4-ethynylpyridine derivatives useful as gcn2 inhibitors

Abstract

The invention provides compounds of formula I, wherein the substituents are as set out in further detail in the specification. The compounds are potent inhibitors of GCN2 and they have excellent pharmacokinetic properties. The compounds are useful for the treatment or prevention of a variety of conditions, particularly cancer. The invention further provides pharmaceutical compositions comprising the compounds of the invention and uses of the compounds and the compositions.

1 . A compound of formula (I), or a pharmaceutically acceptable ester, amide, carbamate or salt thereof, including a pharmaceutically acceptable salt of such an ester, amide or carbamate: 
       
         
           
           
               
               
           
         
         wherein 
         Cy is a 5-, 6-, 7-, 8-, 9- or 10-membered mono or bicyclic heteroaryl group comprising at least 1 N heteroatom and optionally 1, 2 or 3 further heteroatoms selected from the group consisting of N, S and O; 
         m is 0 or 1; 
         n is 0, 1 or 2; 
         when present, R 1  is selected from the group consisting of —NH 2 ; —NR A (C 1-6 alkyl); —NR A (C 1-6 alkyl substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen, and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen); —NR A (C(O)C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen); —NR A (C 0-3 alkyene-C 3-6 cycloalkyl, wherein said cycloalkyl is optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen, C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen, C 1-3 alkyl-OH, and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen); —NR A (C 0-3 alkyene-C 3-6 heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen, C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen, C 1-3 alkyl-OH, and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen); —NR A (C(O)C 3-6 cycloalkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen, C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen, C 1-3 alkyl-OH, and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen); and —NR A (5- or 6-membered heteroaryl group comprising at least 1 N heteroatom and optionally 1 or 2 further heteroatoms selected from the group consisting of N, S and O, wherein said 5- or 6-membered heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; halogen; —O—C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; OH; NH 2 ; NH(C 1-6 alkyl); N(C 1-6 alkyl) 2 ; cyano; C 3-4 cycloalkyl optionally substituted by 1, 2, or 3 groups independently selected from the group consisting of OH, halogen, C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen, C 1-3 alkyl-OH, and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen); 
         when present, R A  is selected from the group consisting of hydrogen; —C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; —C 0-3 alkyene-C 3-6 cycloalkyl, wherein said cycloalkyl is optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen, C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen, C 1-3 alkyl-OH, and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen; —C 0-3  alkyene-C 3-6 heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen, C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen, C 1-3 alkyl-OH, and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen; —C(O)C 3-6 cycloalkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen, C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen, C 1-3 alkyl-OH, and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen; —C(O)C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen; —C(O)C 3-6 cycloalkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen, C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen, C 1-3 alkyl-OH, and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen; and 5- or 6-membered heteroaryl group comprising at least 1 N heteroatom and optionally 1 or 2 further heteroatoms selected from the group consisting of N, S and O, wherein said 5- or 6-membered heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; halogen; —O—C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; OH; NH 2 ; NH(C 1-6 alkyl); N(C 1-6 alkyl) 2 ; cyano; C 3-4 cycloalkyl optionally substituted by 1, 2, or 3 groups independently selected from the group consisting of OH, halogen, C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen, C 1-3 alkyl-OH, and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen; 
         when present, each R 2  is independently selected from the group consisting of oxo, C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; halogen; —O—C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; OH; ═O; NH 2 ; NH(C 1-6 alkyl); N(C 1-6 alkyl) 2 ; cyano; and C 3-6 cycloalkyl optionally substituted by 1, 2, or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; 
         R 3  is halogen; 
         R 4  is selected from the group consisting of hydrogen and halogen; 
         A is selected from the group consisting of phenyl; naphthyl; and 5-, 6-, 7-, 8-, 9-, 10- or 11-membered heteroaryl group comprising 1 N heteroatom and optionally 1 or 2 further heteroatoms selected from the group consisting of N, S and O; 
         R 5  is selected from the group consisting of hydrogen; halogen; OH; cyano; C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; O—C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; NH 2 ; NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2 ; and 
         R 6  is selected from the group consisting of hydrogen; halogen; OH; cyano; C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; O—C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; NH 2 ; NH(C 1-6 alkyl); N(C 1-6 alkyl) 2 ; optionally substituted phenyl; optionally substituted naphthyl; optionally substituted 5-, 6-, 7-, 8-, 9-, 10- or 11-membered heteroaryl group comprising 1 N heteroatom and optionally 1 or 2 further heteroatoms independently selected from the group consisting of N, S and O (preferably N and S); optionally substituted 5-, 6-, 7-, 8-, 9-, 10- or 11-membered non-aromatic heterocycle group comprising 1 N heteroatom and optionally 1 or 2 further heteroatoms independently selected from the group consisting of N, S and O (preferably N and S); and optionally substituted C 3-10 cycloalkyl; wherein said phenyl, naphthyl, 5-, 6-, 7-, 8-, 9-, 10- or 11-membered heteroaryl group, 5-, 6-, 7-, 8-, 9-, 10- or 11-membered non-aromatic heterocycle group, and C 3-11 cycloalkyl are optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen; OH; C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; O—C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; and 
         R 7  is selected from the group consisting of hydrogen; halogen; OH; cyano; C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; and O—C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; NH 2 ; NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2 . 
       
     
     
         2 . The compound according to  claim 1 , wherein A is selected from the group consisting of phenyl; and 6-, or 7-membered heteroaryl group comprising 1 N heteroatom and optionally 1 or 2 further heteroatoms selected from the group consisting of N, S and O (for example, A is selected from the group consisting of phenyl; and 6-, or 7-membered heteroaryl group comprising 1 N heteroatom and optionally 1 further N heteroatom). 
     
     
         3 . The compound according to  claim 1 , wherein A is an optionally substituted 6-membered aryl, a non-aromatic heterocycle group or a heteroaryl ring of formula B: 
       
         
           
           
               
               
           
         
         wherein two of Y 1 , Y 2  and Y 3  are CH and the remaining one is a CH or N; 
         R 5  is selected from the group consisting of halogen; OH; C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl; and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl; 
         R 6  is selected from the group consisting of halogen; OH; C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl; O—C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl; and a ring for formula: 
       
       
         
           
           
               
               
           
         
         wherein ring C is an optionally substituted 6-membered aromatic ring; and ring D is an optionally further substituted 5-, 6- or 7-membered ring; 
         one of Y 4  and Y 4  is a carbon atom, and the other one is carbon atom or a nitrogen atom; wherein said C ring is optionally substituted with a halogen; OH; C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl; O—C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl; and wherein said D ring is optionally substituted with a halogen; OH; C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl; O—C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl. 
       
     
     
         4 . The compound according to  claim 1 , wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         more preferably, A is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 1 , wherein R 5  is selected from the group consisting of hydrogen, halogen; OH; cyano; C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; and
 R 6  is selected from the group consisting of hydrogen, halogen; OH; cyano; C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; O—C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen. 
 
     
     
         6 . The compound according to  claim 1 , wherein R 7  is hydrogen. 
     
     
         7 . The compound according to  claim 1 , wherein R 4  is H. 
     
     
         8 . The compound according to  claim 1 , wherein Cy is a 5-, 6-, 9- or 10-membered heteroaryl group comprising at least 1 N heteroatom and optionally 1, 2 or 3 further heteroatoms selected from the group consisting of N and S; for example Cy is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or, for example, Cy is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The compound according to  claim 1 , wherein Cy is a 5-, 6-, 7-, 8-, 9- or 10-membered heteroaryl group comprising 1, 2 or 3 N heteroatoms. 
     
     
         10 . The compound according to  claim 1 , wherein m is 0 or 1; and n is 0 or 1. 
     
     
         11 . The compound according to  claim 1 , wherein when present, R 1  is selected from the group consisting of —NH 2 ; —NR A (C 1-6 alkyl); —NR A (C 1-6 alkyl substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen, and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen); —NR A  (C(O)C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen); —NR A (C 0-3 alkyene-C 3-6 cycloalkyl, wherein said cycloalkyl is optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen, C 1-3  alkyl, C 1-3  alkyl-OH, and O—C 1-3  alkyl); —NR A (C 0-3 alkyene-C 3-6 heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen, C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen, C 1-3 alkyl-OH, and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen); and —NR A (C(O)C 3-6 cycloalkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of OH, halogen, C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen, C 1-3 alkyl-OH, and O—C 1-3  alkyl optionally substituted by 1, 2 or 3 halogen). 
     
     
         12 . The compound according to  claim 1 , wherein, when present, R A  is hydrogen. 
     
     
         13 . The compound according to  claim 1 , wherein when present, R 1  is —NH 2 . 
     
     
         14 . The compound according to  claim 1 , wherein, when present, each R 2  is independently selected from the group consisting of C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; halogen; —O—C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; and OH. 
     
     
         15 . The compound according to  claim 1 , wherein R 5  is selected from the group consisting of hydrogen; halogen; OH; cyano; C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; O—C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; NH 2 ; NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2 ;
 R 6  is selected from the group consisting of hydrogen; OH; cyano; C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; O—C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; NH 2 ; NH(C 1-6 alkyl); N(C 1-6 alkyl) 2 ; optionally substituted phenyl; optionally substituted naphthyl; optionally substituted 5-, 6-, 7-, 8-, 9-, 10- or 11-membered heteroaryl group comprising 1 N heteroatom and optionally 1 or 2 further heteroatoms independently selected from the group consisting of N, S and O (preferably N and S); optionally substituted 5-, 6-, 7-, 8-, 9-, 10- or 11-membered non-aromatic heterocycle group comprising 1 N heteroatom and optionally 1 or 2 further heteroatoms independently selected from the group consisting of N, S and O (preferably N and S); and optionally substituted C 3-10 cycloalkyl; wherein said phenyl, naphthyl, 5-, 6-, 7-, 8-, 9-, 10- or 11-membered heteroaryl group, 5-, 6-, 7-, 8-, 9-, 10- or 11-membered non-aromatic heterocycle group, and C 3-11 cycloalkyl are optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen; OH; C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; O—C 1-3 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; and 
 R 7  is selected from the group consisting of hydrogen; OH; cyano; C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; and O—C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; NH 2 ; NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2  (more preferably, R 7  is hydrogen); for example 
 R 5  is selected from the group consisting of hydrogen; halogen; OH; cyano; C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; O—C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; NH 2 ; NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2 ; 
 R 6  is selected from the group consisting of hydrogen; OH; cyano; C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; and O—C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; NH 2 ; NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2 ; and 
 R 7  is selected from the group consisting of hydrogen; OH; cyano; C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; and O—C 1-6 alkyl optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of halogen, OH and O—C 1-3 alkyl optionally substituted by 1, 2 or 3 halogen; NH 2 ; NH(C 1-6 alkyl); and N(C 1-6 alkyl) 2 . More preferably, R 7  is hydrogen. 
 
     
     
         16 . The compound according to  claim 1 , wherein said compound is selected from the group consisting of:
 N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (example 1);   N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-chloropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (example 2);   N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]-5-chloro-2-methoxypyridine-3-sulfonamide (example 3);   N-{4-[2-(8-amino-1,7-naphthyridin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (example 4);   5-chloro-N-{4-[2-(pyrido[3,4-b]pyrazin-8-yl)ethynyl]-3-fluoropyridin-2-yl}-2-methoxypyridine-3-sulfonamide (example 5);   5-chloro-N-{4-[2-(1,6-naphthyridin-8-yl)ethynyl]-3-fluoropyridin-2-yl}-2-methoxypyridine-3-sulfonamide (example 6);   N-{4-[2-(7-aminopyrazolo[1,5-a]pyrimidin-3-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (example 7);   N-{4-[2-(8-aminoimidazo[1,2-a]pyridin-3-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (example 8);   5-chloro-N-{4-[2-(quinoxalin-2-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (example 9);   N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3,5-difluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (example 10);   N-{4-[2-(8-aminoimidazo[1,2-a]pyrazin-3-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (example 11);   5-chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]-2-methoxybenzene-1-sulfonamide (example 12);   N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxybenzene-1-sulfonamide (example 13);   2,5-dichloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]benzene-1-sulfonamide (example 14);   N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-2,5-dichlorobenzene-1-sulfonamide (example 15);   N-{4-[2-(2-aminopyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-2,5-dichloro-3-(hydroxymethyl)benzene-1-sulfonamide (example 16);   2,5-dichloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]-3-(hydroxymethyl)benzene-1-sulfonamide (example 17);   5-chloro-N-[3-fluoro-4-(2-{1-methyl-1H-imidazo[4,5-c]pyridin-7-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 18);   5-chloro-N-[3-fluoro-4-(2-{[1,3]thiazolo[4,5-c]pyridin-7-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 19);   5-chloro-N-[3-fluoro-4-(2-{1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 20);   5-chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-c]pyridin-4-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 21);   5-chloro-N-[3-fluoro-4-(2-{2-methyl-2H-pyrazolo[3,4-c]pyridin-4-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 22);   5-chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[4,3-c]pyridin-4-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 23);   5-chloro-N-[3-fluoro-4-(2-{1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 24);   5-chloro-N-(3-fluoro-4-{2-[2-(methylamino)pyrimidin-5-yl]ethynyl}pyridin-2-yl)-2-methoxypyridine-3-sulfonamide (example 25);   5-chloro-N-[3-fluoro-4-(2-{2-oxo-1H,2H,3H-imidazo[4,5-b]pyridin-6-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 26);   5-chloro-N-[3-fluoro-4-(2-{1H-pyrazolo[3,4-b]pyrazin-5-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 27);   5-chloro-N-[3-fluoro-4-(2-{2-oxo-1H,2H,3H-imidazo[4,5-b]pyrazin-5-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 28);   5-chloro-N-[3-fluoro-4-(2-{3H-imidazo[4,5-b]pyridin-6-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 29);   5-chloro-N-[3-fluoro-4-(2-{pyrazolo[1,5-a]pyrimidin-6-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 30);   5-chloro-N-[3-fluoro-4-(2-{pyrazolo[1,5-a]pyrimidin-3-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 31);   5-chloro-N-[3-fluoro-4-(2-{2-oxo-1H,2H,3H-imidazo[4,5-b]pyridin-6-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 32);   5-chloro-N-[3-fluoro-4-(2-{3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 33);   N-{4-[2-(2-amino-4-methylpyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (example 34);   N-{4-[2-(2-amino-4-methoxypyrimidin-5-yl)ethynyl]-3-fluoropyridin-2-yl}-5-chloro-2-methoxypyridine-3-sulfonamide (example 35);   5-chloro-N-[3-fluoro-4-(2-{1-methyl-2-oxo-1H,2H,3H-imidazo[4,5-b]pyridin-6-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 36);   5-chloro-N-[3-fluoro-4-(2-{3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl}ethynyl)pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (example 37); and   N-[4-(2-{5-aminopyrido[3,4-b]pyrazin-8-yl}ethynyl)-3-fluoropyridin-2-yl]-5-chloro-2-methoxypyridine-3-sulfonamide (example 38),   or a pharmaceutically acceptable ester, amide, carbamate or salt thereof, including a pharmaceutically acceptable salt of such an ester, amide or carbamate.   
     
     
         17 . A pharmaceutical composition comprising a compound according to  claim 1  and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         18 . The pharmaceutical composition according to  claim 17 , wherein said composition further comprises at least one further therapeutic agent. 
     
     
         19 . The pharmaceutical composition according to  claim 18 , wherein the further therapeutic agent is 1-asparaginase or a proteasome inhibitor. 
     
     
         20 . (canceled) 
     
     
         21 . A method for the treatment or prophylaxis of a disease or disorder in a mammal in which the inhibition of GCN2 provides a therapeutic effect, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition of  claim 17 . 
     
     
         22 . The method of  claim 21 , wherein the disease or disorder is cancer, diabetic retinopathy, myocardial ischemia, diabetic cardiomyopathy, allergic airway inflammation, doxorubicin-induced cardiotoxicity or nonalcoholic fatty liver disease (NAFLD). 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 22 , wherein the cancer is a solid cancer or hematological cancer. 
     
     
         27 . The method of  claim 22 , wherein the cancer is colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophagus cancer, gastric cancer, duodenal cancer, small intestinal cancer, breast cancer, ovarian cancer, testis tumor, prostate, liver cancer, thyroid cancer, renal cancer, uterine cancer, gestational choriocarcinoma, brain tumor, retina blastoma, skin cancer, sarcoma, malignant bone tumor, urinary bladder cancer, and hematologic cancer, or cancer of unknown primary nucleus. 
     
     
         28 . The method of  claim 22 , wherein the cancer is rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, pancreatic duct cancer, pancreatic endocrine tumor, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma, invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer, ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low malignant potential tumor, hormone-dependent prostate cancer, non-hormone dependent prostate cancer, castration-resistant prostate cancer, hepatoma, primary liver cancer, extrahepatic bile duct cancer, medullary thyroid carcinoma, renal cell carcinoma, transitional cell carcinoma of renal pelvis and ureter, cervix cancer, uterine body cancer, uterus sarcoma, medulloblastoma, glioma, glioblastoma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, hypophyseal adenoma, basal cell carcinoma, malignant melanoma, rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma, or osteosarcoma. 
     
     
         29 . The method of  claim 26 , wherein the hematological cancer is multiple myeloma, smouldering myeloma, plasmacytoma, leukemia, non-Hodgkin's lymphoma, malignant lymphoma, Hodgkin's disease, or chronic myeloproliferative disease. 
     
     
         30 . The method of  claim 29 , wherein the leukemia is acute myeloid leukemia or acute lymphocytic leukemia. 
     
     
         31 . The method of  claim 29 , wherein the leukemia is blast crisis of chronic leukemia. 
     
     
         32 . The method of  claim 22 , wherein disease or disorder is a cancer in which there is a mutation in the MYC gene. 
     
     
         33 . The method according to  claim 21 , wherein said method comprises administering one or more further therapeutic agents. 
     
     
         34 . The method according to  claim 33 , wherein the one or more further therapeutic agents include 1-asparaginase or a proteasome inhibitor.