Amido heteroaromatic compounds

Abstract

The specification relates to compounds of Formula (I):and to pharmaceutically acceptable salts thereof, to processes and intermediates used for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of diseases such as liver disease.

1 . A compound of Formula (I); 
       
         
           
           
               
               
           
         
         wherein, 
         A is selected from 
       
       
         
           
           
               
               
           
         
         each R A  is independently selected from H, halo, R X , —OR x , and —CN, wherein each R X  is independently C 1-3  alkyl optionally substituted with one to three F; 
         R B  is halo, —CHF 2 , —CF 3 , —OCHF 2  or —OCF 3 ; 
         one of X 1 , X 2  and X 3  is selected from NH, O and S and the other two of X 1 , X 2  and X 3  are independently selected from N and CR Y , wherein each R Y  is independently H, —CN, —C(═O)N(R 7 ) 2  or R XA , wherein R XA  is independently C 1-3  alkyl optionally substituted with one to three F; 
         R 1  and R 2  are such that; 
         (i) R 1  and R 2 , taken together with the N atom to which they are attached, form a ring system, wherein the ring system is optionally substituted with one or more R C , wherein each R C  is independently selected from F, R 3 , R 4 , —O(R 4 ), —O(R 5 ), R 3 , R 6 , —OH, —CN, oxo and —C(═O)N(R 7A ) 2 ; 
         (ii) R 1  is selected from R 8  and R 4A , and R 2  is selected from R 8A  and H; or 
         (iii) R 1  is R 5A  and R 2  is R 8B ; 
         each R 3  is independently C 1-4  alkyl or C 3-6  cycloalkyl, each of which are optionally substituted with one or more groups independently selected from R 4X , R 5x , —O(R 4X ), —O(R 5X ) and F; 
         each R 3X  is independently C 1-4  alkyl or C 3-6  cycloalkyl, each of which are optionally substituted with one or more F; 
         each R 4  and R 4B  are independently monocyclic or bicyclic 5 to 9 membered heteroaryl, each of which are optionally substituted with one or more groups independently selected from R 4X , —O(R 4X ), R 5X , —O(R 5X ), —OH, —CN, C 1-4  alkoxy, —C(═O)OH, —C(═O)O(C 1-4  alkyl), —C(═O)N(R 7B ) 2 , R 3  and halo; 
         R 4A  is a 5 membered monocyclic heteroaryl, optionally substituted with one or more groups independently selected from R 4X , —O(R 4X ), R 5X , —O(R 5X ), —OH, —CN, C 1-4  alkoxy, —C(═O)OH, —C(═O)O(C 1-4  alkyl), —C(═O)N(R 7B ) 2 , R 3  and halo; 
         each R 5 , R 5A  and R 5B  are independently phenyl, each of which are optionally substituted with one or more groups independently selected from R 4X , —O(R 4X ), R 5X , —O(R 5X ), —OH, —CN, C 1-4  alkoxy, —C(═O)OH, —C(═O)O(C 1-4  alkyl), —C(═O)N(R 7B ) 2 , R 3  and halo; 
         each R 4X  is independently monocyclic or bicyclic 5 to 9 membered heteroaryl, each of which are optionally substituted with one or more groups independently selected from —OH, —CN, C 1-4  alkoxy, —C(═O)OH, —C(═O)N(R 7B ) 2 , R 3X  and halo; 
         each R 5X  is independently phenyl, each of which are optionally substituted with one or more groups independently selected from —OH, —CN, C 1-4  alkoxy, —C(═O)OH, —C(═O)N(R 7B ) 2 , R 3x , and halo; 
         R 6  is C 1-4  alkoxy optionally substituted with one or more groups independently selected from R 4X , R 5x  and F; 
         each R 7 , R 7A , R 7B  and R 7C  are independently H, C 1-4  alkyl or C 3-6  cycloalkyl; 
         R 8 , R 8A , R 8B  are independently C 1-4  alkyl or C 3-6  cycloalkyl, each of which are optionally substituted with one or more groups independently selected from R 4B , R 5B , F, —OH, —CN, C 1-4  alkoxy, —C(═O)O(C 1-4  alkyl) and —C(═O)N(R 7C ) 2 ; 
         wherein the ring system is a saturated or partly saturated, monocyclic, bicyclic or tricyclic, 4-13 membered ring comprising one N atom, and optionally one or two further heteroatoms independently selected from N, O and S; and 
         wherein each heteroaryl is independently an aromatic ring containing one or more heteroatoms independently selected from N, O and S, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 (i) X 1  is N, X 2  is O and X3 is N;   (ii) X 1  is N, X 2  is N and X3 is O;   (iii) X 1  is CR Y , X 2  is CR Y  and X 3  is S;   (iv) X 1  is O, X 2  is N and X 3  is CR Y ;   (v) X 1  is N, X 2  is O and X 3  is CR Y ;   (vi) X 1  is CR Y , X 2  is N and X 3  is O;   (vii) X 1  is O, X2 is N and X3 is N;   (viii) X 1  is N, X 2  is N and X3 is S;   (ix) X 1  is CR Y , X 2  is S and X 3  is CR Y ; or   (x) X 1  is CR Y , X 2  is N and X3 is S.   
     
     
         3 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein one of X 1 , X 2  and X 3  is O and the other two of X 1 , X 2  and X 3  are independently selected from N and CR Y . 
     
     
         4 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein X 1  is N, X 2  is O and X 3  is N. 
     
     
         5 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein one of X 1 , X 2  and X 3  is S and the other two of X 1 , X 2  and X 3  are independently CR Y . 
     
     
         6 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein each R A  is independently H or halo. 
     
     
         7 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein each R A  is independently H or F. 
     
     
         8 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein R B  is F. 
     
     
         10 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein R 1  and R 2 , taken together with the N atom to which they are attached, form a ring system, wherein the ring system is optionally substituted with one or more R C . 
     
     
         11 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein the ring system is an aliphatic, monocyclic or bicyclic, 4-11 membered ring comprising one N atom, and optionally one further heteroatom selected from N, O and S. 
     
     
         12 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein R 1  and R 2 , taken together with the N atom to which they are attached form a ring system selected from a 4-8 membered monocyclic heterocycloalkyl, an 8-11 membered spirocyclic bicyclic heterocycloalkyl and a 7-10 membered fused bicyclic heterocycloalkyl, wherein the ring system is optionally substituted with one or more R C , and wherein heterocycloalkyl is a saturated ring comprising one N atom, and optionally one further heteroatom selected from N, O and S. 
     
     
         13 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein R 1  and R 2 , taken together with the N atom to which they are attached form a ring system that is a 4-8 membered monocyclic heterocycloalkyl optionally substituted with one or more R C , wherein heterocycloalkyl is a saturated ring comprising one N atom, and optionally one further heteroatom selected from N, O and S. 
     
     
         14 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein R 1  and R 2 , taken together with the N atom to which they are attached form a ring system that is a 5-7 membered monocyclic heterocycloalkyl optionally substituted with one or more R C , wherein heterocycloalkyl is a saturated ring comprising one N atom, and one further heteroatom selected from N, O and S. 
     
     
         15 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein the ring system is optionally substituted with one to three groups independently selected from R 3 , R 4  and R 5 . 
     
     
         16 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , that is a compound of Formula (II): 
       
         
           
           
               
               
           
         
         wherein 
         J is selected from O, S, CH 2 , NH and a covalent bond, 
         G is either absent or, together with the carbon atoms to which it is attached, forms a C 3-6  cycloalkane ring; 
         Z is such that 
         (i) where G is absent and J is selected from O, S, CH 2  and a covalent bond, Z is selected from CH 2 , CH 2 CH 2  and C 3-6  cycloalkylidyne, 
         (ii) where G is absent and J is NH, Z is selected from CH 2 , CH 2 CH 2 , C 3-6  cycloalkylidyne and C(═O), and 
         (iii) where G, together with the carbon atoms to which it is attached, forms a C 3-6  cycloalkane ring, Z is CH 2 ; 
         x is selected from 0 to 3; and 
         each R 9  is independently selected from R 3 , R 4  and R 5 , 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , that is a compound of Formula (III): 
       
         
           
           
               
               
           
         
         wherein 
         J is selected from O, S, CH 2 , NH and a covalent bond, 
         x is selected from 0 to 3; 
         each R 9  is independently selected from R 3 , R 4  and R 5 ; and 
         R E  is H or halo, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         18 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 16 , wherein J is O. 
     
     
         19 - 24 . (canceled) 
     
     
         25 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein each R 3  is independently C 1-4  alkyl optionally substituted with one to three F. 
     
     
         26 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein each R 4  and R 4B  are independently monocyclic or bicyclic 5 to 9 membered heteroaryl, each of which are optionally substituted with one or more groups independently selected from OH, —CN, C 1-4  alkoxy, —C(═O)OH, —C(═O)O(C 1-4  alkyl) —C(═O)N(R 7B ) 2 , R 3X  and halo. 
     
     
         27 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein each R 5 , R 5A  and R 5B  are independently phenyl, each of which are optionally substituted with one or more groups independently selected from OH, —CN, C 1-4  alkoxy, —C(═O)OH, —C(═O)O(C 1-4  alkyl), —C(═O)N(R 7B ) 2 , R 3X  and halo. 
     
     
         28 . A pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
         29 .- 32 . (canceled) 
     
     
         33 . A method of treating liver disease in a patient comprising administering to the patient a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 .