US2018098987A1PendingUtilityA1
PRMT5 Inhibitors and Uses Thereof
Est. expiryDec 21, 2032(~6.4 yrs left)· nominal 20-yr term from priority
C07D 401/14C07D 405/12C07D 217/04C07D 217/12C07D 405/14A61K 31/506C07D 401/12C12N 9/1007C07D 413/12A61P 3/04A61P 3/10A61K 31/538A61P 35/00A61K 31/496A61P 7/06A61K 31/498A61K 31/4725A61K 31/5377A61K 31/472Y02A50/30
68
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Claims
Abstract
Described herein are compounds of Formula (I), 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.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . 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;
L 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)—;
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;
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;
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, —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 a heterocyclic ring; and
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits.
2 . The compound of claim 1 , wherein the compound is of Formula (I-a):
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 , wherein the compound is of Formula (I-b):
or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 , wherein the compound is of Formula (I′):
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 4 , wherein the compound is of Formula (I′-a):
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 4 , wherein the compound is of Formula (I′-b):
or a pharmaceutically acceptable salt thereof.
7 . The compound of any one of claims 1 - 7 , wherein L is —C(O)N(R)—.
8 . The compound of any one of claims 1 - 7 , wherein L is —NHC(O)NH—.
9 . The compound of any one of claims 1 - 7 , wherein L is —OC(O)NH—.
10 . The compound of claim 1 , wherein the compound is of Formula (II):
or a pharmaceutically acceptable salt thereof.
11 . The compound of claim 10 , wherein the compound is of Formula (II-a):
or a pharmaceutically acceptable salt thereof.
12 . The compound of claim 10 , wherein the compound is of Formula (II-b):
or a pharmaceutically acceptable salt thereof.
13 . The compound of any one of claims 1 - 12 , wherein R 1 is hydrogen.
14 . The compound of any one of claims 1 - 13 , wherein n is 0.
15 . The compound of any one of claims 1 - 13 , wherein n is 1.
16 . The compound of any one of claims 1 - 13 , wherein n is 2.
17 . The compound of any one of claims 1 - 16 , wherein Ar is phenyl.
18 . The compound of any one of claims 1 - 16 , wherein Ar is heteroaryl.
19 . The compound of claim 18 , wherein Ar is a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
20 . The compound of claim 19 , wherein Ar is pyridyl.
21 . The compound of any one of claims 1 - 20 , wherein Ar is unsubstituted.
22 . The compound of any one of claims 1 - 20 , wherein Ar is substituted with 1 or 2 R y groups.
23 . The compound of claim 22 , wherein Ar is substituted with one R y group.
24 . The compound of claim 1 , wherein the compound is of Formula (III):
or a pharmaceutically acceptable salt thereof.
25 . The compound of claim 24 , wherein the compound is of Formula (III-a):
or a pharmaceutically acceptable salt thereof.
26 . The compound of claim 24 , wherein the compound is of Formula (III-b):
or a pharmaceutically acceptable salt thereof.
27 . The compound of claim 1 , wherein the compound is of Formula (IV):
or a pharmaceutically acceptable salt thereof.
28 . The compound of claim 1 , wherein the compound is of Formula (IV-a):
or a pharmaceutically acceptable salt thereof.
29 . The compound of claim 1 , wherein the compound is of Formula (IV-b):
or a pharmaceutically acceptable salt thereof.
30 . The compound of claim 1 , wherein the compound is of Formula (V):
or a pharmaceutically acceptable salt thereof.
31 . The compound of claim 1 , wherein the compound is of Formula (V-a):
or a pharmaceutically acceptable salt thereof.
32 . The compound of claim 1 , wherein the compound is of Formula (V-b):
or a pharmaceutically acceptable salt thereof.
33 . The compound of claim 1 , wherein the compound is of Formula (VI):
or a pharmaceutically acceptable salt thereof.
34 . The compound of claim 1 , wherein the compound is of Formula (VI-a):
or a pharmaceutically acceptable salt thereof.
35 . The compound of claim 1 , wherein the compound is of Formula (VI-b):
or a pharmaceutically acceptable salt thereof.
36 . The compound of claim 1 , wherein the compound is of Formula (VII):
or a pharmaceutically acceptable salt thereof.
37 . The compound of claim 1 , wherein the compound is of Formula (VII-a):
or a pharmaceutically acceptable salt thereof.
38 . The compound of claim 1 , wherein the compound is of Formula (VII-b):
or a pharmaceutically acceptable salt thereof.
39 . The compound of claim 1 , wherein the compound is of Formula (VIII):
or a pharmaceutically acceptable salt thereof.
40 . The compound of claim 1 , wherein the compound is of Formula (VIII-a):
or a pharmaceutically acceptable salt thereof.
41 . The compound of claim 1 , wherein the compound is of Formula (VIII-b):
or a pharmaceutically acceptable salt thereof.
42 . The compound of claim 1 , wherein the compound is of Formula (IX):
or a pharmaceutically acceptable salt thereof.
43 . The compound of claim 1 , wherein the compound is of Formula (IX-a):
or a pharmaceutically acceptable salt thereof.
44 . The compound of claim 1 , wherein the compound is of Formula (IX-b):
or a pharmaceutically acceptable salt thereof.
45 . The compound of claim 1 , wherein the compound is of Formula (X):
or a pharmaceutically acceptable salt thereof.
46 . The compound of claim 1 , wherein the compound is of Formula (X-a):
or a pharmaceutically acceptable salt thereof.
47 . The compound of claim 1 , wherein the compound is of Formula (X-b):
or a pharmaceutically acceptable salt thereof.
48 . The compound of claim 1 , wherein the compound is of Formula (XI):
or a pharmaceutically acceptable salt thereof.
49 . The compound of claim 1 , wherein the compound is of Formula (XI-a):
or a pharmaceutically acceptable salt thereof.
50 . The compound of claim 1 , wherein the compound is of Formula (XI-b):
or a pharmaceutically acceptable salt thereof.
51 . The compound of claim 1 , wherein the compound is of Formula (XII):
or a pharmaceutically acceptable salt thereof.
52 . The compound of claim 1 , wherein the compound is of Formula (XII-a):
or a pharmaceutically acceptable salt thereof.
53 . The compound of claim 1 , wherein the compound is of Formula (XII-b):
or a pharmaceutically acceptable salt thereof.
54 . The compound of claim 1 , wherein the compound is of Formula (XIII):
or a pharmaceutically acceptable salt thereof.
55 . The compound of claim 1 , wherein the compound is of Formula (XIII-a):
or a pharmaceutically acceptable salt thereof.
56 . The compound of claim 1 , wherein the compound is of Formula (XIII-b):
or a pharmaceutically acceptable salt thereof.
57 . The compound of claim 1 , wherein the compound is of Formula (XV):
or a pharmaceutically acceptable salt thereof.
58 . The compound of claim 1 , wherein the compound is of Formula (XVI):
or a pharmaceutically acceptable salt thereof.
59 . The compound of claim 1 , wherein the compound is of Formula (XVII):
or a pharmaceutically acceptable salt thereof.
60 . The compound of claim 1 , wherein the compound is of Formula (XVIII):
or a pharmaceutically acceptable salt thereof.
61 . The compound of claim 1 , wherein the compound is of Formula (XV-a):
or a pharmaceutically acceptable salt thereof.
62 . The compound of claim 1 , wherein the compound is of Formula (XVI-a):
or a pharmaceutically acceptable salt thereof.
63 . The compound of claim 1 , wherein the compound is of Formula (XVII-a):
or a pharmaceutically acceptable salt thereof.
64 . The compound of claim 1 , wherein the compound is of Formula (XVIII-a):
or a pharmaceutically acceptable salt thereof.
65 . The compound of claim 1 , wherein the compound is of Formula (XV-b):
or a pharmaceutically acceptable salt thereof.
66 . The compound of any one of claims 1 - 20 and 22 - 65 , wherein at least one R y is heteroaryl or heterocyclyl.
67 . The compound of claim 66 , wherein at least one R y is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
68 . The compound of claim 67 , wherein at least one R y is a 6-membered heteroaryl having 1-3 nitrogens.
69 . The compound of claim 68 , wherein at least one R y is pyridyl.
70 . The compound of claim 67 , wherein at least one R y is a 5-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
71 . The compound of claim 70 , wherein at least one R y is optionally substituted pyrazole.
72 . The compound of claim 70 , wherein at least one R y is pyrrole.
73 . The compound of claim 66 , wherein at least one R y is a 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
74 . The compound of claim 73 , wherein at least one R y is a 5-membered heterocyclyl having one heteroatom selected from nitrogen, oxygen, and sulfur.
75 . The compound of claim 74 , wherein at least one R y is optionally substituted pyrrolidine.
76 . The compound of claim 73 , wherein at least one R y is a 6-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
77 . The compound of claim 76 , wherein at least one R y is optionally substituted piperazine.
78 . The compound of claim 76 , wherein at least one R y is morpholine.
79 . The compound of any one of claims 1 - 20 and 22 - 65 , wherein at least one R y is optionally substituted aliphatic.
80 . The compound of claim 79 , wherein at least one R y is optionally substituted C 1-6 alkyl.
81 . The compound of claim 80 , wherein at least one R y is C 1-6 alkyl substituted with an aryl, heteroaryl, or heterocyclyl.
82 . The compound of claim 81 , wherein at least one R y is —CH 2 -aryl, —CH 2 -heteroaryl, or —CH 2 -heterocyclyl.
83 . The compound of any one of claims 1 - 20 and 22 - 65 , wherein at least one R y is —N(R B ) 2 .
84 . The compound of claim 83 , wherein one R B is optionally substituted heterocyclyl, and the other R B is C 1-4 alkyl.
85 . The compound of claim 83 , wherein one R B is optionally substituted heteroaryl, and the other R B is C 1-4 alkyl.
86 . The compound of claim 83 , wherein one R B is optionally substituted cycloalkyl, and the other R B is C 1-4 alkyl.
87 . The compound of claim 83 , wherein at least one R y is —NHR B .
88 . The compound of claim 87 , wherein R B is optionally substituted heterocyclyl.
89 . The compound of claim 87 , wherein R B is optionally substituted heteroaryl.
90 . The compound of claim 87 , wherein R B is optionally substituted cycloalkyl.
91 . The compound of any one of claims 1 - 20 and 22 - 65 , wherein at least one R y is —SO 2 N(R B ) 2 .
92 . The compound of claim 91 , wherein at least one R y is —SO 2 NHR B .
93 . The compound of claim 92 , wherein at least one R y is —SO 2 NH 2 .
94 . The compound of any one of claims 1 - 20 and 22 - 65 , wherein at least one R y is —C(O)N(R B ) 2 .
95 . The compound of claim 94 , wherein at least one R y is —C(O)NHR B .
96 . The compound of claim 95 , wherein at least one R y is —C(O)NH 2 .
97 . The compound of any one of claims 1 - 20 and 22 - 65 , wherein at least one R y is —NR B C(O)R A .
98 . The compound of claim 97 , wherein at least one R y is —NHC(O)R A .
99 . The compound of claim 98 , wherein at least one R y is —NHC(O)CH 3 .
100 . The compound of any one of claims 1 - 20 and 22 - 65 , wherein at least one R y is —NR B SO 2 R A .
101 . The compound of claim 100 , wherein at least one R y is —NHSO 2 R A .
102 . The compound of claim 101 , wherein at least one R y is —NHSO 2 CH 3 .
103 . The compound of any one of claims 1 - 20 and 22 - 65 , wherein at least one R y is —OR A .
104 . The compound of claim 103 , wherein R A is optionally substituted heterocyclyl.
105 . The compound of claim 103 , wherein R A is optionally substituted heteroaryl.
106 . The compound of claim 103 , wherein R A is optionally substituted cycloalkyl.
107 . The compound of any one of claims 1 - 16 , wherein Ar is selected from the group consisting of:
108 . The compound of claim 1 , wherein the compound is selected from the group consisting of the compounds listed in Table 1.
109 . A pharmaceutical composition comprising a compound of any one of claims 1 - 108 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
110 . A kit or packaged pharmaceutical comprising a compound of any one of claims 1 - 108 and instructions for use thereof.
111 . A method of inhibiting PRMT5 comprising contacting a cell with an effective amount of a compound of any one of claims 1 - 108 or a pharmaceutically acceptable salt thereof.
112 . A method of altering gene expression comprising contacting a cell with an effective amount of a compound of any one of claims 1 - 108 or a pharmaceutically acceptable salt thereof.
113 . A method of altering transcription comprising contacting a cell with an effective amount of a compound of any one of claims 1 - 108 or a pharmaceutically acceptable salt thereof.
114 . The method of any one of claims 111 - 113 , wherein the cell is in vitro.
115 . The method of any one of claims 111 - 113 , wherein the cell is in a subject.
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 any one of claims 1 - 108 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 109 .
117 . The method of claim 116 , wherein the disorder is a proliferative 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 . The method of claim 116 , wherein the disorder is a metabolic disorder.
121 . The method of claim 121 , wherein the metabolic disorder is diabetes.
122 . The method of claim 121 , wherein the metabolic disorder is obesity.
123 . The method of claim 116 , wherein the disorder is a blood disorder.
124 . The method of claim 123 , wherein the disorder is a hemoglobinopathy.
125 . The method of claim 124 , wherein the disorder is sickle cell anemia.
126 . The method of claim 124 , wherein the disorder is β-thalessemia.Join the waitlist — get patent alerts
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