canceled) 
     
     
         13 . A method of treating cancer, wherein the cancer is brain cancer, breast cancer, kidney cancer, cervical cancer, prostate cancer, gastrointestinal cancer, skin cancer, or epithelial cancer,
 comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of:   
       
         
           
                 
                 
                 
               
                     
                 
                   Cmpd  
                     
                     
                 
                   No. 
                   Structure 
                   Compound Name 
                 
                     
                 
                     
                 
                 
                 
                 
               
                   1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-4-methoxy-pyridin-3-yl)- piperazin-1-yl]-[5-(4-fluoro-phenoxy)-4- methoxy-pyridin-2-yl]-methanone 
                 
                     
                 
                   2 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methyl-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]-bipyridinyl-1′-yl)-[5-(4-fluoro- phenoxy)-4-methoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   3 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-3′,4′,5′,6′-tetrahydro-2′H- [3,4′]bipyridinyl-1′-yl)-(4-methoxy-5- phenoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   4 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-[5-(4-fluoro- phenoxy)-4-methoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   5 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-4-methoxy-pyridin-3-yl)- piperazin-1-yl]-(4-methoxy-5-phenoxy- pyridin-2-yl)-methanone 
                 
                     
                 
                   6 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- [5-(4-isopropoxy-phenoxy)-4-methoxy- pyridin-2-yl]-methanone 
                 
                     
                 
                   7 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [(R)-4-(6-Amino-4-methyl-pyridin-3-yl)-2- hydroxymethyl-piperazin-1-yl]-[5-(4- fluoro-phenoxy)-4-methoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   8 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [7-(6-Amino-4-methoxy-pyridin-3-yl)-4,7- diaza-spiro[2.5]oct-4-yl]-(4-methoxy-5- phenoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   9 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [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 
                 
                     
                 
                   10 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methyl-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-(4-methoxy-5- phenoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   11 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-5-methoxy-pyridazin-3-yl)- piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4- methoxy-pyridin-2-yl]-methanone 
                 
                     
                 
                   12 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridin-3-yl)-piperazin-1-yl]- [4-methoxy-5-(4-methoxy-phenoxy)- pyridin-2-yl]-methanone 
                 
                     
                 
                   13 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridin-3-yl)-piperazin-1-yl]- [5-(4-fluoro-phenoxy)-4-methoxy-pyridin- 2-yl]-methanone 
                 
                     
                 
                   14 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-3′,4′,5′,6′-tetrahydro-2′H- [3,4′]bipyridinyl-1′-yl)-[5-(4-fluoro- phenoxy)-4-methoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   15 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridin-3-yl)-piperazin-1-yl]- (4-methoxy-5-phenoxy-pyridin-2-yl)- methanone 
                 
                     
                 
                   16 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- (4-methoxy-5-phenoxy-pyridin-2-yl)- methanone 
                 
                     
                 
                   17 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-l-yl]- [5-(4-fluoro-phenoxy)-4-methoxy-pyridin- 2-yl]-methanone 
                 
                     
                 
                   18 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [(R)-4-(6-Amino-4-methyl-pyridin-3-yl)-2- hydroxymethyl-piperazin-1-yl]-(4- methoxy-5-phenoxy-pyridin-2-yl)- methanone 
                 
                     
                 
                   19 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-[5-(2-fluoro- benzyloxy)-4-methoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   20 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [(R)-4-(6-Amino-pyridin-3-yl)-2- hydroxymethyl-piperazin-1-yl]-[5-(4- fluoro-phenoxy)-4-methoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   21 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-5-methoxy-pyridazin-3-yl)- piperidin-1-yl]-(4-methoxy-5-phenoxy- pyridin-2-yl)-methanone 
                 
                     
                 
                   22 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-3′,4′,5′,6′-tetrahydro-2′H- [3,4′]bipyridinyl-1′-yl)-[4-methoxy-5-(4- methoxy-phenoxy)-pyridin-2-yl]- methanone 
                 
                     
                 
                   23 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-(4-methoxy-5- phenoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   24 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (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 
                 
                     
                 
                   25 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- (5-cyclobutylmethoxy-4-methoxy-pyridin- 2-yl)-methanone 
                 
                     
                 
                   26 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (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 
                 
                     
                 
                   27 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)- 2-methoxymethyl-piperazin-1-yl]-(4- methoxy-5-phenoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   28 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-[4-methoxy-5- (4-methoxy-phenoxy)-pyridin-2-yl]- methanone 
                 
                     
                 
                   29 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-4-methyl-pyridazin-3-yl)- piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4- methoxy-pyridin-2-yl]-methanone 
                 
                     
                 
                   30 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-(5- cyclohexyloxy-4-methoxy-pyridin-2-yl)- methanone 
                 
                     
                 
                   31 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-4-methyl-pyridazin-3-yl)- piperidin-1-yl]-(4-methoxy-5-phenoxy- pyridin-2-yl)-methanone 
                 
                     
                 
                   32 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-[5-(4-fluoro- benzyloxy)-4-methoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   33 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- [4-methoxy-5-(4-trifluoromethyl-phenoxy)- pyridin-2-yl]-methanone 
                 
                     
                 
                   34 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- [5-(4-chloro-phenoxy)-4-methoxy-pyridin- 2-yl]-methanone 
                 
                     
                 
                   35 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-(5- cyclopentyloxy-4-methoxy-pyridin-2-yl)- methanone 
                 
                     
                 
                   36 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- (5-isobutoxy-4-methoxy-pyridin-2-yl)- methanone 
                 
                     
                 
                   37 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-(5- cyclopropylmethoxy-4-methoxy-pyridin-2- yl)-methanone 
                 
                     
                 
                   38 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [3-(6-Amino-4-methoxy-pyridin-3-yl)-3,8- diaza-bicyclo[3.2.1]oct-8-yl]-[5-(4-fluoro- phenoxy)-4-methoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   39 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-(5-isobutoxy-4- methoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   40 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- [5-(4-cyclopropoxy-phenoxy)-4-methoxy- pyridin-2-yl]-methanone 
                 
                     
                 
                   41 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- [5-(4-fluoro-benzyloxy)-4-methoxy-pyridin- 2-yl]-methanone 
                 
                     
                 
                   42 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2- hydroxymethyl-piperazin-1-yl]-[5-(4-fluoro- phenoxy)-4-methoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   43 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-(5-benzyloxy-4- methoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   44 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- [4-methoxy-5-(4-methoxy-phenoxy)- pyridin-2-yl]-methanone 
                 
                     
                 
                   45 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-[5-(3,3-difluoro- cyclobutylmethoxy)-4-methoxy-pyridin-2- yl]-methanone 
                 
                     
                 
                   46 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-(4-methoxy-5- propoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   47 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-4-methoxy-pyridazin-3-yl)- piperidin-1-yl]-(4-methoxy-5-phenoxy- pyridin-2-yl)-methanone 
                 
                     
                 
                   48 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-[5-(2-cyclopropyl- ethoxy)-4-methoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   49 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-4-methoxy-pyridazin-3-yl)- piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4- methoxy-pyridin-2-yl]-methanone 
                 
                     
                 
                   50 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (1R)-1 -[(2R)-4-(6-amino-4-methoxypyridin- 3-yl)-1-(5-phenoxypyridine-2- carbonyl)piperazin-2-yl]ethan-1-ol 
                 
                     
                 
                   51 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [3-(6-Amino-4-methoxy-pyridin-3-yl)-3,8- diaza-bicyclo[3.2.1]oct-8-yl]-(4-methoxy-5- phenoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   52 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-(4-methoxy-5- phenethyloxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   53 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-(5- cyclobutylmethoxy-4-methoxy-pyridin-2- yl)-methanone 
                 
                     
                 
                   54 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- [5-(4-difluoromethoxy-phenoxy)-4- methoxy-pyridin-2-yl]-methanone 
                 
                     
                 
                   55 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2- methoxymethyl-piperazin-1-yl]-[5-(4-fluoro- phenoxy)-4-methoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   56 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-4-methoxy-pyridazin-3-yl)- piperidin-1-yl]-[4-methoxy-5-(4- trifluoromethyl-phenoxy)-pyridin-2-yl]- methanone 
                 
                     
                 
                   57 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- [5-(2-fluoro-benzyloxy)-4-methoxy-pyridin- 2-yl]-methanone 
                 
                     
                 
                   58 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (1S)-1-[(2R)-4-(6-amino-4-methoxypyridin- 3-yl)-1-(5-phenoxypyridine-2- carbonyl)piperazin-2-yl]ethan-1-ol 
                 
                     
                 
                   59 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-[5-(2,2-dimethyl- propoxy)-4-methoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   60 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-5-methoxy-pyridazin-3-yl)- piperidin-1-yl]-[4-methoxy-5-(4-methoxy- phenoxy)-pyridin-2-yl]-methanone 
                 
                     
                 
                   61 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-4-methoxy-pyridin-3-yl)- piperazin-1-yl]-(5-cyclopropylmethoxy-4- methoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   62 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- (5-cyclohexyloxy-4-methoxy-pyridin-2-yl)- methanone 
                 
                     
                 
                   63 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [(S)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2- hydroxymethyl-piperazin-1-yl]-[5-(4-fluoro- phenoxy)-4-methoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   64 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (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 
                 
                     
                 
                   65 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-(5-ethoxy-4- methoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   66 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-4-methoxy-pyridazin-3-yl)- piperidin-1-yl]-[4-methoxy-5-(4-methoxy- phenoxy)-pyridin-2-yl]-methanone 
                 
                     
                 
                   67 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- [5-(2-cyclopropyl-ethoxy)-4-methoxy- pyridin-2-yl]-methanone 
                 
                     
                 
                   68 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [7-(6-Amino-4-methoxy-pyridin-3-yl)-3- oxa-9-aza-bicyclo[3.3.1]non-9-yl]-(4- methoxy-5-phenoxy-pyridin-2-yl)- methanone 
                 
                     
                 
                   69 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2- hydroxymethyl-piperazin-1-yl]-(4-methoxy- 5-phenoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   70 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (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 
                 
                     
                 
                   71 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [(S)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2- hydroxymethyl-piperazin-1-yl]-(4-methoxy- 5-phenoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   72 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-methoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-(5-isopropoxy-4- methoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   73 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-l-yl]- (4-methoxy-5-phenethyloxy-pyridin-2-yl)- methanone 
                 
                     
                 
                   74 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- [5-(2,2-dimethyl-propoxy)-4-methoxy- pyridin-2-yl]-methanone 
                 
                     
                 
                   75 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-l-yl]- [4-methoxy-5-(1-methyl- cyclopropylmethoxy)-pyridin-2-yl]- methanone 
                 
                     
                 
                   76 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- (4-methoxy-5-propoxy-pyridin-2-yl)- methanone 
                 
                     
                 
                   77 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (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 
                 
                     
                 
                   78 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-4-methyl-pyridazin-3-yl)- piperidin-1-yl]-(5-cyclopropylmethoxy-4- methoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   79 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- [5-((S)-1-cyclopropyl-ethoxy)-4-methoxy- pyridin-2-yl]-methanone 
                 
                     
                 
                   80 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- [4-methoxy-5-(4-trifluoromethoxy- phenoxy)-pyridin-2-yl]-methanone 
                 
                     
                 
                   81 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [(R)-4-(6-Am ino-pyridin-3-yl)-2- hydroxymethyl-piperazin-1-yl]-(4-methoxy- 5-phenoxy-pyridin-2-yl)-methanone 
                 
                     
                 
                   82 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [(R)-4-(6-Amino-pyridin-3-yl)-2- hydroxymethyl-piperazin-1-yl]-[4-methoxy- 5-(4-methoxy-phenoxy)-pyridin-2-yl]- methanone 
                 
                     
                 
                   83 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- [5-(phenoxy)-4-ethoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   84 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Am ino-4-cyclopropoxy-3′,4′,5′,6′- tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-[5- (phenoxy)-4-methoxy-pyridin-2-yl]- methanone 
                 
                     
                 
                   85 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-4-ethoxy-pyridazin-3-yl)- piperidin-1-yl]-[4-methoxy-5-(phenoxy)- pyridin-2-yl]-methanone 
                 
                     
                 
                   86 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (6-Amino-4-propoxy-3′,4′,5′,6′-tetrahydro- 2′H-[3,4′]bipyridinyl-1′-yl)-[5-(phenoxy)-4- methoxy-pyridin-2-yl]-methanone 
                 
                     
                 
                   87 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   5-ethoxy-6-(1-[4-methoxy-5-[4- (trifluoromethyl)phenoxy]pyridine-2- carbonyl]piperidin-4-yl)pyridazine-3-amine 
                 
                     
                 
                   88 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [4-(6-Amino-pyridazin-3-yl)-piperidin-l-yl]- [5-(4-fluoro-phenoxy)-4-ethoxy-pyridin-2- yl]-methanone 
                 
                     
                 
                   89 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   [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 
                 
                     
                 
                   90 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   6-(1-{4-Methoxy-5-[4- (trifluoromethyl)phenoxy]pyridine-2- carbonyl}piperidin-4-yl)-5-methylpyridazin- 3-amine 
                 
                     
                 
                   91 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   5-Methoxy-6-(1-{5-[4-(trifluoromethyl)- phenoxy]-pyridine-2-carbonyl}piperidin-4- yl)-pyridazin-3-amine 
                 
                     
                 
                   92 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   4-methoxy-5-[1-(4-methoxy-5-[trans-3- (trifluoromethyl)cyclobutylmethoxy]pyridine- 2-carbonyl)piperidin-4-yl]-pyridin-2-amine 
                 
                     
                 
                   93 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   4-methoxy-5-[1-(4-methoxy-5-[cis-3- (trifluoromethyl)cyclobutylmethoxy]pyridine- 2-carbonyl)pipenclin-4-yl]-pyridin-2-amine 
                 
                     
                 
                   94 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   4-methoxy-5-[1-(4-methoxy-5-[3,3,3- trifluoro-2-methylpropoxy]pyridine-2- carbonyl)piperidin-4-yl]-pyridin-2-amine 
                 
                     
                 
                   95 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   5-(1-{5-[(2,2-Difluorocyclobutyl)-methoxy]- 4-methoxy-pyridine-2-carbonyl}-piperidin- 4-yl)-4-methoxypyridin-2-amine; 
                 
                     
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         14 . The method of  claim 13 , wherein the compound is 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]-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.   
     
     
         15 . The method of  claim 14 , wherein the compound is 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]-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.   
     
     
         16 . The compound according to  claim 13 , wherein the compound is selected from the group consisting of:
 [4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone;   [4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone;   [4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone;   [4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2-yl]-methanone;   [4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone;   [4-(6-Amino-4-ethoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(phenoxy)-pyridin-2-yl]-methanone;   5-ethoxy-6-(1-[4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl]piperidin-4-yl)pyridazine-3-amine; and   6-(1-{4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5-methylpyridazin-3-amine;   or a pharmaceutically acceptable salt thereof.   
     
     
         17 . The compound according to  claim 16 , wherein the compound is selected from the group consisting of:
 [4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone;   [4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone;   [4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone;   [4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridin-2-yl]-methanone;   [4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl]-methanone;   [4-(6-Amino-4-ethoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(phenoxy)-pyridin-2-yl]-methanone;   5-ethoxy-6-(1-[4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl]piperidin-4-yl)pyridazine-3-amine; and   6-(1-{4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5-methylpyridazin-3-amine.   
     
     
         18 . The method of  claim 13 , wherein the cancer is brain cancer. 
     
     
         19 . The method of  claim 18 , wherein the brain cancer is glioblastoma multiforme. 
     
     
         20 . The method of  claim 18 , wherein the brain cancer is a glioma. 
     
     
         21 . The method of  claim 13 , wherein the cancer is breast cancer. 
     
     
         22 . The method of  claim 13 , wherein the cancer is kidney cancer. 
     
     
         23 . The method of  claim 22 , wherein the kidney cancer is renal cell carcinoma. 
     
     
         24 . The method of  claim 13 , wherein the cancer is cervical cancer. 
     
     
         25 . The method of  claim 13 , wherein the cancer is prostate cancer. 
     
     
         26 . The method of  claim 13 , wherein the cancer is gastrointestinal cancer. 
     
     
         27 . The method of  claim 26 , wherein the gastrointestinal cancer is esophageal squamous cell carcinoma. 
     
     
         28 . The method of  claim 13 , wherein the cancer is skin cancer. 
     
     
         29 . The method of  claim 28 , wherein the skin cancer is squamous cell carcinoma. 
     
     
         30 . The method of  claim 13 , wherein the cancer is epithelial cancer.

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