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.

1 .- 17 . (canceled) 
     
     
         18 . A method for increasing tissue oxygenation in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of 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 Rib, 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 ) 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 e , —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 , —(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  wherein 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  wherein 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) 2 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; where 
         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 ; 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 ;
 and 
 W is selected from the group consisting of pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 
 
       
         
           
           
               
               
           
         
       
       wherein W is optionally substituted with one to three R a , and wherein the wavy line signifies the point of attachment to Y; provided that when W is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, then W is substituted with one to three R a ;
 and provided that when R 5  is OH or —NR d R d  where each R d  is hydrogen or C 1-8  alkyl, or —NR d COR e  where R d  is hydrogen or C 1-8 alkyl and R c  is C 1-8 alkyl, and R 2 , R 3  and R 4  are independently hydrogen, halo, C 1-8 alkyl optionally substituted with one to three halo, OC 1-8  alkyl, or OH, then Q is not aryl substituted with R a  where R a  is cyano, carboxy or tetrazolyl. 
 
     
     
         19 . A method for treating a condition associated with oxygen deficiency in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of 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 Rib, 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 , —(CH2) 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 e , —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 , —(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  wherein 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; where 
         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 ; 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 ;
 and 
 W is selected from the group consisting of pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 
 
       
         
           
           
               
               
           
         
       
       wherein W is optionally substituted with one to three R a , and wherein the wavy line signifies the point of attachment to Y; provided that when W is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, then W is substituted with one to three R a ;
 and provided that when R 5  is OH or —NR d R d  where each R d  is hydrogen or C 1-8 alkyl, or —NR d COR e  where R d  is hydrogen or C 1-8 alkyl and R c  is C 1-8 alkyl, and R 2 , R 3  and R 4  are independently hydrogen, halo, C 1-8 alkyl optionally substituted with one to three halo, OC 1-8 alkyl, or OH, then Q is not aryl substituted with R a  where R a  is cyano, carboxy or tetrazolyl. 
 
     
     
         20 . The method of  claim 19 , 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 distress syndrome, and a wound. 
     
     
         21 . The method of  claim 20 , wherein the condition is sickle cell disease. 
     
     
         22 . The method of  claim 20 , wherein the condition is acute respiratory distress syndrome. 
     
     
         23 . The method of  claim 20 , wherein the condition is a pulmonary disorder. 
     
     
         24 . The method of  claim 18 , wherein Q is selected from the group consisting of heteroaryl and heterocycloalkyl, each of which is optionally substituted with one to three R a . 
     
     
         25 . The method of  claim 18 , wherein:
 Y is O or CH 2 ;   X is O or CH 2 ;   Q is selected from the group consisting of:
 i) 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 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 
 
 ii) 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 e , —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 e , —(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 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 , (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  wherein 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; and 
 R 6  and R 7  together form oxo. 
 
   
     
     
         26 . The method of  claim 18 , wherein:
 Y is CH 2 ; and X is CH 2 ; and   R 6  and R 7  together form oxo.   
     
     
         27 . The method of  claim 25 , 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 . 
     
     
         28 . The method of  claim 27 , 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.   
     
     
         29 . The method of  claim 18 , wherein Q is selected from the group consisting of pyridin-3-yl and piperidin-1-yl, each of which is optionally substituted with one to three R a . 
     
     
         30 . The method of  claim 29 , wherein R 5  is selected from the group consisting of hydroxy and fluoro. 
     
     
         31 . The method of  claim 18 , wherein the compound or a tautomer or pharmaceutically acceptable salt thereof, is selected from the group consisting of:
 2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxy-benzaldehyde,   2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde,   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, and   2-fluoro-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde,   or a tautomer or pharmaceutically acceptable salt thereof.   
     
     
         32 . The method of  claim 18 , wherein the compound is 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde; or a tautomer or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method of  claim 32  wherein the compound is 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde. 
     
     
         34 . The method of  claim 21 , wherein Q is selected from the group consisting of heteroaryl and heterocycloalkyl, each of which is optionally substituted with one to three R a . 
     
     
         35 . The method of  claim 21 , wherein:
 Y is O or CH 2 ;   X is O or CH 2 ;   Q is selected from the group consisting of:
 i) 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 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 
 
 (ii) 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 e , —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 e , —(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 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 , (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 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; and 
 R 6  and R 7  together form oxo. 
 
   
     
     
         36 . The method of  claim 21 , wherein:
 Y is CH 2 ; and X is CH 2 ; and   R 6  and R 7  together form oxo.   
     
     
         37 . The method of  claim 35 , 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 . 
     
     
         38 . The method of  claim 37 , 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.   
     
     
         39 . The method of  claim 21 , wherein Q is selected from the group consisting of pyridin-3-yl and piperidin-1-yl, each of which is optionally substituted with one to three R a . 
     
     
         40 . The method of  claim 39 , wherein R 5  is selected from the group consisting of hydroxy and fluoro. 
     
     
         41 . The method of  claim 21 , wherein the compound or a tautomer or pharmaceutically acceptable salt thereof, is selected from the group consisting of:
 2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxy-benzaldehyde,   2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde,   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, and   2-fluoro-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde,   or a tautomer or pharmaceutically acceptable salt thereof.   
     
     
         42 . The method of  claim 21 , wherein the compound is 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde, or a tautomer or a pharmaceutically acceptable salt thereof. 
     
     
         43 . The method of  claim 42 , wherein the compound is 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde. 
     
     
         44 . The method of  claim 23 , wherein Q is selected from the group consisting of heteroaryl and heterocycloalkyl, each optionally substituted with one to three R a . 
     
     
         45 . The method of  claim 23 , wherein:
 Y is O or CH 2 ;   X is O or CH 2 ;   Q is selected from the group consisting of:
 i) 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 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 
 
 ii) 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 e , —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 e , —(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 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 , (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 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; and 
 R 6  and R 7  together form oxo. 
 
   
     
     
         46 . The method of  claim 23 , wherein:
 Y is CH 2 ; and X is CH 2 ; and   R 6  and R 7  together form oxo.   
     
     
         47 . The method of  claim 45 , 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 . 
     
     
         48 . The method of  claim 47 , 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.   
     
     
         49 . The method of  claim 23 , wherein Q is selected from the group consisting of pyridin-3-yl and piperidin-1-yl, each of which is optionally substituted with one to three R a . 
     
     
         50 . The method of  claim 49 , wherein R 5  is selected from the group consisting of hydroxy and fluoro. 
     
     
         51 . The method of  claim 23 , wherein the compound or a tautomer or pharmaceutically acceptable salt thereof, is selected from the group consisting of:
 2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxy-benzaldehyde,   2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde,   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, and   2-fluoro-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde,   or a tautomer or pharmaceutically acceptable salt thereof.   
     
     
         52 . The method of  claim 23 , wherein the compound is 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-benzaldehyde, or a tautomer or a pharmaceutically acceptable salt thereof. 
     
     
         53 . The method of  claim 52 , wherein the compound is 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde.