TETRAHYDRO- AND DIHYDRO-ISOQUINOLINE PRMT5 INHIBITORS AND USES THEREOF
Described herein are compounds of Formula (A), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. 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 .- 110 . (canceled)
111 . A method of inhibiting PRMT5, altering gene expression, or altering transcription, the method comprising contacting a cell with an effective amount of a compound of Formula (A):
or a pharmaceutically acceptable salt thereof,
wherein:
represents a single or double bond;
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, optionally substituted acyl, or 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 is —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—, or —OC(O)N(R)—;
each R is independently hydrogen or optionally substituted C 1-6 aliphatic;
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; or
Ar is a monocyclic or bicyclic heterocyclic ring having 1-4 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 , and —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;
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 5 , R 6 , R 7 , and R 8 are independently hydrogen, halo, or optionally substituted aliphatic; each R x is independently selected from the group consisting of halo, —CN, optionally substituted aliphatic, and —N(R″) 2 ;
each R″ is independently hydrogen or optionally substituted aliphatic, or two R″ are taken together with their intervening atoms to form a heterocyclic ring; and
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits:
provided the compound is not:
112 .- 115 . (canceled)
116 . 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 Formula (A):
or a pharmaceutically acceptable salt thereof;
wherein:
represents a single or double bond;
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 2 , or —OR 1 ;
R A1 and R A2 are each independently hydrogen, optionally substituted C 1-3 alkyl, optionally substituted acyl, or 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 is —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—, or —OC(O)N(R)—;
each R is independently hydrogen or optionally substituted C 1-6 aliphatic;
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; or
Ar is a monocyclic or bicyclic heterocyclic ring having 1-4 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 , and —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;
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 5 , R 6 , R 7 , and R 8 are independently hydrogen, halo, or optionally substituted aliphatic;
each R x is independently selected from the group consisting of halo, —CN, optionally substituted aliphatic, and —N(R″) 2 ;
each R″ is independently hydrogen or optionally substituted aliphatic, or two R″ are taken together with their intervening atoms to form a heterocyclic ring; and
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits;
provided the compound is not:
117 . The method of claim 116 , wherein the disorder is a proliferative disorder, a metabolic disorder, or a blood disorder.
118 . The method of claim 117 , wherein the disorder is cancer.
119 . The method of claim 118 , wherein the cancer is hematopoietic cancer, lung cancer, prostate cancer, melanoma, or pancreatic cancer.
120 . (canceled)
121 . The method of claim 117 , wherein the metabolic disorder is diabetes or obesity.
122 . (canceled)
123 . (canceled)
124 . The method of claim 117 , wherein the disorder is a hemoglobinopathy.
125 . The method of claim 124 , wherein the disorder is sickle cell anemia or β-thalessemia.
126 . (canceled)
127 . The method of claim 116 , wherein L is —C(O)N(R)—.
128 . The method of claim 116 , wherein R 13 is —OR 1 , and R 1 is hydrogen.
129 . The method of claim 116 , wherein Ar is phenyl or heteroaryl.
130 . The method of claim 129 , wherein Ar is a 6-membered heteroaryl having 1-3 nitrogens.
131 . The method of claim 130 , wherein Ar is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.
132 . The method of claim 116 , wherein Ar is substituted with 1 or 2 R y groups.
133 . The method of claim 116 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
134 . The method of claim 116 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
135 . The method of claim 116 , wherein the compound is of Formula (A-7):
or a pharmaceutically acceptable salt thereof.
136 . The method of claim 116 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
137 . The method of claim 116 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
138 . A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (A):
or a pharmaceutically acceptable salt thereof;
wherein:
represents a single or double bond;
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, optionally substituted acyl, or 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 is —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—, or —OC(O)N(R)—;
each R is independently hydrogen or optionally substituted C 1-6 aliphatic;
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; or
Ar is a monocyclic or bicyclic heterocyclic ring having 1-4 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 , and —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;
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 5 , R 6 , R 7 , and R 8 are independently hydrogen, halo, or optionally substituted aliphatic;
each R x is independently selected from the group consisting of halo, —CN, optionally substituted aliphatic, and —N(R″) 2 ;
each R″ is independently hydrogen or optionally substituted aliphatic, or two R″ are taken together with their intervening atoms to form a heterocyclic ring; and
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits;
provided the compound is not: