Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation

Abstract

Provided are substituted benzaldehydes and derivatives thereof that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions comprising the modulators, and methods for their use in treating disorders mediate by hemoglobin and disorders that would benefit from increased tissue oxygenation.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a tautomer or pharmaceutically acceptable salt thereof,
 wherein Q is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl, each optionally substituted with one to three R a ; 
 Y is O or CR 1a R 1b , where R 1a  is H or halo and R 1b  is selected from the group consisting of H, halo, and OH; 
 X is selected from the group consisting of O, >CH(CH 2 ) n R 8 , and C(R 9 ) 2  where n is 0 or 1, R 8  is OH, and R 9  is independently H or halo; or Y—X taken together is —NHC(O)— or —C(O)NH—; 
 R 2 , R 3 , R 4 , and R 5  are independently selected from the group consisting of hydrogen, halo, R b , OR d , —O(CH 2 ) z OR d , —O(CH 2 ) z NR d R d , OC(O)R e , SR d , CN, NO 2 , CO 2 R d , CONR d R d , C(O)R d , OC(O)NR d R d , NR d R d , NR d C(O)R e , NR d C(O) 2 R e , NR d C(O)NR d R d , S(O)R e , S(O) 2 R e , NR d S(O) 2 R e , S(O) 2 NR d R d , and N 3 , where z is 0, 1, 2, 3, 4, 5, or 6; or R 5  is —(CH 2 ) p R 5a  where p is 0 or 1 and R 5a  is OH; 
 R 6  and R 7  together form oxo or an aldehyde protecting group, or R 6  together with R 1b , R 8 , or R 5  forms a cyclic ether where one of R 1b , R 8 , or R 5a  is O, R 6  is a bond, and R 7  is selected from the group consisting of OH, C 1-8 alkoxy, and haloC 1-8 alkoxy; 
 each R a  is independently selected from the group consisting of halo, oxo, R b , OR d , O(CH 2 ) u OR d , O(CH 2 ) u NR d R d , O(CH 2 ) u NR d C(O)R e , O(CH 2 ) u NR d C(O) 2 R e , O(CH 2 ) u NR d S(O) 2 R e , NH 2 , —(CH 2 ) k OC(O)R e , —(CH 2 ) k SR d , CN, NO 2 , —(CH 2 ) k CO 2 (C 1-8 alkyl)OH, —(CH 2 ) k CO 2 (C 1-8 alkyl)(heteroaryl)C(O)(C 1-8 alkyl), —(CH 2 ) k CO 2 R d , —(CH 2 ) k CONR d R d , —(CH 2 ) k NR d C(O)R e , —(CH 2 ) k NR d C(O) 2 R e , —(CH 2 )C(O)R d , (CH 2 ) k OC(O)NR d R d , —NR d (CH 2 ) u OR d , —NR d (CH 2 ) u NR d R d , —NR d (CH 2 ) u NR d C(O)R e , —NR d (CH 2 ) u NR d C(O) 2 R c , —NR d (CH 2 ) u NR d S(O) 2 R e , —(CH 2 ) k NR d C(O)R e , —(CH 2 ) k NR d C(O) 2 R d , —(CH 2 ) k NR d C(O)NR d R d , —(CH 2 ) k S(O)R e , —(CH 2 ) k S(O) 2 R e , —(CH 2 ) k NR d S(O) 2 R e , —(CH 2 ) k S(O) 2 NR d R d , N 3 , —(CH 2 ) k aryl optionally substituted with one to three R e , —NR d (CH 2 ) k aryl optionally substituted with one to three R c , —(CH 2 ) k heteroaryl optionally substituted with one to three R c , —NR d (CH 2 ) k heteroaryl optionally substituted with one to three R c , —(CH 2 ) k heterocycloalkyl optionally substituted with one to three R c , and —NR d (CH 2 ) k heterocycloalkyl optionally substituted with one to three R c  where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6; 
 each R b  is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 2-8  alkynyl, each optionally independently substituted with one to three halo, OR d , or NR d R d ; 
 each R c  is independently selected from the group consisting of halo, C 1-8 alkyl, haloC 1-8 alkyl, C 2-8 alkenyl, haloC 2-8  alkenyl, C 2-8 alkynyl, haloC 2-8 alkynyl, (CH 2 ) m OR f , OC(O)R g , SR f , CN, NO 2 , CO 2 R f , CONR f R f , C(O)R f , OC(O)NR f R f , (CH 2 ) m NR f R f , NR f C(O)R g , NR f C(O) 2 R g , NR f C(O)NR f R f , S(O)R g , S(O) 2 R g , NR f S(O) 2 R g , S(O) 2 NR f R f , N 3 , heteroaryl optionally substituted with one to three R h , and heterocycloalkyl optionally substituted with one to three R h  where m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; 
 each R h  is independently selected from the group consisting of halo, C 1-8 alkyl, haloC 1-8 alkyl, OR j , OC(O)R, SR j , NO 2 , CO 2 R j , CONR j R j , C(O)R j , OC(O)NR j R j , NR j R j , NR j C(O)R t , NR j C(O) 2 R t , NR j C(O)NR j R j , S(O)R t , S(O) 2 R t , NR j S(O) 2 R t , and S(O) 2 NR j R j ; 
 R d , R f , and R j  are each independently selected from the group consisting of hydrogen, C 1-8  alkyl, haloC 1-8 alkyl, C 2-8  alkenyl, haloC 2-8 alkenyl, C 2-8  alkynyl, and haloC 2-8 alkynyl; and 
 R e , R g , and R t  are each independently selected from the group consisting of C 1-8 alkyl, haloC 1-8 alkyl, C 2-8  alkenyl, haloC 2-8 alkenyl, C 2-8  alkynyl, and haloC 2-8 alkynyl; 
 provided that X and Y are not both O; 
 provided that when X is O, R 1b  is not OH; 
 provided that when Y is O, and n is 0, R 8  is not OH; and 
 provided that when R 6  and R 7  together are oxo, Y is CH 2 , X is O or CH 2 , and R 5  is H, halo, OH, CHO, or OCH 3 , then Q is V or W; 
 V is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and naphthalene containing three to four ring nitrogen atoms; wherein V is optionally substituted with one to three R a ; and
 W is selected from the group consisting of pyridin-2-yl, and pyridine-4-yl, 
 
       
         
           
           
               
               
           
         
       
       wherein W is optionally substituted with one to three R a  or is substituted with one to three R a  when W is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, and wherein the wavy line signifies the point of attachment to Y, provided that when V is 
       
         
           
           
               
               
           
         
       
       optionally substituted with one R a , then at least one of R 2 , R 3 , R 4 , and R 5  is OR d ; and provided that when V is 
       
         
           
           
               
               
           
         
       
       then V is substituted with one to three R a . 
     
     
         2 . A compound according to  claim 1 , wherein:
 Y is O or CH 2 ;   X is O or CH 2 ,   Q is selected from the group consisting of:   iii) imidazopyridinyl, methylimidazopyridinyl, indazolyl, pyrrolopyridinyl, pyrrolopyrazinyl, pyrazolopyridinyl, pyrazolopyrazinyl, and quinolinyl, each of which is optionally substituted with one to three R a ; wherein
 R 2 , R 3 , R 4 , and R 5 , are independently selected from the group consisting of hydrogen, halo, R b , OR d , O(CH 2 ) z OR d , O(CH 2 ) z NR d R d , OC(O)R e , SR d , CN, NO 2 , CO 2 R d , CONR d R d , C(O)R d , OC(O)NR d R d , NR d R d , NR d C(O)R e , NR d C(O) 2 R e , NR d C(O)NR d R d , S(O)R c , S(O) 2 R e , NR d S(O) 2 R e , S(O) 2 NR d R d , and N 3  where z is 1, 2, or 3; and 
   iv) pyridinyl and piperidinyl, each of which is optionally substituted with one to three R a ; wherein
 R 2 , R 3 , and R 4  are independently selected from the group consisting of hydrogen, halo, R b , OR d , O(CH 2 ) z OR d , O(CH 2 ) z NR d R d , OC(O)R e , SR d , CN, NO 2 , CO 2 R d , CONR d R d , C(O)R d , OC(O)NR d R d , NR d R d , NR d C(O)R e , NR d C(O) 2 R e , NR d C(O)NR d R d , S(O)R e , S(O) 2 R e , NR d S(O) 2 R e , S(O) 2 NR d R d , and N 3  where z is 1, 2, or 3; and 
 R 5  is selected from the group consisting of halo and OR d ; 
   R 6  and R 7  together form oxo or an aldehyde protecting group;   each R a  is independently selected from the group consisting of halo, oxo, R b , OR d , O(CH 2 ) u OR d , O(CH 2 ) u NR d R d , O(CH 2 ) u NR d C(O)R e , O(CH 2 ) u NR d C(O) 2 R e , O(CH 2 ) u NR d S(O) 2 R e , NH 2 , —(CH 2 ) k OC(O)R e , —(CH 2 ) k SR d , CN, NO 2 , —(CH 2 ) k CO 2 (C 1-8 alkyl)OH, —(CH 2 ) k CO 2 (C 1-8 alkyl)(heteroaryl)C(O)(C 1-8 alkyl), —(CH 2 ) k CO 2 R d , —(CH 2 ) k CONR d R d , —(CH 2 ) k NR d C(O)R e , —(CH 2 ) k NR d C(O) 2 R e , —(CH 2 ) k C(O)R d , —(CH 2 ) k OC(O)NR d R d , —NR d (CH 2 ) u OR d , —NR d (CH 2 ) u NR d R d , —NR d (CH 2 ) u NR d C(O)R d , —NR d (CH 2 ) u NR d C(O) 2 R e , —NR d (CH 2 ) u NR d S(O) 2 R e , —(CH 2 ) k NR d C(O)R e , —(CH 2 ) k NR d C(O) 2 R d , —(CH 2 ) k NR d C(O)NR d R d , —(CH 2 ) k S(O)R e , —(CH 2 ) k S(O) 2 R e , —(CH 2 ) k NR d S(O) 2 R e , —C(O)(CH 2 ) k NR d S(O) 2 R c , —(CH 2 ) k C(O)NR d S(O) 2 R e , —(CH 2 ) k S(O) 2 NR d R d , N 3 , —(CH 2 ) k aryl optionally substituted with one to three R c , —NR d (CH 2 ) k aryl optionally substituted with one to three R c , —(CH 2 ) k heteroaryl optionally substituted with one to three R c , —NR d (CH 2 ) k heteroaryl optionally substituted with one to three R c , —(CH 2 ) k heterocycloalkyl optionally substituted with one to three R c , and —NR d (CH 2 ) k heterocycloalkyl optionally substituted with one to three R c  where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6;   each R b  is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 2-8 alkynyl, each optionally independently substituted with one to three halo, OR d , or NR d R d ;   each R e  is independently selected from the group consisting of halo, C 1-8 alkyl, haloC 1-8 alkyl, C 2-8 alkenyl, haloC 2-8 alkenyl, C 2-8 alkynyl, haloC 2-8 alkynyl, (CH 2 ) m OR f , OC(O)R g , SR f , CN, NO 2 , (CH 2 ) m CO 2 R f , CONR f R f , C(O)R f , OC(O)NR f R f , (CH 2 ) m NR f R f , NR f C(O)R g , NR f C(O) 2 R g , NR f C(O)NR f R f , S(O)R g , S(O) 2 R g , NR f S(O) 2 R g , S(O) 2 NR f R f , N 3 , (R f ) m SiC 1-8 alkyl, heteroaryl optionally substituted with one to three R h , cycloalkyl optionally substituted with one to three R h , and heterocycloalkyl optionally substituted with one to three R h  where m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6;   each R h  is independently selected from the group consisting of halo, C 1-8 alkyl, haloC 1-8 alkyl, OR j , OC(O)R, SR j , NO 2 , CO 2 R j , CONR j R j , C(O)R j , OC(O)NR j R j , NR j R j , NR j C(O)R t , NR j C(O) 2 R t , NR j C(O)NR j R j , S(O)R t , S(O) 2 R t , NR j S(O) 2 R t , and S(O) 2 NR j R j ;   R d , R f , and R j  are each independently selected from the group consisting of hydrogen, C 1-8  alkyl, haloC 1-8 alkyl, C 2-8  alkenyl, haloC 2-8 alkenyl, C 2-8  alkynyl, and haloC 2-8 alkynyl; and   R c , R g , and R t  are each independently selected from the group consisting of C 1-8 alkyl, haloC 1-8 alkyl, C 2-8  alkenyl, haloC 2-8 alkenyl, C 2-8  alkynyl, and haloC 2-8 alkynyl.   
     
     
         3 . A compound according to  claim 1 , wherein:
 Y is CH 2 ; and X is CH 2 .   
     
     
         4 . A compound according to  claim 2 , or a tautomer or pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of imidazo[1,5-a]pyridin-8-yl, imidazo[1,5-a]pyridin-6-yl, imidazo[1,5-a]pyridin-5-yl, imidazo[1,2-a]pyridin-8-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-3-yl, 8-methylimidazo[1,2-a]pyridin-2-yl, indazol-4-yl, pyrrolo[2,3-b]pyridin-4-yl, pyrrolo[1,2-a]pyrazin-6-yl, pyrrolo[1,2-a]pyrazin-4-yl, pyrazolo[3,4-b]pyridin-4-yl, pyrazolo[1,5-a]pyrazin-3-yl, and quinolin-5-yl, each of which is optionally substituted with one to three R a . 
     
     
         5 . A compound according to  claim 4 , or a tautomer or pharmaceutically acceptable salt thereof, wherein R 2  is selected from the group consisting of H and OR d ;
 R 3  is selected from the group consisting of H, CN, halo, and OR d ;   R 4  is selected from the group consisting of H, CN, and OR d ; and   R 5  is H.   
     
     
         6 . A compound according to  claim 5 , or a tautomer or pharmaceutically acceptable salt thereof, wherein R 4  is methoxy. 
     
     
         7 . A compound according to  claim 3 , or a tautomer or pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of pyridine-3-yl and piperidin-1-yl. 
     
     
         8 . A compound according to  claim 7 , or a tautomer or pharmaceutically acceptable salt thereof, wherein R 5  is selected from the group consisting of hydroxy and fluoro. 
     
     
         9 . A compound according to any of the preceeding claims, or a tautomer or pharmaceutically acceptable salt thereof, wherein R 6  and R 7  together form oxo. 
     
     
         10 . A compound according to  claim 1  selected from the group consisting of:
 2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-5-methoxybenzaldehyde, 
 4-formyl-3-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzonitrile, 
 2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-4-methoxybenzaldehyde, 
 2-(imidazo[1,2-a]pyridin-6-ylmethoxy)-5-methoxybenzaldehyde, 
 2-(imidazo[1,5-a]pyridin-8-ylmethoxy)-4-methoxybenzaldehyde, 
 2-(imidazo[1,5-a]pyridin-8-ylmethoxy)-5-methoxybenzaldehyde, 
 2-(imidazo[1,2-a]pyridin-7-ylmethoxy)-5-methoxybenzaldehyde, 
 2-(imidazo[1,2-a]pyridin-3-ylmethoxy)-5-methoxybenzaldehyde, 
 5-methoxy-2-(quinolin-5-ylmethoxy)benzaldehyde, 
 5-bromo-2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde, 
 4-chloro-2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde, 
 2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde, 
 4-fluoro-2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde, 
 2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-3-methoxybenzaldehyde, 
 2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-5-methylbenzaldehyde, 
 5-methoxy-2-(pyrrolo[1,2-a]pyrazin-4-ylmethoxy)benzaldehyde, 
 2-(imidazo[1,5-a]pyridin-6-ylmethoxy)-4-methoxybenzaldehyde, 
 2-(imidazo[1,5-a]pyridin-5-ylmethoxy)-5-methoxybenzaldehyde, 
 3-formyl-4-(imidazo[1,5-a]pyridin-5-ylmethoxy)benzonitrile, 
 2-((1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)-5-methoxybenzaldehyde, 
 5-ethyl-2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde, 
 5-methoxy-2-((1-methyl-1H-indazol-4-yl)methoxy)benzaldehyde, 
 5-methoxy-2-((8-methylimidazo[1,2-a]pyridin-2-yl)methoxy)benzaldehyde, 
 2-((1H-indazol-4-yl)methoxy)-5-methoxybenzaldehyde, 
 2-((1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)-5-methoxybenzaldehyde, 
 3-formyl-4-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzonitrile, 
 5-methoxy-2-(pyrrolo[1,2-a]pyrazin-6-ylmethoxy)benzaldehyde, 
 6-((2-formyl-4-methoxyphenoxy)methyl)pyrrolo[1,2-a]pyrazine-7-carbonitrile, 
 6-((2-formyl-4-methoxyphenoxy)methyl)pyrrolo[1,2-a]pyrazine-7-carboxamide, 
 2-((1H-pyrazolo[3,4-b]pyridin-4-yl)methoxy)-5-methoxybenzaldehyde, 
 5-methoxy-2-(pyrazolo[1,5-a]pyrazin-3-ylmethoxy)benzaldehyde, 
 5-methoxy-2-(pyrrolo[1,2-a]pyrazin-6-ylmethoxy)benzaldehyde, 
 2-(imidazo[1,5-a]pyridin-6-ylmethoxy)-5-methoxybenzaldehyde, 
 3-formyl-4-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzonitrile, 
 3-(imidazo[1,2-a]pyridin-8-ylmethyl)-1,3-dihydroisobenzofuran-1-ol, 
 2-(imidazo[1,2-a]pyridin-5-ylmethoxy)-5-methoxybenzaldehyde, 
 N-(2-formyl-4-methoxyphenyl)imidazo[1,2-a]pyridine-8-carboxamide, 
 N-(2-formylphenyl)imidazo[1,2-a]pyridine-8-carboxamide, 
 2-formyl-N-(imidazo[1,2-a]pyridin-8-yl)benzamide, 
 2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxybenzaldehyde, 
 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde 
 2-((3-(2H-tetrazol-5-yl)benzyl)oxy)-6-hydroxybenzaldehyde, 
 2-((4-(2H-tetrazol-5-yl)benzyl)oxy)-6-hydroxybenzaldehyde, 
 2-hydroxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, 
 2-hydroxy-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, 
 2-fluoro-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, 
 2-fluoro-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, 
 2-fluoro-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, and 
 1-(2-formyl-3-hydroxyphenethyl)piperidine-4-carboxylic acid 
 or a tautomer or pharmaceutically acceptable salt thereof. 
 
     
     
         11 . A compound according to  claim 1  selected from the group consisting of:
 2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-5-methoxybenzaldehyde, 
 2-(imidazo[1,5-a]pyridin-8-ylmethoxy)-5-methoxybenzaldehyde, 
 5-methoxy-2-(quinolin-5-ylmethoxy)benzaldehyde, 
 5-methoxy-2-((1-methyl-1H-indazol-4-yl)methoxy)benzaldehyde, 
 5-methoxy-2-((8-methylimidazo[1,2-a]pyridin-2-yl)methoxy)benzaldehyde, 
 2-((1H-indazol-4-yl)methoxy)-5-methoxybenzaldehyde, 
 2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxybenzaldehyde, 
 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, 
 2-((3-(2H-tetrazol-5-yl)benzyl)oxy)-6-hydroxybenzaldehyde, 
 2-((4-(2H-tetrazol-5-yl)benzyl)oxy)-6-hydroxybenzaldehyde, 
 2-hydroxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, 
 2-hydroxy-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, 
 2-fluoro-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, 
 2-fluoro-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, 
 2-fluoro-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, and 
 1-(2-formyl-3-hydroxyphenethyl)piperidine-4-carboxylic acid, 
 or a tautomer or pharmaceutically acceptable salt thereof. 
 
     
     
         12 . A pharmaceutical composition comprising a compound of any of the preceding claims or a tautomer or pharmaceutically acceptable salt thereof. 
     
     
         13 . A method for increasing tissue oxygenation, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the preceding claims or a tautomer or pharmaceutically acceptable salt thereof. 
     
     
         14 . A method for treating a condition associated with oxygen deficiency, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the preceding claims or a tautomer or pharmaceutically acceptable salt thereof. 
     
     
         15 . The method of  claim 14 , wherein the condition is selected from the group consisting of sickle cell disease, cancer, a pulmonary disorder, stroke, high altitude sickness, an ulcer, a pressure sore, Alzheimer's disease, acute respiratory disease syndrome, and a wound 
     
     
         16 . The method of any of  claims 13 - 15 , wherein the compound is selected from the group consisting of:
 2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-5-methoxybenzaldehyde,   4-formyl-3-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzonitrile,   2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-4-methoxybenzaldehyde,   2-(imidazo[1,2-a]pyridin-6-ylmethoxy)-5-methoxybenzaldehyde,   2-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-methoxybenzaldehyde,   2-(imidazo[1,5-a]pyridin-8-ylmethoxy)-4-methoxybenzaldehyde,   2-(imidazo[1,5-a]pyridin-8-ylmethoxy)-5-methoxybenzaldehyde,   2-(imidazo[1,2-a]pyridin-7-ylmethoxy)-5-methoxybenzaldehyde,   2-(imidazo[1,2-a]pyridin-3-ylmethoxy)-5-methoxybenzaldehyde,   5-methoxy-2-(quinolin-5-ylmethoxy)benzaldehyde,   5-bromo-2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde,   4-chloro-2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde,   2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde,   4-fluoro-2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde,   2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-3-methoxybenzaldehyde,   2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-5-methylbenzaldehyde,   5-methoxy-2-(pyrrolo[1,2-a]pyrazin-4-ylmethoxy)benzaldehyde,   2-(imidazo[1,5-a]pyridin-6-ylmethoxy)-4-methoxybenzaldehyde,   2-(imidazo[1,5-a]pyridin-5-ylmethoxy)-5-methoxybenzaldehyde,   3-formyl-4-(imidazo[1,5-a]pyridin-5-ylmethoxy)benzonitrile,   2-((1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)-5-methoxybenzaldehyde,   5-ethyl-2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde,   5-methoxy-2-((1-methyl-1H-indazol-4-yl)methoxy)benzaldehyde,   5-methoxy-2-((8-methylimidazo[1,2-a]pyridin-2-yl)methoxy)benzaldehyde,   2-((1H-indazol-4-yl)methoxy)-5-methoxybenzaldehyde,   2-((1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)-5-methoxybenzaldehyde,   3-formyl-4-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzonitrile,   5-methoxy-2-(pyrrolo[1,2-a]pyrazin-6-ylmethoxy)benzaldehyde,   6-((2-formyl-4-methoxyphenoxy)methyl)pyrrolo[1,2-a]pyrazine-7-carbonitrile,   6-((2-formyl-4-methoxyphenoxy)methyl)pyrrolo[1,2-a]pyrazine-7-carboxamide,   2-((1H-pyrazolo[3,4-b]pyridin-4-yl)methoxy)-5-methoxybenzaldehyde,   5-methoxy-2-(pyrazolo[1,5-a]pyrazin-3-ylmethoxy)benzaldehyde,   5-methoxy-2-(pyrrolo[1,2-a]pyrazin-6-ylmethoxy)benzaldehyde,   2-(imidazo[1,5-a]pyridin-6-ylmethoxy)-5-methoxybenzaldehyde,   3-formyl-4-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzonitrile,   3-(imidazo[1,2-a]pyridin-8-ylmethyl)-1,3-dihydroisobenzofuran-1-ol,   2-(imidazo[1,2-a]pyridin-5-ylmethoxy)-5-methoxybenzaldehyde,   N-(2-formyl-4-methoxyphenyl)imidazo[1,2-a]pyridine-8-carboxamide,   N-(2-formylphenyl)imidazo[1,2-a]pyridine-8-carboxamide,   2-formyl-N-(imidazo[1,2-a]pyridin-8-yl)benzamide,   5-methoxy-2-(pyridin-3-ylmethoxy)benzaldehyde,   4-((2-formyl-3-hydroxyphenoxy)methyl)benzoic acid,   2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxybenzaldehyde,   2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,   2-((3-(2H-tetrazol-5-yl)benzyl)oxy)-6-hydroxybenzaldehyde,   2-((4-(2H-tetrazol-5-yl)benzyl)oxy)-6-hydroxybenzaldehyde,   methyl 4-((2-formylphenoxy)methyl)benzoate,   4-((2-formylphenoxy)methyl)benzoic acid,   methyl 3-((2-formylphenoxy)methyl)benzoate,   2-hydroxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,   2-hydroxy-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,   2-fluoro-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,   2-fluoro-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,   2-fluoro-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, and   1-(2-formyl-3-hydroxyphenethyl)piperidine-4-carboxylic acid   or a tautomer or pharmaceutically acceptable salt thereof.   
     
     
         17 . The method of any of  claims 13 - 15 , wherein the compound is selected from the group consisting of:
 2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-5-methoxybenzaldehyde,   4-formyl-3-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzonitrile,   2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-4-methoxybenzaldehyde,   2-(imidazo[1,2-a]pyridin-6-ylmethoxy)-5-methoxybenzaldehyde,   2-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-methoxybenzaldehyde,   2-(imidazo[1,5-a]pyridin-8-ylmethoxy)-4-methoxybenzaldehyde,   2-(imidazo[1,5-a]pyridin-8-ylmethoxy)-5-methoxybenzaldehyde,   2-(imidazo[1,2-a]pyridin-7-ylmethoxy)-5-methoxybenzaldehyde,   2-(imidazo[1,2-a]pyridin-3-ylmethoxy)-5-methoxybenzaldehyde,   5-methoxy-2-(quinolin-5-ylmethoxy)benzaldehyde,   5-bromo-2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde,   4-chloro-2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde,   2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde,   4-fluoro-2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde,   2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-3-methoxybenzaldehyde,   2-(imidazo[1,2-a]pyridin-8-ylmethoxy)-5-methylbenzaldehyde,   5-methoxy-2-(pyrrolo[1,2-a]pyrazin-4-ylmethoxy)benzaldehyde,   2-(imidazo[1,5-a]pyridin-6-ylmethoxy)-4-methoxybenzaldehyde,   2-(imidazo[1,5-a]pyridin-5-ylmethoxy)-5-methoxybenzaldehyde,   3-formyl-4-(imidazo[1,5-a]pyridin-5-ylmethoxy)benzonitrile,   2-((1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)-5-methoxybenzaldehyde,   5-ethyl-2-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzaldehyde,   5-methoxy-2-((1-methyl-1H-indazol-4-yl)methoxy)benzaldehyde,   5-methoxy-2-((8-methylimidazo[1,2-a]pyridin-2-yl)methoxy)benzaldehyde,   2-((1H-indazol-4-yl)methoxy)-5-methoxybenzaldehyde,   2-((1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)-5-methoxybenzaldehyde,   3-formyl-4-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzonitrile,   5-methoxy-2-(pyrrolo[1,2-a]pyrazin-6-ylmethoxy)benzaldehyde,   6-((2-formyl-4-methoxyphenoxy)methyl)pyrrolo[1,2-a]pyrazine-7-carbonitrile,   6-((2-formyl-4-methoxyphenoxy)methyl)pyrrolo[1,2-a]pyrazine-7-carboxamide,   2-((1H-pyrazolo[3,4-b]pyridin-4-yl)methoxy)-5-methoxybenzaldehyde,   5-methoxy-2-(pyrazolo[1,5-a]pyrazin-3-ylmethoxy)benzaldehyde,   5-methoxy-2-(pyrrolo[1,2-a]pyrazin-6-ylmethoxy)benzaldehyde,   2-(imidazo[1,5-a]pyridin-6-ylmethoxy)-5-methoxybenzaldehyde,   3-formyl-4-(imidazo[1,2-a]pyridin-8-ylmethoxy)benzonitrile,   3-(imidazo[1,2-a]pyridin-8-ylmethyl)-1,3-dihydroisobenzofuran-1-ol,   2-(imidazo[1,2-a]pyridin-5-ylmethoxy)-5-methoxybenzaldehyde,   N-(2-formyl-4-methoxyphenyl)imidazo[1,2-a]pyridine-8-carboxamide,   N-(2-formylphenyl)imidazo[1,2-a]pyridine-8-carboxamide,   2-formyl-N-(imidazo[1,2-a]pyridin-8-yl)benzamide,   5-methoxy-2-(pyridin-3-ylmethoxy)benzaldehyde,   4-((2-formyl-3-hydroxyphenoxy)methyl)benzoic acid,   2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxybenzaldehyde,   2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,   2-((3-(2H-tetrazol-5-yl)benzyl)oxy)-6-hydroxybenzaldehyde,   2-((4-(2H-tetrazol-5-yl)benzyl)oxy)-6-hydroxybenzaldehyde,   methyl 4-((2-formylphenoxy)methyl)benzoate,   4-((2-formylphenoxy)methyl)benzoic acid,   methyl 3-((2-formylphenoxy)methyl)benzoate,   2-hydroxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,   2-hydroxy-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,   2-fluoro-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,   2-fluoro-6-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde,   2-fluoro-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, and   1-(2-formyl-3-hydroxyphenethyl)piperidine-4-carboxylic acid   or a tautomer or pharmaceutically acceptable salt thereof.