PRMT5 INHIBITORS AND USES THEREOF
Described herein are compounds of Formula (A), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof: wherein Y1 is of formula (x) or formula (y):Ring Y is a 5- to 6-membered heteroaryl ring; and V 4 , V 5 , R x , x, y, and n are as defined herein. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described.
1 . A compound of Formula (A):
or a pharmaceutically acceptable salt thereof,
wherein:
R 12 is hydrogen, halogen, or optionally substituted C 1-3 alkyl;
R 13 is hydrogen, halogen, optionally substituted C 1-3 alkyl, —NR A1 R A2 , or —OR 1 ;
R A1 and R A2 are each independently hydrogen, optionally substituted C 1-3 alkyl, a nitrogen protecting group, or R A1 and R A2 are taken together with the intervening nitrogen atom to form an optionally substituted 3-6 membered heterocyclic ring;
R 1 is hydrogen, R z , or —C(O)R z , wherein R z is optionally substituted C 1-6 alkyl;
L z is a linker or is absent;
Ring Z is an optionally substituted, monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R 21 , R 22 , R 23 , and R 24 are independently hydrogen, halo, or optionally substituted aliphatic;
Y 1 is of formula (x) or formula (y)
Ring Y is a 5- to 6-membered heteroaryl ring;
each instance of V 4 and V 5 is independently C or N;
each R x is independently selected from the group consisting of halo, —CN, optionally substituted aliphatic, —OR′, —N(R″) 2 , optionally substituted aryl, optionally substituted heteroaryl, and if attached to a nitrogen atom, a nitrogen protecting group;
R′ is hydrogen or optionally substituted aliphatic;
R″ is hydrogen or optionally substituted aliphatic, or two R″ are taken together with their intervening atoms to form a heterocyclic ring;
n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
corresponds to a single or double bond; and
x is 0 and y is 2, 3, or 4; or
x is 1 and y is 1; or
x is 1 and y is 3.
2 . The compound of claim 1 , wherein Y 1 is of formula (x-1)
wherein:
each instance of V 1 , V 2 , and V 3 is independently O, S, N, NH, NR x , CH, or CR x ; and
V 4 is N or C.
3 . The compound of claim 1 , wherein Y 1 is of formula (y-1)
wherein:
each instance of V 1 , V 2 , and V 3 is independently O, S, N, NH, NR x , CH, or CR x ; and
V 4 is N or C.
4 . The compound of claim 3 , wherein Y 1 is of formula (x-1a):
5 . The compound of claim 4 , wherein Y 1 is of formula (x-1b):
6 . The compound of claim 5 , wherein Y 1 is of formula (x-1c):
7 . The compound of claim 1 , wherein Y 1 is of formula (i), (ii), or (iii):
wherein:
each instance of A 1 and A 3 is independently N, CH, or CR x ; and
A 2 is O, S, NH, or NR x .
8 . The compound of claim 7 , wherein Y 1 is of formula (i-a), (ii-a), or (iii-a):
9 . The compound of claim 8 , wherein Y 1 is selected from the group consisting of:
wherein the ring system fused to Ring Y comprises 0, 1, 2, 3, or 4 R x substituents, and Ring Y comprises 0, 1, or 2 R x substituents, as valency permits.
10 . The compound of claim 1 , wherein Y 1 is selected from the group consisting of:
wherein the ring system fused to Ring Y comprises 0, 1, 2, 3, or 4 R x substituents, and Ring Y comprises 0, 1, 2, or 3 R x substituents, as valency permits.
11 . The compound of claim 1 , wherein Y 1 is of formula (iv):
wherein each instance of A 4 , A 5 , A 6 , and A 7 is independently N, CH, or CR x , provided at least one of A 4 , A 5 , A 6 , and A 7 is N.
12 . The compound of claim 12 , wherein Y 1 is of formula (iv-a):
13 . The compound of claim 13 , wherein Y 1 is selected from the group consisting of:
wherein the ring system fused to Ring Y comprises 0, 1, 2, 3, or 4 R x substituents, and Ring Y comprises 0, 1, 2, or 3 R x substituents, as valency permits.
14 . The compound of claim 1 , wherein Y 1 is selected from the group consisting of:
wherein the ring system fused to Ring Y comprises 0, 1, 2, 3, or 4 R x substituents, and Ring Y comprises 0, 1, 2, or 3 R x substituents, as valency permits.
15 . The compound of claim 1 , wherein the compound is of Formula:
or a pharmaceutically acceptable salt thereof.
16 . The compound of claim 1 , wherein the compound is of Formula:
or a pharmaceutically acceptable salt thereof.
17 . The compound of claim 1 , wherein the compound is of Formula (A-3):
or a pharmaceutically acceptable salt thereof.
18 . The compound of claim 1 , wherein the compound is of Formula:
or a pharmaceutically acceptable salt thereof.
19 . The compound of any one of claims 1 - 18 , wherein L z is a linker:
—X A —C(R 2A )(R 3A )C(═O)N(R)—
wherein:
X A is a bond, —O—, —N(R)—, —CR 4A R 5A —, —O—CR 4A R 5A , —N(R)—CR 4A R 5A —, —O—CR 4A R 5A O—, —N(R)—CR 4A R 5A —O, —N(R)—CR 4A R 5A —N(R)—, —O—CR 4A R 5A —N(R)—, —CR 4A R 5A —O—, —CR 4A R 5A —N(R)—, —O—CR 4A R 5A —CR 6A R 7A —, —N(R)—CR 4A R 5A —CR 6A R 7A —, —CR 6A R 7A —CR 4A R 5A —O—, —CR 6A R 7A —CR 4A R 5A —N(R)—, or —CR 6A R 7A —CR 4A R 5A —;
R is independently hydrogen or optionally substituted C 1-6 aliphatic;
R 4A and R 5A are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 ; or R 4A and R 5A are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;
R 6A and R 7A are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 ; or R 6A and R 7A are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;
R 2A and R 3A are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 ; or R 2A and R 3A are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;
each R A is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and
each R B is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring.
20 . The compound of any one of claims 1 - 18 , wherein L z is a linker L B , wherein L B is —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)N(R)—, —N(R)C(O)O—, or —OC(O)N(R)—, and each R is independently hydrogen or optionally substituted C 1-6 aliphatic.
21 . The compound of any one of claims 1 - 18 , wherein L z is a linker L D , wherein:
L D is the linker L B wherein L B is —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)N(R)—, —N(R)C(O)O—, or —OC(O)N(R)— and each R is independently hydrogen or optionally substituted C 1-6 aliphatic; or
L D is a linker selected from the group consisting of —O—, —N(R)—, —C(R 2A )(R 3A )—, —O—CR 2A R 3A , —N(R)—CR 2A R 3A —, —O—CR 2A R 3A —O—, —N(R)—CR 2A R 3A —O, —N(R)—CR 2A R 3A —N(R)—, —O—CR 2A R 3A —N(R)_, —CR 2A R 3A —O—, —CR 2A R 3A —N(R), —O—CR 2A R 3A —CR 9 R 10 —, —N(R)—CR 2A R 3A CR 9 R 10 —, —CR 2A R 3A —CR 9 R 10 —O—, —CR 2A R 3A —CR 9 R—N(R)—, or —CR 2A R 3A —CR 9 R 10 —;
each R is independently hydrogen or optionally substituted C 1-6 aliphatic;
R 2A and R 3A are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl; optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 ; or R 2A and R 3A are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;
each R A is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R B is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; and
R 9 and R 10 are independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl; optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 ; or R 9 and R 10 are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring.
22 . The compound of any one of claims 1 - 18 , wherein L z is absent.
23 . The compound of any one of claims 1 - 22 , wherein Ring Z is a group Cy A , wherein:
Cy A is a monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy A is substituted with 0, 1, 2, 3, or 4 R y groups; and
each R y is independently selected from the group consisting of halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 .
24 . The compound of claim 23 , wherein the compound is of Formula (A-I A ):
or a pharmaceutically acceptable salt thereof.
25 . The compound of claim 24 , wherein the compound is a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein each instance of A 1 and A 3 is independently N, CH, or CR x , and A 2 is O, S, NH, or NR x .
26 . The compound of claim 24 , wherein the compound is a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein each instance of A 1 and A 3 is independently N, CH, or CR x , and A 2 is O, S, NH, or NR x .
27 . The compound of claim 24 , wherein the compound is a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein each instance of A 1 and A 3 is independently N, CH, or CR x , and A 2 is O, S, NH, or NR x .
28 . The compound of claim 24 , wherein the compound is a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein each instance of A 4 , A 5 , A 6 , and A 7 is independently N, CH, or CR x , provided at least one of A 4 , A 5 , A 6 , and A 7 is N.
29 . The compound of any one of claims 1 - 18 , wherein Ring Z is a group Ar, wherein:
Ar is a monocyclic or bicyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ar is substituted with 0, 1, 2, 3, 4, or 5 R y groups, as valency permits;
each R y is independently selected from the group consisting of halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 ;
each R A is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and
each R B is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring.
30 . The compound of claim 29 , wherein the compound is of Formula (A-I B ):
or a pharmaceutically acceptable salt thereof.
31 . The compound of any one of claims 1 - 22 , wherein Ring Z is Ring C of formula:
wherein:
Ring C is an optionally substituted, 5- to 12-membered, monocyclic or bicyclic, heterocyclyl or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
Y is O or S.
32 . The compound of claim 31 , wherein the compound is of Formula (A-I C ):
or a pharmaceutically acceptable salt thereof.
33 . The compound of any one of claims 1 - 22 , wherein Ring Z is Ring A of formula:
wherein:
Ring A is a monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R 4 is -L 1 -Cy D ;
L 1 is a bond, —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—, —N(R)C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)O—, —OC(O)N(R)—, —SO 2 —, —SO 2 N(R)—, —N(R)SO 2 —, —OC(O)—, —C(O)O—, or an optionally substituted, straight or branched, C 1-6 aliphatic chain wherein one, two, or three methylene units of L 1 are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—, —N(R)C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)O—, —OC(O)N(R)—, —SO 2 —, —SO 2 N(R)—, —N(R)SO 2 —, —OC(O)—, or —C(O)O—;
each R is independently hydrogen or optionally substituted C 1-6 aliphatic;
Cy D is an optionally substituted, monocyclic, bicyclic or tricyclic, saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R y is independently selected from the group consisting of halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted carbocyclyl; optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(O)OR A , —C(O)SR A , —C(O)N(R B ) 2 , —C(O)N(R B )N(R B ) 2 , —OC(O)R A , —OC(O)N(R B ) 2 , —NR B C(O)R A , —NR B C(O)N(R B ) 2 , —NR B C(O)N(R B )N(R B ) 2 , —NR B C(O)OR A , —SC(O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(O)R A , —OS(O) 2 R A , —SO 2 R A , —NR B SO 2 R A , or —SO 2 N(R B ) 2 ;
m is 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits; and
q is 0 or 1.
34 . The compound of claim 33 , wherein the compound is of Formula (A-I D ):
or a pharmaceutically acceptable salt thereof.
35 . The compound of claim 34 , wherein the compound is of Formula (A-V D ):
or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , and X 4 are independently selected from the group consisting of N, CH, and CR y , provided that at least one of X 2 , X 3 , and X 4 is not N
36 . The compound of claim 35 , wherein the compound is a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein each instance of A 1 and A 3 is independently N, CH, or CR x , and A 2 is O, S, NH, or NR x .
37 . The compound of claim 35 , wherein the compound is a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein each instance of A 1 and A 3 is independently N, CH, or CR x , and A 2 is O, S, NH, or NR x .
38 . The compound of claim 35 , wherein the compound is a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein each instance of A 1 and A 3 is independently N, CH, or CR x , and A 2 is O, S, NH, or NR x .
39 . The compound of claim 35 , wherein the compound is a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein each instance of A 4 , A 5 , A 6 , and A 7 is independently N, CH, or CR x , provided at least one of A 4 , A 5 , A 6 , and A 7 is N.
40 . The compound of claim 35 , wherein the compound is of Formula:
or a pharmaceutically acceptable salt thereof,
wherein:
each instance of V 1 , V 2 , and V 3 is independently O, S, N, NH, NR x , CH, or CR x ; and
V 4 is N or C.
41 . The compound of claim 35 , wherein the compound is of Formula:
or a pharmaceutically acceptable salt thereof.
42 . The compound of any one of claims 1 - 15 and 19 - 41 , wherein R 12 is hydrogen and R 13 is —OR 1 .
43 . The compound of any one of claims 1 - 15 and 19 - 41 , wherein R 12 is optionally substituted C 1-3 alkyl and R 13 is —OR 1 .
44 . The compound of any one of claims 1 - 15 and 19 - 41 , wherein R 12 is hydrogen and R 13 is hydrogen.
45 . The compound of any one of claims 1 - 15 and 19 - 41 , wherein R 12 is hydrogen and R 13 is halogen.
46 . The compound of any one of claims 1 - 15 and 19 - 41 , wherein the carbon attached to R 12 has (S)-stereochemistry.
47 . The compound of any one of claims 1 - 15 and 19 - 41 , wherein the carbon attached to R 12 has (R)-stereochemistry.
48 . The compound of claims 1 - 47 , wherein the compound is selected from the group consisting of the compounds in Table 1A, 1B, 1C, 1D, and 1E and pharmaceutically acceptable salts thereof.
49 . A pharmaceutical composition comprising a compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
50 . A kit or packaged pharmaceutical comprising a compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, and instructions for use thereof.
51 . A method of inhibiting PRMT5 comprising contacting a cell with an effective amount of a compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof.
52 . A method of altering gene expression comprising contacting a cell with an effective amount of a compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof.
53 . A method of altering transcription comprising contacting a cell with an effective amount of a compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof.
54 . The method of any one of claims 51 - 53 , wherein the cell is in vitro.
55 . The method of any one of claims 51 - 53 , wherein the cell is in a subject.
56 . A method of treating a PRMT5-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 49 .
57 . The method of claim 56 , wherein the disorder is a proliferative disorder.
58 . The method of claim 57 , wherein the proliferative disorder is cancer.
59 . The method of claim 58 , wherein the cancer is hematopoietic cancer, lung cancer, prostate cancer, melanoma, or pancreatic cancer.
60 . The method of claim 56 , wherein the disorder is a metabolic disorder.
61 . The method of claim 60 , wherein the metabolic disorder is diabetes.
62 . The method of claim 60 , wherein the metabolic disorder is obesity.
63 . The method of claim 56 , wherein the disorder is a blood disorder.
64 . The method of claim 63 , wherein the blood disorder is a hemoglobinopathy.
65 . The method of claim 63 , wherein the blood disorder is sickle cell anemia.
66 . The method of claim 63 , wherein the blood disorder is β-thalessemia.