BICYCLIC HETEROARENES 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, including frontotemporal dementia, chronic traumatic encephalopathy, Alzheimer's disease, limbic-predominant age-related TDP-43 encephalopathy (LATE), or frontotemporal lobar degeneration.
1 . A compound of formula (I):
or a pharmaceutically acceptable salt thereof,
wherein
is a single bond, X 1 is (C(R A ) 2 ) m or —OC(R A ) 2 —R X , and X 2 is C(R A ) 2 or CO; or is a double bond, and each of X 1 and X 2 is independently CR A or N, wherein R X is a bond to X 2 ;
R 1 is —(L) n —R B ; halo, cyano, hydrogen, optionally substituted C 1-6 alkoxy, optionally substituted C 1-9 heterocyclyl comprising at least one endocyclic oxygen, optionally substituted C 1 -C 6 alkyl, optionally substituted piperazin-1-yl, optionally substituted pyrrolidine-3-yl, pyrimidinyl optionally substituted with cyclopropyl or optionally substituted C 6 -C 10 aryl, optionally substituted pyridazinyl, optionally substituted oxazolyl, pyrid-2-on-1-yl, optionally substituted isoindolinyl, unsubstituted pyridin-4-yl, unsubstituted pyridin-2-yl, optionally substituted furan-3-yl, unsubstituted pyridin-3-yl, or optionally substituted pyrazol-1-yl;
R 2 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted piperidin-4-yl, optionally substituted tetrahydropyran-4-yl, optionally substituted pyrimidin-5-yl, optionally substituted pyrimidin-4-yl, optionally substituted pyridine-3-yl, optionally substituted pyridazin-4-yl, optionally substituted pyrazol-1-yl, optionally substituted pyrazol-4-yl, optionally substituted pyrazol-3-yl, optionally substituted pyridine-2-yl, optionally substituted triazolyl, optionally substituted benzodioxol-2-yl, optionally substituted benzodioxan-2-yl, optionally substituted C 6 -C 10 aryl C 1 -C 10 alkyl, or optionally substituted acyl;
R 3 is a group of the following structure:
each R A is independently H, optionally substituted C 1-6 alkyl, or optionally substituted C 6 -C 10 aryl, or two R A , together with the atom to which they are attached, combine to form oxo; wherein when two R A , together with the atom to which they are attached, combine to form oxo, then is a single bond;
R B is optionally substituted C 6-10 aryl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 3-8 cycloalkyl, —N═CH—R D , or optionally substituted C 1 -C 9 heterocyclyl, optionally substituted C 2 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 2 -C 9 heterocyclyl C 1-6 alkyl;
R C is H or optionally substituted C 1 -C 6 alkyl;
R D is optionally substituted C 6 -C 10 aryl; or
each L is independently optionally substituted C 1-6 alkylene, optionally substituted C 1 -C 6 heteroalkylene, optionally substituted C 3 -C 8 cycloalkylene, optionally substituted C 2 -C 6 alkynylene, O, or NR C —;
n is 1, 2, or 3; and
m is 0, 1, or 2.
2 . The compound of claim 1 , wherein is a single bond.
3 . The compound of claim 1 or 2 , wherein X 1 is (C(R A ) 2 ) m .
4 . The compound of claim 3 , wherein m is 1.
5 . The compound of any one of claims 1 to 4 , wherein X 2 is C(R A ) 2 .
6 . The compound of any one of claims 1 to 5 , wherein each R A is hydrogen.
7 . The compound of claim 1 , wherein the compound is of formula (1a):
or a pharmaceutically acceptable salt thereof.
8 . The compound of claim 1 , wherein the compound is of formula 1a′):
or a pharmaceutically acceptable salt thereof.
9 . The compound of claim 1 , wherein the compound is of formula (1b):
or a pharmaceutically acceptable salt thereof.
10 . The compound of claim 1 , wherein the compound is of formula (1c):
or a pharmaceutically acceptable salt thereof.
11 . The compound of claim 1 , wherein the compound is of formula (1d):
or a pharmaceutically acceptable salt thereof.
12 . The compound of claim 1 , wherein the compound is of formula (1e):
or a pharmaceutically acceptable salt thereof.
13 . The compound of any one of claims 1 to 12 , wherein R 1 is —O—(L) (n-1) —R B .
14 . The compound of any one of claims 1 to 13 , wherein n is 2.
15 . The compound of any one of claims 1 to 13 , wherein n is 1.
16 . The compound of any one of claims 1 to 15 , wherein at least one L is optionally substituted C 1-6 alkylene.
17 . The compound of claim 16 , wherein L is methylene.
18 . The compound of claim 16 , wherein L is ethylene.
19 . The compound of any one of claims 1 to 18 , wherein R B is optionally substituted C 1-9 heterocyclyl.
20 . The compound of any one of claims 1 to 18 , wherein R B is optionally substituted C 1-9 heteroaryl.
21 . The compound of any one of claims 1 to 18 , wherein R B is optionally substituted C 1-6 alkyl.
22 . The compound of any one of claims 1 to 21 , wherein R A is optionally substituted C 1-6 alkyl.
23 . The compound of claim 22 , wherein R A is methyl.
24 . The compound of any one of claims 1 to 21 , wherein R 1 is optionally substituted C 1 -C 6 alkyl.
25 . The compound of claim 24 , wherein R 1 is optionally substituted C 1-6 alkyl.
26 . The compounds of claims 24 or 25 , wherein R 1 is substituted with hydroxyl.
27 . The compound of any one of claims 1 to 21 , wherein R 1 is optionally substituted piperazin-1-yl.
28 . The compound of claim 27 , wherein R 1 is substituted with methyl.
29 . The compound of any one of claims 1 to 28 , wherein R 2 is optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl.
30 . The compound of claim 29 , wherein R 2 is optionally substituted C 6 -C 10 aryl C 1 -C 2 alkyl.
31 . The compound of claim 29 or 30 , wherein R 2 is substituted with oxo.
32 . The compound of any one of claims 1 to 28 , wherein R 2 is optionally substituted C 1 -C 6 alkyl.
33 . The compound of claim 32 , wherein R 2 is optionally substituted C 4 alkyl.
34 . The compound of claim 32 or 33 , wherein R 2 is substituted with hydroxyl.
35 . The compound of any one of claims 1 to 28 , wherein R 2 is an optionally substituted C 6 -C 10 aryl.
36 . The compound of claim 35 , wherein R 2 is optionally substituted phenyl.
37 . The compound of claim 35 or 36 , wherein R 2 is substituted with fluoro, cyano, or methoxy.
38 . The compound of any one of claims 1 to 12 or 29 to 37 , wherein R 1 is:
methyl, or methoxy.
39 . The compound of claim 38 , wherein R 1 is
or methoxy.
40 . The compound of any one of claims 1 to 28 or 38 , wherein R 2 is:
41 . The compound of claim 40 , wherein R 2 is:
42 . The compound of any one of claims 1 to 41 , wherein R 3 is:
43 . The compound of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof,
wherein R 2 is optionally substituted pyrimidin-3-yl or optionally substituted pyrimidin-4-yl; and
R 4 is hydrogen or optionally substituted C 6 -C 10 aryl.
44 . The compound of claim 43 , wherein R 4 is hydrogen.
45 . The compound of claim 44 , wherein R 4 is optionally substituted C 6 -C 10 aryl.
46 . The compound of claim 45 , wherein R 4 is phenyl.
47 . The compound of claim 45 or 46 , wherein R 4 is substituted with fluoro.
48 . The compound of claim 45 or 46 , wherein R 4 is substituted with methoxy.
49 . The compound of any one of claims 43 to 48 , wherein R 2 is optionally substituted pyridin-3-yl.
50 . The compound of any one of claims 43 to 48 , wherein R 2 is pyridin-4-yl.
51 . The compound of claim 1 or 29 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof,
wherein R 5 is hydrogen or optionally substituted C 6 -C 10 aryl; and
R 2 is optionally substituted triazolyl, optionally substituted pyrazol-4-yl, optionally substituted pyrazol-3-yl, optionally substituted pyrimidin-4-yl, or optionally substituted C 6 -C 10 aryl C 1-6 alkyl.
52 . The compound of claim 51 , wherein R 5 is hydrogen.
53 . The compound of claim 51 , wherein R 5 is phenyl.
54 . The compound of any one of claims 51 to 53 , wherein R 2 is substituted with phenyl.
55 . The compound of any one of claims 51 to 54 , wherein R 2 is
56 . The compound of claim 51 , wherein R 2 is
57 . The compound of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof,
wherein R 2 is optionally substituted pyridin-3-yl.
58 . The compound of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof,
wherein R 2 is optionally substituted C 6 -C 10 aryl; or optionally substituted pyridzin-4-yl.
59 . The compound of claim 58 , wherein R 2 is 3-fluoro-phenyl.
60 . The compound of claim 58 , wherein R 2 is pyridazin-4-yl.
61 . The compound of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof,
wherein R 2 is optionally substituted pyridin-3-yl.
62 . The compound of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof,
wherein L is optionally substituted C 3 -C 8 cycloalkylene or C 2 -C 6 alkynylene; and
R B is optionally substituted C 6 -C 10 aryl.
63 . The compound of claim 62 , wherein L is
64 . The compound of claim 63 , wherein L is
65 . The compound of any one of claims 62 to 64 , wherein R B is 3-methoxy-phenyl.
66 . The compound of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof,
wherein L—R B is —NHN═CHR D ;
R 2 is optionally substituted pyridine-3-yl; and
R D is optionally substituted C 6 -C 10 aryl.
67 . The compound of claim 66 , wherein R D is 3-methyl-phenyl.
68 . The compound of claim 66 or 67 , wherein R 2 is pyridin-3-yl.
69 . The compound of any one of claims 66 to 68 , wherein the compound has the structure
or a pharmaceutically acceptable salt thereof.
70 . The compound of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof,
wherein R 2 is optionally substituted pyridine-3-yl; and
R 6 is optionally substituted C 6 -C 10 aryl.
71 . The compound of claim 70 , wherein Re is 3-methyl-phenyl or phenyl.
72 . A compound, or pharmaceutically acceptable salt thereof, having the structure:
or a pharmaceutically acceptable salt thereof,
wherein X 2 is N or CH;
R A is optionally substituted C 2 -C 9 heteroaryl; or optionally substituted C 6 -C 10 aryl;
R 1 is optionally substituted C 2 -C 9 heteroaryl or —O—R 7 ;
R 2 is hydrogen or optionally substituted C 1 -C 6 alkyl; and
R 7 is optionally substituted C 2 -C 9 heteroaryl C 1-6 alkyl.
73 . The compound of claim 72 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
74 . The compound of claim 72 or 73 , wherein R 2 is 2-hydroxy-ethyl.
75 . The compound of claim 72 or 73 , wherein R 2 is hydrogen.
76 . The compound of claim 72 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
77 . The compound of claim 72 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
78 . The compound of any one of claims 72 to 77 , wherein R A is optionally substituted phenyl.
79 . The compound of any one of claims 72 to 77 , wherein R A is optionally substituted pyridine-2-yl, optionally substituted pyrimidin-4-yl, optionally substituted pyrimidin-2-yl, optionally substituted pyrazol-4-yl, optionally substituted pyridine-3-yl, optionally substituted pyrazol-4-yl, optionally substituted 7-aza-5,6,7,8-tetrahydroindolizin-1-yl, optionally substituted pyridazin-3-yl, or optionally substituted pyridine-4-yl.
80 . The compound of any one of claims 72 to 77 , wherein R A is optionally substituted C 2 -C 9 heteroaryl or C 6 -C 10 aryl substituted with optionally substituted C 2 -C 9 heteroaryl.
81 . The compound of any one of claims 72 to 80 , wherein R A is substituted with cyclopropyl, methyl, methoxy or
82 . The compound of claim 80 , wherein R A is phenyl substituted with pyrazol-1-yl.
83 . The compound of any one of claims 72 to 77 , wherein R A is
84 . The compound of any one of claims 72 to 83 , wherein R 1 is pyridine-3-yl, pyridine-4-yl, or
85 . The compound of claim 76 , wherein the compound has the structure
or a pharmaceutically acceptable salt thereof.
86 . The compound of claim 77 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
87 . A compound of the following structure:
#
Compound
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
53
54
55
56
57
58
59
60
61
62
63
64
65
66
76
77
78
79
80
81
86
87
88
89
90
91
92
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
126
127
128
129
130
132
135
151
or a pharmaceutically acceptable salt thereof.
88 . A compound of the following structure:
#
Compound
51
52
67
68
69
70
71
72
73
74
75
82
83
84
85
93
94
95
96
97
122
123
124
125
131
133
134
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
89 . A pharmaceutical composition comprising the compound of any one of claims 1 to 88 , or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable excipient.
90 . 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 any one of claims 1 to 88 , or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 89 .
91 . The method of claim 90 , wherein the neurological disorder is FTLD-TDP, chronic traumatic encephalopathy, ALS, Alzheimer's disease, LATE, or frontotemporal lobar degeneration.
92 . The method of claim 91 , wherein the neurological disorder is ALS.
93 . A method of inhibiting toxicity in a cell related to a protein, the method comprising contacting the cell with the compound of any one of claims 1 to 88 or a pharmaceutically acceptable salt thereof.
94 . The method of claim 93 , wherein the toxicity is TDP-43-related toxicity.
95 . The method of claim 93 , wherein the toxicity is C 9 orf72-related toxicity.
96 . A method of inhibiting PIKfyve in a cell expressing PIKfyve protein, the method comprising contacting the cell with the compound of any one of claims 1 to 88 or a pharmaceutically acceptable salt thereof.
97 . The method of any one of claims 93 to 96 , wherein the cell is a mammalian neural cell.
98 . The method of any one of claims 93 to 97 , wherein the cell is in a subject.
99 . The method of claim 98 , wherein the subject suffers from a neurological disorder.
100 . A method of treating a TDP-43-associated disorder in a subject, the method comprising administering to the subject in need thereof an effective amount of the compound of formula (14):
or a pharmaceutically acceptable salt thereof,
wherein
is a single bond, X 1 is (C(R A ) 2 ) m or —OC(R A ) 2 —R X , and X 2 is C(R A ) 2 or CO; or is a double bond, and each of X 1 and X 2 is independently CR A or N, wherein R X is a bond to X 2 ;
R 1 is —(L) n —R B , hydrogen, halogen, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heterocyclyl, or optionally substituted C 1-9 heteroaryl;
R 2 is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heterocyclyl, optionally substituted C 1-9 heteroaryl, or optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl;
R 3 is a group of the following structure:
each R A is independently H, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, or two geminal R A groups, together with the atom to which they are attached, combine to form oxo;
R B is optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, optionally substituted C 3-8 cycloalkyl, —N═CH—R D , or optionally substituted C 1-9 heterocyclyl, optionally substituted C 2 -C 9 heteroaryl C 1-6 alkyl, optionally substituted C 2 -C 9 heterocyclyl C 1-6 alkyl;
R C is H or optionally substituted C 1 -C 6 alkyl;
R D is optionally substituted C 6 -C 10 aryl;
each L is independently optionally substituted alkylene, optionally substituted C 1 -C 6 heteroalkylene, optionally substituted C 3 -C 8 cycloalkylene, optionally substituted C 2 -C 6 alkynylene, O, or NR C ; and
n is 1, 2, or 3; and
m is 0, 1, or 2.