Tricyclic compounds for use in treatment of proliferative disorders

1. A compound of formula IC, or a salt, solvate or hydrate thereof,

wherein,

Y 1 is a group selected from one of formula A and B,

X is selected from CH and NR 7 ;

X 1 is selected from C and N;

Y is selected from a fused phenyl group, a fused pyridyl group and a fused pyrimidinyl group where each group is optionally substituted with one or more R 11 ;

Z is selected from phenyl optionally substituted by one or more R 10 , C 3-7 cycloalkyl optionally substituted by one or more R 10 , and 3-7 membered heterocycloalkyl optionally substituted by one or more R 10 , 5-6 membered heteroaryl optionally substituted by one or more R 10 ;

R 7 is selected from hydrogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, phenyl and C 3-6 cycloalkyl, wherein said C 1-6 alkyl, phenyl and C 3-6 cycloalkyl are optionally substituted by one or more substituents selected from hydroxyl, halogen, ═0, CN, COR a , NR a R b , C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-11 aryl, 3-7 membered heterocycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl;

each R 10 is independently selected from hydrogen, hydroxyl, ═O, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, O—C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered heterocycloalkyl, —C(═O)R d , —C(═O)NR d , —C(═O)NR e R d , —C(O)C(═O)R d , —NR e R d , —NR e C(═O)R d , —NR e C(═O)OR d , —NR e C(═O)NR e R d , —NR e S(═O) 2 R d , —NR e S(═O) 2 NR e R d , —OR d , —SR d , —OC(═O)R d , —OC(═O)NR e R d , —OC(═O)OR d , —S(═O) 2 R d , —S(═O)R d , —OS(═O)R d , —OS(═O) 2 R d , —OS(═O) 2 R d , —S(═O)NR e R d , —OS(═O) 2 NR e R d , and —S(═O) 2 NR e R d , where said C 3-6 cycloalkyl, C 1-6 alkyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, ═O, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl;

R 11 is selected from hydrogen, hydroxyl, halogen, CN, NR a R b, C 1-6 haloalkyl, 3-7 membered heterocycloalkyl, C 3-6 cycloalkyl, C 1-6 alkyl, O—C 1-6 alkyl and phenyl, wherein said C 1-6 alkyl, phenyl, 3-7 membered heterocycloalkyl and C 3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, ═O, halogen, CN, COR a , NR a R b , C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-11 aryl, 3-7 membered heterocycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl;

each R a and R b is independently selected from hydrogen and C 1-6 alkyl;

each R d is independently selected from hydrogen, hydroxyl, halogen, CN, C 1-6 haloalkyl, 3-7 membered heterocycloalkyl, C 3-6 cycloalkyl, C 1-6 alkyl, O—C 1-6 alkyl and C 6-11 aryl, wherein said C 1-6 alkyl, C 6-11 aryl, 3-7 membered heterocycloalkyl and C 3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, ═O, halogen, CN, COR a , NR a R b , C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-11 aryl, 3-7 membered heterocycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl;

each R e is independently selected from hydrogen, hydroxyl, halogen, CN, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl; or

R e and R d , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered heterocycloalkyl ring, optionally substituted with one or more substituent selected from hydroxyl, ═O, halogen, CN, COR a , NR a R b , C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-11 aryl, 3-7 membered heterocycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl.

2. A compound according to claim 1 , or a salt, solvate or hydrate thereof, wherein X is NR 7 .

3. A compound according to claim 1 , or a salt, solvate or hydrate thereof, wherein X 1 is C.

4. A compound according to claim 1 , or a salt, solvate or hydrate thereof, wherein R 7 is selected from hydrogen and methyl.

5. A compound according to claim 1 , or a salt, solvate or hydrate thereof, wherein R 11 is selected from hydrogen, halogen, CN, NR a R b C 1-6 haloalkyl, C 1-6 alkyl, O—C 1-6 alkyl and phenyl, wherein said C 1-6 alkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, COR a , NR a R b , C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-11 aryl, 3-7 membered heterocycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl.

6. A compound according to claim 1 , or a salt, solvate or hydrate thereof, wherein R 11 is selected from hydrogen, halogen, C 1-3 alkyl and O—C 1-3 alkyl.

7. A compound according to claim 1 , or a salt, solvate or hydrate thereof, wherein Y 1 is selected from:

8. A compound according to claim 1 , or a salt, solvate or hydrate thereof, of formula ID:

wherein

Y 3 is selected from,

where R 13 is selected from hydrogen, hydroxyl, halogen, CN, NR a R b , C 1-6 haloalkyl, 3-7 membered heterocycloalkyl, C 3-6 cycloalkyl, C 1-6 alkyl, O—C 1-6 alkyl and phenyl, wherein said C 1-6 alkyl, phenyl, 3-7 membered heterocycloalkyl and C 3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, ═O, halogen, CN, COR a , NR a R b , C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-11 aryl, 3-7 membered heterocycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl.

9. A compound according to claim 1 , or a salt, solvate or hydrate thereof, wherein Z is selected from phenyl optionally substituted by one or more R 10 and 6 membered heteroaryl optionally substituted by one or more R 10 .

10. A compound according to claim 1 , or a salt, solvate or hydrate thereof, wherein Z is a pyrimidinyl ring optionally substituted by one or more R 10 .

11. A compound according to claim 1 , or a salt, solvate or hydrate thereof, wherein Z is selected from:

12. A compound according to claim 1 , or a salt, solvate or hydrate thereof, wherein each R 10 is independently selected from hydrogen, hydroxyl, ═O, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, O—C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered heterocycloalkyl, —C(═O)R d , —C(═O)OR d , —C(═O)NR e R d , —C(O)C(═O)R d , -NR e R d , —NR e C(═O)R d , where said C 3-6 cycloalkyl, C 1-6 alkyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, ═O, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 1-6 alkyl and O—C 1-6 alkyl.

13. A compound according to claim 1 , or a salt, solvate or hydrate thereof, wherein Z is selected from:

14. A compound according to claim 1 , selected from:

6-(cyclobutylamino)-N-(2-hydroxy-3-{1H,2H,3H,4H,5H-pyrido[4,3-b]indol-2-yl}propyl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

2-(cyclobutylamino)-N-(2-hydroxy-3-{1H,2H,3H,4H,5H-pyrido[4,3-b]indol-2-yl}propyl)-6-(4-methylpiperazin-1-yl)pyridine-4-carboxamide;

6-(cyclobutylamino)-N-(2-hydroxy-3-{1H,2H,3H,4H,5H-pyrido[4,3-b]indol-2-yl}propyl)pyrimidine-4-carboxamide;

6-[(1-acetylpiperidin-4-yl)amino]-N-(2-hydroxy-3-{1H,2H,3H,4H,5H-pyrido[4,3-b]indol-2-yl}propyl)pyrimidine-4-carboxamide;

N-(2-hydroxy-3-{1H,2H,3H,4H,5H-pyrido[4,3-b]indol-2-yl}propyl)-4-({3-oxa-8-azabicyclo[3.2.1] octan-8-yl} carbonyl)benzamide;

6-(cycl ° butyl amino)-N-(2-hydroxy-3-{5-methyl-1H,2H,3H,4H,5H-pyri do [4,3-b]indol-2-yl}propyl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

2-(cycl ° butyl amino)-N-(2-hydroxy-3-{5-methyl- 1H,2H, 3H,4H, 5H-pyri do [4,3-b]indol-2-yl}propyl)-6-(4-methylpiperazin-1-yl)pyridine-4-carboxamide;

N-(2-hydroxy-3-{5-methyl- 1H,2H,3H,4H, 5H-pyrido[4,3-b]indol-2-yl}propyl)-4-({3-oxa-8-azabicyclo[3.2.1] octan-8-yl} carbonyl)benzamide;

6-(cyclobutylamino)-N-(2-hydroxy-3-{1H,2H, 3H,4H, 9H-pyrido[3,4-b]indol-2-yl}propyl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

2-(cyclobutylamino)-N-(2-hydroxy-3-{1H,2H, 3H,4H, 9H-pyrido[3,4-b]indol-2-yl}propyl)-6-(4-methylpiperazin-1-yl)pyridine-4-carboxamide;

6-(Cyclobutylamino)-N-(2-hydroxy-3-{1H,2H,3H,4H, 9H-pyrido[3,4-b]indol-2-yl}propyl)pyrimidine-4-carboxamide;

6(1-acetylpiperidin-4-yl)amino]-N-(2-hydroxy-3- {1H,2H,3H,4H,9H-pyrido[3,4-b]indol-2-yl}propyl)pyrimidine-4-carboxamide;

N-(2-hydroxy-3-{1H,2H,3H,4H,9H-pyrido[3,4-b]indol-2-yl}propyl)-4-[(morpholin-4-yl )carbonyl]benzamide;

N-(2-hydroxy-3-{1H,2H, 3H,4H,9H-pyrido[3,4-b]indol-2-yl}propyl)-4-({3-oxa-8-azabicyclo[3.2.1] octan-8-yl} carbonyl)benzamide;

6-(cyclobutylamino)-N-(2-hydroxy-3- {9-methyl- 1H,2H, 3H,4H,9H-pyri do [3,4-b]indol-2-yl}propyl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxamide;

2-(cyclobutylamino)-N-(2-hydroxy-3- {9-methyl- 1H,2H, 3H,4H,9H-pyri do [3,4-b]indol-2-yl}propyl)-6-(4-methylpiperazin-1-yl)pyridine-4-carboxamide;

6-(cyclobutylamino)-N-(2-hydroxy-3- {9-methyl- 1H,2H, 3H,4H,9H-pyrido [3,4-b]indol-2-yl}propyl)pyrimidine-4-carboxamide;

6(1-acetylpiperidin-4-yl)amino]-N-(2-hydroxy-3- {9-methyl- 1H,2H,3H,4H,9H-pyrido[3,4-b]indol-2-yl}propyl)pyrimidine-4-carboxamide;

N-(2-hydroxy-3-{9-methyl- 1H,2H,3H,4H, 9H-pyrido[3,4-b]indol-2-yl}propyl)-4-({3-oxa-8-azabicyclo[3.2.1] octan-8-yl} carbonyl)benzamide;

N-(2-hydroxy-3-(1,3,4,9-tetrahydro-2H-pyrido [3,4-b]indol-2-yl)propyl)-3-phenyl pyrrolidine-1-carboxamide;

N-(2-hydroxy-3-(1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propyl)-3-phenylpiperidine-1-carboxamide;

(S)-6-((1-acetylpiperidin-4-yl)amino)-N-(2-hydroxy-3-(1,3 ,4, 9-tetrahydro-2H-pyrido [3,4-b]indol-2-yl)propyl)pyrimidine-4-carboxamide;

(R)-6-((1-acetylpiperidin-4-yl)amino)-N-(2-hydroxy-3-(1,3,4,9-tetrahydro-2H-pyrido [3,4-b]indol-2-yl)propyl)pyrimidine-4-carboxamide; and

6-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide;

or a salt, solvate or hydrate thereof.

15. A non-prophylactic method of treating a PRMT5-mediated disorder, said method comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the PRMT5-mediated disorder is a cancer selected from lung cancer, gastric cancer, melanoma, and prostate cancer.

16. The non-prophylactic method of claim 15 , wherein the treating a PRMT5-mediated disorder is an ameliorative, palliative or curative treatment.