Amine Derivatives as Potassium Channel Blockers

Abstract

The present invention relates to compounds useful in the modulation of potassium channel activity in cells, in particular the activity of Kv1.3 channels found in T cells. The invention also relates to the use of these compounds in the treatment or prevention of autoimmune and inflammatory diseases, including multiple sclerosis, pharmaceutical compositions containing these compounds and methods for their preparation.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         X is selected from a single bond, an alkylene group having 1 to 6 carbon atoms optionally substituted with 1 or 2 substituents selected from fluoro or C 1 -C 6 -alkyl, 
         Y is selected from an alkylene group having 1 to 6 carbon atoms optionally substituted one or two times with C 3 -C 8 -cycloalkyl or C 1 -C 3 -alkyl; or a 3-8-membered cycloalkylene group, 
         Q is selected from O, NH or a single bond, 
         W is selected from SO, SO 2  or a single bond, 
         U is cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl, each of the above groups being optionally substituted with 1 to 3 substituents selected from Hal, NO 2 , CN, —SO 2 —C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, NMe 2 , C 1 -C 6 -alkyl, —C(O)O—C 1 -C 6 -alkyl, O—C 1 -C 6 -alkyl, —(CH 2 ) m —O—C 1 -C 6 -alkyl, —C 1 -C 6 -halo-alkyl, or a 5-6-membered heteroaromatic group being optionally substituted by Hal, 
         V is an aryl group optionally substituted with 1 to 3 substituents selected from Hal, NO 2 , CN, SO 2 —C 1 -C 6  alkyl, NMe 2 , C 1 -C 6 -alkyl, O—C 1 -C 6 -alkyl, —(CH 2 ) m —O—C 1 -C 6 -alkyl, —C 1 -C 6 -halo-alkyl, O—C 1 -C 6 -halo-alkyl or a 5-6-membered heteroaromatic group, 
         T denotes phenyl, triazolyl, thiazolyl, oxazolyl, oxadiazolyl, or pyrazolyl, 
         R 1  is Hal, —C 1 -C 6 -alkyl, O—C 1 -C 6 -alkyl, —(CH 2 ) m —O—C 1 -C 6 -alkyl, O—C 1 -C 6 -halo-alkyl, —(CH 2 ) m —O—C 1 -C 6 -halo-alkyl, —SO 2 —C 1 -C 6 -alkyl, —(CH 2 ) m —SO 2 —C 1 -C 6 -alkyl, —SO 2 —C 1 -C 6 -halo-alkyl, —(CH 2 ) m —SO 2 —C 1 -C 6 -halo-alkyl, —SO 2 -3-8-cycloalkyl, —(CH 2 ) m —SO 2 -3-8-cycloalkyl, cyano or —C 1 -C 6 -halo-alkyl, 
         R 2  and R 2′  are independently from one another H, Hal, —C1-C6-alkyl, —O—C1-C6-alkyl, —(CH2)m-O—C1-C6-alkyl, O—C1-C6-halo-alkyl, —(CH2)m-O—C1-C6-halo-alkyl, —SO2-C1-C6-alkyl, —(CH2)m-SO2-C1-C6-alkyl, —SO2-C1-C6-halo-alkyl, —(CH2)m-SO2-C1-C6-halo-alkyl, —SO2-3-8-cycloalkyl, —(CH2)m-SO2-3-8-cycloalkyl, —C1-C6-halo-alkyl, or 
         R 1  and R 2  are linked to form with the ring T to which they are attached a 7-12-membered fused heterocyclyl or 7-12-membered fused cycloalkyl, each of which may be optionally substituted with 1 to 3 Hal, —C 1 -C 6 -halo-alkyl, NO 2 , CN, C 1 -C 6 -alkyl, —(CH 2 ) m —O—C 1 -C 6 -alkyl, or —O—C 1 -C 6 -alkyl, 
         R 3  is C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —(CH 2 ) m —O—C 1 -C 6 -alkyl, or —(CH 2 ) m —O—C 1 -C 6 -haloalkyl; a 3-8-membered cycloalkyl group, optionally substituted with 1 to 3 substituents independently selected from Hal, —C 1 -C 6 -halo-alkyl, or C 1 -C 6 -alkyl; or a 3-8-membered heterocyclic group, optionally substituted with 1 to 3 substituents independently selected from Hal, —C 1 -C 6 -halo-alkyl, NO 2 , CN, C 1 -C 6 -alkyl, —(CH 2 ) m —O—C 1 -C 6 -alkyl, —(CH 2 ) m —SO 2 —C 1 -C 6 -alkyl, —SO 2 —C 1 -C 6 -alkyl, —O—C 1 -C 6 -alkyl, —(CH 2 ) m —O—C 1 -C 6 -halo-alkyl, —(CH 2 ) m —SO 2 —C 1 -C 6 -halo-alkyl, —SO 2 —C 1 -C 6 -halo-alkyl, —O—C 1 -C 6 -halo-alkyl, —C(O)—C 1 -C 6 -alkyl, or —C(O)O—C 1 -C 6 -alkyl, 
         R 4  denotes H, C 1 -C 6 -alkyl, or forms together with R 3  a 3-8-membered cycloalkyl ring, optionally substituted with Hal, —C 1 -C 6 -halo-alkyl, NO 2 , CN, C 1 -C 6 -alkyl, —(CH 2 ) m —O—C 1 -C 6 -alkyl, —O—C 1 -C 6 -alkyl, —C(O)—C 1 -C 6 -alkyl, or —C(O)O—C 1 -C 6 -alkyl, 
         m is selected from 1, 2, 3 or 4, 
         Hal is F, Cl, Br, or I, 
         wherein C(O)—Y—W— together is at least 3 atoms in length, 
         or a pharmaceutically acceptable salts thereof, or an enantiomeric mixture of 2 enantiomers in all ratios, and/or as a mixture of diastereoisomers in all ratios. 
       
     
     
         2 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein V is a phenyl group optionally substituted with 1 to 3 substituents selected from Hal, NO 2 , CN, SO 2 —C 1 -C 6  alkyl, NMe 2 , C 1 -C 6 -alkyl, O—C 1 -C 6 -alkyl, —(CH 2 ) m —O—C 1 -C 6 -alkyl, —C 1 -C 6 -halo-alkyl, O—C 1 -C 6 -halo-alkyl or a 5-6-membered heteroaromatic group. 
     
     
         3 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein V is a phenyl group optionally substituted with 1 to 3 substituents selected from Hal, —C 1 -C 6 -halo-alkyl, O—C 1 -C 6 -halo-alkyl or SO 2 —C 1 -C 6  alkyl. 
     
     
         4 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein U is a 5-6-membered cycloalkyl group, a 5-12-membered heterocyclyl or a 5-6 membered heteroaryl, each of the above groups being optionally substituted with 1 to 3 substituents selected from Hal, NO 2 , CN, SO 2 , NMe 2 , C 1 -C 6 -alkyl, O—C 1 -C 6 -alkyl, —(CH 2 ) m —O—C 1 -C 6 -alkyl, —C(O)O—C 1 -C 6 -alkyl, —SO 2 —C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, —C 1 -C 6 -halo-alkyl, or a 5-6-membered heteroaromatic group being optionally substituted by Hal. 
     
     
         5 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein U is selected from pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, tetrahydropyranyl, cyclohexyl, 8-azabicyclo[3.2.1]octan-3-yl, triazolyl and piperidinyl, each of the above groups being optionally substituted with 1 to 3 substituents selected from Hal, NO 2 , CN, SO 2 , NMe 2 , C 1 -C 6 -alkyl, O—C 1 -C 6 -alkyl, —(CH 2 ) m —O—C 1 -C 6 -alkyl, —C(O)O—C 1 -C 6 -alkyl, —SO 2 —C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, —C 1 -C 6 -halo-alkyl, or a 5-6-membered heteroaromatic group being optionally substituted by Hal. 
     
     
         6 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein U is selected from pyridinyl, pyridazinyl and pyrazolyl, each of the above groups being optionally substituted with 1 to 3 substituents selected from CF 3 , —SO 2 —C 1 -C 6 -alkyl, C 1 -C 6 -alkyl or Hal. 
     
     
         7 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein T is phenyl, triazolyl, or oxadiazolyl. 
     
     
         8 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein T is phenyl. 
     
     
         9 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein R 1  is O—C 1 -C 6 -alkyl, Hal, —(CH 2 ) m —O—C 1 -C 6 -alkyl, —C 1 -C 6 -alkyl, O—C 1 -C 6 -halo-alkyl, —SO 2 —C 1 -C 6 -alkyl, —C 1 -C 6 -halo-alkyl, —SO 2 -3-8-cycloalkyl, or cyano, in which m is 1. 
     
     
         10 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein R 2  and R 2′  are H or Hal. 
     
     
         11 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein R 2  is H or Hal and R 2′  is H. 
     
     
         12 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein R 1  is O—C 1 -C 6 -alkyl, Hal, —(CH 2 ) m —O—C 1 -C 6 -alkyl, —C 1 -C 6 -alkyl, O—C 1 -C 6 -halo-alkyl, —SO 2 —C 1 -C 6 -alkyl, —C 1 -C 6 -halo-alkyl, —SO 2 -3-8-cycloalkyl, or cyano, in which m is 1, R 2  is H or Hal and R 2′  is H. 
     
     
         13 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein R 1  and R 2  are linked to form with the ring T to which they are attached a dihydrobenzofuranyl, an indanyl, 
       
         
           
           
               
               
           
         
       
       each of these groups being optionally substituted with 1 to 3 Hal, —C 1 -C 6 -halo-alkyl, NO 2 , CN, C 1 -C 6 -alkyl, —(CH 2 ) m —O—C 1 -C 6 -alkyl, or —O—C 1 -C 6 -alkyl. 
     
     
         14 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein T is phenyl, triazolyl, oxadiazolyl or diazolyl; R 1  is O—C 1 -C 6 -alkyl, Hal, —(CH 2 ) m —O—C 1 -C 6 -alkyl, —C 1 -C 6 -alkyl, O—C 1 -C 6 -halo-alkyl, —SO 2 —C 1 -C 6 -alkyl, —C 1 -C 6 -halo-alkyl, —SO 2 -3-8-cycloalkyl, or cyano, in which m is 1; R 2  is H or Hal and R 2′  is H; or R 1  and R 2  are linked to form with the ring T to which they are attached a dihydrobenzofuranyl, an indanyl, 
       
         
           
           
               
               
           
         
       
       each of these groups being optionally substituted by 1 to 3 —C 1 -C 6 -alkyl. 
     
     
         15 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein R 4  is H and R 3  is C 1 -C 6  alkyl, cyclopropyl, or a 3-8-membered heterocyclic group. 
     
     
         16 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein R 4  is H and R 3  is C 1 -C 6  alkyl or cyclopropyl. 
     
     
         17 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein R 4  is H and R 3  is cyclopropyl. 
     
     
         18 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein R 4  is H and R 3  is ethyl. 
     
     
         19 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein R 3  and R 4  are independently C 1 -C 3 -alkyl. 
     
     
         20 . The compound according to  claim 19  or a pharmaceutically acceptable salt thereof wherein R 3  and R 4  are both methyl. 
     
     
         21 . The compound according to  claim 1  wherein R 3  and R 4  are methyl and T is phenyl and R 1 , R 2 , and R 2′  are all H. 
     
     
         22 . The compound according to  claim 1  represented by formula (Ia): 
       
         
           
           
               
               
           
         
       
     
     
         23 .- 42 . (canceled) 
     
     
         43 . The compound according to  claim 22  or a pharmaceutically acceptable salt thereof represented by one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 2′ , R 3  and R 4 , T, Q, U and V are as defined above for compounds of formula (Ia). 
       
     
     
         44 - 65 . (canceled) 
     
     
         66 . The compound according to  claim 1  represented by formula (Ic): 
       
         
           
           
               
               
           
         
         wherein: 
         Y is an alkylene group having 1 to 6 carbon atoms. 
       
     
     
         67 - 86 . (canceled) 
     
     
         87 . The compound according to  claim 66  or a pharmaceutically acceptable salt thereof represented by one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 2′ , R 3  and R 4 , T, Q, U and V are as defined above for compounds of formula (Ia). 
       
     
     
         88 - 105 . (canceled) 
     
     
         106 . A pharmaceutical composition comprising a compound according to  claim 1  together with a pharmaceutically acceptable vehicle. 
     
     
         107 . A method of treating a condition selected from autoimmune disorders, immune-mediated disorders, inflammatory disorders, or other disorders, or conditions which benefit clinically from immunosuppressants, including multiple sclerosis, type-1 diabetes mellitus, type-2 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, contact dermatitis, obesity, graft-versus host disease, transplant rejection, and delayed type hypersensitivity, including the step of administering an effective amount of a compound according to  claim 1 . 
     
     
         108 . A method of treating a condition selected from Multiple sclerosis, Rheumatoid arthritis, Psoriasis, Type 1 Diabetes, Type II Diabetes, Systemic lupus nephritis, Oncology, Glomerulonephritis, Sjögrens's syndrome, Transplant rejection, Graft versus host disease, Allergic contact dermatitis, Neointimal hyperplasia/restenosis, Periodontal disease, Leprosy, or Obesity, including the step of administering an effective amount of a compound according to  claim 1 . 
     
     
         109 - 112 . (canceled) 
     
     
         113 . A process of making compounds of Formula (I) as defined in  claim 1  comprising the steps of reacting a compound of Formula 5, wherein R 1 , R 2 , R 2′ , R 3 , R 4 , X, Q, T and U are as defined in  claim 1 , with a compound of Formula 8, wherein Y, W, and V are as defined in  claim 1  and wherein LG is a suitable leaving group, 
       
         
           
           
               
               
           
         
         or reacting a compound of Formula 7, wherein R 1 , R 2 , R 2′ , R 3 , R 4 , Y, W, T and V are as defined in  claim 1 , with a compound of Formula 9, wherein X, Q and U are as defined in  claim 1  and wherein LG denotes a suitable leaving group: