PYRIDOPYRIMIDINES AND METHODS OF THEIR USE
Disclosed are compounds useful in the treatment of neurological disorders. The compounds described herein, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing neurological diseases.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein
X 1 is N or CR 1 ;
X 2 is N or CR 2 ;
X 3 is N or CR 3 ;
X 4 is N or CR 4 ;
R 5 is
L 1 is
optionally substituted C 1-9 heteroarylene having at least one 5-membered ring, or optionally substituted C 2 -C 9 heterocyclylene and R 6 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, or optionally substituted C 2 -C 9 heterocyclyl C 1 -C 6 alkyl; or L 1 and R 6 combine to form an optionally substituted C 2 -C 9 oxyheteroaryl, optionally substituted pyrimidin-4-yl, optionally substituted indazol-1-yl, optionally substituted indazol-2-yl, optionally substituted indazol-3-yl, optionally substituted benzotriazol-1-yl, optionally substituted pyrazin-2-yl, or optionally substituted pyrid-2-yl, or a C 6 -C 10 aryl optionally substituted with an optionally substituted C 2 -C 9 heteroaryl;
R 1 is hydrogen, halogen, or optionally substituted C 1-6 alkyl;
R 2 is hydrogen or optionally substituted C 2 -C 9 heterocyclyl;
R 3 is hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or
R 4 is hydrogen, halogen, or optionally substituted C 1-6 alkyl;
L 2 is absent,
R 7 is optionally substituted C 6-10 aryl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 1-9 heteroaryl, or optionally substituted C 1-9 heterocyclyl;
each of R N1 , R N2 , and R N3 is, independently, hydrogen or optionally substituted C 1-6 alkyl; and
m is 0, 1, 2, or 3;
wherein one and only one of X 1 , X 2 , X 3 , and X 4 is N.
2 . The compound of claim 1 , wherein R 5 is
3 . (canceled)
4 . The compound of claim 1 , wherein the compound has the structure of Formula Ta:
or a pharmaceutically acceptable salt thereof;
or the compound has the structure of Formula II:
or a pharmaceutically acceptable salt thereof;
or the compound has the structure of Formula IIa:
or a pharmaceutically acceptable salt thereof;
or the compound has the structure of Formula IIb:
or a pharmaceutically acceptable salt thereof;
or the compound has the structure of Formula IIc:
or a pharmaceutically acceptable salt thereof;
or the compound has the structure of Formula IId:
or a pharmaceutically acceptable salt thereof.
5 - 16 . (canceled)
17 . The compound of claim 1 , wherein R 3 is hydrogen, Br,
18 - 20 . (canceled)
21 . The compound of claim 1 , wherein R 3 is
wherein L 2 is absent, or wherein L 2 is
22 - 31 . (canceled)
32 . The compound of claim 1 , wherein R 7 is
33 - 44 . (canceled)
45 . The compound of claim 1 , wherein the compound has the structure of Formula IId:
or a pharmaceutically acceptable salt thereof;
or the compound has the structure of Formula IIe:
or a pharmaceutically acceptable salt thereof;
or the compound has the structure of Formula IIf:
or a pharmaceutically acceptable salt thereof;
or the compound has the structure of Formula IIg:
or a pharmaceutically acceptable salt thereof.
46 - 49 . (canceled)
50 . The compound of claim 1 , wherein R 2 is
51 . (canceled)
52 . The compound of claim 1 , wherein the compound has the structure of Formula III:
or a pharmaceutically acceptable salt thereof;
or the compound has the structure of Formula IIIa:
or a pharmaceutically acceptable salt thereof;
or the compound has the structure of Formula IV:
or a pharmaceutically acceptable salt thereof;
or the compound has the structure of Formula IVa:
or a pharmaceutically acceptable salt thereof;
or the compound has the structure of Formula V:
or a pharmaceutically acceptable salt thereof;
or the compound has the structure of Formula Va:
or a pharmaceutically acceptable salt thereof.
53 - 57 . (canceled)
58 . The compound of claim 1 , wherein L 1 is
wherein R N1 is hydrogen or
or L 1 is
wherein R N2 is hydrogen or
and wherein m is 1.
59 - 75 . (canceled)
76 . The compound of claim 1 , wherein L 1 is
wherein R N4 is hydrogen or optionally substituted C 1-6 alkyl; or
L 1 is
77 - 92 . (canceled)
93 . The compound of claim 1 , wherein R 6 is
94 - 116 . (canceled)
117 . The compound of claim 1 , wherein -L 1 -R 6 is
118 - 120 . (canceled)
121 . The compound of claim 1 , wherein L 1 and R 6 combine to form
122 - 133 . (canceled)
134 . A compound of the following structure:
#
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
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23
24
25
26
27
28
29
30
31
32
33
34
35
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38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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63
64
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71
72
73
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86
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90
91
92
93
94
95
[[92]] 96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
135 . (canceled)
136 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
137 . A method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
138 . The method of claim 137 , wherein the neurological disorder is FTLD-TDP, chronic traumatic encephalopathy, ALS, Alzheimer's disease, LATE, or frontotemporal lobar degeneration.
139 . (canceled)
140 . A method of inhibiting toxicity in a cell related to a protein, the method comprising contacting the cell with the compound of claim 1 or a pharmaceutically acceptable salt thereof.
141 . The method of claim 140 , wherein the toxicity is TDP-43-related toxicity, or C9orf72-related toxicity.
142 - 147 . (canceled)