Tetrahydronaphthyridine Derivatives

Abstract

The present invention relates to tetrahydronaphthyridine derivatives of the general formula (I): or of the general formula (I′) in which A and R 1 are as defined within, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, including the treatment diseases mediated by H3 ligands, in particular inflammatory, allergic and respiratory diseases, disorders and conditions.

1 - 11 . (canceled) 
   
   
       12 . A method of treating a condition in a mammal for which an H 3  ligand is indicated, said method comprising administering to a mammal in need of such treatment a therapeutically effective amount of:
 a) a compound of, formula (I):   
     
       
         
         
             
             
         
       
     
     or formula (I′): 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is het 1  optionally substituted with one or two halogen; (C 1 -C 4 )alkyl optionally substituted with halogen; (C 1 -C 4 )alkoxy optionally substituted with halogen; CN; morpholino; —NR 2 R 3 ; —(CH 1 ) n C(O)NR 2 R 3 ; —(CH 2 ) n C(O)O—R 4 ; —(CH 2 ) n —NR 5 —C(O)—R 4 ; —(CH 2 ) n , —NR 5 —C(O)—NR 2 R 3 ; —SO, —NR 2 R 3 ; —SO 2 (C 1 -C 4  alkyl); —R 6 ; or —O—R 6 ; 
 n is 0, 1, 2 or 3; 
 R 2  and R 3  are taken separately and are independently hydrogen or (C 1 -C 4 alkyl; or R 2  and R 3  are taken together with the N atom to which they are attached to form a 4-, 5-, 6- or 7-membered saturated heterocycle; 
 R 4  and R 5  are taken separately and are independently hydrogen or (C 1 -C 4 alkyl; 
 R 6  is phenyl optionally substituted with halogen, (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy; 
 A is a group of formula: 
 
     
       
         
         
             
             
         
       
     
     wherein m is 2, 3, 4, 5 or 6; R 7  and R 8  are taken separately and are independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl or hydroxy(C 1 -C 6 )alkyl; or R 7  and R 8  are taken together with the N atom to which they are attached to form a 4-, 5-, 6- or 7-membered saturated heterocycle wherein one ring —CH 2  group of said heterocycle is optionally replaced by NH, O, S, SO or SO 2  and wherein said saturated heterocycle is optionally and independently substituted with one or two (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, hydroxy, C(O)O(C 1 -C 4 )alkyl, —C(O)(C 1 -C 4 )alkyl-NH, —C(O)—NH 2 , halo, amino, (C 1 -C 4 )alkylamino, or di[(C 1 -C 4 )alkyl]amino; or
 A is a group of formula: 
 
     
       
         
         
             
             
         
       
       wherein p is 0, 1 or 2; Q is a 4-, 5- or 6-membered saturated heterocycle optionally substituted with hydrogen, (C 1 -C 6  alkyl, (C 3 -C 7 )cycloalkyl, hydroxy(C 1 -C 6  alkyl), —(C 1 -C 4 )alkyl-COOH or —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl-COOH; 
       het 1  is a monocyclic or bicyclic heteroaromatic group comprising a 5- to 10-membered ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S; a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or stereoisomer; or 
       b) a pharmaceutical composition comprising a compound of formula (I) or formula (I′), a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or stereoisomer, and pharmaceutically acceptable vehicle, excipient or diluent; wherein said condition is rhinitis, chronic sinusitis, allergy, an allergy-induced airway response, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial or seasonal rhinitis, nasal congestion or allergic congestion. 
     
   
   
       13 . The method of  claim 12 , wherein said rhinitis is allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial rhinitis or seasonal rhinitis. 
   
   
       14 - 19 . (canceled) 
   
   
       20 . A method of  claim 12  wherein said compound is selected from the group consisting of: 
     6-pyrimidin-2-yl-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-pyridin-2-yl-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-pyrazin-2-yl-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(3-methylpyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(6-methylpyridin-3-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-(3-pyrrolidin-1-ylpropoxy)-6-[5-(trifluoromethyl)pyridin-2-yl]-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-(3-pyrrolidin-1-ylpropoxy)-6-[6-(trifluoremethyl)pyridin-2-yl]-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-(3-pyrrolidin-1-ylpropoxy)-6-[4-(trifluoremethyl)pyridin-2-yl]-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-(3-pyrrolidin-1-ylpropoxy)-6-[6-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(5-fluoropyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(6-methoxypyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-(3-pyrrolidin-1-ylpropoxy)-6-quinolin-2-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-[2-(3-pyrrolidin-1-ylpropoxy)-7,6-dihydro-1,6-naphthyridin-6(6h)-yl]-1,5-naphthyridine; 
     6-(4-ethyl-5-fluoropyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(4-ethylpyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(6-ethylpyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(4-propoxypyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(3-chloropyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     N,N-dimethyl-6-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-nahpthyridin-6(5h)-yl]pyridine-2-amine; 
     N,N-dimethyl-6-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]pyridine-2-sulfonamide; 
     6-pyridazin-3-yl-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-{3-[(2r)-2-methylpyrrolidin-1-yl]propoxy}-6-pyridazin-3-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-{3-[(2r)-2-methylpyrrolidin-1-yl]propoxy}-6-pyrazin-2-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(6-methylpyridin-3-yl)-2-{3-[(2r)-2-methylpyrrolidin-1-yl]propoxy}-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-{3-[(2s)-2-methylpyrrolidin-1-yl]propoxy}-6-pyridazin-3-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-{3-[(2s)-2-methylpyrrolidin-1-yl]propoxy}-6-pyrazin-2-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(6-methylpyridin-3-yl)-2-{3-[(2s)-2-methylpyrrolidin-1-yl]propoxy}-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-{3-[(2r,5r)-2,5-dimethylpyrrolidin-1-yl]propoxy}-6-(6-methylpyridin-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-(3-piperidin-1-ylpropoxy)-6-pyridazin-3-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-(3-azepan-1-ylpropoxy)-6-pyridazin-3-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     7-pyridin-2-yl-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     7-pyridazin-3-yl-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-pyrimidin-4-yl-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(6-methylpyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(5-methylpyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(4-methylpyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(5-chloropyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(4-methoxypyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(3-methoxypyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(6-morpholin-4-ylpyridin-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-(3-piperidin-1-ylpropoxy)-6-pyridin-2-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]nicotinonitrile; 
     6-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]nicotinamide; 
     N-methyl-6-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]nicotinamide; 
     N,N-dimethyl-6-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]nicotinamide; 
     N,N-dimethyl-6-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]-pyridine-3-sulfonamide; 
     6-[2-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]nicotinamide; 
     6-[2-(3-[piperidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]nicotinamide; 
     6-(1,3-benzoxazol-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(1-methyl-1h-benzimidazol-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(1,3-oxazol-2-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-[5-(4-methoxyphenyl)pyrimidin-2-yl]-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-[5-(4-methoxyphenoxy)pyrimidin-2-yl]-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(6-methyoxypyrimidin-4-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(9-ethyl-9h-purin-6-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-(3-pyrrolidin-1-ylpropoxy)-6-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(9-methyl-9h-purin-6-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(9h-purin-6-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-(3-piperidin-1-ylpropoxy)-6-pyrazin-2-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-{3-[(2r,5r)-2,5-dimethylpyrrolidin-1-yl]propoxy}-6-pyridazin-3-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     5-[2-{3-[(2r)-2-methylpyrrolidin-1-yl]propoxy}-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]pyridin-2-carboxylic acid; 
     5-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]pyridin-2-carboxylic acid; 
     5-[2-[(1-isopropylpiperidin-4-yl)oxy]-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]pyridin-2-carboxylic acid; 
     N-methyl-5-[2-{3-[(2r)-2-methylpyrrolidin-1-yl]propoxy}-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]pyridin-2-carboxamide; 
     N-methyl-5-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]pyridin-2-carboxamide; 
     5-[2-[(1-isopropylpiperidin-4-yl)oxy]-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]pyridin-2-carboxamide; 
     N,N-dimethyl-5-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]pyridin-2-carboxamide; 
     N-methyl-6-[2-{3-[(2r)-2-methylpyrrolidin-1-yl]propoxy}-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]nicotinamide; 
     N-methyl-6-[2-{3-[(2s)-2-methylpyrrolidin-1-yl]propoxy}-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]nicotinamide; 
     6-[2-[(1-isopropylpiperidin-4-yl)oxy]-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]-n-methylnicotinamide; 
     2-[(1-isopropylpiperidin-4-yl)oxy]-6-pyrazin-2-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-[(1-isopropylpiperidin-4-yl)oxy]-6-(6-methylpiperidin-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine; and 
     5-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]pyridin-2-carboxamide; 
     or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or stereo isomer. 
   
   
       21 . A method of  claim 20  wherein said compound is selected from the group consisting of: 
     7-pyridazin-3-yl-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-pyrazin-2-yl-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(6-methylpyridin-3-yl)-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-pyridazin-3-yl-2-(3-pyrrolidin-1-ylpropoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     N-methyl-6-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]nicotinamide; 
     6-[2-(3-[piperidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]nicotinamide; 
     2-(3-piperidin-1-ylpropoxy)-6-pyridazin-3-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     N,N-dimethyl-6-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]nicotinamide; 
     2-{3-[(2r)-2-methylpyrrolidin-1-yl]propoxy}-6-pyridazin-3-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(6-methylpyridin-3-yl)-2-{3-[(2r)-2-methylpyrrolidin-1-yl]propoxy}-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-{3-[(2r)-2-methylpyrrolidin-1-yl]propoxy}-6-pyrazin-2-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     N-methyl-5-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]pyridin-2-carboxamide; 
     2-{3-[(2s)-2-methylpyrrolidin-1-yl]propoxy}-6-pyridazin-3-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     2-{3-[(2s)-2-methylpyrrolidin-1-yl]propoxy}-6-pyrazin-2-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-(6-methylpyridin-3-yl)-2-{3-[(2s)-2-methylpyrrolidin-1-yl]propoxy}-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     N-methyl-6-[2-{3-[(2r)-2-methylpyrrolidin-1-yl]propoxy}-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]nicotinamide; 
     2-[(1-isopropylpiperidin-4-yl)oxy]-6-pyrazin-2-yl-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     N,N-dimethyl-5-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]pyridin-2-carboxamide; 
     N-methyl-5-[2-{3-[(2r)-2-methylpyrrolidin-1-yl]propoxy}-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]pyridin-2-carboxamide; 
     N-methyl-6-[2-{3-[(2s)-2-methylpyrrolidin-1-yl]propoxy}-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]nicotinamide; 
     2-[(1-isopropylpiperidin-4-yl)oxy]-6-(6-methylpiperidin-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine; 
     6-[2-[(1-isopropylpiperidinyl)oxy]-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]-n-methylnicotinamide; 
     5-[2-[(1-isopropylpiperidin-4-yl)oxy]-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]pyridin-2-carboxamide; and 
     5-[2-(3-pyrrolidin-1-ylpropoxy)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl]pyridin-2-carboxamide; or
 a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or stereoisomer. 
 
   
   
       22 . A method of  claim 21  wherein said compound is 6-[2-[(1-isopropylpiperidin-4-yl)oxy]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]-N-methylnicotinamide, a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or stereoisomer.