Nitrogen-containing aromatic heterocyclic compound

Abstract

As a result of studies on compounds having FGFR inhibitory action, the present inventors have found that the nitrogen-containing aromatic heterocyclic compounds of the present invention have inhibitory action on FGFR1, FGFR2, and/or FGFR3, particularly, mutant FGFR3, and thus, the present invention has been accomplished. The nitrogen-containing aromatic heterocyclic compound of the present invention can be used as a therapeutic agent for various cancers related to FGFR1, FGFR2, and/or FGFR3, such as lung cancer and hormone therapy-resistant breast cancer, stomach cancer, triple negative breast cancer, endometrial cancer, bladder cancer, and glioblastoma, particularly as a prophylactic and/or therapeutic agent for mutant FGFR3-positive bladder cancer.

1 : A compound of formula (I) or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein X and Y are each independently CH or N, with the proviso that X and Y are not N simultaneously; 
         L 1  is -lower alkylene-, -lower alkylene-O—, —O-lower alkylene-, or -lower alkynylene-; 
         Z is N or CH; 
         each R 1  is independently lower alkyl optionally substituted with halogen, —O-(lower alkyl optionally substituted with halogen), halogen, cyano, or —N(lower alkyl) 2 ; 
         p is an integer of from 2 to 4; 
         ring W is an optionally substituted aromatic carbocyclic ring, an optionally substituted aromatic heterocyclic ring, or an optionally substituted non-aromatic heterocyclic ring; 
         Q is -L 2 -R 2  or R 3 ; 
         L 2  is an optionally substituted aromatic heterocyclic ring or an optionally substituted non-aromatic heterocyclic ring; 
         R 2  is a non-aromatic heterocyclic group optionally substituted with lower alkyl, optionally substituted cycloalkyl, lower alkyl optionally substituted with at least one selected from the group consisting of —OH and —O-lower alkyl, —C(O)—R 0 , —C(O)-optionally substituted cycloalkyl, —NH—R 0 , —N(lower alkyl)-R 0 , an -L 3 -optionally substituted non-aromatic heterocyclic group, or H; 
         R 0  is lower alkyl optionally substituted with —OH; 
         L 3  is a bond, —NH—, —N(lower alkyl)-, or lower alkylene; and 
         R 3  is: 
         a lower alkyl optionally substituted with at least one selected from the group consisting of —C(O)OH, —OH, —O—R 0 , amino optionally substituted with one or two R 0 , carbamoyl optionally substituted with one or two R 0 , an optionally substituted aromatic heterocyclic group, an optionally substituted non-aromatic heterocyclic group, and a —C(O)-optionally substituted non-aromatic heterocyclic group, 
         —O-(lower alkyl optionally substituted with at least one selected from the group consisting of —C(O)OH, —OH, —O—R 0 , carbamoyl optionally substituted with one or two R 0 , an optionally substituted non-aromatic heterocyclic group, and a —C(O)-optionally substituted non-aromatic heterocyclic group), 
         —NH-(lower alkyl optionally substituted with at least one selected from the group consisting of —OH, a non-aromatic heterocyclic group optionally substituted with lower alkyl, and carbamoyl optionally substituted with one or two R 0 ), 
         —N(lower alkyl)-(lower alkyl optionally substituted with at least one selected from the group consisting of —OH, a non-aromatic heterocyclic group optionally substituted with lower alkyl, and carbamoyl optionally substituted with one or two R 0 ), 
         —C(O)OH, 
         —C(O)-optionally substituted non-aromatic heterocyclic group, 
         —O-(a non-aromatic heterocyclic group optionally substituted with lower alkyl), or 
         carbamoyl optionally substituted with one or two R 0 . 
       
     
     
         2 : The compound or salt thereof according to  claim 1 ,
 wherein X is N;   Y is CH; and   L 1  is lower alkylene or -lower alkylene-O—.   
     
     
         3 : The compound or salt thereof according to  claim 2 ,
 wherein Z is CH;   each R 1  is independently —O-lower alkyl or halogen;   p is 2 or 4; and   ring W is an optionally substituted aromatic carbocyclic ring or an optionally substituted aromatic heterocyclic ring.   
     
     
         4 : The compound or salt thereof according to  claim 3 ,
 wherein L 1  is ethylene or -methylene-O—;   p is 4; and   ring W is an optionally substituted benzene ring or optionally substituted pyrazole.   
     
     
         5 : The compound or salt thereof according to  claim 2 ,
 wherein Q is -L 2 -R 2 ;   L 2  is an optionally substituted non-aromatic heterocyclic ring; and   R 2  is lower alkyl optionally substituted with at least one selected from the group consisting of —OH and —O-lower alkyl, —NH-(lower alkyl optionally substituted with —OH), an optionally substituted non-aromatic heterocyclic group, -lower alkylene-(an optionally substituted non-aromatic heterocyclic group), or H.   
     
     
         6 : The compound or salt thereof according to  claim 5 ,
 wherein p is 4;   L 2  is piperazine optionally substituted with one or more methyl, piperidine optionally substituted with one or more methyl, or 3,9-diazaspiro[5.5]undecane; and   R 2  is piperazine optionally substituted with methyl, piperidine optionally substituted with methyl, 2-hydroxyethylamino, or H.   
     
     
         7 : The compound or salt thereof according to  claim 6 ,
 wherein each R 1  is independently —O-methyl or F;   L 1  is -methylene-O—;   ring W is a benzene ring optionally substituted with —O-methyl;   L 2  is piperidine or 4-methylpiperazine; and   R 2  is 4-methylpiperazine, 2-hydroxyethylamino, or H.   
     
     
         8 : The compound or salt thereof according to  claim 2 ,
 wherein ring W is optionally substituted pyrazole;   Q is R 3 ; and   R 3  is lower alkyl substituted with at least one selected from the group consisting of —C(O)OH, carbamoyl optionally substituted with one or two R 0 , —OH, an optionally substituted non-aromatic heterocyclic group, and —C(O)-(an optionally substituted non-aromatic heterocyclic group).   
     
     
         9 : The compound or salt thereof according to  claim 8 ,
 wherein p is 4; and   R 3  is lower alkyl substituted with at least one selected from the group consisting of —OH, a non-aromatic heterocyclic group optionally substituted with lower alkyl, and —C(O)-(a non-aromatic heterocyclic group optionally substituted with —OH).   
     
     
         10 : The compound or salt thereof according to  claim 9 ,
 wherein each R 1  is independently —O-methyl or F;   L 1  is -methylene-O—;   ring W is pyrazole optionally substituted with methyl; and   R 3  is 2-hydroxyethyl, 2,3-dihydroxypropyl, or 4-methylpiperazin-1-ylmethyl.   
     
     
         11 : The compound or salt thereof according to  claim 1 , wherein the compound is selected from the group consisting of:
 5-[2-(2,6-difluoro-3,5-dimethoxyphenyl)ethyl]-N-[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]pyrimidin-2-amine,   (2S)-3-[4-({5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-yl}amino)-1H-pyrazol-1-yl]propane-1,2-diol,   5-[2-(2,6-difluoro-3,5-dimethoxyphenyl)ethyl]-N-{3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-2-amine,   5-[2-(2,6-difluoro-3,5-dimethoxyphenyl)ethyl]-N-{3-fluoro-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-2-amine,   5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-{3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-2-amine,   5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]pyrimidin-2-amine,   5-[(2,6-dichloro-3,5-dimethoxybenzyl)oxy]-N-[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine,   5-[(2,6-dichloro-3,5-dimethoxybenzyl)oxy]-N-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine,   5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-{3-methoxy-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}pyrimidin-2-amine,   5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-{3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-2-amine,   5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-{4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-methoxyphenyl}pyrimidin-2-amine,   N-[4-(3,9-diazaspiro[5.5]undec-3-yl)-3-methoxyphenyl]-5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-amine,   2-[4-({5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-yl}amino)-1H-pyrazol-1-yl]ethanol,   5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-{1-[2-(4-methylpiperazin-1-yl)ethyl]-1 H-pyrazol-4-yl}pyrimidin-2-amine,   2-[4-({5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-yl}amino)-1H-pyrazol-1-yl]-1-(3-hydroxyazetidin-1-yl)ethanone,   (2R)-3-[4-({5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-yl}amino)-1H-pyrazol-1-yl]propane-1,2-diol,   2-({1-[4-({5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-yl}amino)phenyl]piperidin-4-yl}amino)ethanol,   5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-{1-methyl-5-[(4-methylpiperazin-1-yl)methyl]-1H-pyrazol-3-yl}pyrimidin-2-amine, and   5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidin-2-amine.   
     
     
         12 : A pharmaceutical composition, comprising:
 the compound or salt thereof according to  claim 1  and   a pharmaceutically acceptable excipient.   
     
     
         13 : The pharmaceutical composition according to  claim 12 , wherein the compound is suitable for treatment of mutant FGFR3-positive cancer. 
     
     
         14 : A method of manufacturing a pharmaceutical composition, the method comprising:
 manufacturing the pharmaceutical composition with the compound or salt thereof according to  claim 1 ,   wherein the pharmaceutical composition is suitable for treatment of mutant FGFR3-positive cancer.   
     
     
         15 . (canceled) 
     
     
         16 : The compound or salt thereof according to  claim 1 , wherein the compound is suitable for treatment of mutant FGFR3-positive cancer. 
     
     
         17 : A method of treating mutant FGFR3-positive cancer, the method comprising:
 administering an effective amount of the compound or salt thereof according to  claim 1  to a subject in need thereof.