S1p3 antagonists

Abstract

The present invention relates to antagonists of the S1P3 receptor formula (A) as herein described and pharmaceutical compositions thereof. The compounds of formula (A) are useful in the preparation of a medicament, in particular for the treatment of Alzheimer's disease.

1 . A compound of formula (A), 
       
         
           
           
               
               
           
         
         wherein 
         ●—R 1  is 
       
       
         
           
           
               
               
           
         
         X 1 , X 6 , X 7 , X 9  and X 10  are halogen, C 1 -C 4  linear branched or cyclic alkyl optionally substituted with one or more fluorine atoms; 
         X 2 , X 3 , X 4 , X 5  and X 8 , are hydrogen, halogen, C 1 -C 4  linear branched or cyclic alkyl optionally substituted with one or more fluorine atoms; 
         with the proviso that at least one of X 2 , X 3 , X 4 , and X 5  is not hydrogen R 2  is a C 3 -C 6  linear branched or cyclic alkyl optionally substituted with phenyl, with one or more fluorine atoms or with trifluoromethyl-furanyl; 
         R 2 ′ is hydrogen, F, C 1 -C 3  linear or branched alkyl optionally substituted with one or more fluorine atoms; 
         or R 2  and R 2 ′ together with the carbon atom they are attached to form a C 3 -C 6  cycloalkyl ring; 
         ●—R 3  is 
       
       
         
           
           
               
               
           
         
         Y 1  is halogen; 
         Y 1 ′ is C 1 -C 3  linear branched or cyclic alkyl optionally substituted with one or more fluorine atoms; 
         Y 2  is cyano or methoxyphenyl, C 1 -C 3  linear branched or cyclic alkyl optionally substituted with one or more fluorine atoms; 
         Y 3  is hydrogen, halogen or methoxyphenyl; 
         Y 4  is hydrogen, halogen, N-methylpyrazolyl or a C 1 -C 3  linear branched or cyclic alkoxy optionally substituted with one or more fluorine atoms, 
         Y 5  is hydrogen halogen, cyano, or a C 1 -C 3  linear branched or cyclic alkyl optionally substituted with one or more fluorine atoms; 
         with the proviso that at least one of Y 4  and Y 5  is not hydrogen; 
         Y 6  is halogen, C 1 -C 3  linear branched or cyclic alkyl optionally substituted with one or more fluorine atoms, or a C 1 -C 3  linear branched or cyclic alkoxy optionally substituted with one or more fluorine atoms; 
         enantiomers, enantiomerically enriched mixtures, and pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The compound of  claim 1  wherein
 X 1  is halogen; 
 X 2  is hydrogen, halogen or methyl; 
 X 3  is hydrogen, halogen or trifluoromethyl; 
 X 4  is hydrogen or methyl; 
 X 5  is hydrogen or halogen; 
 X 6  is halogen; 
 with the proviso that at least one of X 2 , X 3 , X 4 , and X 5  is not hydrogen; 
 X 7  is t-butyl or trifluoromethyl, preferably t-butyl; 
 X 8  is hydrogen, methyl or t-butyl; 
 X 9  is halogen; 
 X 10  is t-butyl; 
 R 2  is n-propyl, 3-phenyl-n-propyl, i-propyl, n-butyl, cyclohexyl, (5-trifluoromethyl-furan-2yl)-methyl; 
 R 2 ′ is hydrogen, F, methyl; 
 or R 2  and R 2 ′ together with the carbon atom they are attached to form a cyclobutyl or cyclopentyl group; 
 Y 1  is halogen; 
 Y 1 ′ is methyl; 
 Y 2  is methyl, n-propyl, cyano, trifluoromethyl or 4-methoxyphenyl; 
 Y 3  is hydrogen, halogen, or 4-methoxyphenyl; 
 Y 4  is hydrogen, halogen, methoxy or 1-methyl-pyrazol-4-yl; 
 Y 5  is hydrogen, halogen, cyano or methyl; 
 with the proviso that at least one of Y 4  and Y 5  is not hydrogen; 
 Y 6  halogen, methoxy or difluoromethoxy. 
 
     
     
         3 . The compound of  claim 1  or  2 , wherein ●-R 1  is selected from 
       
         
           
           
               
               
           
         
         and wherein R 2 , R 2 ′, R 3 , X 1 , X 2 , X 3 , X 4 , X 5 , X 8 , X 9 , Y 1 , Y 1 ′, Y 2 , Y 3 , Y 4 , Y 5  and Y 6  are as defined in  claim 1  or  2 . 
       
     
     
         4 . The compound of  claim 3 , which is selected from the group consisting of
 1-(5-Chloro-pyridin-3-yl)-cyclobutanecarboxylic acid (5-chloro-pyridin-2-yl)-amide;   2-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic acid (5-chloro-pyrazin-2-yl)-amide;   2-(6-Chloro-5-fluoro-pyridin-3-yl)-pentanoic acid (5-bromo-pyrazin-2-yl)-amide;   2-(6-Bromo-pyridin-2-yl)-pentanoic acid (5-bromo-pyrazin-2-yl)-amide;   2-(2-Bromo-pyridin-4-yl)-pentanoic acid (5-bromo-pyridin-2-yl)-amide;   2-(2-Methoxy-pyridin-4-yl)-pentanoic acid (5-bromo-pyridin-2-yl)-amide;   2-(6-Methoxy-pyridin-3-yl)-pentanoic acid (5-bromo-pyridin-2-yl)-amide;   2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid (5-bromo-pyrazin-2-yl)-amide;   2-(2-Difluoromethoxy-pyridin-4-yl)-pentanoic acid (5-bromo-pyridin-2-yl)-amide;   2-[6-(1-Methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acid (5-chloro-thiazol-2-yl)-amide;   2-(5-Bromo-pyridin-3-yl)-pentanoic acid (5-bromo-pyrazin-2-yl)-amide;   2-(5-Bromo-pyridin-3-yl)-pentanoic acid (5-bromo-3-methyl-pyridin-2-yl)-amide;   2-(5-Bromo-pyridin-3-yl)-pentanoic acid (5-bromo-6-fluoro-pyridin-2-yl)-amide;   2-(5-Bromo-pyridin-3-yl)-pentanoic acid (5-chloro-pyrazin-2-yl)-amide;   2-(5-Bromo-pyridin-3-yl)-2-fluoro-pentanoic acid (5-chloro-pyridin-2-yl)-amide;   2-(2-Bromo-pyridin-4-yl)-pentanoic acid (5-bromo-pyrazin-2-yl)-amide;   2-(2-Bromo-pyridin-4-yl)-pentanoic acid (5-chloro-pyridin-2-yl)-amide;   2-(5-Bromo-pyridin-3-yl)-pentanoic acid (5-fluoro-pyridin-2-yl)-amide;   2-(2-Methoxy-pyridin-4-yl)-pentanoic acid (5-bromo-thiazol-2-yl)-amide;   2-(2-Methoxy-pyridin-4-yl)-pentanoic acid (5-bromo-pyrazin-2-yl)-amide;   2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid (5-bromo-pyridin-2-yl)-amide;   2-(4-Bromo-3-cyano-pyrazol-1-yl)-pentanoic acid (5-bromo-pyridin-2-yl)-amide;   2-(5-Bromo-pyridin-3-yl)-hexanoic acid (5-bromo-pyrazin-2-yl)-amide;   2-(4-[4-methoxy-phenyl]-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid (5-bromo-pyrazin-2-yl)-amide;   2-(4-Bromo-3-methyl-pyrazol-1-yl)-pentanoic acid (5-bromo-pyrazin-2-yl)-amide;   2-(4-Bromo-imidazol-1-yl)-pentanoic acid (5-bromo-pyridin-2-yl)-amide;   2-[3-(4-Methoxy-phenyl)-pyrazol-1-yl]-pentanoic acid (5-bromo-pyrazin-2-yl)-amide;   2-(4-Bromo-3-cyano-pyrazol-1-yl)-pentanoic acid (5-bromo-pyrazin-2-yl)-amide;   2-[5-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acid (5-chloro-pyrazin-2-yl)-amide;   2-[5-Cyano-6-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acid (5-chloro-pyrazin-2-yl)-amide;   2-(5-Bromo-pyridin-3-yl)-N-(5-bromo-pyrazin-2-yl)3-methyl-butyramide;   N-(5-Bromo-3-fluoro-pyridin-2-yl)-2-(5-bromo-pyridin-3-yl)-3-methyl-butyramide;   N-(5-Bromo-pyrazin-2-yl)-2,2-dicyclohexyl-acetamide;   1-(5-Bromo-pyridin-3-yl)-cyclobutanecarboxylic acid (5-bromo-pyrazin-2-yl)-amide;   1-(5-Chloro-pyridin-3-yl)-cyclobutanecarboxylic acid (5-bromo-pyrazin-2-yl)-amide;   2-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic acid (5-bromo-pyrazin-2-yl)-amide;   2-(5-Chloro-pyridin-3-yl)-pentanoic acid (5-bromo-pyrazin-2-yl)amide;   2-(5-Chloro-pyridin-3-yl)-pentanoic acid (5-chloro-pyrazin-2-yl)-amide;   2-(6-Chloro-5-methyl-pyridin-3-yl)-pentanoic acid (5-chloro-pyrazin-2-yl)-amide;   and 2-(2-Chloro-pyridin-4-yl)-pentanoic acid (5-bromo-pyrazin-2-yl)-amide.   
     
     
         5 . The compound of  claim 1  or  2  wherein ●-R 1  is 
       
         
           
           
               
               
           
         
         and wherein R 2 , R 2 ′, R 3 , X 7 , Y 1 , Y 1 ′, Y 2 , Y 3 , Y 4 , Y 5  and Y 6  are as defined in  claim 1  or  2 . 
       
     
     
         6 . The compound of  claim 5 , which is selected from the group consisting of 2-(5-Bromo-pyridin-3-yl)-pentanoic acid (3-tert-butyl-isoxazol-5-yl)-amide and 2-(5-Bromo-pyridin-3-yl)-hexanoic acid (3-tert-butyl-isoxazol-5-yl)-amide. 
     
     
         7 . The compound of  claim 1  or  2 , wherein ●-R 3  is selected from 
       
         
           
           
               
               
           
         
         and wherein R 1 , R 2 , R 2 ′, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , Y 2 , Y 3 , Y 4 , Y 5  and Y 6  are as defined in  claim 1  or  2 . 
       
     
     
         8 . The compound of  claim 3  or  5 , wherein ●-R 3  is selected from 
       
         
           
           
               
               
           
         
         and wherein R 1 , R 2 , R 2 ′, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , Y 2 , Y 3 , Y 4 , Y 5  and Y 6  are as defined in  claim 3  or  5 . 
       
     
     
         9 . A pharmaceutical composition containing a compound according to  claims 1 - 8 . 
     
     
         10 . The compound of  claims 1 - 8  for use as medicaments. 
     
     
         11 . The compound of  claim 10  for use in the treatment of arthritis, fibrosis, inflammatory syndromes, atherosclerosis, vascular diseases, asthma, bradycardia, acute lung injury, lung inflammation, cancer, ocular hypertension, glaucoma, neuroinflammatory diseases, neurodegenerative diseases, Sandhoff s disease, kidney ischemia-reperfusion injury, pain, diabetic heart disease. 
     
     
         12 . The compound of  claim 10  for use in the treatment of Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease and Multiple Sclerosis. 
     
     
         13 . The compounds of  claim 10  for use in the treatment of Alzheimer's disease.