2h-chromene compound and derivative thereof

Abstract

Provided is a 2H-chromene compound or a derivative thereof which has an excellent S1P1 agonist action. The 2H-chromene compound or derivative is particularly useful for preventing and/or treating a disease induced by undesirable lymphocyte infiltration or a disease induced by abnormal proliferation or accumulation of cells.

1 . A method for preventing or treating a disease induced by undesirable lymphocyte infiltration associated with S1P 1 , comprising administering to a patient an effective amount of a 2H-chromene compound represented by the following formula (1): 
       
         
           
           
               
               
           
         
         (wherein A represents lower alkyl, cycloalkyl, aryl, or heteroaryl, wherein aryl and heteroaryl may respectively be substituted with one to five R 1 s which are the same as or different from each other, other; 
         R 1  represents halogen, —CN, —NO 2 , lower alkyl, lower alkenyl, lower alkynyl, halogeno-lower alkyl, aryl, heteroaryl, cycloalkyl, —OH, —O-(lower alkyl), —O-(halogeno-lower alkyl), —O-(aryl), —O-(cycloalkyl), —O-(heteroaryl), —NH 2 , —NH(lower alkyl), —NH(halogeno-lower alkyl), —N(lower alkyl) 2 , or cyclic amino, wherein aryl, heteroaryl, cycloalkyl, and cyclic amino may respectively be substituted with one to five substituents which are the same as or different from each other and selected from the group consisting of halogen, —CN, lower alkyl and halogeno-lower alkyl; 
         L represents lower alkylene, lower alkenylene, lower alkynylene, -(lower alkylene)-O—, —O-(lower alkylene)-, or -(lower alkylene)-O-(lower alkylene)-; 
         Q represents S or —C(R 2B )═C(R 2C )—; 
         R 2A , R 2B , and R 2C  independently represent —H, halogen, lower alkyl, halogeno-lower alkyl, —O-(lower alkyl), or —O-(halogeno-lower alkyl); 
         Y represents O, S, or —CH 2 —, provided that wherein Y is —CH 2 —, Q is S; 
         m represents 0 or 1; 
         R 3  represents —H, halogen, lower alkyl, halogeno-lower alkyl, or aryl; 
         R 4A  represents —H or lower alkyl; 
         R 4B  represents lower alkyl substituted with a group selected from Group G or cycloalkyl substituted with a group selected from Group G; 
         or R 4A  and R 4B  are combined with N to which they bind to form cyclic amino substituted with a group selected from Group G, in which the cyclic amino may further contain one to four substituents which are the same as or different from each other and selected from the group consisting of halogen, lower alkyl, and halogeno-lower alkyl; and 
         Group G represents, —C(═O)OH, tetrazolyl, —C(═O)NHS(═O) 2 (lower alkyl), -(lower alkylene)-C(═O)OH, or 
       
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         2 . The method as described in  claim 1 , wherein Y is O, Q is —C(R 2B )═C(R 2C )—, and m is 0. 
     
     
         3 . The method as described in  claim 2 , wherein R 4A  and R 4B  are combined with N to which they bind to form azetidinyl, pyrrolidinyl, piperidinyl or tetrahydropyridyl, which is substituted with a group selected from Group G, and which may further be substituted with lower alkyl or halogen. 
     
     
         4 . The method as described in  claim 3 , wherein the group represented by Group G is —C(═O)OH or —C(═O)NHS(═O) 2 CH 3 . 
     
     
         5 . The method as described in  claim 4 , wherein A is phenyl, pyridyl, or thienyl, substituted with one to three R 1 s which are the same as or different from each other. 
     
     
         6 . The method as described in  claim 5 , wherein L is -(lower alkylene)-O—, lower alkenylene, or lower alkynylene. 
     
     
         7 . The method as described in  claim 6 , wherein R 2A  is —H or lower alkyl; R 2B  is —H; R 2C  is —H or halogen; R 3  is —H or halogen; R 1  is halogen, lower alkyl, halogeno-lower alkyl, phenyl, pyrrolyl, cycloalkyl, —O-(lower alkyl), or —O-(halogeno-lower alkyl); and L is —CH 2 —O—, —CH═CH—, or 3-butynylene. 
     
     
         8 . The method as described in  claim 7 , wherein R 4A  and R 4B  are combined with N to which they bind to form piperidinyl or tetrahydropyridyl, which is substituted with —C(═O)OH; L is —CH 2 —O—; R 2A  and R 2B  are —H; R 2C  is —H or halogen; R 3  is —H; and A is phenyl or pyridyl, which is substituted with two R 1 s which are independently halogen, halogeno-lower alkyl, —O-(lower alkyl) or —O-(halogeno-lower alkyl). 
     
     
         9 . The method as described in  claim 8 , wherein R 4A  and R 4B  are combined with N to which they bind to form piperidinyl which is substituted with —C(═O)OH; and A is phenyl which is substituted with two R 1 s which are the same as or different from each other. 
     
     
         10 . The method as described in  claim 8 , wherein R 4A  and R 4B  are combined with N to which they bind to form tetrahydropyridyl which is substituted with —C(═O)OH; and A is pyridyl which is substituted with two R 1 s which are the same as or different from each other. 
     
     
         11 . The method of  claim 1 , wherein said 2H-chromene compound is:
 1-{[7-({3-chloro-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]benzyl}oxy)-2H-chromen-3-yl]methyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid,   1-({7-[(3-chloro-4-isopropylbenzyl)oxy]-2H-chromen-3-yl}methyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid,   1-[(7-{[4-isopropoxy-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid,   1-{[7-({3-chloro-4-[2-fluoro-1-(fluoromethyl)ethoxy]benzyl}oxy)-2H-chromen-3-yl]methyl}-1,2,3,6-tetrahydropyridine-4-carboxylic acid,   1-{[7-({5-chloro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridin-3-yl}methoxy)-2H-chromen-3-yl]methyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid,   (3R)-1-{[7-({4-[(1,3-difluoropropan-2-yl)oxy]-3-(trifluoromethyl)benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}piperidine-3-carboxylic acid,   1-[(7-{[4-cyclopentyl-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid,   (3R)-1-{[7-({3-chloro-4-[(1,3-difluoropropan-2-yl)oxy]benzyl)oxy)-5-fluoro-2H-chromen-3-yl]methyl}piperidine-3-carboxylic acid,   (3S)-1-{[7-({4-[(1,3-difluoropropan-2-yl)oxy]-3-(trifluoromethyl)benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}piperidine-3-carboxylic acid,   (3R)-1-[(7-{[4-(2,2,2-trifluoroethoxy)-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,   (3R)-1-[(7-{[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,   (3S)-1-[(7-{[4-(2,2,2-trifluoroethoxy)-3-(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid,   (3R)-1-{[7-({4-[(1,3-difluoropropan-2-yl)oxy]-3-(trifluoromethyl)benzyl}oxy)-5-fluoro-2H-chromen-3-yl]methyl}-N-(methylsulfonyl)piperidine-3-carboxamide, or   1-[(7-{[4-(2,2,2-trifluoroethoxy)-3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-4-carboxylic acid,   or a pharmaceutically acceptable salt thereof.   
     
     
         12 - 14 . (canceled) 
     
     
         15 . The method as described in  claim 1 , wherein the disease is autoimmune or inflammatory disease in human or an animal. 
     
     
         16 . The method as described in  claim 15 , wherein the disease is rejection or graft-versus-host diseases from organ, bone marrow, or tissue transplantation in human or an animal. 
     
     
         17 . The method as described in  claim 15 , wherein the disease is multiple sclerosis. 
     
     
         18 - 20 . (canceled) 
     
     
         21 . A method for preventing or treating a disease induced by undesirable lymphocyte infiltration associated with S1P 1 , comprising administering to a patient an effective amount of compound of the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . The method as described in  claim 21 , wherein the disease is autoimmune or inflammatory disease in human or an animal. 
     
     
         23 . The method as described in  claim 22 , wherein the disease is rejection or graft-versus-host diseases from organ, bone marrow, or tissue transplantation in human or an animal. 
     
     
         24 . The method as described in  claim 22 , wherein the disease is multiple sclerosis.