PIKFYVE KINASE INHIBITORS
The present invention relates to compounds of formula (I) (shown below) useful as inhibitors of phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) as well as their use for treating diseases and disorders associated with PIKfyve.
1 . A compound of the formula (I)
or a pharmaceutically acceptable salt thereof, wherein
R 1 is hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl;
each occurrence of R 2 is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl;
R 3 is a nitrogen- or oxygen-containing moiety;
Ring A is (i) a 5 or 6-membered heteroaryl or 5-6 or 6-5 membered bicyclic heteroaryl, each having at least one nitrogen or oxygen ring atom, or (ii) phenyl;
L 1 is absent, C 1 -C 2 alkylene, —NR c —, —O—, —S—, —C(O)—, —NHC(O)—, or —C(O)NH—;
L 2 is —O—(CR a R b ) m —, —(CR a R b ) m —, —NR c —(CR a R b ) m —, or —S—(CR a R b ) m —;
X 1 is CH, N, or CR c ;
each occurrence of R a and R b are independently hydrogen, hydroxy, hydroxy(C 1-4 )alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl, halogen, nitro, —OR d , —SR d , —NR d R e , —C(O)R d , —C(S)R d , —OC(O)R d —SC(O)R d , OC(S)R d , SC(S)R d , —NR c C(O)R d , —NR c C(S)R d , —SO 2 R c , —S(O)R c , —NR c SO 2 R d , —OS(O) 2 R d , —OP(O)R d R e , or —P(O)R d R e ;
R c is a hydrogen or C 1-6 alkyl;
each occurrence of R d and R e are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl;
m is 1-4; and
p is 1 or 2.
2 . The compound of claim 1 , wherein R 1 is heterocyclyl or heteroaryl.
3 . The compound of claim 1 or 2 , wherein R 1 is be selected from (the squiggly lines indicate the point of attached to the rest of the molecule)
4 . The compound of claim 1 , wherein R 1 is hydroxy.
5 . The compound of any of the preceding claims, wherein each occurrence of R 2 is independently substituted or unsubstituted phenyl.
6 . The compound of claim 5 , wherein R 2 is phenyl, a halogen-substituted phenyl, an alkyl-substituted phenyl, a halogenated alkyl-substituted phenyl, or an alkoxy-substituted phenyl.
7 . The compound of claim 5 , wherein R 2 is selected from phenyl, 3-methoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, and 3-chlorophenyl.
8 . The compound of any of the preceding claims, wherein R 3 is a substituted or unsubstituted, saturated or unsaturated nitrogen- or oxygen-containing heterocyclyl.
9 . The compound of any of the preceding claims, wherein R 3 is selected from
10 . The compound of any of the preceding claims, wherein R 3 is selected from
11 . The compound of any of the preceding claims, wherein ring A is a 5-membered heteroaryl having at least one nitrogen ring atom.
12 . The compound of any of the preceding claims, wherein ring A is selected from
13 . The compound of any of the preceding claims, wherein ring A can be selected from
14 . The compound of any of the preceding claims, wherein L 1 is absent.
15 . The compound of any of the preceding claims, wherein L 1 is —NH—, —N(CH 3 )—, —O—, or —CH 2 —.
16 . The compound of any of the preceding claims, wherein L 2 is —O—(CR a R b ) m —.
17 . The compound of any of the preceding claims, wherein L 2 is —OCH 2 CH 2 —, —OCH 2 —, or —OCH 2 CH 2 CH(OH)CH 2 —.
18 . The compound of any of the preceding claims, wherein L 2 is —(CR a R b ) m —.
19 . The compound of any of the preceding claims, wherein -L 2 -R 1 is —OCH 2 CH 2 CH(OH)CH 2 OH.
20 . The compound of any of the preceding claims, wherein X 1 is CH.
21 . The compound of any of the preceding claims, wherein each occurrence of R a and R b are independently hydrogen, hydroxy, or hydroxy(C 1-4 )alkyl.
22 . The compound of any of the preceding claims, wherein each occurrence of R a and R b are independently hydrogen or hydroxy.
23 . The compound of any of the preceding claims, wherein m is 1.
24 . The compound of any of the preceding claims, wherein m is 2.
25 . The compound of any of the preceding claims, wherein p is 1.
26 . The compound of any of the preceding claims, wherein p is 2.
27 . The compound of any of the preceding claims, wherein the moiety
is selected from
28 . A compound of the formula (II)
or a pharmaceutically acceptable salt thereof, wherein
R 1 is hydroxy, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl;
R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl;
R 3 is a substituted or unsubstituted oxygen-containing heterocyclyl;
Ring A is a 5-membered heteroaryl having at least one nitrogen ring atom;
L 2 is —O—(CR a R b ) m —;
each occurrence of R a and R b are independently hydrogen, hydroxy, or hydroxy(C 1-4 )alkyl; and
m is 1-4.
29 . The compound of claim 28 , wherein R 1 is heterocyclyl or heteroaryl.
30 . The compound of claim 28 or 29 , wherein R 1 is selected from
31 . The compound of any one of claims 28 - 30 , wherein R 2 is substituted phenyl.
32 . The compound of claim 31 , wherein R 2 is 3-methoxyphenyl or 3-methylphenyl.
33 . The compound of any one of claims 28 - 32 , wherein R 3 is selected from
34 . The compound of claim 33 , wherein R 3 is
35 . The compound of claim 33 , wherein R 3 is
36 . The compound of any one of claims 28 - 35 , wherein ring A is a 5-membered heteroaryl having (i) two nitrogen ring atoms or (ii) one nitrogen ring atom and one sulfur ring atom.
37 . The compound of any one of claims 28 - 36 , wherein ring A is selected from
38 . The compound of any one of claims 28 - 37 , wherein L 2 is —OCH 2 —, —OCH 2 CH 2 —, —OCH 2 CH 2 CH(OH)CH 2 —, or —CH 2 CH 2 —.
39 . The compound of claim 38 , wherein L 2 is —OCH 2 —, —OCH 2 CH 2 —, or —OCH 2 CH 2 CH(OH)CH 2 —.
40 . A compound selected from
and pharmaceutically acceptable salts thereof.
41 . A method of inhibiting PIKfyve in a subject in need thereof comprising administering an effective amount of a compound of any one of claims 1 - 40 .
42 . A method for treating a disease or disorder associated with PIKfyve in a human subject in need thereof comprising administering an effective amount of a compound of any one of claims 1 - 40 .
43 . A method of treating a subject having a neurological disease comprising administering to the subject an effective amount of a compound of any one of claims 1 - 40 .
44 . The method of claim 43 , wherein the neurological disease is amyotrophic lateral sclerosis (ALS).
45 . The method of claim 43 , wherein the neurological disease is frontotemporal dementia (FTD).
46 . The method of claim 43 , wherein the neurological disease is Alzheimer's disease.
47 . The method of claim 43 , wherein the neurological disease is Parkinson's disease.
48 . The method of claim 43 , wherein the neurological disease is Huntington's disease.
49 . The method of claim 43 , wherein the neurological disease is Charcot-Marie-Tooth disease (CMT).
50 . A method of treating a viral infection in a subject in need thereof comprising administering an effective amount of a compound of any one of claims 1 - 40 .
51 . The method of claim 50 wherein the virus is Ebola virus.
52 . The method of claim 50 wherein the virus is middle east respiratory syndrome virus (MERS).
53 . The method of claim 50 wherein the virus is JC polyomavirus (JC).
54 . The method of claim 50 wherein the virus is BK polyomavirus (BK).
55 . The method of claim 50 wherein the virus is Herpes Simplex Virus (HSV).
56 . The method of claim 50 wherein the virus is Marburg virus (MarV).
57 . The method of claim 50 wherein the virus is Venezuelan equine encephalitis virus (VEEV).
58 . The method of claim 50 wherein the virus is Lymphocytic choriomeningitis virus (LCMV).