ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF
Described herein are compounds of Formula (S-I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.
1 . A compound of Formula (S-I):
or a pharmaceutically acceptable salt thereof,
wherein
each of X, Y, and Z is independently O, S, N, NR 4 , or CR 5 , as valency permits;
R x is optionally substituted C 1-4 alkyl or optionally substituted C 3-4 cycloalkyl;
M is —NR W1 — or —CR W2 —;
each of R W1 and R W2 is independently substituted cyclohexenyl, substituted cyclohexyl, or substituted tetrahydropyran;
each of R 3a and R 3b is independently hydrogen, optionally substituted C 1-4 alkyl, or optionally substituted C 3-4 cycloalkyl;
each instance of R 4 is independently hydrogen or optionally substituted C 1-6 alkyl; and
each instance of R 5 is independently hydrogen, halo, —CN, NO 2 , optionally substituted C 1-4 alkyl, or optionally substituted C 3-4 cycloalkyl; and
provided that when M is —CR W2 —, at most one of X, Y, and Z is CR 5 ;
provided that the compound is not one of the compounds in Table 1.
2 . The compound of claim 1 , wherein the compound is of Formula (S-I-a):
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 , wherein the compound is of Formula (S-II):
or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 , wherein the compound is of Formula (S-III):
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 , wherein the compound is of Formula (S-IV):
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 , wherein the compound is of Formula (S-V):
or a pharmaceutically acceptable salt thereof.
7 . The compound of claim 1 , wherein the compound is of Formula (S-VI):
or a pharmaceutically acceptable salt thereof.
8 . The compound of claim 1 , wherein the compound is of Formula (S-VII):
or a pharmaceutically acceptable salt thereof.
9 . The compound of claim 1 , wherein the compound is of Formula (S-VIII):
or a pharmaceutically acceptable salt thereof.
10 . The compound of claim 1 , wherein the compound is of Formula (S-IX):
or a pharmaceutically acceptable salt thereof.
11 . The compound of claim 1 , wherein the compound is of Formula (S-X):
or a pharmaceutically acceptable salt thereof.
12 . The compound of claim 1 , wherein the compound is of Formula (S-XI):
or a pharmaceutically acceptable salt thereof.
13 . The compound of claim 1 , wherein the compound is of Formula (S-XII):
or a pharmaceutically acceptable salt thereof.
14 . The compound of claim 1 , wherein the compound is of Formula (S-XIII):
or a pharmaceutically acceptable salt thereof.
15 . The compound of claim 1 , wherein the compound is of Formula (S-XIV):
or a pharmaceutically acceptable salt thereof.
16 . The compound of any one of claims 1 - 15 , wherein R W2 is substituted cyclohexyl.
17 . The compound of any one of claims 1 - 16 , wherein R W2 is of Formula (S-i):
wherein:
each of R sa , R sb , R se , and R sf is independently hydrogen, optionally substituted C 1-6 alkyl, —OR SO , or —C(═O)N(R SN1 ) 2 ;
each of R sc and R sd is independently optionally substituted C 1-6 alkyl, —OR SO , —C(═O)N(R SN1 ) 2 , or —N(R SN2 ) 2 ;
each instance of R SN1 and R SN2 is independently hydrogen or optionally substituted alkyl;
each instance of R SO is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl; and
R sa and R sb are optionally taken together with the intervening atom to form an optionally substituted carbocylic ring or an optionally substituted heterocyclic ring;
R sc and R sd are optionally taken together with the intervening atom to form an optionally substituted carbocylic ring or an optionally substituted heterocyclic ring; and
R se and R sf are optionally taken together with the intervening atom to form an optionally substituted carbocylic ring or an optionally substituted heterocyclic ring.
18 . The compound of claim 17 , wherein R W2 is of Formula (S-i-a):
19 . The compound of claim 18 , wherein R sc is —OR SO .
20 . The compound of claim 19 , wherein R SO is optionally substituted heterocyclyl.
21 . The compound of claim 20 , wherein R SO is optionally substituted six-membered heterocyclyl.
22 . The compound of claim 21 , wherein R SO is substituted tetrahydropyran.
23 . The compound of claim 18 , wherein R sc is unsubstituted C 1-6 alkyl.
24 . The compound of claim 23 , wherein R sc is methyl.
25 . The compound of claim 23 , wherein R sc is ethyl.
26 . The compound of claim 18 , wherein R sc is substituted C 1-6 alkyl.
27 . The compound of claim 26 , wherein
R sc is —CH 2 —O—(CH 2 ) sn —X sc or —CH 2 —O—(CH 2 ) sm —O—X sd ;
sn is 0, 1, 2, 3, 4, 5, or 6;
sm is 1, 2, 3, 4, 5, or 6;
X sc is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; and
X sd is optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.
28 . The compound of claim 27 , wherein R sc is —CH 2 —O—X sc ; and X sc is C 1-6 haloalkyl.
29 . The compound of claim 28 , wherein R sc is —CH 2 —O—CH 2 CF 3 .
30 . The compound of claim 17 , wherein R W2 is of Formula (S-i-b):
31 . The compound of claim 30 , wherein each instance of R sc and R sd is independently substituted C 1-6 alkyl.
32 . The compound of claim 31 , wherein each instance of R sc and R sd is independently —C 1-6 alkyl-OH.
33 . The compound of claim 32 , wherein R sc and R sd are —CH 2 —OH.
34 . The compound of claim 31 , wherein
each instance of R sc and R sd is independently —CH 2 —O—(CH 2 ) sn —X sc or —CH 2 —O—(CH 2 ) sm —O—X sd ;
sn is 0, 1, 2, 3, 4, 5, or 6;
sm is 1, 2, 3, 4, 5, or 6;
X sc is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; and
X sd is optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.
35 . The compound of claim 34 , wherein X sc is optionally substituted C 1-6 alkyl.
36 . The compound of claim 35 , wherein X sc is ethyl or n-propyl.
37 . The compound of claim 34 , wherein X sc is optionally substituted C 3-6 carbocyclyl.
38 . The compound of claim 37 , wherein X sc is cyclopropyl.
39 . The compound of claim 34 , wherein X sc is optionally substituted heterocyclyl.
40 . The compound of claim 39 , wherein X sc is tetrahydropyran.
41 . The compound of any one of claims 34 - 40 , wherein X sd is optionally substituted alkyl.
42 . The compound of claim 41 , wherein X sd is substituted alkyl.
43 . The compound of claim 41 , wherein X sd is unsubstituted alkyl.
44 . The compound of claim 43 , wherein X sd is ethyl.
45 . The compound of claim 17 , wherein R W2 is of Formula (S-i-c):
46 . The compound of claim 45 , wherein each of R sc and R sd is independently unsubstituted C 1-6 alkyl; and R sb is optionally substituted alkyl, —C(═O)N(R SN1 ) 2 , or —OR SO .
47 . The compound of claim 46 , wherein R sc and R sd are methyl.
48 . The compound of any one of claims 45 - 47 , wherein R sb is independently substituted C 1-6 alkyl.
49 . The compound of claim 48 , wherein:
R sb is —CH 2 —O—(CH 2 ) sn —X sc or —CH 2 —O—(CH 2 ) sm —O—X sd ;
sn is 0, 1, 2, 3, 4, 5, or 6;
sm is 1, 2, 3, 4, 5, or 6;
X sc is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; and
X sd is optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.
50 . The compound of claim 49 , wherein R sb is —CH 2 —O—(CH 2 ) sn —X sc and X sc is hydrogen.
51 . The compound of claim 50 , wherein R sb is —CH 2 —OH.
52 . The compound of claim 49 , wherein R sb is —CH 2 —O—(CH 2 ) sn —X sc and X sc is optionally substituted C 1-6 alkyl.
53 . The compound of claim 50 , wherein R sb is —CH 2 —O—(CH 2 ) sn —C 2 H 5 .
54 . The compound of claim 49 , wherein R sb is —CH 2 —O—(CH 2 ) sm —O—X sd ; and X sd is unsubstituted alkyl.
55 . The compound of claim 54 , wherein R sb is —CH 2 —O—(CH 2 ) sm —O—CH 3 .
56 . The compound of any one of claims 45 - 55 , wherein R sb is —OR SO ; and R SO is optionally substituted alkyl.
57 . The compound of claim 56 , wherein R sb is —O-isobutyl.
58 . The compound of claim 17 , wherein R sc and R sd are taken together with the intervening atom to form a substituted heterocyclic ring of Formula (S-i-d):
wherein each instance of R s1 and R s2 is independently optionally substituted C 1-6 alkyl.
59 . The compound of claim 58 , wherein each instance of R s1 and R s2 is independently unsubstituted C 1-6 alkyl.
60 . The compound of claim 59 , wherein both R s1 and R s2 are methyl.
61 . The compound of claim 17 , wherein R sc and R sd are taken together with the intervening atom to form a substituted heterocyclic ring of Formula (S-i-e):
wherein each instance of R s3 and R s4 is independently optionally substituted C 1-6 alkyl.
62 . The compound of claim 61 , wherein each instance of R s3 and R s4 is independently unsubstituted C 1-6 alkyl.
63 . The compound of claim 62 , wherein both of R s3 and R s4 are methyl.
64 . The compound of claim 17 , wherein R sc and R sd are taken together with the intervening atom to form a substituted heterocyclic ring of Formula (S-i-f1) or (S-i-f2):
wherein each of R s5 and R s6 is independently C 1-6 alkyl.
65 . The compound of claim 64 , wherein each of R s5 and R s6 is independently unsubstituted C 1-6 alkyl.
66 . The compound of claim 65 , wherein R s5 and R s6 are both methyl.
67 . The compound of claim 17 , wherein R sc and R sd are taken together with the intervening atom to form a heterocyclic ring of Formula (S-i-g):
68 . The compound of claim 17 , wherein R sc and R sd are taken together with the intervening atom to form a heterocyclic ring of Formula (S-i-h):
69 . The compound of claim 17 , wherein R sc and R sd are taken together with the intervening atom to form a substituted heterocyclic ring of Formula (S-i-i):
wherein each instance of R s7 is optionally substituted alkyl.
70 . The compound of claim 69 , wherein R s7 is optionally substituted C 4-8 alkyl.
71 . The compound of claim 70 , wherein R s7 is isopentyl.
72 . The compound of claim 17 , wherein R sc and R sd are taken together with the intervening atom to form a substituted heterocyclic ring of Formula (S-i-j).
wherein each instance of R s8 and R s9 is independently hydrogen or optionally substituted C 1-6 alkyl; and R nj is independently hydrogen, optionally substituted C 1-6 alkyl, or a nitrogen protecting group.
73 . The compound of claim 72 , wherein R s8 and R s9 are both methyl or ethyl.
74 . The compound of any one of claims 72 - 73 , wherein R nj is hydrogen or methyl.
75 . The compound of claim 16 , wherein R sc and R sd are taken together with the intervening atom to form a carbocyclic ring of Formula (S-i-l):
wherein R s10 is —OR sl ; and R sl is optionally substituted alkyl.
76 . The compound of claim 75 , wherein R sl is methyl.
77 . The compound of claim 17 , wherein R sa and R sb are taken together with the intervening atom to form a carbocyclic ring of Formula (S-i-m)
wherein R sc is optionally substituted C 1-6 alkyl.
78 . The compound of claim 77 , wherein R sc is substituted C 1-6 alkyl.
79 . The compound of claim 78 , wherein
R sc is independently —CH 2 —O—(CH 2 ) sn —X sc ;
sn is 0, 1, 2, 3, 4, 5, or 6;
X sc is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.
80 . The compound of claim 79 , wherein R sc is —(CH 2 ) sn —O—CH 3 .
81 . The compound of claim 17 , wherein R W2 is of Formula (S-i-n):
wherein:
each of R s11 and R s12 is independently hydrogen or optionally substituted C 1-6 alkyl; and
R sb is optionally substituted C 1-6 alkyl.
82 . The compound of claim 81 , wherein R sb is ethyl.
83 . The compound of claim 17 , wherein R W2 is of Formula (S-i-o):
wherein:
each of R s13 , R s14 , R s15 , and R s16 is independently hydrogen or optionally substituted C 1-6 alkyl.
84 . The compound of claim 83 , wherein R s14 and R s16 are both hydrogen.
85 . The compound of claim 83 , wherein R s14 and R s16 are both methyl, isobutyl, or isopentyl.
86 . The compound of any one of claim 83 , wherein R s14 is hydrogen and R s16 is methyl.
87 . The compound of any one of claims 83 - 86 , wherein R s13 and R s15 are both isobutyl.
88 . The compound of any one of claims 83 - 86 , wherein:
each of R s13 and R s15 is independently —(CH 2 ) sd —OX sd ;
sd is 1, 2, 3, 4, or 5; and
X sd is optionally substituted C 1-6 alkyl.
89 . The compound of claim 88 , wherein R s13 and R s15 are both —(CH 2 ) 2 —OCH 3 .
90 . The compound of any one of claims 83 - 86 , wherein R s13 is methyl or ethyl and R s15 is isopentyl.
91 . The compound of claim 1 , wherein R W2 is of Formula (S-ii):
wherein:
each of R e1 , R e2 , R e3 , R e4 , R e5 , and R e6 is independently hydrogen, optionally substituted C 1-6 alkyl, or —OR eo ;
R eo is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and
R e1 and R e2 are optionally taken with the intervening atom to form an optionally substituted carbocyclic ring; and
R e3 and R e4 are optionally taken with the intervening atom to form an optionally substituted carbocyclic ring.
92 . The compound of claim 91 , wherein R W2 is of Formula (S-ii-a):
93 . The compound of claim 92 , wherein each of R e3 and R e4 is independently optionally substituted C 1-6 alkyl.
94 . The compound of claim 93 , wherein each of R e3 and R e4 is independently C 1-6 haloalkyl.
95 . The compound of claim 93 , wherein:
each of R e3 and R e4 is independently hydrogen or —CH 2 —O—X e1 , and
X e1 is optionally substituted C 1-6 alkyl.
96 . The compound of claim 95 , wherein X e1 is substituted C 1-6 alkyl.
97 . The compound of claim 96 , wherein X e1 is —CH 2 —CF 3 .
98 . The compound of claim 95 , wherein X e1 is unsubstituted C 1-6 alkyl.
99 . The compound of claim 98 , wherein X e1 is ethyl.
100 . The compound of claim 92 , wherein R e3 and R e4 are taken with the intervening atom to form an optionally substituted heterocyclyl.
101 . The compound of claim 100 , wherein R W2 is of Formula (S-ii-a1):
wherein each of R e7 and R e8 is independently optionally substituted C 1-6 alkyl.
102 . The compound of claim 101 , wherein R e7 and R e8 are methyl.
103 . The compound of claim 91 , wherein R W2 is of Formula (S-ii-b):
104 . The compound of claim 103 , wherein R e1 and R e2 are taken with the intervening atom to form an optionally substituted carbocyclic ring.
105 . The compound of claim 104 , wherein R e1 and R e2 are taken with the intervening atom to form an optionally substituted cyclopentyl ring.
106 . The compound of any one of claims 103 - 105 , wherein
R e3 is —OR eo ; and
R eo is optionally substituted C 1-6 alkyl.
107 . The compound of claim 106 , wherein
R e3 is —O—(CH 2 ) eb —O—X e2 ;
X e2 is optionally substituted C 1-6 alkyl; and
eb is 1, 2, 3, 4, 5, or 6.
108 . The compound of claim 107 , wherein R e3 is —O—(CH 2 ) 3 —O—CH 3 .
109 . The compound of claim 1 , wherein R W2 is optionally substituted tetrahydropyran.
110 . The compound of claim 109 , wherein R W2 is of Formula (S-iii):
wherein each of R h1 and R h2 is independently hydrogen, halo, —CN, NO 2 , or optionally substituted C 1-6 alkyl.
111 . The compound of claim 110 , wherein R h1 is optionally substituted C 1-6 alkyl.
112 . The compound of claim 111 , wherein R h1 is unsubstituted C 1-6 alkyl.
113 . The compound of claim 112 , wherein R h1 is ethyl.
114 . The compound of any one of claims 110 - 113 , wherein R h2 is optionally substituted C 1-6 alkyl.
115 . The compound of claim 114 , wherein R h2 is unsubstituted C 1-6 alkyl.
116 . The compound of claim 115 , wherein R h2 is ethyl.
117 . The compound of claim 1 , wherein the compound is of Formula (S-I-b):
or a pharmaceutically acceptable salt thereof.
118 . The compound of claim 117 , wherein the compound is of Formula (S-XV):
or a pharmaceutically acceptable salt thereof, wherein each of R 5a and R 5b is independently hydrogen, halo, —CN, NO 2 , or optionally substituted C 1-4 alkyl.
119 . The compound of claim 117 , wherein the compound is of Formula (S-XVI):
or a pharmaceutically acceptable salt thereof, wherein each of R 5a and R 5b is independently hydrogen, halo, —CN, NO 2 , or optionally substituted C 1-6 alkyl.
120 . The compound of claim 1 , wherein the compound is of Formula (S-XVII):
or a pharmaceutically acceptable salt thereof, wherein each of R 5a and R 5b is independently hydrogen, halo, —CN, NO 2 , or optionally substituted C 1-6 alkyl.
121 . The compound of any one of claims 118 - 120 , wherein R 5a is hydrogen.
122 . The compound of any one of claims 118 - 120 , wherein R 5a is optionally substituted C 1-6 alkyl.
123 . The compound of claim 122 , wherein R 5a is unsubstituted C 1-6 alkyl.
124 . The compound of claim 123 , wherein R 5a is methyl.
125 . The compound of any one of claims 118 - 120 , wherein R 5a is halogen.
126 . The compound of claim 125 , wherein R 5a is Cl.
127 . The compound of any one of claims 118 - 126 , wherein R 5b is hydrogen.
128 . The compound of any one of claims 118 - 126 , wherein R 5b is optionally substituted C 1-6 alkyl.
129 . The compound of claim 128 , wherein R 5b is unsubstituted C 1-6 alkyl.
130 . The compound of claim 129 , wherein R 5b is methyl.
131 . The compound of any one of claims 118 - 126 , wherein R 5b is halogen.
132 . The compound of claim 131 , wherein R 5b is Cl.
133 . The compound of claim 1 , wherein the compound is of Formula (S-XVIII):
or a pharmaceutically acceptable salt thereof.
134 . The compound of claim 1 , wherein the compound is of Formula (S-XIX):
or a pharmaceutically acceptable salt thereof.
135 . The compound of claim 1 , wherein the compound is of Formula (S-XX):
or a pharmaceutically acceptable salt thereof.
136 . The compound of any one of claims 117 - 135 , wherein R W1 is substituted cyclohexyl of Formula (S-iii):
wherein:
each of R sg , R sh , R sk , and R sl is independently hydrogen or optionally substituted C 1-6 alkyl,
each of R si and R sj is independently optionally substituted C 1-6 alkyl; and
R sg and R sh are optionally taken together with the intervening atom to form an optionally substituted carbocylic ring or an optionally substituted heterocyclic ring;
R si and R sj are optionally taken together with the intervening atom to form an optionally substituted carbocylic ring or an optionally substituted heterocyclic ring; and
R sk and R sl are optionally taken together with the intervening atom to form an optionally substituted carbocylic ring or an optionally substituted heterocyclic ring.
137 . The compound of claim 136 , wherein R si and R sj are the same.
138 . The compound of claim 136 , wherein R si and R sj are different.
139 . The compound of any one of claims 136 - 138 , wherein each of R si and R sj is independently substituted C 1-6 alkyl.
140 . The compound of claim 139 , wherein each of R si and R sj is independently —CH 2 —O—(CH 2 ) sp —X si , or —CH 2 —O—(CH 2 ) sq —O—X sj ;
each instance of sp is 0, 1, 2, 3, 4, 5, or 6;
each instance of sq is 0, 1, 2, 3, 4, 5, or 6; and
each instance of X si and X sj is independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.
141 . The compound of claim 140 , wherein each of R si and R sj is independently —CH 2 —O—(CH 2 ) sp —X si .
142 . The compound of claim 141 , wherein X si is hydrogen.
143 . The compound of claim 141 , wherein X si is optionally substituted C 1-6 alkyl.
144 . The compound of claim 139 , wherein each of R si and R sj is independently —CH 2 —O—(CH 2 ) sq —O—X sj .
145 . The compound of claim 144 , wherein X sj is hydrogen.
146 . The compound of claim 144 , wherein X sj is optionally substituted C 1-6 alkyl.
147 . The compound of claim 136 , wherein R si and R sj are taken together with the intervening atom to form an optionally substituted heterocyclic ring of Formula (S-iii-a):
wherein each of R s17 and R s18 is independently optionally substituted C 1-6 alkyl.
148 . The compound of claim 147 , wherein R s17 is hydrogen.
149 . The compound of claim 147 , wherein R s17 is C 1-4 alkyl.
150 . The compound of claim 147 , wherein R s17 is methyl.
151 . The compound of any one of claims 147 - 150 , wherein R s18 is hydrogen.
152 . The compound of claim 151 , wherein R s18 is C 1-4 alkyl.
153 . The compound of claim 152 , wherein R s18 is methyl.
154 . The compound of claim 136 , wherein R si and R sj are taken together with the intervening atom to form a heterocyclic ring of Formula (S-iii-b):
wherein each of R s19 and R s20 is independently hydrogen or optionally substituted C 1-6 alkyl.
155 . The compound of claim 154 , wherein R s19 is hydrogen.
156 . The compound of claim 154 , wherein R s19 is C 1-4 alkyl.
157 . The compound of claim 156 , wherein R s19 is methyl.
158 . The compound of any one of claims 154 - 157 , wherein R s20 is hydrogen.
159 . The compound of claim 158 , wherein R s20 is C 1-4 alkyl.
160 . The compound of claim 159 , wherein R s20 is methyl.
161 . The compound of any one of claims 1 - 160 , wherein R 4 is hydrogen.
162 . The compound of any one of claims 1 - 160 , wherein R 4 is optionally substituted C 1-6 alkyl.
163 . The compound of claim 162 , wherein R 4 is unsubstituted C 1-6 alkyl.
164 . The compound of claim 163 , wherein R 4 is methyl.
165 . The compound of any one of claims 1 - 164 , wherein R 5 is hydrogen.
166 . The compound of any one of claims 1 - 164 , wherein R 5 is halogen.
167 . The compound of claim 166 , wherein R 5 is Cl.
168 . The compound of any one of claims 1 - 164 , wherein R 5 is optionally substituted C 1-4 alkyl.
169 . The compound of claim 168 , wherein R 5 is unsubstituted C 1-4 alkyl.
170 . The compound of claim 169 , wherein R 5 is methyl.
171 . The compound of any one of claims 1 - 170 , wherein R x is optionally substituted C 1-4 alkyl.
172 . The compound of claim 171 , wherein R x is unsubstituted C 1-4 alkyl.
173 . The compound of claim 172 , wherein R x is methyl.
174 . The compound of any one of claims 1 - 173 , wherein R 3a is hydrogen.
175 . The compound of claim 174 , wherein R 3a is optionally substituted C 1-4 alkyl.
176 . The compound of claim 175 , wherein R 3a is unsubstituted C 1-4 alkyl.
177 . The compound of claim 176 , wherein R 3a is methyl.
178 . The compound of any one of claims 1 - 177 , wherein R 3b is hydrogen.
179 . The compound of claim 178 , wherein R 3b is optionally substituted C 1-4 alkyl.
180 . The compound of claim 179 , wherein R 3b is unsubstituted C 1-4 alkyl.
181 . The compound of claim 180 , wherein R 3b is methyl.
182 . The compound of claim 1 , wherein the compound is selected from the group consisting of the compounds depicted in Table 2, and pharmaceutically acceptable salts thereof.
183 . A pharmaceutical composition comprising a compound of any one of claims 1 - 182 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
184 . A kit or packaged pharmaceutical comprising a compound of any one of claims 1 - 182 or a pharmaceutically acceptable salt thereof, and instructions for use thereof.
185 . A method of inhibiting an arginine methyl tranferase (RMT) comprising contacting a cell with an effective amount of a compound of any one of claims 1 - 182 or a pharmaceutically acceptable salt thereof.
186 . The method of claim 185 , wherein the arginine methyl transferase is PRMT1.
187 . The method of claim 185 , wherein the arginine methyl transferase is PRMT6.
188 . The method of claim 185 , wherein the arginine methyl transferase is PRMT3.
189 . The method of claim 185 , wherein the arginine methyl transferase is PRMT8.
190 . The method of claim 185 , wherein the arginine methyl transferase is CARM1.
191 . A method of modulating gene expression comprising contacting a cell with an effective amount of a compound of any one of claims 1 - 182 or a pharmaceutically acceptable salt thereof.
192 . A method of modulating transcription comprising contacting a cell with an effective amount of a compound of any one of claims 1 - 182 or a pharmaceutically acceptable salt thereof.
193 . The method of any one of claims 185 - 192 , wherein the cell is in vitro.
194 . The method of any one of claims 185 - 192 , wherein the cell is in a subject.
195 . A method of treating a RMT-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 - 182 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 183 .
196 . The method of claim 195 , wherein the RMT-mediated disorder is a PRMT1-mediated disorder.
197 . The method of claim 195 , wherein the RMT-mediated disorder is a PRMT6-mediated disorder.
198 . The method of claim 195 , wherein the RMT-mediated disorder is a PRMT3-mediated disorder.
199 . The method of claim 195 , wherein the RMT-mediated disorder is a PRMT8-mediated disorder.
200 . The method of claim 195 , wherein the RMT-mediated disorder is a CARM1-mediated disorder.
201 . The method of claim 195 , wherein the disorder is a proliferative disorder.
202 . The method of claim 195 , wherein the disorder is cancer.
203 . The method of claim 195 , wherein the disorder is a neurological disorder.
204 . The method of claim 203 , wherein the disorder is amyotrophic lateral sclerosis.
205 . The method of claim 195 , wherein the disorder is a muscular dystrophy.
206 . The method of claim 195 , wherein the disorder is an autoimmune disorder.
207 . The method of claim 195 , wherein the disorder is a vascular disorder.
208 . The method of claim 195 , wherein the disorder is a metabolic disorder.