PRMT5 INHIBITORS AND USES THEREOF

1 .- 107 . (canceled)

108 . A method of treating a disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein

represents a single or double bond;

R 1 is hydrogen, R z , or —C(O)R z , wherein R z is optionally substituted C 1-6 alkyl;

X is a bond, —O—, —N(R)—, —CR 4 R 5 —, —O—CR 4 R 5 , —N(R)—CR 4 R 5 —, —O—CR 4 R 5 —O—, —N(R)—CR 4 R 5 —O, —N(R)—CR 4 R 5 —N(R)—, —O—CR 4 R 5 —N(R)—, —CR 4 R 5 —O—, —CR 4 R 5 —N(R)—, —O—CR 4 R 5 —CR 6 R 7 —, —N(R)—CR 4 R 5 —CR 6 R 7 —, —CR 6 R 7 —CR 4 R 5 —O—, —CR 6 R 7 —CR 4 R 5 —N(R)—, or —CR 6 R 7 —CR 4 R 5 —;

each R is independently hydrogen or optionally substituted C 1-6 aliphatic;

R 2 and R 3 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 , and —SO 2 N(R B ) 2 ; or R 2 and R 3 are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;

R 4 and R 5 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 , and —SO 2 N(R B ) 2 ; or R 4 and R 5 are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;

R 6 and R 7 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 , and —SO 2 N(R B ) 2 ; or R 6 and R 7 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;

R 8 , R 9 , R 10 , and R 11 are independently hydrogen, halo, or optionally substituted aliphatic;

Cy is a monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0, 1, 2, 3, or 4 R y groups;

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 , and —SO 2 N(R B ) 2 ; or an R y group may be optionally taken together with R 2 or R 3 to form an optionally substituted 5- to 6-membered carbocyclic or heterocyclic ring fused to Cy;

each R x is independently selected from the group consisting of halo, —CN, optionally substituted aliphatic, —OR′, and —N(R″) 2 ;

R′ is hydrogen or optionally substituted aliphatic;

each R″ is independently hydrogen or optionally substituted aliphatic, or two R″ are taken together with their intervening atoms to form an optionally substituted heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits.

109 . The method of claim 108 , wherein the disorder is a proliferative disorder, a metabolic disorder, or a blood disorder.

110 . The method of claim 109 , wherein the disorder is cancer.

111 . The method of claim 110 , wherein the cancer is hematopoietic cancer, lung cancer, prostate cancer, melanoma, or pancreatic cancer.

112 . (canceled)

113 . The method of claim 109 , wherein the metabolic disorder is diabetes or obesity.

114 . (canceled)

115 . (canceled)

116 . The method of claim 109 , wherein the disorder is a hemoglobinopathy.

117 . The method of claim 116 , wherein the disorder is sickle cell anemia or β-thalessemia.

118 . (canceled)

119 . The method of claim 108 , wherein R 1 is hydrogen.

120 . The method of claim 108 , wherein n is 0.

121 . The method of claim 108 , wherein R 2 and R 3 are each hydrogen.

122 . The method of claim 108 , wherein R is hydrogen.

123 . The method of claim 108 , wherein Cy is phenyl substituted with 1 or 2 R y groups.

124 . The method of claim 108 , wherein Cy is a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is substituted with 1 or 2 R y groups.

125 . The method of claim 108 , wherein Cy is a bicyclic saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 1 or 2 R y groups.

126 . The method of claim 108 , wherein Cy is substituted with 1 or 2 R y groups, and at least one R y is halo, —CN, —OR A , —N(R B ) 2 , C 1-6 alkyl, —C(O)NHR B , —SO 2 R A , —N(R B )C(O)R A , —N(R B )SO 2 R A , —SO 2 N(R B ) 2 , —C(O)R A , an optionally substituted 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

127 . The method of claim 108 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

128 . The method of claim 108 , wherein X is a bond.

129 . The method of claim 108 , wherein X is —O—, —N(R)—, or —CR 4 R 5 —, wherein each instance of R, R 4 , and R 5 is hydrogen.

130 . The method of claim 108 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

131 . The method of claim 108 , wherein the subject is a human.