GCN2 MODULATOR COMPOUNDS

Abstract

The disclosures herein relate to novel compounds of Formula (1): or a salt thereof, wherein X, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with General Control Nondepressible 2 (GCN2).

##STR00001##

Claims

1. A compound according to Formula (I): ##STR00354## or a salt thereof, wherein; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of H, halo and C.sub.1-3 alkyl optionally substituted with 1-6 fluoro, wherein at least one of R.sup.1, R.sup.2 R.sup.3 and R.sup.4 is halo or C.sub.1-3 alkyl optionally substituted with 1-6 fluoro, or R.sup.4 is joined to R.sup.5 to form 5 or 6-membered heterocyclic ring, wherein the 5 or 6-membered heterocyclic ring is optionally substituted with halo and C.sub.1-3 alkyl optionally substituted with 1-6 fluoro; R.sup.5 is selected from the group consisting of H and C.sub.1-3 alkyl optionally substituted with 1-6 fluoro; X is a 9 or 10-membered fused heterobicyclic ring comprising 1-4 annular heteroatoms being nitrogen, wherein the 9 or 10-membered fused heterobicyclic ring is substituted with NR.sup.8R.sup.9 and optionally further substituted with halo, C.sub.1-3 alkyl or NH.sub.2; R.sup.8 and R.sup.9 are independently selected from the group consisting of H, C.sub.1-6 alkyl, —C(O)NH.sub.2, —C(O)—C.sub.1-6 alkyl, and 5 or 6-membered carbocyclic or heterocyclic, wherein the C.sub.1-6 alkyl, —C(O)—C.sub.1-6 alkyl, and 5 or 6-membered carbocyclic or heterocyclic are independently optionally substituted with 1-6 substituents selected from the group consisting halo, OH and phenyl, or R.sup.8 and R.sup.9 taken together with the nitrogen form a 6-membered heterocyclic ring; Y is a 5, 6, 9 or 10-membered carbocyclic or heterocyclic ring; or NH.sub.2, wherein the 5, 6, 9 or 10-membered carbocyclic or heterocyclic ring is optionally substituted with 1-3 substituents selected from the group consisting of halo, OH, CN, —C(O)NR.sup.13R.sup.14, —NR.sup.13COR.sup.14, —C(O)OR.sub.13, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, wherein the C.sub.1-6 alkyl and C.sub.1-6 alkoxy are optionally substituted with 1-6 substituents selected from the group consisting of halo and OH; R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl; and  provided that when X is a 9-membered fused heterobicyclic ring comprising 1-4 annular heteroatoms being nitrogen, then the 9 membered fused heterobicyclic ring is substituted with NR.sup.8R.sup.9 only, and Y is a 6-membered heterocyclic ring comprising 1-4 annular heteroatoms being nitrogen, wherein the 6-membered heterocyclic ring is optionally substituted with 1-3 substituents selected from the group consisting of halo, OH, CN, —C(O)NR.sup.13R.sup.14, —NR.sup.13COR.sup.14, —C(O)OR.sub.13, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, wherein the C.sub.1-6 alkyl and C.sub.1-6 alkoxy are optionally substituted with 1-6 substituents selected from the group consisting of halo and OH; and when X is a 10-membered fused heterobicyclic ring comprising 1-4 annular heteroatoms being nitrogen, wherein the 10 membered fused heterobicyclic ring is substituted with NH.sub.2 only, one of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is halo or C.sub.1-3 alkyl, the remainder of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are H, R.sup.5 is H, and Y is 5 or 6-membered carbocyclic or heterocyclic ring, then the 5 or 6-membered carbocyclic or heterocyclic ring is substituted with 2 or 3 substituents selected from the group consisting of halo, OH, CN, —C(O)NR.sup.13R.sup.14, —NR.sup.13COR.sup.14, —C(O)OR.sub.13, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, wherein the C.sub.1-6 alkyl and C.sub.1-6 alkoxy are optionally substituted with 1-6 substituents selected from the group consisting of halo and OH.

2. The compound of claim 1, wherein X is selected from the group consisting of: ##STR00355## ##STR00356## wherein R.sup.6 and R.sup.7 may be attached at any available position of the heterobicyclic ring, one of R.sup.6 and R.sup.7 is NR.sup.8R.sup.9 and the other is H, NH.sub.2 or halo.

3. The compound of claim 2, wherein X is: ##STR00357##

4. The compound of claim 1, wherein NR.sup.8R.sup.9 is NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, NHCH.sub.2CH.sub.2OH, NHCH(CH.sub.3)CH.sub.2OH, NHCH(CH.sub.2OH).sub.2, NHCH(CH.sub.2OH)(C.sub.6H.sub.5), NHCOCH.sub.3, NHCOCH.sub.2CH.sub.3, NHCOCH(CH.sub.3).sub.2, NHCOC(CH.sub.3).sub.3, ##STR00358##

5. The compound of claim 2, wherein R.sup.6 is H and R.sup.7 is NR.sup.8R.sup.9.

6. The compound of claim 5, wherein R.sup.6 is H and R.sup.7 is NH.sub.2.

7. The compound of claim 1, wherein X is selected from the group consisting of: ##STR00359## ##STR00360## ##STR00361##

8. The compound of claim 1, wherein Y is selected from the group consisting of: ##STR00362## ##STR00363##

9. The compound of claim 1, which is a compound of formula (1b): ##STR00364## or a salt thereof, wherein Q is N, C or CH, and R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, halo, OH, CN, —C(O)NR.sup.13R.sup.14, —NR.sup.13COR.sup.14, —C(O)OR.sub.13, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, wherein the C.sub.1-6 alkyl and C.sub.1-6 alkoxy are optionally substituted with 1-6 substituents selected from the group consisting of halo and OH, wherein R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl.

10. The compound of claim 1, which is a compound of formula (3a): ##STR00365## or a salt thereof, wherein Q is N, C or CH, and R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, halo, OH, CN, —C(O)NR.sup.13R.sup.14, —NR.sup.13COR.sup.14, —C(O)OR.sub.13, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, wherein the C.sub.1-6 alkyl and C.sub.1-6 alkoxy are optionally substituted with 1-6 substituents selected from the group consisting of halo and OH, wherein R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl.

11. The compound of claim 1, which is a compound of formula (4a): ##STR00366## or a salt thereof, wherein Q is N, C or CH, and R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, halo, OH, CN, —C(O)NR.sup.13R.sup.14, —NR.sup.13COR.sup.14, —C(O)OR.sub.13, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, wherein the C.sub.1-6 alkyl and C.sub.1-6 alkoxy are optionally substituted with 1-6 substituents selected from the group consisting of halo and OH, wherein R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl.

12. The compound of claim 1, which is a compound of formula (4b): ##STR00367## or a salt thereof, wherein Q is N, C or CH, and R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, halo, OH, CN, —C(O)NR.sup.13R.sup.14, —NR.sup.13COR.sup.14, —C(O)OR.sub.13, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, wherein the C.sub.1-6 alkyl and C.sub.1-6 alkoxy are optionally substituted with 1-6 substituents selected from the group consisting of halo and OH, wherein R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl.

13. The compound of claim 1, wherein Q is N.

14. The compound of claim 1, wherein R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, Cl, F, OCH.sub.3, CF.sub.3, CH.sub.3, CH.sub.2OH, OH, CONH.sub.2, COOH, CONHCH.sub.3 and COOCH.sub.3.

15. The compound of claim 1, wherein the moiety: ##STR00368## is selected from the group consisting of: ##STR00369##

16. The compound of claim 15, wherein the moiety: ##STR00370## is: ##STR00371##

17. The compound of claim 1, wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of H, F and CH.sub.3.

18. The compound of claim 17, wherein R.sup.1 and R.sup.4 are F and R.sup.2 and R.sup.3 are H.

19. The compound of claim 1, wherein R.sup.5 is H.

20. The compound of claim 1, which is a compound of formula (5b) or (5c): ##STR00372## or a salt thereof, wherein Q is N, C or CH; R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, halo, OH, CN, —C(O)NR.sup.13R.sup.14, —NR.sup.13COR.sup.14, —C(O)OR.sub.13, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, wherein the C.sub.1-6 alkyl and C.sub.1-6 alkoxy are optionally substituted with 1-6 substituents selected from the group consisting of halo and OH, wherein R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl; and R.sup.15 and R.sup.16 are independently selected from H, halo and C.sub.1-3 alkyl optionally substituted with 1 to 6 fluoro.

21. The compound according to claim 1, which is a compound of formula (5d) or (5e): ##STR00373## or a salt thereof, wherein Q is N, C or CH; R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, halo, OH, CN, —C(O)NR.sup.13R.sup.14, —NR.sup.13COR.sup.14, —C(O)OR.sub.13, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, wherein the C.sub.1-6 alkyl and C.sub.1-6 alkoxy are optionally substituted with 1-6 substituents selected from the group consisting of halo and OH, wherein R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl; and R.sup.15 and R.sup.16 are independently selected from H, halo and C.sub.1-3 alkyl optionally substituted with 1 to 6 fluoro.

22. The compound according to claim 1 which is selected from the group consisting of: TABLE-US-00006 N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,5-dichlorobenzene-1-sulfonamide N-{3-[(2-aminopyrimidin-5-yl)ethynyl]-2,4-difluorophenyl}-5-chloro-2- methoxypyridine-3-carboxamide N-{3-[6-(2-aminopyrimidin-5-yl)pyridin-3-yl]-2,4-difluorophenyl}-5-chloro-2- methoxypyridine-3-sulfonamide N-[3-(2-aminoquinazolin-7-yl)-2,4-difluorophenyl]-2,5-dichlorobenzene-1-sulfonamide N-[3-(2-aminoquinazolin-7-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide 5-({3-[5-(5-chloro-2-methoxypyridin-3-yl)-1,3,4-oxadiazol-2-yl]-2,6- difluorophenyl}ethynyl)pyrimidin-2-amine N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,5-difluorobenzene-1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-3,4-dichlorobenzene-1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxybenzene-1- sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2-methylphenyl]-2,5-dichlorobenzene-1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,6-difluorophenyl]-2,5-dichlorobenzene-1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2-fluorophenyl]-2,5-dichlorobenzene-1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-5-fluorophenyl]-2,5-dichlorobenzene-1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,4-dichlorobenzene-1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-4-methylphenyl]-2,5-dichlorobenzene-1-sulfonamide N-[3-(4-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,5-dichlorobenzene-1-sulfonamide 2,5-dichloro-N-[2,4-difluoro-3-(7-fluoro-1H-benzimidazol-5-yl)phenyl]benzene-1- sulfonamide N-[3-(2-aminoquinazolin-6-yl)-4-fluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(2-aminoquinolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(3-aminoisoquinolin-7-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(2-aminopyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl]-5-chloro-2- methoxypyridine-3-sulfonamide N-[3-(2-aminopyrido[3,2-d]pyrimidin-6-yl)-2,4-difluorophenyl]-5-chloro-2- methoxypyridine-3-sulfonamide N-[3-(6-aminopyrido[2,3-b]pyrazin-2-yl)-2,4-difluorophenyl]-5-chloro-2- methoxypyridine-3-sulfonamide N-[3-(7-aminopyrido[3,4-b]pyrazin-3-yl)-2,4-difluorophenyl]-5-chloro-2- methoxypyridine-3-sulfonamide N-[3-(2-aminopteridin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(2-aminoquinoxalin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(6-amino-9H-purin-8-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(2-amino-9H-purin-8-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(6-amino-9H-purin-2-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(8-amino-9H-purin-2-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide 5-chloro-N-[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2- methoxypyridine-3-sulfonamide 5-chloro-N-[2,4-difluoro-3-(7H-pyrrolo[3,2-d]pyrimidin-2-yl)phenyl]-2- methoxypyridine-3-sulfonamide N-[3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl]-5-chloro-2- methoxypyridine-3-sulfonamide N-[3-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl]-5-chloro-2- methoxypyridine-3-sulfonamide N-[3-(4-amino-7H-pyrrolo[3,2-d]pyrimidin-2-yl)-2,4-difluorophenyl]-5-chloro-2- methoxypyridine-3-sulfonamide N-[3-(6-amino-7H-pyrrolo[3,2-d]pyrimidin-2-yl)-2,4-difluorophenyl]-5-chloro-2- methoxypyridine-3-sulfonamide 5-chloro-N-[2,4-difluoro-3-(1H-indazol-6-yl)phenyl]-2-methoxypyridine-3-sulfonamide 5-chloro-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl]-2-methoxypyridine-3- sulfonamide N-[3-(2-amino-1H-pyrrolo[2,3-b]pyridin-6-yl)-2,4-difluorophenyl]-5-chloro-2- methoxypyridine-3-sulfonamide N-[3-(4-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(3-amino-1H-indazol-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide 5-chloro-N-[3-(2,4-diaminoquinolin-6-yl)-2,4-difluorophenyl]-2-methoxypyridine-3- sulfonamide N-[3-(2-aminoquinazolin-8-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(2-aminoquinazolin-5-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide 5-chloro-N-(2,4-difluoro-3-{2-[(2-hydroxyethyl)amino]quinazolin-6-yl}phenyl)-2- methoxypyridine-3-sulfonamide 5-chloro-N-{2,4-difluoro-3-[2-(methylamino)quinazolin-6-yl]phenyl}-2- methoxypyridine-3-sulfonamide N-[3-(1H-benzimidazol-5-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(2-amino-1H-benzimidazol-5-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine- 3-sulfonamide 5-chloro-N-[2,4-difluoro-3-(7-fluoro-1H-benzimidazol-5-yl)phenyl]-2-methoxypyridine- 3-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2-methylphenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2-fluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(2-aminoquinazolin-6-yl)-5-fluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,6-difluorophenyl]-5-chloro-2-methoxypyridine-3- sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2,4-difluorobenzene-1- sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]sulfuric diamide N-[3-(2-aminoquinazolin-6-yl)-4-fluorophenyl]-2,5-dichlorobenzene-1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-(trifluoromethyl)benzene- 1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-3,5-dichlorobenzene-1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2-chloro-5-methylbenzene-1- sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methylbenzene-1- sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,3-dichlorobenzene-1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-3-chloro-5-(trifluoromethyl)benzene- 1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]isoquinoline-5-sulfonamide 5-chloro-N-[2,4-difluoro-3-(2-{[(1r,4r)-4-hydroxycyclohexyl]amino}quinazolin-6- yl)phenyl]-2-methoxypyridine-3-sulfonamide 5-chloro-N-[2,4-difluoro-3-(2-{[(2R)-1-hydroxypropan-2-yl]amino}quinazolin-6- yl)phenyl]-2-methoxypyridine-3-sulfonamide 2,5-dichloro-N-[2,4-difluoro-3-(2-{[(1r,4r)-4-hydroxycyclohexyl]amino}quinazolin-6- yl)phenyl]benzene-1-sulfonamide 2,5-dichloro-N-[2,4-difluoro-3-(2-{[(2R)-1-hydroxypropan-2-yl]amino}quinazolin-6- yl)phenyl]benzene-1-sulfonamide 2,5-dichloro-N-[2,4-difluoro-3-(2-{[(1r,4r)-4-hydroxycyclohexyl]amino}quinazolin-6- yl)phenyl]-3-(hydroxymethyl)benzene-1-sulfonamide 2,5-dichloro-N-[2,4-difluoro-3-(2-{[(2R)-1-hydroxypropan-2-yl]amino}quinazolin-6- yl)phenyl]-3-(hydroxymethyl)benzene-1-sulfonamide 6-[1-(5-chloro-2-methoxypyridine-3-sulfonyl)-5-fluoro-1H-indol-4-yl]quinazolin-2-amine 6-[1-(5-chloro-2-methoxypyridine-3-sulfonyl)-1H-indol-4-yl]quinazolin-2-amine 6-[1-(5-chloro-2-methoxypyridine-3-sulfonyl)-5-fluoro-2,3-dihydro-1H-indol-4- yl]quinazolin-2-amine 6-[1-(5-chloro-2-methoxypyridine-3-sulfonyl)-2,3-dihydro-1H-indol-4-yl]quinazolin-2- amine 6-[1-(2,5-dichlorobenzene-1-sulfonyl)-5-fluoro-1H-indol-4-yl]quinazolin-2-amine 6-[1-(2,5-dichlorobenzene-1-sulfonyl)-1H-indol-4-yl]quinazolin-2-amine {3-[4-(2-aminoquinazolin-6-yl)-5-fluoro-1H-indole-1-sulfonyl]-2,5- dichlorophenyl}methanol 6-[1-(2,5-dichlorobenzene-1-sulfonyl)-5-fluoro-2,3-dihydro-1H-indol-4-yl]quinazolin-2- amine 6-[1-(2,5-dichlorobenzene-1-sulfonyl)-2,3-dihydro-1H-indol-4-yl]quinazolin-2-amine {3-[4-(2-aminoquinazolin-6-yl)-5-fluoro-2,3-dihydro-1H-indole-1-sulfonyl]-2,5- dichlorophenyl}methanol N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]cyclohexanesulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]piperidine-4-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-1-methylpiperidine-4-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]piperidine-1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]piperazine-1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-methylpiperazine-1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]oxane-4-sulfonamide (1r,4r)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-hydroxycyclohexane-1- sulfonamide (1s,4s)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-hydroxycyclohexane-1- sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]thiane-4-sulfonamide (1r,4r)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-methoxycyclohexane-1- sulfonamide (1s,4s)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-methoxycyclohexane-1- sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]morpholine-4-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-hydroxypiperidine-1-sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-(hydroxymethyl)piperidine-1- sulfonamide N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]thiomorpholine-4-sulfonamide (1r,4r)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4- (hydroxymethyl)cyclohexane-1-sulfonamide (1s,4s)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4- (hydroxymethyl)cyclohexane-1-sulfonamide 3-{[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]sulfamoyl}cyclohexane-1- carboxamide 3-{[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]sulfamoyl}cyclohexane-1-carboxylic acid N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]piperidine-3-sulfonamide 3-{[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]sulfamoyl}-N-methylcyclohexane-1- carboxamide methyl 3-{[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]sulfamoyl}cyclohexane-1- carboxylate N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-6-methylpiperidine-3-sulfonamide N-(6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)quinazolin-2- yl)pivalamide N-(6-(3((2,5-dichlorophenyl)sulfonamido)2,6-difluorophenyl)quinazolin-2-yl)acetamide N-(3-(2-aminoquinolin-6-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dichloro-3- (hydroxymethyl)benzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chloro-2,5- dimethylbenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-fluoro-2- methoxybenzenesulfonamide N-(3-(2-aminoquinazolin-5-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,5-difluorobenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,5-dimethylbenzenesulfonamide N-(5-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)quinazolin-2- yl)pivalamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,4-dimethoxybenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-fluorobenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-methoxy-3- methylbenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2-methoxy-5- methylbenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dimethoxybenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-ethyl-2- methoxybenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5- bis(trifluoromethyl)benzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)benzofuran-5-sulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-fluoro-5- (trifluoromethyl)benzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,3-difluorobenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-methylbenzenesulfonamide 2,5-dichloro-N-(3,5-difluoro-4-(2-((2-hydroxyethyl)amino)quinazolin-6-yl)pyridin-2- yl)benzenesulfonamide 5-chloro-N-(2,4-difluoro-3-(2-(((1s,4s)-4-hydroxycyclohexyl)amino)quinazolin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)pyridine-3-sulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-dichlorophenyl)-5-chloro-2-methoxypyridine-3- sulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,4-difluorobenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-fluoro-2- methylbenzenesulfonamide 2,5-dichloro-N-(2,4-difluoro-3-(2-((2-hydroxyethyl)amino)quinazolin-6-yl)phenyl)-3- (hydroxymethyl)benzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2-fluoro-5- (trifluoromethyl)benzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-fluoro-3- (trifluoromethyl)benzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chloro-2- (trifluoromethyl)benzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)quinoxaline-5-sulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3- (trifluoromethoxy)benzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)thiophene-3-sulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-isopropylbenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)thiophene-2-sulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-fluoro-3- methoxybenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,5- bis(trifluoromethyl)benzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3- (trifluoromethyl)benzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chloro-3-fluorobenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-chloro-4- methylbenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-chloro-4- methoxybenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chloro-3- (trifluoromethyl)benzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,4,5-trichlorobenzenesulfonamide 5-chloro-N-(3-(2-((1,3-dihydroxypropan-2-yl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide (R)-5-chloro-N-(2,4-difluoro-3-(2-((2-hydroxy-1-phenylethyl)amino)quinazolin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide 5-chloro-N-(3-(2-(dimethylamino)quinazolin-6-yl)-2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide 5-chloro-N-(2,4-difluoro-3-(2-(piperidin-1-yl)quinazolin-6-yl)phenyl)-2- methoxypyridine-3-sulfonamide (S)-5-chloro-N-(2,4-difluoro-3-(2-((1-hydroxypropan-2-yl)amino)quinazolin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-chloro-4-fluorobenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-fluoro-4- methylbenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-fluoro-3- methylbenzenesulfonamide N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,3-dihydro-1H-indene-5- sulfonamide 2,5-dichloro-N-(2,4-difluoro-3-(2-(methylamino)quinazolin-6-yl)phenyl)-3- (hydroxymethyl)benzenesulfonamide (S)-5-chloro-N-(2,4-difluoro-3-(2-((2-hydroxy-1-phenylethyl)amino)quinazolin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4-hydroxycyclohexyl)amino)quinazolin-6- yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide 5-chloro-N-(2,4-difluoro-3-(2-(((1s,4s)-4-hydroxycyclohexyl)amino)quinazolin-6- yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide (S)-5-chloro-N-(2,4-difluoro-3-(2-((2-hydroxy-1-phenylethyl)amino)quinazolin-6- yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide (R)-5-chloro-N-(2,4-difluoro-3-(2-((2-hydroxy-1-phenylethyl)amino)quinazolin-6- yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide 2,5-dichloro-N-(2,4-difluoro-3-(2-((tetrahydrofuran-3-yl)amino)quinazolin-6- yl)phenyl)benzenesulfonamide or a salt thereof.

23. A pharmaceutically acceptable salt of a compound of claim 1.

24. A pharmaceutical composition comprising a compound of claim 1, or a salt thereof, and a pharmaceutically acceptable excipient.

25-30. (canceled)

31. A method of treating a disease or disorder characterized by activation of GCN2 in an individual in need thereof, comprising administering to the individual an effective amount of a compound of claim 1, a salt thereof.

32. The method of claim 31, wherein the disease or disorder is cancer, a neurodegenerative disease, or a chronic infection.

33. The method of claim 31, further comprising administering a second therapeutic agent, wherein the second therapeutic agent is PEG-arginase, asparaginase, anti-angiogenic factors, cysteinase or sulfasalazine.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0507] FIG. 1A shows the viability of primary CD4+ T cells treated with Compound 1, in response to tryptophan (Trp) starvation. Cell viability was assessed following five days of culture in increasing amounts of tryptophan and GCN2 inhibitor. Provided are representative results (mean) of one donor out of four associated with Compound 1.

[0508] FIG. 1B shows the proliferation of primary CD4+ T cells treated with Compound 1 in response to tryptophan (Trp) starvation. Cell proliferation was assessed following five days of culture in increasing amounts of tryptophan and GCN2 inhibitor. Provided are representative results (mean) of one donor out of four associated with Compound 1.

[0509] FIG. 1C shows the CD25 expression of primary CD4+ T cells treated with Compound 1 in response to tryptophan (Trp) starvation. Cell CD25 expression was assessed following five days of culture in increasing amounts of tryptophan and GCN2 inhibitor. Provided are representative results (mean) of one donor out of four associated with Compound 1. MFI is mean fluoresce intensity.

[0510] FIG. 1D shows the Granzyme B concentration in the supernatant of primary CD4+ T cells treated with Compound 1 in response to tryptophan starvation. The supernatant of cells was analysed for Granzyme B following five days of culture in increasing amounts of tryptophan and GCN2 inhibitor. Provided are representative results (mean) of one donor out of four associated with Compound 1.

[0511] FIG. 1E shows the IFN-γ concentration in the supernatant of primary CD4+ T cells treated with Compound 1 in response to tryptophan (Trp_starvation. The supernatant of cells was analysed for IFN-γ following five days of culture in increasing amounts of tryptophan and GCN2 inhibitor. Provided are representative results (mean) of one donor out of four associated with Compound 1.

[0512] FIG. 1F shows the IL-10 concentration in the supernatant of primary CD4+ T cells treated with Compound 1 in response to tryptophan (Trp) starvation. The supernatant of cells was analysed for IL-10 following five days of culture in increasing amounts of tryptophan and GCN2 inhibitor. Provided are representative results (mean) of one donor out of four associated with Compound 1.

[0513] FIG. 2A shows phosphorylated GCN2 (P-GCN2) expression in colorectal cancer cell lines HT29 and HCT116. Cells were cultured in medium containing decreasing concentrations of arginine (256 μM, 64 μM, or 4 μM, respectively) for 24 hours before samples were harvested and analyzed via Western blot. Alpha-actinin was used as a loading control.

[0514] FIG. 2B shows total GCN2, phosphorylated GCN2 (P-GCN2), and p21 expression in colorectal cancer cell lines HT29 (left) and HCT116 (right). Cells were cultured in the presence (+) or absence (−) of the indicated compounds for 24 hours before samples were harvested and analyzed via Western blot. Alpha-actinin was used as a loading control.

[0515] FIG. 3A shows HT29 cell density and morphology following treatment with Compound 1 or Compound 2. HT29 cells were seeded at 4,000 cells/well in 96-well flat bottom plates in media containing a physiological concentration of arginine (64 μM). After 24 hours, cells were treated with 10 μM vehicle control (Control; 0.1% DMSO), 10 μM Compound 1, or 10 μM Compound 2, in addition to 100 nM fluorescent apoptosis stain (e.g., YO-PRO™-1 Iodide; Thermo Fisher) uptake to detect apoptotic cells. The plates were placed in an live-cell imaging and analysis platform (e.g., IncuCyte ZOOM®; Essenbio), and scanned every 4 hours for up to 96 hours. Representative images at 10× magnification are shown.

[0516] FIG. 3B shows the number of apoptotic HT29 cells, as indicated by fluorescent apoptosis stain (e.g., YO-PRO™-1 Iodide; Thermo Fisher) uptake, per well over time. Cells were treated with vehicle control (0.1% DMSO; open circles), 10 μM Compound 1 (asterisks), or 10 μM Compound 2 (open squares). Data represent the mean±SEM of three technical replicates, with three images collected per well, per time point.

[0517] FIG. 3C shows the confluence of HT29 cells per well over time. Cells were treated with vehicle control (0.1% DMSO; open circles), 10 μM Compound 1 (asterisks) or 10 μM Compound 2 (open squares). Data represent the mean±SEM of three technical replicates, with three images collected per well, per time point.

[0518] FIG. 4A shows the relative spheroid size and morphology of HT29 cells following treatment with Compound 1 or Compound 2. HT29 cells were seeded at 5,000 cells/well in 96-well ultra-low adherence round bottom plates in media containing a physiological concentration of arginine (64 μM). Spheroids were allowed to form for three days before addition of the indicated compounds (Compound 1 or Compound 2; 10 μM) or vehicle control (Ctrl; 0.1% DMSO), in addition a DNA stain to stain live cells (e.g., Nuclear ID®-Red; Enzo Life Sciences) and determine relative spheroid size. Plates were placed in a live-cell imaging and analysis platform (e.g., IncuCyte ZOOM®; Essenbio) and the plates were scanned every 4 hours for up to 120 hours. Representative images at 10× magnification are shown.

[0519] FIG. 4B shows the relative quantification of spheroid size of HT29 cells following treatment with Compound 1 (diamonds), Compound 2 (inverted triangles), or Compound 108 (squares), expressed as a percentage of the vehicle control spheroid over time. The relative quantification was calculated by determining the total surface area of DNA stained (e.g., Nuclear ID®-Red; Enzo Life Sciences) cells. Data represent the mean±SEM of three individual experiments performed in quadruplicate. A student's t-test was performed for each time point to determine whether each compound had a significant effect on spheroid size relative to the vehicle control-treated spheroids (set at 100%, as indicated by the dotted line).

[0520] FIG. 5A shows the relative increase of CHOP positive (mCherry) murine 3T3 wildtype (WT) fibroblasts stably transduced with a CHOP reporter construct. Cells were treated with increasing amounts of Compound 1 (left), Compound 2 (middle), or Compound 108 (right), and 1 μM halofuginone. The increase of CHOP positive cells is expressed as a fraction of cell confluence determined by a live-cell imaging and analysis platform (e.g., IncuCyte ZOOM®; Essenbio). An untreated control (Ctrl, grey inverted triangles) was also included. The data represents the mean±SEM of three technical replicates, with three images collected per well, per time point.

[0521] FIG. 5B shows the relative increase of CHOP positive (mCherry) murine 3T3 wildtype (WT) fibroblasts stably transduced with a CHOP reporter construct. Cells were treated with increasing amounts of Compound 1 (left), Compound 2 (middle), or Compound 108 (right), and 5 mM histidinol. The increase of CHOP positive cells is expressed as a fraction of cell confluence determined by a live-cell imaging and analysis platform (e.g., IncuCyte ZOOM®; Essenbio). An untreated control (Ctrl, grey inverted triangles) was also included. The data represents the mean±SEM of three technical replicates, with three images collected per well, per time point.

[0522] FIG. 5C shows increase of CHOP positive (mCherry) murine 3T3 GCN2 knock out (KO) stably transduced with a CHOP reporter construct. Cells were treated with increasing amounts of Compound 1 (left), Compound 2 (middle), or Compound 108 (right), and 1 μM halofuginone. The increase of CHOP positive cells is expressed as a fraction of cell confluence determined by a live-cell imaging and analysis platform (e.g., IncuCyte ZOOM®; Essenbio). An untreated control (Ctrl, grey inverted triangles) was also included. The data represents the mean±SEM of three technical replicates, with three images collected per well, per time point.

[0523] FIG. 5D shows increase of CHOP positive (mCherry) murine 3T3 GCN2 knock out (KO) stably transduced with a CHOP reporter construct. Cells were treated with increasing amounts of Compound 1 (left), Compound 2 (middle), or Compound 108 (right), and 5 mM histidinol. The increase of CHOP positive cells is expressed as a fraction of cell confluence determined by a live-cell imaging and analysis platform (e.g., IncuCyte ZOOM®; Essenbio). An untreated control (Ctrl, grey inverted triangles) was also included. The data represents the mean±SEM of three technical replicates, with three images collected per well, per time point.

[0524] FIG. 6A shows the relative increase of fluorescent apoptosis stain (e.g., YO-PRO™-1 Iodide; Thermo Fisher) positive cells in murine 3T3 wildtype (WT) fibroblasts stably transduced with a CHOP reporter construct. Cells were treated with increasing amounts of Compound 1 (left), Compound 2 (middle), or Compound 108 (right), and 1 μM halofuginone. The increase of CHOP positive cells is expressed as a fraction of cell confluence determined by in a live-cell imaging and analysis platform (e.g., IncuCyte ZOOM®; Essenbio). An untreated control (Ctrl, grey inverted triangles) was also included. The data represents the mean±SEM of three technical replicates, with three images collected per well, per time point.

[0525] FIG. 6B shows the relative increase of fluorescent apoptosis stain (e.g., YO-PRO™-1 Iodide; Thermo Fisher) positive cells in murine 3T3 wildtype (WT) fibroblasts stably transduced with a CHOP reporter construct. Cells were treated with increasing amounts of Compound 1 (left), Compound 2 (middle), or Compound 108 (right), and 5 mM histidinol. The increase of CHOP positive cells is expressed as a fraction of cell confluence determined by in a live-cell imaging and analysis platform (e.g., IncuCyte ZOOM®; Essenbio). An untreated control (Ctrl, grey inverted triangles) was also included. The data represents the mean±SEM of three technical replicates, with three images collected per well, per time point.

[0526] FIG. 6C shows the relative increase of fluorescent apoptosis stain (e.g., YO-PRO™-1 Iodide; Thermo Fisher) positive cells in murine 3T3 GCN2 knock out (KO) fibroblasts stably transduced with a CHOP reporter construct. Cells were treated with increasing amounts of Compound 1 (left), Compound 2 (middle), or Compound 108 (right), and 1 μM halofuginone. The increase of CHOP positive cells is expressed as a fraction of cell confluence determined by in a live-cell imaging and analysis platform (e.g., IncuCyte ZOOM®; Essenbio). An untreated control (Ctrl, grey inverted triangles) was also included. The data represents the mean±SEM of three technical replicates, with three images collected per well, per time point.

[0527] FIG. 6D shows the relative increase of fluorescent apoptosis stain (e.g., YO-PRO™-1 Iodide; Thermo Fisher) positive cells in murine 3T3 GCN2 knock out (KO) fibroblasts stably transduced with a CHOP reporter construct. Cells were treated with increasing amounts of Compound 1 (left), Compound 2 (middle), or Compound 108 (right), and 5 mM histidinol. The increase of CHOP positive cells is expressed as a fraction of cell confluence determined by in a live-cell imaging and analysis platform (e.g., IncuCyte ZOOM®; Essenbio). An untreated control (Ctrl, grey inverted triangles) was also included. The data represents the mean±SEM of three technical replicates, with three images collected per well, per time point.

[0528] FIG. 7A shows CHOP induction by tunicamycin treatment in murine 3T3 wildtype (WT) fibroblasts stably transduced with a CHOP reporter construct. WT 3T3 cells were either treated with vehicle control (circles; ◯/.circle-solid.), 3 nM tunicamycin (squares; □/.square-solid.) or 10 nM tunicamycin (triangles; Δ/.box-tangle-solidup.), after 24 h pre-treatment with vehicle (open symbols) or 1 μM Compound 1 (closed symbols). The data represents the mean±SEM of three technical replicates, with three images collected per well, per time point.

[0529] FIG. 7B shows CHOP induction by tunicamycin treatment in murine 3T3 GCN2 knock out (KO) cells stably transduced with a CHOP reporter construct. KO 3T3 cells were either treated with vehicle control (circles; ◯/.circle-solid.), 3 nM tunicamycin (squares; □/.square-solid.) or 10 nM tunicamycin (triangles; Δ/.box-tangle-solidup.), after 24 h pre-treatment with vehicle (open symbols) or 1 μM Compound 1 (closed symbols). The data represents the mean±SEM of three technical replicates, with three images collected per well, per time point.

EMBODIMENTS

Set 1

[0530] Embodiment 1. A compound according to Formula (1):

##STR00317##

or a salt thereof, wherein;
X is an optionally substituted 9 or 10-membered fused heterobicyclic ring system comprising 1-4 N heteroatoms;
Y is an optionally substituted 6-membered carbocyclic or heterocyclic ring; or NH.sub.2;
R.sup.1, R.sup.2 and R.sup.3 are independently selected from H, halo and C.sub.1-3 alkyl optionally substituted with 1-6 fluorine atoms;
R.sup.4 is selected from H, halo and C.sub.1-3 alkyl optionally substituted with 1-6 fluorine atoms; or is joined to R.sup.5 to form an optionally substituted ring;
R.sup.5 is selected from H and C.sub.1-3 alkyl optionally substituted with 1-6 fluorine atoms; or is joined to R.sup.4 to form an optionally substituted ring.

[0531] Embodiment 2. The compound according to embodiment 1, wherein X is selected from the group consisting of:

##STR00318## ##STR00319##

wherein R.sup.6 and R.sup.7 may be attached at any available position of the bicyclic ring system and are independently selected from H, NR.sup.8R.sup.9 and halo;
wherein R.sup.8 and R.sup.9 are independently selected from H and C.sub.1-6 alkyl optionally substituted with 1 to 6 fluorine atoms or optionally substituted with OH.

[0532] Embodiment 3. The compound according to embodiment 2, wherein R.sup.6 and R.sup.7 are independently selected from: H, NH.sub.2, NHCH.sub.3, F, NHCH.sub.2CH.sub.2OH, NHCH(CH.sub.3)CH.sub.2OH and

##STR00320##

[0533] Embodiment 4. The compound according to embodiment 2, wherein R.sup.6 is H and R.sup.7 is NH.sub.2.

[0534] Embodiment 5. The compound according to embodiment 1, wherein X is selected from the group consisting of:

##STR00321## ##STR00322## ##STR00323##

[0535] Embodiment 6. The compound according to embodiment 1, which is a compound of formula (2):

##STR00324##

or a salt thereof.

[0536] Embodiment 7. The compound according to any one of embodiments 1 to 6, wherein Y is selected from: an optionally substituted phenyl ring, an optionally substituted pyridyl ring, an optionally substituted cyclohexane ring, an optionally substituted piperidine ring, an optionally substituted piperazine ring, an optionally substituted tetrahydropyran ring, an optionally substituted thiane ring, an optionally substituted morpholine ring and an optionally substituted thiomorpholine ring;

wherein the optional substituents are the groups R.sup.10, R.sup.11 and R.sup.12 which are themselves independently selected from the group consisting of: H, halo, CN, C.sub.1-6 alkyl optionally substituted with 1 to 6 fluorine atoms or optionally substituted with OH, C.sub.1-6 alkoxy optionally substituted with 1 to 6 fluorine atoms, CONR.sup.13R.sup.14, NR.sup.13COR.sup.14 and COOR.sup.13; wherein R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl.

[0537] Embodiment 8. The compound according to embodiment 7, wherein Y is a group of formula:

##STR00325##

wherein Q is C or N.

[0538] Embodiment 9. The compound according to embodiment 1, which is a compound of formula (3):

##STR00326##

or a salt thereof, wherein;

Q is C or N;

[0539] R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, halo, CN, C.sub.1-6 alkyl optionally substituted with 1 to 6 fluorine atoms or optionally substituted with OH, C.sub.1-6 alkoxy optionally substituted with 1 to 6 fluorine atoms, CONR.sup.13R.sup.14, NR.sup.13COR.sup.14 and COOR.sup.13;
wherein R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl.

[0540] Embodiment 10. The compound according to embodiment 1, which is a compound of formula (3a):

##STR00327##

or a salt thereof, wherein;

Q is C or N;

[0541] R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, halo, CN, C.sub.1-6 alkyl optionally substituted with 1 to 6 fluorine atoms or optionally substituted with OH, C.sub.1-6 alkoxy optionally substituted with 1 to 6 fluorine atoms, CONR.sup.13R.sup.14, NR.sup.13COR.sup.14 and COOR.sup.13;
wherein R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl.

[0542] Embodiment 11. The compound according to any one of embodiments 7 to 10, wherein R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, Cl, F, OCH.sub.3, CF.sub.3, CH.sub.3, CH.sub.2OH, OH, CONH.sub.2, COOH, CONHCH.sub.3 and COOCH.sub.3.

[0543] Embodiment 12. The compound according to any one of embodiments 1 to 7, wherein Y is selected from the group consisting of:

##STR00328## ##STR00329##

[0544] Embodiment 13. The compound according to embodiment 12, wherein Y is:

##STR00330##

[0545] Embodiment 14. The compound according to any one of embodiments 1 to 13, wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from H, F and CH.sub.3.

[0546] Embodiment 15. The compound according to embodiment 14, wherein R.sup.1 and R.sup.4 are F and R.sup.2 and R.sup.3 are H.

[0547] Embodiment 16. The compound according to any one of embodiments 1 to 15, wherein R.sup.5 is H.

[0548] Embodiment 17. The compound according to embodiment 1 which is a compound of formula (4):

##STR00331##

or a salt thereof.

[0549] Embodiment 18. The compound according to embodiment 1 which is a compound of formula (4a):

##STR00332##

or a salt thereof, wherein;

Q is C or N;

[0550] R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, halo, CN, C.sub.1-6 alkyl optionally substituted with 1 to 6 fluorine atoms or optionally substituted with OH, C.sub.1-6 alkoxy optionally substituted with 1 to 6 fluorine atoms, CONR.sup.13R.sup.14, NR.sup.13COR.sup.14 and COOR.sup.13;
wherein R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl.

[0551] Embodiment 19. The compound according to embodiment 1 which is a compound of formula (4b):

##STR00333##

or a salt thereof, wherein;

Q is C or N;

[0552] R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, halo, CN, C.sub.1-6 alkyl optionally substituted with 1 to 6 fluorine atoms or optionally substituted with OH, C.sub.1-6 alkoxy optionally substituted with 1 to 6 fluorine atoms, CONR.sup.13R.sup.14, NR.sup.13COR.sup.14 and COOR.sup.13;
wherein R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl.

[0553] Embodiment 20. The compound according to any one of embodiments 1 to 13, wherein R.sup.1, R.sup.2 and R.sup.3 are independently selected from H, F and CH.sub.3 and R.sup.4 is joined to R.sup.5 to form a ring.

[0554] Embodiment 21. The compound according to embodiment 1 which is a compound of formula (5) or (5a):

##STR00334##

or a salt thereof; wherein;
R.sup.15 and R.sup.16 are independently selected from H, halo and C.sub.1-3 alkyl optionally substituted with 1 to 6 fluorine atoms.

[0555] Embodiment 22. The compound according to embodiment 1 which is a compound of formula (5b) or (5c):

##STR00335##

or a salt thereof, wherein;

Q is C or N;

[0556] R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, halo, CN, C.sub.1-6 alkyl optionally substituted with 1 to 6 fluorine atoms or optionally substituted with OH, C.sub.1-6 alkoxy optionally substituted with 1 to 6 fluorine atoms, CONR.sup.13R.sup.14, NR.sup.13COR.sup.14 and COOR.sup.13;
wherein R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl;
and R.sup.15 and R.sup.16 are independently selected from H, halo and C.sub.1-3 alkyl optionally substituted with 1 to 6 fluorine atoms.

[0557] Embodiment 23. The compound according to embodiment 1 which is a compound of formula (5d) or (5e):

##STR00336##

or a salt thereof, wherein;

Q is C or N;

[0558] R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, halo, CN, C.sub.1-6 alkyl optionally substituted with 1 to 6 fluorine atoms or optionally substituted with OH, C.sub.1-6 alkoxy optionally substituted with 1 to 6 fluorine atoms, CONR.sup.13R.sup.14, NR.sup.13COR.sup.14 and COOR.sup.13;
wherein R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl;
and R.sup.15 and R.sup.16 are independently selected from H, halo and C.sub.1-3 alkyl optionally substituted with 1 to 6 fluorine atoms.

[0559] Embodiment 24. A pharmaceutically acceptable salt of a compound according to any one of embodiments 1 to 23.

[0560] Embodiment 25. A pharmaceutical composition comprising a compound as defined in any one of embodiments 1 to 24 and a pharmaceutically acceptable excipient.

[0561] Embodiment 26. The compound or composition according to any one of embodiments 1 to 25 for use in the treatment of a disease or disorder characterised by activation of GCN2.

[0562] Embodiment 27. The compound or composition according to any one of embodiments 1 to 25 for use in the treatment of cancer, a neurodegenerative disease, or chronic infections.

[0563] Embodiment 28. The compound or composition according to any one of embodiments 1 to 25 for use in the treatment of cancer.

[0564] Embodiment 29. The compound or composition for use according to embodiment 28, wherein the cancer is breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, bone sarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal carcinoma, adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma, cancer of secretory cells, myelodysplastic syndrome, myeloproliferative neoplasm, malignant glioma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, monoclonal gammopathy of undetermined significance (MGUS), plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia. small cell lung cancer, malignant pleural mesothelioma, Head and neck squamous cell carcinoma, glioblastoma multiforme, sarcoma or pediatric neuroblastoma.

[0565] Embodiment 30. The compound or composition for use according to any one of embodiments 26 to 29, wherein the compound or composition is administered in combination with a second therapeutic agent.

[0566] Embodiment 31. The compound or composition for use according to embodiment 30, wherein the second therapeutic agent is PEG-arginase, asparaginase, anti-angiogenic factors, cysteinase or sulfasalazine.

Set 2

[0567] Clause 1. A compound according to Formula (3):

##STR00337##

or a salt thereof, wherein;

Q is C or N;

[0568] R.sup.1, R.sup.2 and R.sup.3 are independently selected from H, halo and C.sub.1-3 alkyl optionally substituted with 1-6 fluorine atoms;
R.sup.4 is selected from H, halo and C.sub.1-3 alkyl optionally substituted with 1-6 fluorine atoms; or is joined to R.sup.5 to form an optionally substituted ring;
R.sup.5 is selected from H and C.sub.1-3 alkyl optionally substituted with 1-6 fluorine atoms; or is joined to R.sup.4 to form an optionally substituted ring;
R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, halo, CN, C.sub.1-6 alkyl optionally substituted with 1 to 6 fluorine atoms or optionally substituted with OH, C.sub.1-6 alkoxy optionally substituted with 1 to 6 fluorine atoms, CONR.sup.13R.sup.14, NR.sup.13COR.sup.14 and COOR.sup.13;
wherein R.sup.13 and R.sup.14 are independently H or C.sub.1-3 alkyl;
X is selected from the group consisting of:

##STR00338## ##STR00339##

wherein R.sup.6 and R.sup.7 may be attached at any available position of the bicyclic ring system and are independently selected from H, NR.sup.8R.sup.9 and halo;
wherein R.sup.8 and R.sup.9 are independently selected from H, C.sub.1-6 alkyl optionally substituted with 1 to 6 fluorine atoms or optionally substituted with OH and —C(O)—C.sub.1-6 alkyl optionally substituted with 1 to 6 fluorine atoms or optionally substituted with OH.

[0569] Clause 2. The compound according to clause 1, wherein X is:

##STR00340##

[0570] Clause 3. The compound according to clause 1 or clause 2, wherein R.sup.6 and R.sup.7 are independently selected from: H, NH.sub.2, NHCH.sub.3, F, NHCH.sub.2CH.sub.2OH, NHCH(CH.sub.3)CH.sub.2OH, NHCOCH.sub.3, NHCOCH.sub.2CH.sub.3, NHCOCH(CH.sub.3).sub.2, NHCOC(CH.sub.3).sub.3 and

##STR00341##

[0571] Clause 4. The compound according to clause 1 or clause 2, wherein R.sup.6 is H and R.sup.7 is NH.sub.2.

[0572] Clause 5. The compound according to clause 1, wherein X is selected from the group consisting of:

##STR00342## ##STR00343## ##STR00344##

[0573] Clause 6. The compound according to clause 1, which is a compound of formula (3a):

##STR00345##

[0574] or a salt thereof.

[0575] Clause 7. The compound according to any one of clauses 1 to 6, wherein R.sup.10, R.sup.11 and R.sup.12 are independently selected from the group consisting of: H, Cl, F, OCH.sub.3, CF.sub.3, CH.sub.3, CH.sub.2OH, OH, CONH.sub.2, COOH, CONHCH.sub.3 and COOCH.sub.3.

[0576] Clause 8. The compound according to any one of clauses 1 to 7, wherein Q is N.

[0577] Clause 9. The compound according to any one of clauses 1 to 6, wherein the moiety:

##STR00346##

is selected from the group consisting of:

##STR00347##

[0578] Clause 10. The compound according to clause 9, wherein the moiety:

##STR00348##

is:

##STR00349##

[0579] Clause 11. The compound according to any one of clauses 1 to 10, wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from H, F and CH.sub.3.

[0580] Clause 12. The compound according to clause 11, wherein R.sup.1 and R.sup.4 are F and R.sup.2 and R.sup.3 are H.

[0581] Clause 13. The compound according to any one of clauses 1 to 12, wherein R.sup.5 is H.

[0582] Clause 14. The compound according to clause 1 which is a compound of formula (4a):

##STR00350##

or a salt thereof.

[0583] Clause 15. The compound according to clause 1 which is a compound of formula (4b):

##STR00351##

or a salt thereof.

[0584] Clause 16. The compound according to clause 1 which is a compound of formula (5b) or (5c):

##STR00352##

or a salt thereof.

[0585] Clause 17. The compound according to clause 1 which is a compound of formula (5d) or (5e):

##STR00353##

or a salt thereof.

[0586] Clause 18. A pharmaceutically acceptable salt of a compound according to any one of clauses 1 to 17.

[0587] Clause 19. A pharmaceutical composition comprising a compound as defined in any one of clauses 1 to 18 and a pharmaceutically acceptable excipient.

[0588] Clause 20. The compound or composition according to any one of clauses 1 to 19 for use in the treatment of a disease or disorder characterised by activation of GCN2.

[0589] Clause 21. The compound or composition according to any one of clauses 1 to 20 for use in the treatment of cancer, a neurodegenerative disease, or chronic infections.

[0590] Clause 22. The compound or composition according to any one of clauses 1 to 20 for use in the treatment of cancer.

[0591] Clause 23. The compound or composition for use according to clause 22, wherein the cancer is breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, bone sarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal carcinoma, adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma, cancer of secretory cells, myelodysplastic syndrome, myeloproliferative neoplasm, malignant glioma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, monoclonal gammopathy of undetermined significance (MGUS), plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia. small cell lung cancer, malignant pleural mesothelioma, Head and neck squamous cell carcinoma, glioblastoma multiforme, sarcoma or pediatric neuroblastoma.

[0592] Clause 24. The compound or composition for use according to any one of clauses 20 to 23, wherein the compound or composition is administered in combination with a second therapeutic agent, wherein the second therapeutic agent is PEG-arginase, asparaginase, anti-angiogenic factors, cysteinase or sulfasalazine.