PRMT5 INHIBITORS AND USES THEREOF

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein

R 1 is —SR 1a or —N(R 1a ) 2 ;

each R 1a is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, —C(═O)R Z , —C(═NH)R Z , a nitrogen protecting group when attached to nitrogen, a sulfur protecting group when attached to sulfur, or two instances of R 1a can be taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring;

R Z is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;

R 2 is hydrogen or —NH 2 ;

Z is CH or N; and

Q is CH 2 or O.

2 . The compound of claim 1 , wherein the compound is of Formula (I-a):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1a is —CH 3 ;

R 1b is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and

each R 1c is independently hydrogen, —CH 3 , or —CH 2 CH 3 .

3 . The compound of claim 2 , wherein the compound is of Formula (I-a1):

or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 1 , wherein the compound is of Formula (I-b):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1a is substituted or unsubstituted alkyl;

each R 1e is independently hydrogen, —CH 3 , or —CO 2 H; and

t is 0, 1, or 2.

5 . The compound of claim 4 , wherein the compound is of Formula (I-b1):

or a pharmaceutically acceptable salt thereof.

6 . The compound of claim 1 , wherein the compound is of Formula (I-c):

or a pharmaceutically acceptable salt thereof,

wherein:

each R 1f is independently substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, a nitrogen protecting group, or two of R 1f can be taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring; and

R 1a is substituted or unsubstituted alkyl.

7 . The compound of claim 6 , wherein the compound is of Formula (I-c1):

or a pharmaceutically acceptable salt thereof.

8 . The compound of claim 1 , wherein the compound is of Formula (I-d):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1h is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(═O)NHR 1ha , or a nitrogen protecting group;

R 1ha is substituted or unsubstituted aryl; and

R 1a is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.

9 . The compound of claim 8 , wherein the compound is of Formula (I-d1):

or a pharmaceutically acceptable salt thereof.

10 . The compound of claim 1 , wherein the compound is of Formula (I-e):

or a pharmaceutically acceptable salt thereof,

wherein:

each R 1a is independently —CH 3 , —C(═O)R Z , —C(═NH)R Z , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or two of R 1a can be taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring; and

R Z is substituted or unsubstituted aryl.

11 . The compound of claim 10 , wherein the compound is of Formula (I-e1):

or a pharmaceutically acceptable salt thereof.

12 . The compound of claim 1 , wherein the compound of Formula (I-f):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1l is hydrogen, —CO 2 H, or —CH 2 OH;

each R 1m is independently hydrogen or two of R 1m can be taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring; and

o is 0, 1, or 2.

13 . The compound of claim 12 , wherein the compound of Formula (I-f1):

or a pharmaceutically acceptable salt thereof.

14 . The compound of claim 1 , wherein the compound is of Formula (I-h):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1a is C 1-3 alkyl optionally substituted with one instance of —CO 2 H.

15 . The compound of claim 14 , wherein the compound is of Formula (I-h1):

or a pharmaceutically acceptable salt thereof.

16 . A compound of Formula (II):

or a pharmaceutically acceptable salt thereof,

wherein:

R 3 is hydrogen, methyl, ethyl, propyl, substituted or unsubstituted heteroarylalkyl, or —CH 2 CH 2 NHC(═O)R 3a ;

R 3S is hydrogen, methyl, ethyl, propyl, substituted or unsubstituted heteroarylalkyl, or —CH 2 CH 2 NHC(═O)R 3a ;

each occurrence of R 3a is independently substituted or unsubstituted alkyl, or substituted or unsubstituted aryl;

each R X is independently selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, halogen, —CN, —NO 2 , —OR X1 , —N(R X2 ) 2 , —SR X1 , —C(═O)R X1 , —C(O)OR X1 , —C(O)SR X1 , —C(O)N(R X2 ) 2 , —C(O)N(R X2 )N(R X2 ) 2 , —OC(O)R X1 , —OC(O)N(R X2 ) 2 , —NR X2 C(O)R X1 , —NRC(O)N(R X2 ) 2 , —NR X2 C(O)N(R X2 )N(R X2 ) 2 , —NR X2 C(O)OR X1 , —SC(O)R X1 , —C(═NR X2 )R X1 , —C(═NNR X2 )R X1 , —C(═NOR X1 )R X1 , —C(═NR X2 )N(R X2 ) 2 , —NR X2 C(═NR X2 )R X2 , C(═S)R X1 , —C(═S)N(R X2 ) 2 , —NR X2 C(═S)R X1 , —S(O)R X1 , —OS(O) 2 R X1 , —SO 2 R X1 , —NRSO 2 R X1 , or —SO 2 N(R X2 ) 2 ;

each R X1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

each R X2 is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or two R X2 groups are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring; and

n is 0, 1, 2, 3, 4, or 5.

17 . A compound of Formula (III):

or a pharmaceutically acceptable salt thereof,

wherein:

R 4 is substituted or unsubstituted aryl;

R 5 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and

u is 0 or 1.

18 . A compound of Formula (IV):

or a pharmaceutically acceptable salt thereof,

wherein:

R 6 is hydrogen or —N(R 6a ) 2 ;

each R 6a is independently substituted or unsubstituted alkyl;

each X is hydrogen, or two X groups are joined to form ═O;

R 7 is hydrogen, halogen, substituted or unsubstituted alkyl, or —N(R 7a ) 2 ;

R 7a is hydrogen or substituted or unsubstituted alkyl;

p is 0 or 1; and

w is 0 or 1,

wherein if p is 0, then two X groups are not joined to form ═O.

19 . The compound of claim 12 , wherein the compound is of Formula (IV-a):

or a pharmaceutically acceptable salt thereof.

20 . The compound of claim 12 , wherein the compound is of Formula (IV-b):

or a pharmaceutically acceptable salt thereof.

21 . The compound of claim 12 , wherein the compound is of Formula (IV-c):

or a pharmaceutically acceptable salt thereof.

22 . The compound of claim 12 , wherein the compound is of Formula (IV-d):

or a pharmaceutically acceptable salt thereof.

23 . A compound of Formula (V):

or a pharmaceutically acceptable salt thereof,

wherein:

each occurrence of R 9 is independently substituted or unsubstituted alkyl, —OR 9a , —C(═O)R 9a , —C(═O)OR 9a , —(C═O)NHR 9a , —NH(C═O)R 9a , —CN, or halogen, or two vicinal R 9 are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring;

each occurrence of R 9a is independently hydrogen, independently substituted or unsubstituted alkyl, or substituted or unsubstituted aryl;

M is a bond or NH;

when is a single bond, then A is N and R 11 is present, or A is CH or C(OH) and R 11 is present;

when is a double bond, then A is N and R 11 is absent, or A is C and R 11 is present; and

R 10 is hydrogen;

R 11 is substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or

R 10 and R 11 are taken together with their intervening atoms to form an unsubstituted fused phenyl ring; and

n5 is 0, 1, 2, 3, 4, or 5; and

z5 is 0 or 1.

24 . A compound of Formula (VI):

or a pharmaceutically acceptable salt thereof,

wherein:

R 6 is hydrogen or —N(R 6a ) 2 ;

each R 6a is independently substituted or unsubstituted alkyl; and

y and i are each independently 0 or 1.

25 . The compound of claim 24 , wherein the compound is of Formula (VI-a):

or a pharmaceutically acceptable salt thereof.

26 . The compound of claim 24 , wherein the compound is of Formula (VI-b):

or a pharmaceutically acceptable salt thereof.

27 . A compound of Formula (VII):

or a pharmaceutically acceptable salt thereof,

wherein:

R 13 is substituted or unsubstituted aryl;

R 14 is substituted or unsubstituted alkyl; and

L is independently CH or N, wherein at least one of L must be N.

28 . The compound of claim 27 , wherein the compound is of Formula (VII-a):

or a pharmaceutically acceptable salt thereof.

29 . The compound of claim 27 , wherein the compound is of Formula (VII-b):

or a pharmaceutically acceptable salt thereof.

30 . A compound of Formula (VIII):

or a pharmaceutically acceptable salt thereof,

wherein:

L 1 is O, C(═O)NH, or C(═O)NMe;

L 2 is a bond or NH;

each R 15 is independently substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl;

R 16 is hydrogen or —NHR 7 ;

R 17 is substituted or unsubstituted heterocyclyl;

each R 18 is independently hydrogen or —CH 3 ;

each R 18a is hydrogen or both instances of R 18a are taken together with their intervening atoms to form a substituted or unsubstituted cyclopropyl ring;

each R 18b is independently hydrogen or —CH 3 ;

or one instance of R 18a and one instance of R 18b are taken together with their intervening atoms to form a substituted or unsubstituted pyrrolidine or piperidine ring; and

each K is independently CH or N, wherein no more than two of K can be N.

31 . The compound of claim 30 , wherein the compound is of Formula (VIII-a):

or a pharmaceutically acceptable salt thereof.

32 . The compound of claim 30 , wherein the compound is of Formula (VIII-b):

or a pharmaceutically acceptable salt thereof.

33 . The compound of claim 31 , wherein the compound is of Formula (VIII-c):

or a pharmaceutically acceptable salt thereof.

34 . The compound of claim 32 , wherein the compound is of Formula (VIII-d):

or a pharmaceutically acceptable salt thereof.

35 . The compound of claim 31 , wherein the compound is of Formula (VIII-e):

or a pharmaceutically acceptable salt thereof.

36 . The compound of claim 32 , wherein the compound is of Formula (VIII-f):

or a pharmaceutically acceptable salt thereof.

37 . The compound of claim 31 , wherein the compound is of Formula (VIII-g):

or a pharmaceutically acceptable salt thereof.

38 . The compound of claim 32 , wherein the compound is of Formula (VIII-h):

or a pharmaceutically acceptable salt thereof.

39 . The compound of claim 31 , wherein the compound is of Formula (VIII-i):

or a pharmaceutically acceptable salt thereof.

40 . The compound of claim 32 , wherein the compound is of Formula (VIII-j):

or a pharmaceutically acceptable salt thereof.

41 . A compound of Formula (IX):

or a pharmaceutically acceptable salt thereof, wherein R 19 is substituted or unsubstituted heterocyclyl.

42 . The compound of claim 41 , wherein the compound is of Formula (IX-a):

or a pharmaceutically acceptable salt thereof.

43 . The compound of claim 41 , wherein the compound is of Formula (IX-b):

or a pharmaceutically acceptable salt thereof.

44 . A compound of Formula (X):

or a pharmaceutically acceptable salt thereof,

wherein:

D is CH or N;

E is C(R 21 ) or N, wherein if E is C(R 21 ) then at least one instance of D is N and if E is N then neither instance of D is N;

G is O or N(R 20 );

R 20 is hydrogen, substituted or unsubstituted alkyl, —SO 2 R 20a , or —C(═O)R 20a ;

R 20a is substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl;

R 21 is hydrogen or substituted or unsubstituted morpholine; and

j and b are each independently 0 or 1.

45 . The compound of claim 44 , wherein the compound is of Formula (X-a):

or a pharmaceutically acceptable salt thereof.

46 . The compound of claim 44 , wherein the compound is of Formula (X-b):

or a pharmaceutically acceptable salt thereof.

47 . The compound of claim 2 or 3 , wherein R 1b is:

48 . The compound of claim 2 or 3 , wherein one R 1c is —CH 3 or —CH 3 .

49 . The compound of claim 4 or 5 , wherein both instances of R 1e are hydrogen.

50 . The compound of claim 4 or 5 , wherein one instance of R 1e is —CO 2 H.

51 . The compound of claim 6 or 7 , wherein one instance of R 1f is —CH 2 (cyclopropyl) wherein, wherein cyclopropyl is substituted or unsubstituted, —CH 2 CH 2 OH,

wherein C 1-6 alkyl is substituted or unsubstituted.

52 . The compound of claim 6 or 7 , wherein two instances of R 1f are taken together to form a ring of formula:

53 . The compound of claim 8 or 9 , wherein R 1h is of formula:

—CH 2 CH 2 OH, —CH(Me)CH 2 OH, —CH 2 CH 2 OMe, —CH(Et)CH 2 OMe, —CH(Me)CH 2 OMe, —CH 2 CH 2 OPh,

wherein C 1-6 alkyl is substituted or unsubstituted,

54 . The compound of claim 8 or 9 , wherein R 1h is —C(═O)NHR 1ha ; and R 1ha is of formula

wherein C 1-6 alkyl is substituted or unsubstituted.

55 . The compound of claim 12 or 13 , wherein two instances of R 1m are taken together to form a ring of formula

56 . The compound of any of claims 1 - 15 , wherein Q is O.

57 . The compound of any of claims 1 - 15 , wherein R 2 is —NH 2 .

58 . The compound of any of claims 1 - 15 , wherein Z is N.

59 . The compound of claim 16 , wherein n is 0.

60 . The compound of claim 16 , wherein R 3 is hydrogen.

61 . The compound of claim 16 , wherein R 3 is —CH 2 CH 2 NHC(═O)R 3a ; and R 3a is unsubstituted phenyl.

62 . The compound of claim 17 , wherein R 4 is of formula:

wherein C 1-6 alkyl is substituted or unsubstituted,

wherein C 1-6 alkyl is substituted or unsubstituted,

or unsubstituted naphthyl.

63 . The compound of claim 17 , wherein R 5 is of formula:

64 . The compound of any of claims 19 - 22 , wherein R 6 is —NMe 2 .

65 . The compound of any of claims 19 - 22 , wherein R 6 is hydrogen, -Me, —F, or —NH 2 .

66 . The compound of claim 23 , wherein the ring system:

corresponds to a ring system of formula:

67 . The compound of claim 23 , wherein M is a bond; and R 9 is —OR 9a .

68 . The compound of claim 23 , wherein M is NH; and R 9 is a halogen.

69 . The compound of any of claims 24 - 26 , wherein R 6 is —NMe 2 .

70 . The compound of any of claims 27 - 29 , wherein R 13 is unsubstituted phenyl.

71 . The compound of any of claims 27 - 29 , wherein R 14 is unsubstituted C 1-6 alkyl.

72 . The compound of any of claims 30 - 40 , wherein L 2 is a bond.

73 . The compound of any of claims 30 - 40 , wherein L 2 is NH.

74 . The compound of any of claims 30 - 40 , wherein R 15 is of formula:

or benzothiazole,

wherein C 1-6 alkyl or cycloalkyl is substituted or unsubstituted.

75 . The compound of any of claims 41 - 43 , wherein R 19 is of formula

76 . The compound of any of claims 44 - 46 , wherein the ring comprising D and E is of formula:

77 . The compound of any of claims 44 - 46 , wherein the ring comprising G is of formula:

78 . A compound selected from the group consisting of the compounds listed in Table 1A-Table 1O, and pharmaceutically acceptable salts thereof.

79 . A pharmaceutical composition comprising a compound of any one of claims 1 - 78 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

80 . A kit or packaged pharmaceutical comprising a compound of any one of claims 1 - 78 and instructions for use thereof.

81 . A method of inhibiting PRMT5 comprising contacting a cell with an effective amount of a compound of any one of claims 1 - 78 or a pharmaceutically acceptable salt thereof.

82 . A method of altering gene expression comprising contacting a cell with an effective amount of a compound of any one of claims 1 - 78 or a pharmaceutically acceptable salt thereof.

83 . A method of altering transcription comprising contacting a cell with an effective amount of a compound of any one of claims 1 - 78 or a pharmaceutically acceptable salt thereof.

84 . The method of any one of claims 81 - 83 , wherein the cell is in vitro.

85 . The method of any one of claims 81 - 83 , wherein the cell is in a subject.

86 . A method of treating or preventing a PRMT5-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 - 78 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 79 .

87 . The method of claim 86 , wherein the disorder is a proliferative disorder.

88 . The method of claim 87 , wherein the disorder is cancer.

89 . The method of claim 88 , wherein the cancer is hematopoietic cancer, lung cancer, prostate cancer, melanoma, or pancreatic cancer.

90 . The method of claim 86 , wherein the disorder is a metabolic disorder.

91 . The method of claim 90 , wherein the metabolic disorder is diabetes.

92 . The method of claim 90 , wherein the metabolic disorder is obesity.

93 . The method of claim 86 , wherein the disorder is a blood disorder.

94 . The method of claim 93 , wherein the disorder is a hemoglobinopathy.

95 . The method of claim 94 , wherein the disorder is sickle cell anemia.

96 . The method of claim 94 , wherein the disorder is β-thalessemia.