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Title:
SELECTIVE INHIBITORS OF PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT5)
Document Type and Number:
WIPO Patent Application WO/2018/152548
Kind Code:
A4
Abstract:
The disclosure is directed to compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI: Methods of their use in inhibiting a protein arginine methyltransferase 5 (PRMT5) enzyme and treating disease, as well as methods of their preparation are also described.

Inventors:
LUENGO JUAN (US)
LEAL RAUL (US)
LIN HONG (US)
SHETTY RUPA (US)
VADDI KRISHNA (US)
Application Number:
PCT/US2018/018856
Publication Date:
October 11, 2018
Filing Date:
February 20, 2018
Export Citation:
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Assignee:
PRELUDE THERAPEUTICS INC (US)
International Classes:
C07D473/00; A61P35/00; C07D473/34; C07D487/04
Attorney, Agent or Firm:
LODISE, Stephanie, A. et al. (US)
Download PDF:
Claims:
AMENDED CLAIMS

received by the International Bureau on 28 August 2018 (28.08.2018)

What is claimed:

1. A compound of Formula I or Formula II:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

A is CH or N;

Q is NH, NR6 or O;

R1 is -Co-C6alk-C3-C6cycloalkyl, -Co-C6alk-C3-C6halocycloalkyl; -C2-C6haloalkenyl, CH(OH)-Ci-C6alkyl, -CH(F)-Ci-C6alkyl, -CH(NH2)-Ci-C6alkyl, -CH(Me)-Ci-C6alkyl, -C(Me)(OH)-Ci-C6alkyl, -CH(OH)-Ci-C6haloalkyl, -CH(F)-Ci-C6haloalkyl, - CH(NH2)-Ci-C6haloalkyl, -CH(Me)-Ci-C6haloalkyl, -C(Me)(OH)-Ci-C6haloalkyl, - Co-Cealk-C≡CH, -Co-C6alk-C≡C-Ci-C6alkyl, -Co-C6alk-C≡C-Ci-C6haloalkyl, -Co- C6alk-C≡C-C3-C6cycloalkyl, -Ci-Cealk-aryl, -Ci-Cealk-S-Ci-Cealkyl, -Ci-Cealk-S- Ci-Cehaloalkyl, -Ci-Cealk-S-Cs-Cecycloalkyl; -Ci-Cealk-S-Cs-Cehalocycloalkyl; -Ci- Cealk-O-Cs-Cecycloalkyl, -Ci-C6alk-S-CH2-aryl, -Ci-C6alk-C(0)NH-aryl, 2-(2- amino-3-bromoquinolin-7-yl)ethyl or 2-(2-amino-3-chloroquinolin-7-yl)ethyl -Ci- C6alk-0-heteroaryl, -Ci-C6alk-S-heteroaryl, or -Ci-C6alk-NH-heteroaryl;

R2 is H, -Ci-Cealkyl, -Ci-Cehaloalkyl, or -Co-Cealk-Cs-Cecycloalkyl;

R3 is H, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -C(0)R7, -C(0)OR7, or -

C(0)NR8aR8 ;

R4 is H, halo, -Ci-Cealkyl, or NH2; R5 is H, halo, CN, -Ci-C6alkyl, -C2-C4alkenyl, -C2-C4haloalkenyl, C2-C4cyanoalkenyl, -Co- Cealk-C≡CH, -Co-C6alk-C≡C-Ci-C6alkyl, -Ci-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2-C6heterocycloalkyl, -C3-C6cycloalkyl, -Co-C3alk-C(0)R9, CR8R8 CN, -CH2NR8R8', -Co-Cealk-OH, -NR8R8 , -N(R9)CN, -0-Ci-C4alkyl, - NR9CONR8R8 , -OCONR8R8', or -NR9C(0)OR9a;

R6 is -Ci-Cealkyl or -Co-Cealk-Cs-Cecycloalkyl;

R7 is H, Ci-Cealkyl, or Co-Cealk-Cs-Cecycloalkyl;

R8a and R8 are each independently H, Ci-Cealkyl, or -Co-Cealk-OCi-Cealkyl, or R8a and R8 , together with the atom to which they are attached, form a C2-C6heterocycloalkyl ring;

R8 and R8 are each independently H, Ci-C6alkyl, or -Co-C6alk-OCi-C6alkyl;

or R8 and R8 , together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a C2-C6heterocycloalkyl ring;

R9 is H, -Ci-C6alkyl, or -Co-C6alk-C3-C6cycloalkyl; and

R9a is -Ci-Cealkyl, or Co-Cealk-Cs-Cecycloalkyl.

(cancelled) (cancelled)

The compound of claim 1 wherein R1 is -CH(OH)-C≡CH, -CH(F)-C≡CH, -CH(NH2)-C≡ CH, -CH(Me)-C≡CH, or -C(Me)(OH)-C≡CH.

The compound of claim 1 wherein R1 is -CH(OH)-C≡C-Ci-C6alkyl, -CH(F)-C≡C-Ci- Cealkyl, -CH(NH2)-C≡C-Ci-C6alkyl, -CH(Me)-C≡C-Ci-C6alkyl, -C(Me)(OH)-C≡C-Ci- Cealkyl, -CH(OH)-C≡C-CH3, -CH(F)-C≡C-CH3, -CH(NH2)-C≡C-CH3, -CH(Me)-C≡C- CH3, or -C(Me)(OH)-C≡C-CH3.

The compound of claim 1 wherein R1 is -CH(OH)-C≡C- Ci-Cehaloalkyl, -CH(F)-C≡C-Ci- Cehaloalkyl, -CH(NH2)-C≡C-Ci-C6haloalkyl, -CH(Me)-C≡C-Ci-C6haloalkyl, - C(Me)(OH)-C≡C-Ci-C6haloalkyl, -CH(OH)-C≡C-CF3, -CH(F)-C≡C-CF3, -CH(NH2)-C ≡C-CF3, -CH(Me)-C≡C-CF3, or -C(Me)(OH)-C≡C-CF3.

7. The compound of claim 1 wherein R1 is -CH(OH)-C≡C-C3-C6cycloalkyl, -CH(F)-C≡C-C3- Cecycloalkyl, -CH(NH2)-C≡C-C3-C6cycloalkyl, -CH(Me)-C≡C-C3-C6cycloalkyl, - C(Me)(OH)-C≡C-C3-C6cycloalkyl, -CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C- cyclopropyl, -CH(NH2)-C≡C-cyclopropyl, -CH(Me)-C≡C-cyclopropyl, or -C(Me)(OH)-C ≡C-cyclopropyl.

8. The compound of claim 1 wherein R1 is -CH(OH)-aryl, -C(OCH3)-aryl, -CH(F)-aryl, - CH(NH2)-aryl, -CH(Me)-aryl, -C(Me)(OH)-aryl, -CH(OH)-4-chlorophenyl, -CH(OH)-3,4- dichlorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)-

3- chloro-4-fluorophenyl, -CH(OH)-4-(trifluoromethyl)phenyl, -CH(OH)-3-fluoro-4- (tnfluoromethyl)phenyl, -CH(OH)-3-methyl-4-(tnfluoromethyl)phenyl, -C(CF3)(OH)-4- chlorophenyl, -CH(OH)-3-methyl-4-chlorophenyl, -CH(OH)-2,3-dihydrobenzofuran-5-yl, - CH(OH)-benzo[d][l,3]dioxol-5-yl, -CH(F)-4-chlorophenyl, -CH(F)-3,4-dichlorophenyl, - CH(F)-3,4-difluorophenyl, -CH(F)-3-fluoro-4-chlorophenyl, -CH(F)- 3-chloro-4- fluorophenyl, -CH(F)-4-(trifluoromethy l)phenyl, -CH(F)-3 -fluoro-4-(trifluoromethy l)phenyl, -CH(F)-3-methyl-4-(trifluoromethyl)phenyl, -C(CF3)(F)-4-chlorophenylphenyl, -CH(F)-3- methyl-4-chlorophenyl, -CH(F)-2,3-dihydrobenzofuran-5-yl, -CH(F)-benzo[d][l,3]dioxol-5- yl, -CH(NH2)-4-chlorophenyl, -CH(NH2)-3,4-dichlorophenyl, -CH(NH2)-3,4-difluorophenyl, -CH(NH2)-3-fluoro-4-chlorophenyl, -CH(NH2)-3-chloro-4-fluorophenyl, -CH(NH2)-4- (trifluoromethyl)phenyl, -CH(NH2)-3-fluoro-4-(trifluoromethyl)phenyl, -CH(NH2)-3-methyl-

4- (trifluoromethyl)phenyl, -C(CF3)(NH2)-4-chlorophenylphenyl, CH(NH2)-3-methyl-4- chlorophenyl, -CH(NH2)-2,3-dihydrobenzofuran-5-yl, -CH(NH2)-benzo[d][l,3]dioxol-5-yl, - CH(Me)-4-chlorophenyl, -CH(Me)-3,4-dichlorophenyl, -CH(Me)-3,4-difluorophenyl, - CH(Me)-3-fluoro-4-chlorophenyl, -CH(Me)-3-chloro-4-fluorophenyl, -CH(Me)-4- (trifluoromethyl)phenyl, -CH(Me)-3-methyl-4-(trifluoromethyl)phenyl, -CH(Me)-3-fluoro-4- (trifluoromethyl)phenyl, -CH(Me)-3-methyl-4-chlorophenyl, -C(CF3)(Me)-4- chlorophenylphenyl, -CH(Me)-2,3-dihydrobenzofuran-5-yl, -CH(Me)-benzo[d][l,3]dioxol-

5- yl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, -C(Me)(OH)-3,4-

- 326 - difluorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, -C(Me)(OH)-3-chloro-4- fluorophenyl, -C(Me)(OH)-4-(tnfluoromethyl)phenyl, -C(Me)(OH)-3-fluoro-4- (trifluoromethyl)phenyl, -C(Me)(OH)-3-methyl-4-(trifluoromethyl)phenyl, -C(Me)(OH)-3- methyl-4-chlorophenyl, -C(Me)(OH)-2,3-dihydrobenzofuran-5-yl, or -C(Me)(OH)- benzo[d] [ 1 ,3] dioxol-5-yl.

9. The compound of claim 1, wherein R1 is -Ci-C6alk-0-heteroaryl,

-Ci-C6alk-S-heteroaryl, or -Ci-C6alk-NH-heteroaryl.

10. The compound of claims 1 or 4 to 9, wherein R2 is H.

11. The compound of claims 1 or 4 to 9, wherein R2 is Ci-C6 alkyl.

12. The compound of any one of claims 1, or 4 to 11, wherein R3 is H.

13. The compound of any one of claims 1, or 4 to 11, wherein R3 is -Ci-C6alkyl or -Ci-C6haloalkyl.

14. (Amended) The compound of any one of claims 1, or 4 to 11, wherein R3 is -C(0)R7,

preferably wherein R7 is Ci-C6alkyl.

15. The compound of any one of claims 1, 4 to 9, or 10 to 14, wherein R4 is H

16. The compound of any one of claims 1, 4 to 9, or 10 to 15, wherein Q is NH.

17. The compound of any one of claims 1, 4 to 9, or 10 to 15, wherein Q is O.

18. The compound of any one of claims 1, 4 to 9, or 10 to 17, which is a compound of Formula I.

19. The compound of claim 18 wherein A is CH.

20. The compound of claim 18 wherein A is N.

21. The compound of any one of claims 18-20, wherein R5 is H.

22. The compound of any one of claims 18-20, wherein R5 is halo.

- 327 -

23. The compound of any one of claims 18-20, wherein R5 is -Ci-C6alkyl.

24. The compound of any one of claims 1, 4 to 9, or 10 to 17, which is a compound of Formula II.

25. A compound of Formula III or Formula IV:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

A is CH, CR10, or N;

Q is NH, NR6, or O;

R1 is -Co-C6alk-C3-C6cycloalkyl, -Co-C6alk-C3-C6halocycloalkyl, -C2-C6alkenyl, -C2- Cehaloalkenyl, -Co-Cealk-Ci-Cealkyl, -Co-Cealk-Ci-Cehaloalkyl, -Co-Cealk-C≡CH, - Co-Cealk-C≡ C-Ci-Cealkyl, -Co-Cealk-C≡ C-Ci-Cehaloalkyl, -Co-Cealk-C≡ C-C3- Cecycloalkyl, -Ci-Cealk-aryl, -Ci-Cealk-S-Ci-Cealkyl, -Ci-Cealk-S-Ci-Cehaloalkyl, - Ci-Cealk-S-Cs-Cecycloalkyl; -Ci-Cealk-S-Cs-Cehalocycloalkyl; -Ci-Cealk-O-Ci- Cealkyl, -Ci-Cealk-O-Cs-Cecycloalkyl, -Ci-C6alk-S-CH2-aryl, -Ci-Cealk-C(0)NH- aryl, -Co-Cealk-S-aryl, -Co-C6alk-S(0)aryl, -Co-C6alk-S(0)2aryl, -Co-Cealk-Oaryl, -Co- C6alk-heteroaryl, -Ci-C6alk-0-heteroaryl, -Ci-C6alk-S-heteroaryl, or -Ci-C6alk-NH- heteroaryl;

R2 is H, -Ci-Cealkyl, -Ci-Cehaloalkyl, or -Co-Cealk-Cs-Cecycloalkyl;

R3 is H, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -C(0)R7, -C(0)OR7, or -

C(0)NR8aR8 ;

R4 is H, halo, -Ci-Cealkyl, or NH2;

R5 is H, halo, CN, -Ci-C6alkyl, -C2-C4alkenyl, -C2-C4haloalkenyl, C2-C4cyanoalkenyl, -Co-

- 328 - Cealk-C≡CH, -Co-C6alk-C≡C-Ci-C6alkyl, -Ci-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2-C6heterocycloalkyl, -C3-C6cycloalkyl, -Co-C3alk-C(0)R9, CR8R8 CN, -CH2NR8R8', -Co-Cealk-OH, -NR8R8 , -N(R9)CN, -0-Ci-C4alkyl, - NR9CONR8R8 , -OCONR8R8', or -NR9C(0)OR9a;

R6 is Ci-Cealkyl, or Co-Cealk-Cs-Cecycloalkyl

R7 is H, Ci-Cealkyl, or Co-Cealk-Cs-Cecycloalkyl;

R8a and R8 are each independently H, Ci-Cealkyl, or -Co-Cealk-OCi-Cealkyl, or R8a and R8 , together with the atom to which they are attached, form a C2-C6heterocycloalkyl ring;

R8 and R8 are each independently H, Ci-C6alkyl, or -Co-C6alk-OCi-C6alkyl;

or R8 and R8 , together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a C2-C6heterocycloalky ring;

R9 is H, -Ci-Cealkyl, or Co-Cealk-Cs-Cecycloalkyl;

R9a is -Ci-Cealkyl, or Co-Cealk-Cs-Cecycloalkyl;

R10 is halo or -Ci-Cealkyl;

R10a is H, halo, or -Ci-Cealkyl; and

R11 is H, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-C3- Cehalocycloalkyl, -Co-Cealk-OH, -Co-C6alk-NH2, -Co-Cealk-NH-Ci-Cealkyl, -Co- C6alk-N(Ci-C6alkyl)-Ci-C6alkyl, -Co-Cealk-NH-Cs-Cecycloalkyl, or -Co-Cealk-N(Ci- C6alkyl)-C3-C6cycloalkyl;

or R11 and R1, together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a heterocycloalkyl ring.

26. The compound of claim 25, wherein Ri is -Co-C6alk-Ci-C6alkyl, preferably -CH(OH)-Ci- Cealkyl, -CH(F)-Ci-C6alkyl, -CH(NH2)-Ci-C6alkyl, -CH(Me)-Ci-C6alkyl, or -C(Me)(OH)- Ci-C6alkyl.

27. The compound of claim 25, wherein Ri is -Co-C6alk-Ci-C6haloalkyl, preferably -CH(OH)- Ci-Cehaloalkyl, -CH(F)-Ci-C6haloalkyl, -CH(NH2)-Ci-C6haloalkyl, -CH(Me)-Ci- Cehaloalkyl, or -C(Me)(OH)-Ci-C6haloalkyl.

28. The compound of claim 25, wherein Ri is -Co-C6alk-C=CH, preferably -CH(OH)-C

- 329 - CH(F)-C≡CH, -CH(NH2)-C≡CH, -CH(Me)-C≡CH, or -C(Me)(OH)-C≡CH.

29. The compound of claim 25, wherein Ri is -Co-C6alk-C≡C-Ci-C6alkyl, preferably -CH(OH)- C≡C-Ci-C6alkyl, -CH(F)-C≡C-Ci-C6alkyl, -CH(NH2)-C≡C-Ci-C6alkyl, -CH(Me)-C≡C- Ci-Cealkyl, or -C(Me)(OH)-C≡C-Ci-C6alkyl, more preferably -CH(OH)-C≡C-CH3, - CH(F)-C≡C-CH3, -CH(NH2)-C≡C-CH3, -CH(Me)-C≡C-CH3, or -C(Me)(OH)-C≡C-CH3.

30. The compound of claim 25, wherein Ri is -Co-C6alk-C≡C-Ci-C6haloalkyl, preferably - CH(OH)-C≡C-Ci-C6haloalkyl, -CH(F)-C≡C-Ci-C6haloalkyl, -CH(NH2)-C≡C-Ci- Cehaloalkyl, -CH(Me)-C≡C-Ci-C6haloalkyl, or -C(Me)(OH)-C≡C-Ci-C6haloalkyl, more preferably -CH(OH)-C≡C-CF3, -CH(F)-C≡C-CF3, -CH(NH2)-C≡C-CF3, -CH(Me)-C≡C- CF3, or -C(Me)(OH)-C≡C-CF3.

31. The compound of claim 25, wherein Ri is -Co-C6alk-C≡C-C3-C6cycloalkyl, preferably - CH(OH)-C≡C-C3-C6cycloalkyl, -CH(F)-C≡C-C3-C6cycloalkyl, -CH(NH2)-C≡C-C3- Cecycloalkyl, -CH(Me)-C≡C-C3-C6cycloalkyl, or -C(Me)(OH)-C≡C-C3-C6cycloalkyl, more preferably -CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH(NH2)-C≡C- cyclopropyl, -CH(Me)-C≡C-cyclopropyl, or -C(Me)(OH)-C≡C-cyclopropyl.

32. The compound of claim 25, wherein Ri is -Ci-C6alk-aryl, preferably -CH2-aryl, -CH(OH)- aryl, -CH(F)-aryl, -CH(NH2)-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl, more preferably - CH2-4-chlorophenyl, -CH2-3,4-dichlorophenyl, -CH2-3,4-difluorophenyl, -CH2-3-fluoro-4- chlorophenyl, -CH2-3-chloro-4-fluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3,4- dichlorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- 3-chloro-4-fluorophenyl, -CH(F)-4-chlorophenyl, -CH(F)-3,4-dichlorophenyl, -CH(F)-3,4- difluorophenyl, -CH(F)-3-fluoro-4-chlorophenyl, -CH(F)-3-chloro-4-fluorophenyl, - CH(NH2)-4-chlorophenyl, -CH(NH2)-3,4-dichlorophenyl, -CH(NH2)-3,4-difluorophenyl, - CH(NH2)-3-fluoro-4-chlorophenyl, -CH(NH2)-3-chloro-4-fluorophenyl, -CH(Me)-4- chlorophenyl, -CH(Me)-3,4-dichlorophenyl, -CH(Me)-3,4-difluorophenyl, -CH(Me)-3-

- 330 - fluoro-4-chlorophenyl, -CH(Me)-3-chloro-4-fluorophenyl, -C(Me)(OH)-4-chlorophenyl, - C(Me)(OH)-3,4-dichlorophenyl, -C(Me)(OH)-3,4-difluorophenyl, -C(Me)(OH)-3-fluoro-4- chlorophenyl, or -C(Me)(OH)-3-chloro-4-fluorophenyl.

33. The compound of claim 25, wherein R1 is -Co-C6alk-S-aryl, preferably -S-4-chlorophenyl, - S-3,4-dichlorophenyl, -S-3,4-difluorophenyl, -S-3-fluoro-4-chlorophenyl, or -S-3-chloro-4- fluorophenyl.

34. The compound of claim 25, wherein R1 is -Co-C6alk-S(0)-aryl, preferably -S(0)-4- chlorophenyl, -S(0)-3,4-dichlorophenyl, -S(0)-3,4-difluorophenyl, -S(0)-3-fluoro-4- chlorophenyl, or -S(0)-3-chloro-4-fluorophenyl.

35. The compound of claim 25, wherein R1 is -Co-C6alk-S(0)2-aryl, preferably -S(0)2-4- chlorophenyl, -S(0)2-3,4-dichlorophenyl, -S(0)2-3,4-difluorophenyl, -S(0)2-3-fluoro-4- chlorophenyl, or -S(0)2-3-chloro-4-fluorophenyl.

36. The compound of claim 25, wherein R1 is -Co-C6alk-0-aryl, preferably -O-4-chlorophenyl, - 0-3,4-dichlorophenyl, -0-3,4-difluorophenyl, -0-3-fluoro-4-chlorophenyl, or -0-3-chloro-4- fluorophenyl.

37. The compound of claim 25, wherein R1 is -Co-C6alk-heteroaryl, preferably 2-(2-amino-3- bromoquinolin-7-yl)ethyl, 2-(2-amino-3-chloroquinolin-7-yl)ethyl, 2-(2- ((cyclopropylmethyl)amino)quinolin-7-yl)ethyl, 2-(2-(methylamino)quinolin-7-yl)ethyl, or 2-(2-aminoquinolin-7-yl)ethyl.

38. The compound of claim 25, wherein R1 is -Ci-C6alk-0-heteroaryl, preferably ((2-amino-3- bromoquinolin-7-yl)oxy)methyl.

39. The compound of claim 25, wherein R1 is -Ci-C6alk-S-heteroaryl, preferably ((2-amino-3- bromoquinolin-7-yl)thio)methyl.

40. The compound of claim 25, wherein R1 is -Ci-C6alk-NH-heteroaryl, preferably 2-amino-3- bromoquinolin-7-yl)amino)methyl.

- 331 -

41. The compound of any one of claims 25 to 40, wherein R2 is H.

42. The compound of any one of claims 25 to 40, wherein R2 is Ci-C6 alkyl.

43. The compound of any one of claims 25 to 42, wherein R3 is H.

44. The compound of any one of claims 25 to 42, wherein R3 is -Ci-C6alkyl.

45. The compound of any one of claims 25 to 42, wherein R3 is -C(0)R7, preferably wherein R7 is -Ci-C6alkyl.

46. The compound of any one of claims 25 to 45, wherein R4 is H.

47. The compound of any one of claims 25 to 46, wherein Q is NH.

48. The compound of any one of claims 25 to 46, wherein Q is O.

49. The compound of any one of claims 25 to 48, wherein R11 is H.

50. The compound of any one of claims 25 to 49, which is a compound of Formula III.

51. The compound of claim 50, wherein A is CH.

52. The compound of claim 50, wherein A is N.

53. The compound of claim 50, wherein A is CR10, preferably wherein the R10 is -Ci-C6alkyl.

54. The compound of any one of claims 50 to 53, wherein R5 is H.

55. The compound of any one of claims 50 to 53, wherein R5 is halo.

56. The compound of any one of claims 50 to 53, wherein R5 is -Ci-C6alkyl.

57. The compound of any one of claims 25 to 50, which is a compound of Formula IV

58. The compound of claim 57 where R10a is H.

- 332 -

59. The compound of claim 57 where R is -Ci-C6alkyl.

60. A compound of Formula V or Formula VI:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

A is CH or N;

R1 is -Ci-C6alk-C≡C-Ci-C6alkyl, -Ci-C6alk-C≡C-Ci-C6haloalkyl, -Ci-C6alk-C≡C-C3-

Cecycloalkyl, -CH(Me)-aryl, -CH(CH2OH)-aryl, -C(Me)(OH)-heteroaryl, -CH(OH)- C≡C-C3-C6cycloalkyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4- dichlorophenyl, -C(Me)(OH)-3,4-difluorophenyl, -C(Me)(OH)-3-fluoro-4- chlorophenyl, -C(Me)(OH)-3-chloro-4-fluorophenyl, -CH(Me)(OH)-3-methyl-4- chlorophenyl, -CH(Me)(OH)-3-fluoro-4-trifluoromethylphenyl, -CH(Me)(OH)-4- trifluoromethylphenyl, -CH(Me)(OH)-3-methyl-4-trifluoromethylphenyl, - CH(Me)(OH)-3-chloro-4-fluorophenyl, -CH(Me)-4-chlorophenyl, -CH(CH2OH)-4- chlorophenyl, -C(Me)(OH)-5-chlorothiophen-2-yl, or -CH(OH)-C≡C-cyclopropyl;

R2 is halo;

R3 is H, halo, NH2, or Ci-Cealkyl; and

R4 is NH2 or CH3.

61. (cancelled)

62. (cancelled)

63. The compound of claim 60, wherein R3 is H.

- 333 -

64. The compound of any one of claims 60 or 63, wherein the compound is a compound of Formula V

65. (cancelled)

66. The compound of claim 64, wherein R2 is fluoro.

67. The compound of any one of claims 60 or 63, wherein the compound is a compound of

Formula VI.

68. The compound of any one of claims 60, 63, 64, 66, or 67, wherein R4 is NH2.

69. The compound of any one of claims 60, 63, 64, 66, or 67, wherein R4 is CH3.

70. A pharmaceutical composition comprising a compound according to any one of claims the preceding claims and a pharmaceutically acceptable excipient.

71. A method of inhibiting a protein arginine methyltransferase 5 (PRMT5) enzyme, comprising: contacting the PRMT5 enzyme with an effective amount of a compound of any one of any one of claims 1, 10-60, 63, 64 or 66-69.

72. A method of treating a disease or disorder associated with aberrant PRMT5 activity in a subject comprising administering to the subject, a compound of any one of claims 1, 10-60, 63, 64, or 66-69.

73. The method of claim 72, wherein the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, hemoglobinopathies such as b-thalassemia and sickle cell disease

- 334 - (SCD), CDKN2A deleted cancers; 9P deleted cancers; MTAP deleted cancers; glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.

- 335 -