Pi4kiiibeta inhibitors

Abstract

The invention relates to compounds of formula (1) which are inhibitors of kinase activity, pharmaceutical formulations containing the compounds and their uses in treating and preventing viral infections and disorders caused or exacerbated by the viral infectionwherein R1, R2, R3, R4a, R4b, R4c, R5, W, X, Y and Z are defined herein.

1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         W is C, X is C, Y is N and Z is C; 
         W is C, X is N, Y is C and Z is C; 
         W is C, X is N, Y is C and Z is N; 
         W is N, X is C, Y is C and Z is N; or 
         W is N, X is C, Y is C and Z is C; 
         R 1  is C 1-4 alkoxy, —C(═O)N(R 1a R 1b ), —S(═O) 2 —N(R 1a R 1b ), —S(═O) 2 —R 1c  or —S(═O)—R 1c , wherein
 R 1a  is C 1-3 alkyl, haloC 1-3 alkyl, hydroxyC 1-3 alkyl, C 1-3 alkoxyC 1-3 alkyl, tetrahydropyranyl or tetrahydrofuranyl; R 1  b is H or C 1-3 alkyl, or R 1a  and R 1b , together with the nitrogen to which they are attached, form a 4- to 7-membered ring, which ring contains ring-carbon atoms and optionally one ring-oxygen atom, wherein the ring is a) optionally substituted by one or two groups selected from C 1-3 alkyl, halo, C 1-3 alkoxy, hydroxy, hydroxyC 1-3 alkyl and oxo, which may be the same or different or b) is ortho- or spiro-fused to an unsubstituted 4-6 membered cycloalkane ring or an unsubstituted 4-6 membered saturated heterocyclic ring; and R 1c  is C 1-3 alkyl, C 1-3 alkoxy, hydroxy, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 1-3 alkyl; 
 
         R 2  is H, C 1-3 alkyl, halo or —O—R 2a , wherein R 2a  is H or an unsubstituted linear C 1-3 alkyl chain, wherein one chain carbon is optionally replaced by oxygen; 
         R 3  is H or halo; 
         and wherein either 
         i) R 4a  is H, C 1-3 alkyl or halo; R 4b  is C 1-3 alkyl, cyclopropyl or hydroxyC 1-2 alkyl; or R 4a  and R 4b  together with the carbon to which they are attached form a 3-6 membered saturated ring containing ring-carbon atoms and optionally a ring-oxygen atom, wherein the ring is optionally substituted by one C 1-3 alkyl group or one hydroxyC 1-2 alkyl group; and R 4c  is OH, hydroxymethyl or hydroxyethyl; 
         ii) R 4a  H, C 1-3 alkyl, halo or OH; R 4b  is H, C 1-3 alkyl or halo; and R 4c  is an unsubstituted ring selected from the list consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl; or 
         iii) R 4a  is H, and R 4b  and R 4c  together with the carbon to which they are attached form an unsubstituted ring selected from the list consisting of oxetane, tetrahydrofuran or tetrahydropyran; and 
         R 5  is 
         a) imidazol-2-yl optionally substituted by a C 1-3 alkyl group at the 1-position and optionally substituted by a methyl group at the 5-position; or 
         b) pyrazol-1-yl optionally substituted by a C 1-3 alkyl group at the 5-position and optionally substituted by a methyl group at the 4-position. 
       
     
     
         2 . The compound according to  claim 1 , wherein the compound is a compound according to formula (Ia) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         X is N or C, Y is N or C and Z is N or C; wherein X and Y cannot both be N or both be C;
 and wherein when Z is N, X is N and Y is C; 
 
         R 1  is C 1-4 alkoxy, —C(═O)N(R 1a R 1b ), —S(═O) 2 —N(R 1a R 1b ), —S(═O) 2 —R 1c  or —S(═O)—R 1c , wherein
 R 1a  is C 1-3 alkyl, haloC 1-3 alkyl, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 1-3 alkyl; R 1b  is H or C 1-3 alkyl, or R 1a  and R 1b , together with the nitrogen to which they are attached, form a 4- to 7-membered ring, which ring contains ring-carbon atoms and optionally one ring-oxygen atom, wherein the ring is a) optionally substituted by one or two groups selected from C 1-3 alkyl, halo, C 1-3 alkoxy, hydroxy and oxo, which may be the same or different or b) is ortho- or spiro-fused to an unsubstituted 4-6 membered cycloalkane ring or an unsubstituted 4-6 membered saturated heterocyclic ring; and 
 R 1c  is C 1-3 alkyl, C 1-3 alkoxy, hydroxy, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 1-3 alkyl; 
 
         R 2  is H, C 1-3 alkyl, chloro or —O—R 2a , wherein R 2a  is H or an unsubstituted linear C 1-3 alkyl chain, wherein one chain carbon is optionally replaced by oxygen; 
         R 3  is H or fluoro; 
         R 4a  is H or methyl; 
         R 4b  is C 1-3 alkyl or hydroxyC 1-2 alkyl; and 
         R 5  is
 a) imidazol-2-yl optionally substituted by a C 1-3 alkyl group at the 1-position and optionally substituted by a methyl group at the 5-position; or 
 b) pyrazol-1-yl optionally substituted by a C 1-3 alkyl group at the 5-position and optionally substituted by a methyl group at the 4-position. 
 
       
     
     
         3 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein:
 i) R 4a  is H, C 1-3 alkyl or fluoro; R 4b  is C 1-3 alkyl, cyclopropyl or hydroxyC 1-2 alkyl; or R 4a  and R 4b  together with the carbon to which they are attached form a 3-6 membered saturated ring containing ring-carbon atoms and optionally a ring-oxygen atom, wherein the ring is optionally substituted by one C 1-3 alkyl group or one hydroxyC 1-2 alkyl group; and R 4c  is OH, hydroxymethyl or hydroxyethyl; 
 ii) R 4a  H, C 1-3 alkyl, fluoro or OH; R 4b  is H, C 1-3 alkyl or fluoro; and R 4c  is an unsubstituted ring selected from the list consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl; or 
 iii) R 4a  is H, and R 4b  and R 4c  together with the carbon to which they are attached form an unsubstituted ring selected from the list consisting of oxetane, tetrahydrofuran or tetrahydropyran. 
 
     
     
         4 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 2  is H, C 1-3 alkyl, chloro or —O—R 2a , wherein R 2a  is H or an unsubstituted linear C 1-3 alkyl chain, wherein one chain carbon is optionally replaced by oxygen; and R 3  is H or fluoro. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 1  is —C(═O)N(R 1a R 1b ) or —S(═O) 2 —R 1c . 
     
     
         8 . The compound according to  claim 7  or a pharmaceutically acceptable salt thereof, wherein R 1  is —C(═O)N(R 1a R 1b ). 
     
     
         9 . The compound according to  claim 8  or a pharmaceutically acceptable salt thereof, wherein R 1a  is hydroxyC 1-3 alkyl or tetrahydropyranyl. 
     
     
         10 . The compound according to  claim 9  or a pharmaceutically acceptable salt thereof, wherein R 1a  is hydroxyC 1-3 alkyl. 
     
     
         11 . The compound according to  claim 10  or a pharmaceutically acceptable salt thereof, wherein R 1a  is 3-hydroxy-1-propyl, 2-hydroxy-1-ethyl or 3-hydroxy-2-propyl. 
     
     
         12 . The compound according to  claim 8  or a pharmaceutically acceptable salt thereof, wherein R 1b  is C 1-3 alkyl. 
     
     
         13 . The compound according to  claim 12  or a pharmaceutically acceptable salt thereof, wherein R 1b  is methyl or ethyl. 
     
     
         14 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 2  is C 1-3 alkyl, chloro or —O—R 2a . 
     
     
         15 . The compound according to  claim 14  or a pharmaceutically acceptable salt thereof, wherein R 2  is C 1-3 alkyl, chloro or methoxy. 
     
     
         16 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 3  is H. 
     
     
         17 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 4a  is methyl. 
     
     
         18 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 4b  is C 1-3 alkyl. 
     
     
         19 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 4a  is methyl and R 4b  is methyl. 
     
     
         20 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 5  is imidazol-2-yl optionally substituted by a C 1-3 alkyl group at the 1-position and optionally substituted by a methyl group at the 5-position. 
     
     
         21 . The compound according to  claim 20  or a pharmaceutically acceptable salt thereof, wherein R 5  is 1-methyl-1H-imidazol-2-yl. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . A method of treating a viral infection, comprising administering a compound defined in  claim 1  or a pharmaceutically acceptable salt thereof, to a patient in need thereof. 
     
     
         32 . A method of treating a disorder caused or exacerbated by a viral infection, comprising administering a compound defined in  claim 1  or a pharmaceutically acceptable salt thereof, to a patient in need thereof. 
     
     
         33 . A pharmaceutical formulation comprising i) a compound defined in  claim 1  or a pharmaceutically acceptable salt thereof, and ii) a pharmaceutically acceptable excipient. 
     
     
         34 . A method of making the compound of  claim 1 , wherein R 4a  and R 4b  are C 1-3 alkyl and R 4c  is OH, as shown in formula (Ix′), 
       
         
           
           
               
               
           
         
         comprising treating a compound of formula (VII) with a oronic ester, in the presence of a catalyst in a solvent with a base.