COMPOUNDS AND COMPOSITIONS THAT INHIBIT PIKFYVE
Pyrazolo[1,5-a]pyrimidines are disclosed. These compounds may be useful in the treatment of neurological disorder, including frontotemporal dementia, chronic traumatic encephalopathy, Alzheimer's disease, limbic-predominant age-related TDP-43 encephalopathy, or frontotemporal lobar degeneration. Further, the invention features a method of inhibiting toxicity in a cell related to a protein TDP-43 or C9orf72. The compounds of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing neurological disorders.
1 . A compound having the structure:
or pharmaceutically acceptable salt thereof,
wherein:
R 1 is optionally substituted C 2 -C 9 heteroaryl; and
each R IA is independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, or optionally substituted C 2 -C 9 heteroaryl; and the remaining R 1 B is optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, or optionally substituted C 2 -C 9 heteroaryl.
2 . The compound of claim 1 , wherein one R 1A is hydrogen, and the remaining R 1A is optionally substituted C 6 -C 10 aryl.
3 . The compound of claim 1 or 2 , wherein R 1 is pyrid-4-yl.
4 . A compound having the structure:
or pharmaceutically acceptable salt thereof,
wherein:
R 1 is optionally substituted pyridin-4-yl;
R 2 is optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted pyridin-2-yl, optionally substituted pyridin-3-yl, optionally substituted pyrimidn-4-yl, optionally substituted thiadiazolyl, optionally substituted oxadiazolyl, optionally substituted dialkylamino, optionally substituted 6-oxo-1,5-dihydropyridazin-1-yl, optionally substituted pyrazinyl, fluoro, cyano, optionally substituted pyrazol-3-yl, optionally substituted pyrazol-5-yl, optionally substituted oxazole, optionally substituted N-tetrahydropyranopyrazolyl, optionally substituted N-tetrahydroindazolyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl C 1 -C 6 heteroalkyl, CONH 2 , —CONH—NHR 1A ,
R 1A is H or optionally substituted C 2 -C 10 acyl;
R 2A is optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 5 heteroaryl, or optionally substituted C 3 -C 6 cycloalkyl; and
R 2B is pyridizin-4-yl, phenyl substituted with fluoro or methoxy, piperidinyl optionally substituted with C 1 -C 6 alkyl, optionally substituted pyrimidin-5-yl, optionally substituted pyridin-2-yl, optionally substituted pyridine-3-yl, optionally substituted C 3 carbocyclyl, azetidin-3-yl, optionally substituted C 1 -C 6 hydroxyalkyl, or C 3 heteroalkyl.
5 . (canceled)
6 . The compound of claim 4 , wherein R 2 is optionally substituted azetidine-3-yl, optionally substituted azetidine-1-yl, optionally substituted piperazin-1-yl optionally substituted piperidin-1-yl optionally substituted morpholin-1-yl, optionally substituted pyrrolidine-2-yl, optionally substituted pyridin-2-yl, optionally substituted pyridin-3-yl, optionally substituted pyrimidin-4-yl, optionally substituted thiadiazolyl, optionally substituted oxadiazolyl, optionally substituted 6-oxo-1,5-dihydropyridazin-1-yl, optionally substituted dialkylamino, optionally substituted pyrazinyl, optionally substituted pyrazol-3-yl, optionally substituted pyrazol-5-yl, optionally substituted oxazolyl, optionally substituted N-tetrahydropyranopyrazolyl, optionally substituted N-tetrahydroindazolyl, or optionally substituted imidazolyl.
7 - 31 . (canceled)
32 . The compound of claim 4 , wherein R 2 is substituted with oxo, optionally substituted phenyl, optionally substituted benzyl, optionally substituted phenoxy, 4-fluorophenoxy, 3-fluorophenoxy, optionally substituted amino, ═NH, optionally substituted C 1 -C 6 alkyl, methyl, halo, bromo, optionally substituted C 1 -C 6 heteroalkyl, methoxy, optionally substituted pyridin-3-yl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted piperidin-3-yl, optionally substituted 1,2,3,6-tetrahydropyridin-3-yl, hydroxyl, or nitro.
33 - 49 . (canceled)
50 . The compound of claim 4 , wherein R 2 is
51 - 74 . (canceled)
75 . A compound, or pharmaceutically acceptable salt thereof, wherein the compound has the structure:
wherein:
R 1 is optionally substituted C 1-6 alkenyl, optionally substituted C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl substituted with dialkyl amino, hydrogen, or optionally substituted C 2 -C 9 heterocyclyl; and
R 2 is optionally substituted pyrazol-1-yl, optionally substituted pyrazol-3-yl, optionally substituted N-tetrahydropyranopyrazolyl, C 6 -C 10 aryl optionally substituted with optionally substituted C 2 -C 9 heteroaryl, or optionally substituted pyrimidin-4-yl.
76 - 78 . (canceled)
79 . The compound of claim 75 , wherein R 1 is
80 - 84 . (canceled)
85 . The compound of claim 75 , wherein R 2 is an optionally substituted pyrazol-3-yl, optionally substituted pyrazol-1-yl, optionally substituted N-tetrahydropyranopyrazolyl, or optionally substituted pyrimidin-4-yl.
86 - 88 . (canceled)
89 . The compound of claim 75 , wherein R 2 is substituted with optionally substituted phenyl, 3-methoxy-phenyl, 2-fluorophenyl, or pyrimidin-3-yl.
90 - 92 . (canceled)
93 . The compound of claim 75 , wherein R 2
94 - 97 . (canceled)
98 . A compound having the structure of any one of compounds 1-152 in Table 1, or a pharmaceutically acceptable salt thereof.
99 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
100 . 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.
101 . The method of claim 100 , wherein the neurological disorder is FTLD-TDP, chronic traumatic encephalopathy, ALS, Alzheimer's disease, LATE, or frontotemporal lobar degeneration.
102 . (canceled)
103 . 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.
104 . The method of claim 103 , wherein the toxicity is TDP-43-related toxicity, or C9orf72-related toxicity.
105 . (canceled)
106 . A method of inhibiting PIKfyve in a cell expressing PIKfyve protein, the method comprising contacting the cell with the compound of claim 1 or a pharmaceutically acceptable salt thereof.
107 - 109 . (canceled)
110 . A method of treating a TDP-43 associate disorder in a subject, the method comprising administering to the subject in need an effective amount of the compound of claim 1 .