PIKfyve Kinase Inhibitors

Abstract

The present invention relates to compounds of formula (I) useful as inhibitors of phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), and their use for treating diseases and disorders associated with PIKfyve. Another embodiment is a method of inhibiting PIKfyve in a subject (such as a human subject) in need thereof, comprising administering to the subject an effective amount of a compound of the invention. Yet another embodiment is a method for treating a disease or disorder associated with PIKfyve in a human subject in need thereof, comprising administering to the subject an effective amount of a compound of the invention.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 363,962, filed May 2, 2022. The aforementioned application is incorporated herein by reference in its entirety.

[0002] The present invention relates to compounds useful as inhibitors of phosphatidylinositol-3-phosphate 5-kinase (PIKfyve). [Background technology]

[0003] Apilimod is recognized as a potent transcriptional inhibitor of IL-12 and IL-23. See Wada et al., Blood 109(2007):1156-1164. IL-12 and IL-23 are proinflammatory cytokines normally produced by immune cells such as B cells and macrophages in response to antigenic stimulation. Autoimmune and other disorders characterized by chronic inflammation are characterized, in part, by inappropriate production of these cytokines. In immune cells, selective inhibition of IL-12 / IL-23 transcription by apilimod was recently shown to be mediated by direct binding of apilimod to phosphatidylinositol-3-phosphate 5-kinase (PIKfyve). See Cai et al., Chemistry and Biol.20(2013):912-921. PIKfyve plays a role in Toll-like receptor signaling, which is important in innate immunity. Based on its activity as an immunomodulator and specific inhibitor of IL-12 / IL-23, apilimod has been proposed to be useful for the treatment of autoimmune and inflammatory diseases and disorders. See U.S. Patent Nos. 6,858,606 and 6,660,733 (which describe a family of pyrimidine compounds, including apilimod, that are allegedly useful for treating diseases and disorders characterized by IL-12 or IL-23 overproduction, such as rheumatoid arthritis, sepsis, Crohn's disease, multiple sclerosis, psoriasis, or insulin-dependent diabetes mellitus). Similarly, based on its activity of inhibiting c-Rel or IL-12 / 23, apilimod has been suggested to be useful for the treatment of certain cancers, especially in cancers in which these cytokines are believed to play a role in promoting abnormal cell proliferation. See WO2006 / 128129 and Baird et al., Frontiers in Oncology 3:1 (respectively, 2013). International Publication Nos. WO2016 / 210372 and WO2019 / 046316, as well as U.S. Patent Publication No. 2018 / 0161335 (incorporated herein by reference), disclose methods of treating neurological diseases, such as amyotrophic lateral sclerosis, using PIKfyve kinase inhibitors. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 6,858,606 [Patent Document 2] U.S. Patent No. 6,660,733 [Patent Document 3] International Publication No. 2006 / 128129 [Patent Document 4] International Publication No. 2016 / 210372 [Patent Document 5] International Publication No. 2019 / 046316 [Patent Document 6] US Patent Application Publication No. 2018 / 0161335 [Non-patent literature]

[0005] [Non-Patent Document 1] Wada et al.,Blood 109(2007):1156-1164 [Non-Patent Document 2] Cai et al., Chemistry and Biol.20(2013):912-921 [Non-Patent Document 3] Baird et al.,Frontiers in Oncology 3:1(2013) Summary of the Invention [Means for solving the problem]

[0006] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, 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; R 2 each occurrence of 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 teeth, [ka] (In the formula, each R gare independently H, substituted or unsubstituted alkyl (e.g., methyl or ethyl), OH, substituted or unsubstituted alkoxy (e.g., methoxy), halogen, CN, and -NHR m (In the formula, R m is a 5- or 6-membered oxygen-containing moiety, such as a moiety selected from H or substituted or unsubstituted alkyl (e.g., methyl or ethyl); Ring A is (i) a 5- or 6-membered heteroaryl, a 5-6, 6-5, or 6-6 membered bicyclic heteroaryl, or a heterocyclyl, each having at least one nitrogen or oxygen ring atom, or (ii) phenyl; L 1 is absent, C1-C2 alkylene, -NR c -, -O-, -S-, -C(O)-, -NHC(O)-, -C(O)NH-, -NR c C(O)- or -NR c C(O)(CR a R b ) m - and L 2 , Absent, -O-, -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 - and (i)X 1 is CH or CR c and X 2 is N, or (ii) X 1 is N and X 2 is N, CH, or CR c and R a and R beach occurrence is independently selected from hydrogen, hydroxy, hydroxy(C1-4)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 , O.C.(S)R d , SC(S)R d , -NR c C(O)R d , -NR c C(S)R d , -SO2R c , -S(O)R c , -NR c SO2R d , -OS(O)2R d , -OP(O)R d R e , or -P(O)R d R e and R c Each occurrence of is independently hydrogen or C 1-6 alkyl (e.g., C1-C4 alkyl); R d and R e each occurrence is 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; each occurrence of m is independently 1 to 4; p is 1 or 2). In one preferred embodiment, R 3 teeth, [ka] (In the formula, each R g are independently H, substituted or unsubstituted alkyl (e.g., methyl or ethyl), OH, substituted or unsubstituted alkoxy (e.g., methoxy or ethoxy), halogen, CN, and -NHR m (In the formula, R m is selected from H, or substituted or unsubstituted alkyl (e.g., methyl or ethyl). In one preferred embodiment, R 3 but [ka] If R g is not hydrogen.

[0007] In one embodiment, X 1 is CH and X 2 is N and L 1 is absent, L 2 is absent.

[0008] In one embodiment, the compound of formula (I) is (i)L 1 -NR c C(O)- or -NR c C(O)(CR a R b ) m -or- (ii) L 2 is -O-, or (iii)X 2 is CH or CR c and

[0009] These compounds are useful as PIKfyve kinase inhibitors.

[0010] In one embodiment, R 1 is heterocyclyl or heteroaryl. For example, R 1may be selected from the following (the wavy line indicates the point of attachment to the remainder of the molecule): [ka]

[0011] In another embodiment, R 1 is hydroxy.

[0012] In yet another embodiment, L 2 If absent, R 1 teeth, [ka] is selected from.

[0013] In yet another embodiment, L 2 If exists (not absent), then R 1 teeth, [ka] is selected from.

[0014] In one embodiment of any of the compounds described herein, R 2 Each occurrence is independently a substituted or unsubstituted heteroaryl, such as substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted 2,2-dimethylindolyl, substituted or unsubstituted indolin-2-one, substituted or unsubstituted 1,3-dihydro-2H-benzo[d]imidazol-2-one, substituted or unsubstituted benzo[b]thiphenyl, substituted or unsubstituted pyrrolo[3,2-b]pyridinyl, substituted or unsubstituted pyrrolo[2,3-b]pyridinyl, or substituted or unsubstituted thieno[2,3-b]pyridinyl.

[0015] In one embodiment of any of the compounds described herein, R 2 Each occurrence of is independently [ka] (In the formula, R h each occurrence is independently selected from H, halogen, substituted or unsubstituted alkyl (e.g., methyl or ethyl), substituted or unsubstituted alkoxy (e.g., methoxy or ethoxy), -CN, -NH, -NHR m , or -NR m 2 or 2 R h are bonded to form a saturated or unsaturated 5- to 7-membered ring, Each R m are independently m is H or substituted or unsubstituted alkyl (e.g., methyl or ethyl); and t is 0, 1, or 2.

[0016] In one embodiment, R 2 Each occurrence of is independently a substituted or unsubstituted aryl, e.g., a substituted or unsubstituted phenyl. For example, R 2 is phenyl, halogen-substituted phenyl, alkyl-substituted phenyl (e.g., C 1-4 In one embodiment, R can be an alkyl substituted phenyl, a halogenated alkyl substituted phenyl, or an alkoxy substituted phenyl. 2 is selected from phenyl, 3-methoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, and 3-chlorophenyl. 2 is selected from phenyl, 3-methoxyphenyl, and 3-methylphenyl.

[0017] In another embodiment, R 2 Each occurrence of is independently a substituted or unsubstituted alkyl (C 1-4 For example, R 2 can be unsubstituted isopropyl.

[0018] In one embodiment, R 3 is a substituted or unsubstituted, saturated or unsaturated nitrogen- or oxygen-containing heterocyclyl. For example, R 3can be a substituted or unsubstituted, saturated or unsaturated 5-10 membered (such as 5-8 membered) monocyclic or bicyclic heterocyclyl having at least one nitrogen or oxygen ring atom. 3 is a substituted or unsubstituted 5-10 membered (such as 5-8 membered) monocyclic or bicyclic heterocyclyl having at least one nitrogen atom and optionally an oxygen ring atom, where the nitrogen ring atom is directly attached to the remainder of the molecule. 3 is a substituted or unsubstituted (unsaturated) 5-membered monocyclic heterocyclyl having an oxygen or a nitrogen ring atom.

[0019] In another embodiment, R 3 is a substituted or unsubstituted, saturated or unsaturated 6-membered monocyclic heterocyclyl having an oxygen ring atom and optionally a nitrogen ring atom. 3 is a saturated 8-membered bicyclic heterocyclyl having a nitrogen ring atom and an oxygen ring atom.

[0020] In one embodiment of any of the compounds described herein, R 3 teeth, [ka] (In the formula, each R g are independently H, substituted or unsubstituted alkyl (e.g., methyl or ethyl), OH, substituted or unsubstituted alkoxy (e.g., methoxy), halogen, CN, and -NHR m (In the formula, R m is selected from H, or substituted or unsubstituted alkyl (e.g., methyl or ethyl), with the proviso that R 3 is selected from the group consisting of aryl, aryl, and aryl, provided that it is not unsubstituted morpholinyl.

[0021] In one embodiment of any of the compounds described herein, ring A is a 5-membered heteroaryl having at least one nitrogen ring atom. In one embodiment of any of the compounds described herein, ring A contains two heteroatoms as ring atoms (such as two nitrogen ring atoms, or one nitrogen ring atom with one sulfur ring atom).

[0022] In one embodiment of any of the compounds described herein (wherein p is 1), Ring A is [ka] (In the formula, Each R k are independently hydrogen, 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; Each wavy line ( [ka] ) are independently the variables L of the ring A. 1 to or R 2 to Ring A (preferably the wavy line to the right of the Ring A group represents the attachment point of L 1 (preferably, L 1 is absent), the wavy line on the left is R 2 (appended to the

[0023] In one embodiment, the wavy line to the right of the ring A group is L 1 (preferably, L 1 is absent), the wavy line on the left is R 2 In another embodiment, L 1 is absent.

[0024] In another embodiment of any of the compounds described herein, ring A is [ka] is selected from.

[0025] For example, ring A is selected from the following: [ka]

[0026] In one embodiment of any of the compounds described herein, R in any of the rings A above is 2 The group is selected from substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl. For example, R 2 can be phenyl, alkyl- or alkoxy-substituted phenyl. In any of the embodiments of the compounds described herein, R 2 is selected from phenyl, 3-methoxyphenyl, and 3-methylphenyl.

[0027] In one embodiment of any of the compounds described herein, Ring A is a heterocyclyl having at least one oxygen ring atom. In one embodiment of any of the compounds described herein, the heterocyclyl is a lactone.

[0028] In one embodiment of any of the compounds described herein, ring A is a heterocyclyl having at least one nitrogen ring atom.In one embodiment of any of the compounds described herein, the heterocyclyl is a lactam.In certain embodiments, the lactam is a 5-membered lactam.

[0029] In one embodiment of any of the compounds described herein, L 1 is absent.

[0030] In another embodiment of any of the compounds described herein, L 1 is -NH-, -N(CH3)-, -O-, or -CH2-. In one embodiment of any of the compounds described herein, L 1In another embodiment of any of the compounds described herein, L 1 is -C(O)NH- (the carbonyl is attached to the remainder of the molecule and the nitrogen is attached to ring A). In yet another embodiment of any of the compounds described herein, L 1 is -NHC(O)- (the nitrogen atom is attached to the rest of the molecule and the carbonyl is attached to ring A).

[0031] In one embodiment of any of the compounds described herein, L 2 is -O-(CR a R b ) m In one embodiment of any of the compounds described herein, L 2 In another embodiment of any of the compounds described herein, L 2 is -OCH2CH2CH(OH)CH2-.

[0032] In another embodiment of any of the compounds described herein, L 2 is -(CR a R b ) m In one embodiment of any of the compounds described herein, L 2 is -CH2CH2-.

[0033] In yet another embodiment of any of the compounds described herein, L 2 -NR c -(CR a R b ) m -, for example, -NH-(CR a R b ) m - (for example, -NH-, -NHCH2-, and -NHCH2CH2-).

[0034] In one embodiment of any of the compounds described herein, -L 2 -R 1is -OCH2CH2CH(OH)CH2OH.

[0035] In one embodiment of any of the compounds described herein, L 2 is -O-.

[0036] In one embodiment of any of the compounds described herein, X 1 is CH. In another embodiment, X 1 is N.

[0037] In one embodiment of any of the compounds described herein, R a and R b Each occurrence of is independently hydrogen, hydroxy, or hydroxy(C1-4)alkyl. In another embodiment, R a and R b Each occurrence of is independently hydrogen or hydroxy.

[0038] In one embodiment of any of the compounds described herein, m is 1. In another embodiment of any of the compounds described herein, m is 2. In an embodiment of any of the compounds described herein, R 1 When R is cyclic, m is 1 or 2. In another embodiment of any of the compounds described herein, R 1 When is acyclic, m is 3 or 4.

[0039] In embodiments of any of the compounds described herein, p is 1.

[0040] In another embodiment of any of the compounds described herein, p is 2.

[0041] In one embodiment of any of the compounds described herein, the moiety [ka] teeth, [ka] (In the formula, R h each occurrence is independently selected from H, halogen, substituted or unsubstituted alkyl (e.g., methyl or ethyl), substituted or unsubstituted alkoxy (e.g., methoxy or ethoxy), -CN, -NH, -NHR m , or -NR m 2 or 2 R h are bonded to form a saturated or unsaturated 5- to 7-membered ring, Each R m are independently m is H or substituted or unsubstituted alkyl (e.g., methyl or ethyl); and t is 0, 1, or 2.

[0042] Variable R h and t is as defined herein.

[0043] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, R 1 is selected from the following: [ka] R 2 Each occurrence of is independently [ka] is selected from R h each occurrence is independently selected from H, halogen, substituted or unsubstituted alkyl (e.g., methyl or ethyl), substituted or unsubstituted alkoxy (e.g., methoxy or ethoxy), -CN, -NH, -NHR m , or -NR m 2 or 2 R hare bonded to form a saturated or unsaturated 5- to 7-membered ring, Each R m are independently H or substituted or unsubstituted alkyl (e.g., methyl or ethyl); t is 0, 1, or 2; R 3 teeth, [ka] is selected from Each R g are independently H, substituted or unsubstituted alkyl (e.g., methyl or ethyl), OH, substituted or unsubstituted alkoxy (e.g., methoxy), halogen, -CN, and -NHR m (In the formula, R m is selected from H, or substituted or unsubstituted alkyl (e.g., methyl or ethyl); Ring A is [ka] is selected from Each R k 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; Each wavy line ( [ka] ) are independently the variables L of the ring A. 1 to or R 2 to Ring A (preferably the wavy line to the right of the Ring A group represents the attachment point of L 1 (preferably, L 1 is absent), the wavy line on the left is R 2 (added to L 1 is absent, C1-C2 alkylene, -NR c-, -O-, -S-, -C(O)-, -NHC(O)-, -C(O)NH-, -NR c C(O)- or -NR c C(O)(CR a R b ) m - and L 2 -O-, -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 - and (i)X 1 is CH or CR c and X 2 is N, or (ii) X 1 is N and X 2 is N, CH, or CR c and R a and R b each occurrence is independently selected from hydrogen, hydroxy, hydroxy(C1-4)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 , O.C.(S)R d , SC(S)R d , -NR c C(O)R d , -NR c C(S)R d, -SO2R c , -S(O)R c , -NR c SO2R d , -OS(O)2R d , -OP(O)R d R e , or -P(O)R d R e and R c Each occurrence of is independently hydrogen or C 1-6 alkyl (e.g., C1-C4 alkyl); R d and R e each occurrence is 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; each occurrence of m is independently 1 to 4; p is 1 or 2).

[0044] Another embodiment is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, R 1 , R 2 , R 3 , L 2 and each of ring A is independently selected from any of the embodiments described herein.

[0045] For example, in one embodiment, R 3 teeth, [ka] (In the formula, each R gare independently H, substituted or unsubstituted alkyl (e.g., methyl or ethyl), OH, substituted or unsubstituted alkoxy (e.g., methoxy), halogen, CN, and -NHR m (In the formula, R m is selected from H, or substituted or unsubstituted alkyl (e.g., methyl or ethyl).

[0046] Yet another embodiment is a compound of formula (III): [ka] or a pharma- ceutically acceptable salt thereof, R 1 , R 2 , R 3 , L 1 , L 2 and each of ring A is independently selected from any of the embodiments described herein; (i) X is CH or CR c and Y is N, or (ii) X is N and Y is N, CH, or CR c and L 3 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 -, -CH2-, -CHR a -, -NH-, -NR a -, -C(O)-, -NHC(O)-, C(O)NH-, or a 5-membered heterocyclyl having at least one nitrogen or one oxygen ring atom, wherein R a , R b , R c and m is as defined above (including in relation to formula (I)).

[0047] For example, in one embodiment, R 3 teeth, [ka] (In the formula, each R g are independently H, substituted or unsubstituted alkyl (e.g., methyl or ethyl), OH, substituted or unsubstituted alkoxy (e.g., methoxy), halogen, CN, and -NHR m (In the formula, R m is selected from H, or substituted or unsubstituted alkyl (e.g., methyl or ethyl).

[0048] Yet another embodiment is a compound of formula (XIII): [ka] or a tautomer or a pharma- ceutically acceptable salt thereof, R 1 , R 2 , R 3 , L 1 , L 2 Each of X, X, and ring A is independently selected from any of the embodiments described herein; R 4 each occurrence independently represents hydrogen, nitro, hydroxyl, halogen, cyano, substituted or unsubstituted amino (e.g., -NH2, -NHMe, -NHMe2), 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, substituted or unsubstituted carboxy (e.g., -COOH, -COO(C 1-6 ) alkyl), substituted or unsubstituted mercaptan, or substituted or unsubstituted heterocyclyl; L 3 is absent, optionally substituted C1-C7 alkylene (e.g., optionally substituted C1-C4 or optionally substituted C1-C4 alkylene), -NR c-, -O-, -S-, -C(O)-, -NR c C(O)-, -C(O)NR c -, -NR c C(O)- or -NR c C(O)(CR a R b ) m - and Ring B is absent or (i) a 5- or 6-membered heteroaryl (e.g., pyridyl), a 5-6, 6-5, or 6-6 membered bicyclic heteroaryl (e.g., indole, azaindole, benzothiophene), or heterocyclyl, each having at least one nitrogen, oxygen, or sulfur ring atom, or (ii) an aryl (e.g., phenyl); R a and R b each occurrence is independently selected from hydrogen, hydroxy, hydroxy(C1-4)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 , O.C.(S)R d , SC(S)R d , -NR c C(O)R d , -NR c C(S)R d , -SO2R c , -S(O)R c , -NR c SO2R d , -OS(O)2R d , -OP(O)R d R e , or -P(O)R d R e and R cis hydrogen or C 1-6 alkyl (e.g., C1-C4 alkyl such as methyl); R d and R e each occurrence is 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; each occurrence of m is independently 0, 1, 2, 3, 4, 5, 6, or 7 (e.g., 1, 2, 3, 4, 5, 6, or 7, e.g., 1, 2, 3, or 4, e.g., 1 or 2); each occurrence of p is independently 0, 1, 2, 3, or 4, e.g., 0, 1, or 2; q is 0, 1, or 2, for example, 0 or 1).

[0049] For example, in one embodiment, R 3 teeth, [ka] (In the formula, each R g are independently H, substituted or unsubstituted alkyl (e.g., methyl or ethyl), OH, substituted or unsubstituted alkoxy (e.g., methoxy), halogen, CN, and -NHR m (In the formula, R m is selected from H, or substituted or unsubstituted alkyl (e.g., methyl or ethyl).

[0050] Yet another embodiment is a compound of formula (XIV): [ka] or a tautomer or a pharma- ceutically acceptable salt thereof (wherein the variables (X, R 1 , R 2 , R 3 , R 4 , L1 , L 2 , L 3 , p, q, ring A, and ring B) are the same as any of the embodiments described above for compounds of formula (XIII).

[0051] For example, in one embodiment, R 3 teeth, [ka] (In the formula, each R g are independently H, substituted or unsubstituted alkyl (e.g., methyl or ethyl), OH, substituted or unsubstituted alkoxy (e.g., methoxy), halogen, CN, and -NHR m (In the formula, R m is selected from H, or substituted or unsubstituted alkyl (eg, methyl or ethyl).

[0052] Yet another embodiment is a compound of formula (XVI): [ka] or a tautomer or a pharma- ceutically acceptable salt thereof, (wherein the variables X, R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , p, q, Ring A, and Ring B are the same as any of the embodiments described above for compounds of formula (XIII); Y is C or N; R c is absent, hydrogen, or C 1-6 alkyl (e.g., C1-C4 alkyl such as methyl); each ---- is independently a single bond or a double bond, provided that a maximum of two ---- are double bonds (adjacent ---- cannot both be double bonds); y is 1, 2, or 3 (e.g., 1 or 2, e.g., 1); z is 1, 2, or 3 (e.g., 1 or 2, e.g., 1); s is 0, 1, 2, 3, or 4 (e.g., 0, 1, or 2).

[0053] For example, in one embodiment, R 3 teeth, [ka] (In the formula, each R g are independently H, substituted or unsubstituted alkyl (e.g., methyl or ethyl), OH, substituted or unsubstituted alkoxy (e.g., methoxy), halogen, CN, and -NHR m (In the formula, R m is selected from H, or substituted or unsubstituted alkyl (eg, methyl or ethyl).

[0054] In one embodiment, the compound of formula (XVI) is a compound of formula (XVI-A), (XVI-B), or (XVI-C): [ka] or a tautomer or a pharma- ceutically acceptable salt thereof, 1 , R 2 , R 3 , R 4 , R c , L 1 , L 2 , p, q, s, y, z, ring A, and ring B) are the same as any of the embodiments described above for compounds of formula (XVI).

[0055] For example, in one embodiment, R 3 teeth, [ka] (In the formula, each R gare independently H, substituted or unsubstituted alkyl (e.g., methyl or ethyl), OH, substituted or unsubstituted alkoxy (e.g., methoxy), halogen, CN, and -NHR m (In the formula, R m is selected from H, or substituted or unsubstituted alkyl (eg, methyl or ethyl).

[0056] Exemplary compounds of the invention include those listed below, as well as tautomers and pharmaceutical salts thereof.

[0057] [ka]

[0058] Another embodiment is a method of inhibiting PIKfyve in a subject (such as a human subject) in need thereof, comprising administering to the subject an effective amount of a compound of the invention.

[0059] Yet another embodiment is a method for treating a disease or disorder associated with PIKfyve in a human subject in need thereof, comprising administering to the subject an effective amount of a compound of the invention.

[0060] Yet another embodiment is a method of treating a subject, preferably a human subject, having a neurological disorder, comprising administering to the subject an effective amount of a compound of the invention. In one embodiment, the neurological disorder is amyotrophic lateral sclerosis (ALS). In another embodiment, the neurological disorder is frontotemporal dementia (FTD). In yet another embodiment, the neurological disorder is Alzheimer's disease. In yet another embodiment, the neurological disorder is Parkinson's disease. In yet another embodiment, the neurological disorder is Huntington's disease. In yet another embodiment, the neurological disorder is Charcot-Marie-Tooth disease (CMT).

[0061] In one embodiment, the effective amount of the compound is an amount effective to inhibit the cellular PIKfyve activity of target cells in a subject.In another embodiment, the effective amount is an amount effective to induce vacuolation and disrupt intracellular transport in target cells.

[0062] In one embodiment, the target cell is a cancer cell. In one embodiment, the cancer cell is a lymphoma cell. In one embodiment, the lymphoma cell is a non-Hodgkin's lymphoma cell.

[0063] In one embodiment, the disease or disorder is selected from cancer, viral infection, or cell proliferation disorder. For example, the cancer may be lymphoma or melanoma. In one embodiment, the cancer is refractory or resistant to standard therapy. In one embodiment, the cancer is non-Hodgkin's lymphoma.

[0064] One embodiment is a method of treating a viral infection in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention. The viral infection can be caused by any type of virus, including RNA and DNA viruses. In one embodiment, the virus is Ebola virus. In another embodiment, the virus is Middle East Respiratory Syndrome virus (MERS). In yet another embodiment, the virus is JC polyomavirus (JC). In yet another embodiment, the virus is BK polyomavirus (BK). In yet another embodiment, the virus is Herpes Simplex virus (HSV). In yet another embodiment, the virus is Marburg virus (MarV). In yet another embodiment, the virus is Venezuelan Equine Encephalitis virus (VEEV). In yet another embodiment, the virus is Lymphocytic Choriomeningitis virus (LCMV).

[0065] Another embodiment is a method of treating Charcot-Marie-Tooth disease (CMT) in a subject, preferably a human subject, in need of such treatment by administering to the subject an effective amount of a compound of the invention.

[0066] In one embodiment, the method for treating lymphoma comprises administering (e.g., an effective amount of) a compound of the present invention and at least one additional active agent. In one embodiment, the at least one additional active agent is selected from ibrutinib, rituximab, doxorubicin, prednisolone, vincristine, velcade, and everolimus, and combinations thereof. In one embodiment, the method comprises a treatment regimen comprising administering a compound of the present invention and a CHOP regimen.

[0067] In one embodiment, the method is a method for treating melanoma, the method further comprising administering to the subject at least one additional active agent in a treatment regimen comprising a compound of the invention and at least one additional active agent, in one embodiment, the at least one additional active agent is selected from dacarbazine, temozolomide, Nab-paclitaxel, carmustine, cisplatin, carboplatin, or vinblastine.

[0068] In one embodiment, the method is for treating a viral infection, the method further comprising administering to the subject at least one additional active agent in a treatment regimen comprising a compound of the invention and the at least one additional active agent, in one embodiment, the at least one additional active agent is selected from the group consisting of apilimod, APY0201, and YM-201636.

[0069] According to any of the methods described herein, the compounds of the present invention may also be administered in combination with a non-therapeutic agent that reduces one or more side effects associated with the compound or increases the bioavailability of the compound. In one embodiment, the non-therapeutic agent is selected from the group consisting of ondansetron, granisetron, dolasetron, and palonosetron. In another aspect, the non-therapeutic agent is selected from the group consisting of pindolol and risperidone. In another aspect, the non-therapeutic agent is selected from a cytochrome P450 3A (CYP3A) inhibitor. In one embodiment, the CYP3A inhibitor is selected from ritonavir and cobicistat.

[0070] In one embodiment, the viral infection is caused by a virus selected from the group consisting of measles, Ebola (EboV), Marburg (MarV), Borna disease, and human immunodeficiency virus (HIV), severe acute respiratory virus (SARS), and Middle East respiratory syndrome virus (MERS). In one embodiment, the viral infection is caused by an EboV virus.

[0071] In one embodiment, the compound is in the form of a pharmaceutical composition comprising the compound and at least one pharma- ceutically acceptable carrier.

[0072] In one embodiment, the compound contains an enantiomeric excess of at least 95% or at least 99% of the (R)-enantiomer.In one embodiment, the compound contains an enantiomeric excess of at least 95% or at least 99% of the (S)-enantiomer.

[0073] Another embodiment is a pharmaceutical composition comprising a compound of the invention, wherein the compound comprises at least 95% or at least 99% enantiomeric excess of the (R)-enantiomer or the (S)-enantiomer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0074] definition As used herein, the following definitions apply unless otherwise indicated. Furthermore, many of the groups defined herein can be optionally substituted. The list of substituents in the definitions is exemplary and should not be construed as limiting the substituents defined elsewhere herein.

[0075] The term "alkyl", unless otherwise specified, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 8 carbon atoms, attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). 1-6 The term "alkyl" refers to an alkyl group as defined above having up to six carbon atoms. 1-3 The term "alkyl" refers to an alkyl group, as defined above, having up to three carbon atoms. In appropriate circumstances, the term "alkyl" refers to a hydrocarbon chain radical, as described above, that is divalent.

[0076] The term "alkenyl," unless otherwise specified, refers to an aliphatic hydrocarbon group that contains one or more carbon-carbon double bonds and can be straight or branched, or branched, having from about 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (aryl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. 2-6 The term "alkenyl" refers to an alkenyl group, as defined above, having up to six carbon atoms. In appropriate circumstances, the term "alkenyl" refers to a hydrocarbon group, as described above, that is divalent.

[0077] The term "alkynyl", unless otherwise specified, refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon triple bond and ranging from 2 up to 12 carbon atoms (currently, radicals having ranging from 2 up to 10 carbon atoms are preferred), e.g., ethynyl, propynyl, and butynyl. 2-6 The term "alkynyl" refers to an alkynyl group, as defined above, having up to six carbon atoms. In appropriate circumstances, the term "alkynyl" refers to a hydrocarbyl radical, as described above, that is divalent.

[0078] The term "alkoxy" refers to an alkyl, cycloalkyl, or cycloalkylalkyl group, as defined above, unless otherwise indicated, attached to the remainder of the molecule through an oxygen linkage. The term "substituted alkoxy" refers to an alkoxy group in which the alkyl moiety is substituted (i.e., -0-(substituted alkyl). For example, "alkoxy" refers to the group -O-alkyl, containing from 1 to 8 carbon atoms of a straight, branched or cyclic configuration, attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy. In appropriate circumstances, the term "alkoxy" refers to groups described above that are divalent.

[0079] The term "cycloalkyl," unless otherwise noted, refers to a non-aromatic monocyclic or polycyclic ring system of about 3 to 12 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of polycyclic cycloalkyl groups include perhydronaphthyl, adamantyl, and norbornyl groups, bridged cyclic groups, and spiro bicyclic groups, e.g., spiro[4.4]non-2-yl. 3-6 The term "cycloalkyl" refers to a cycloalkyl group as defined above having up to 6 carbon atoms.

[0080] The term "cycloalkylalkyl," unless otherwise noted, refers to a cyclic ring-containing radical containing in the range of about 3 up to 8 carbon atoms attached directly to an alkyl group and then attached to the main structure at any carbon from the alkyl group, e.g., cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

[0081] The term "cycloalkenyl," unless otherwise noted, refers to a cyclic ring-containing radical containing in the range of about 3 up to 8 carbon atoms having at least one carbon-carbon double bond, e.g., cyclopropenyl, cyclobutenyl, and cyclopentenyl. The term "cycloalkenylalkyl" refers to a cycloalkenyl group attached directly to an alkyl group and then attached to the main structure at any carbon from the alkyl group.

[0082] The term "aryl", unless otherwise specified, refers to aromatic radicals having in the range of 6 up to 20 carbon atoms, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

[0083] The term "arylalkyl", unless otherwise stated, refers to an aryl group as defined above directly bonded to an alkyl group as defined above, for example, -CH2C6H5 and -C2H5C6H5.

[0084] The term "heterocycle", unless otherwise specified, refers to a non-aromatic 3- to 15-membered ring radical consisting of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen, and sulfur. For purposes of this invention, a heterocyclic ring radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, may include fused, bridged, or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen, or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. Additionally, the nitrogen atom may be optionally quaternized. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom.

[0085] The term "heterocyclyl" refers to a heterocyclic ring radical as defined above, unless otherwise specified. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon ring atom. In appropriate circumstances, the term "heterocyclyl" refers to a hydrocarbon chain radical as described above that is divalent.

[0086] The term "heterocyclylalkyl," unless otherwise specified, refers to a heterocyclic ring radical as defined above directly attached to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0087] The term "heteroaryl," unless otherwise specified, refers to an optionally substituted 5-14 membered aromatic ring having as ring atoms one or more heteroatoms selected from N, O, and S. Heteroaryl can be a monocyclic, bicyclic, or tricyclic ring system. Examples of such "heteroaryl" radicals include oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl, isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidin ... -oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl, pyridazinyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamophorinyl, thiamophorinyl sulfoxide, thiamophorinyl sulfone, dioxaphosphoranyl, oxadiazolyl, chromanyl, and isochromanyl.

[0088] The term "5- or 6-membered heteroaryl" refers to a heteroaryl having 5 or 6 ring atoms. The term "5-6 or 6-5 membered bicyclic heteroaryl" refers to a bicyclic heteroaryl having a 5-membered ring fused to a 6-membered ring, where the 5-membered ring is attached to the remainder of the molecule (referred to as a "5-6 membered bicyclic heteroaryl") or the 6-membered ring is attached to the remainder of the molecule (referred to as a "6-5 membered bicyclic heteroaryl"). The term "6-6 membered bicyclic heteroaryl" refers to a bicyclic heteroaryl having a 6-membered ring fused to another 6-membered ring, where one of the 6-membered rings is attached to the remainder of the molecule.

[0089] The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom. The term "substituted heteroaryl" also includes ring systems substituted with one or more oxide (-O-) substituents, such as pyridinyl N-oxides.

[0090] The term "heteroarylalkyl" refers to a heteroaryl ring radical as defined above directly bonded to an alkyl group, unless otherwise specified. The heteroarylalkyl radical may be attached to the main structure at any carbon atom from the alkyl group.

[0091] The term "cyclic ring" refers to a cyclic ring containing from 3 to 10 carbon atoms.

[0092] The term "substituted" may be the same or different, unless otherwise stated, and includes hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocycle, substituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, -COOR x , -C(O)R x , -C(S)RX, -C(O)NR x R y , -C(O)ONR x R y , -NR y R z , -NR x CONR y R z , -N(R x )SOR y , -N(R x )SO2R y , =N-NR x R y , -NR x C(O)OR y , -NR x R y , -NR x C(O)R y , -NR x C(S)R y -NR x C(S)NR y R z , -SONR x R y , -SO2NR x R y , -OR x , -OR x C(O)NR y R z , -OR x C(O)OR y , -OC(O)Rx , -OC(O)NR x R y , -R x NR y C(O)R z , -R x OR y , -R x C(O)OR y , -R x C(O)NR y R z , -R x C(O)R x , -R x O.C.(O)R y , -SR x ,-SOR x , -SO2R x and -ONO2, or any combination thereof. x , R y , and R z can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocycle, or substituted heterocyclylalkyl ring; or R x , R y , and R z any two of may combine to form a substituted or unsubstituted saturated or unsaturated 3- to 10-membered ring, which may optionally be the same or different, and may include O, NR x (For example, R x is hydrogen or C 1-6The substituents may include a heteroatom selected from , which may be alkyl, or S. The substitutions or combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term stable refers to compounds or structures that do not change substantially when exposed to conditions that allow for their production, detection, and preferably their recovery, purification, and incorporation into pharmaceutical compositions. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, if the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl".

[0093] The terms "halo", "halide", or alternatively, "halogen" mean fluoro, chloro, bromo, or iodo. The terms "haloalkyl", "haloalkenyl", "haloalkynyl", and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures that are substituted with one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, where the halo is fluorine.

[0094] The term "protecting group" or "PG" refers to a substituent used to block or protect a particular functionality. Other functional groups on the compound may remain reactive. For example, an "amino protecting group" is a substituent added to an amino group that blocks or protects the amino functionality in the compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy protecting groups include, but are not limited to, acetyl and silyl. A "carboxy protecting group" refers to a substituent of a carboxy group that blocks or protects the carboxy functionality. Suitable carboxy protecting groups include, but are not limited to, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, and nitroethyl. For a general description of protecting groups and their uses, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0095] Certain compounds described herein contain one or more asymmetric centers and therefore may give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)-. The chemical compounds, pharmaceutical compositions, and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Non-limiting examples of intermediate mixtures include mixtures of isomers in ratios of 10:90, 13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. Where the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, and unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.

[0096] A "leaving group or atom" is any group or atom that is cleaved from the starting material under the reaction conditions, thus facilitating reaction at a particular site. Unless otherwise specified, suitable examples of such groups are halogen atoms, and mesyloxy, p-nitrobenzenesulfonyloxy, and tosyloxy groups.

[0097] The term "prodrug" refers to a compound that is an inactive precursor of a compound that is converted to its active form in the body by normal metabolic processes. Prodrug design is generally discussed in Hardma, et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996). A detailed discussion is provided in Higuchi, et al., Prodrugs as Novel Delivery Systems, Vol. 14, ASCD Symposium Series, and Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). To illustrate, a prodrug can be converted to a pharmacologically active form, for example, by hydrolysis of an ester or amide bond, thereby introducing or exposing a functional group on the resulting product. A prodrug can be designed to react with an endogenous compound to form a water-soluble conjugate that further enhances the pharmacological properties of the compound, for example, increased circulatory half-life. Alternatively, prodrugs can be designed to undergo covalent modification on functional groups, for example, with glucuronic acid, sulfate, glutathione, amino acids, or acetate. The resulting conjugates can be inactivated and excreted in urine, or made more potent than the parent compound. High molecular weight conjugates can also be excreted in bile, undergo enzymatic cleavage, and released back into the circulation, thereby effectively increasing the biological half-life of the originally administered compound.

[0098] In addition, the present invention also provides the substitution of hydrogen with deuterium or tritium, 13 C or 14 Replacement of carbon with C-enriched carbon, or 15 Also included are compounds that differ only in the presence of one or more isotopically enriched atoms, such as the replacement of nitrogen with N.

[0099] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium, iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0100] Pharmaceutically acceptable salts which form part of the invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamines, and thiamine; chiral bases such as alkylphenylamines, glycinol, and phenylglycinol; salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, and serine; quaternary ammonium salts of the compounds of the invention with alkyl halides, and alkyl sulfates. Salts may include, where appropriate, acid addition salts, which are sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides (e.g., hydrochlorides), acetates, tartrates, maleates, citrates, fumarates, succinates, pamoates, methanesulfonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarate salts. Salts may be formed by methods known in the art.

[0101] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or numerical range means that the referenced number or numerical range is approximate within experimental variation (or within statistical experimental error), and thus the number or numerical range may vary, for example, between 1% and 15% of the stated number or numerical range.

[0102] The term "cell proliferation" refers to the phenomenon in which a cell number changes as a result of division. The term also encompasses proliferation of cells in which the cell morphology changes (e.g., increases in size) in concert with proliferation signals.

[0103] As used herein, the terms "co-administration," "administered in combination with," and their grammatical equivalents include the administration of two or more agents to an animal such that both agents and / or their metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration of a single composition in which both agents are present.

[0104] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that is sufficient to perform its intended use, including but not limited to disease treatment, as defined below. A therapeutically effective amount may vary depending on the intended use (in vitro or in vivo), or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in a target cell, such as reduced platelet adhesion and / or cell migration. A particular dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which it is delivered. In one embodiment, the amount of the compound administered ranges from about 0.1 mg to 5 g, about 1 mg to 2.0 g, about 100 mg to 1.5 g, about 200 mg to 1.5 g, about 400 mg to 1.5 g, and about 400 mg to 1.0 g.

[0105] As used herein, the term "treat" refers to an approach to obtain a beneficial or desired result, including, but not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the underlying disorder being treated. Therapeutic benefit is also achieved with eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such that the patient may still be afflicted by the underlying disorder, but improvement is observed in the patient. For prophylactic benefit, the composition may be administered to a patient at risk of developing a particular disease, or to a patient who reports one or more of the physiological symptoms of the disease, even though the diagnosis of the disease may not have been made.

[0106] A "therapeutic effect," as that term is used herein, encompasses the therapeutic and / or prophylactic benefits described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0107] A "neurological disease" is any disease that causes electrical, biochemical, or structural abnormalities in the brain, spine, or neurons. For example, the neurological disease can be a neurodegenerative disease. The neurodegenerative disease can result in, for example, motor neuron degeneration. The neurological disease can be, for example, amyloid lateral sclerosis, Huntington's disease, Alzheimer's disease, or frontotemporal dementia. Further examples of neurological diseases include, but are not limited to, for example, Parkinson's disease, multiple sclerosis, peripheral myopathy, Rasmussen's encephalitis, attention deficit hyperactivity disorder, autism, central pain syndrome, anxiety, and / or depression.

[0108] Neurodegenerative diseases result in the progressive destruction of neurons, which affects neuronal signal transduction. For example, neurodegeneration can be amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Friedreich's ataxia, Lewy body disease, Parkinson's disease, spinal muscular atrophy, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, and pseudobulbar palsy.

[0109] The term "pharmaceutical acceptable excipient" includes, but is not limited to, any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption retarding agents, one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants / flavoring agents, carriers, buffers, stabilizers, solubilizers, and combinations thereof. Insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the present invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0110] "Subject" includes mammals. The mammal can be, for example, any mammal, such as a human, a primate, a vertebrate, a bird, a mouse, a rat, a fowl, a dog, a cat, a cow, a horse, a goat, a camel, a sheep, or a pig. Preferably, the mammal is a human. The term "patient" refers to a human subject.

[0111] According to the methods described herein, a "subject in need" is a subject who has a disease, disorder, or condition, or a subject who is at increased risk of developing a disease, disorder, or condition compared to the overall population. A subject in need thereof may be "non-responsive" or "refractory" to currently available therapies for a disease or disorder, such as cancer. In this context, the terms "non-responsive" and "refractory" refer to a subject's response to a therapy as not clinically adequate to alleviate one or more symptoms associated with a disease or disorder. In one aspect of the methods described herein, a subject in need thereof is a subject with a cancer whose cancer is refractory to standard therapy or whose cancer has recurred after standard therapy.

[0112] Pharmaceutical Compositions One embodiment is a pharmaceutical composition suitable for use in a subject, such as a human. The pharmaceutical composition may include at least one pharma- ceutically acceptable excipient or carrier.

[0113] The pharmaceutical composition may also include at least one additional active agent, such as an alkylating agent, an intercalating agent, a tubulin binding agent, a corticosteroid, or any combination of any of the above.Examples of additional active agents include, but are not limited to, ibrutinib, rituximab, doxorubicin, prednisolone, vincristine, velcade, and everolimus.In one embodiment, the at least one additional active agent is a therapeutic agent selected from cyclophosphamide, hydroxydaunorubicin (also called doxorubicin), vincristine, prednisone, prednisolone, and any combination of any of the above.

[0114] The pharmaceutical composition may include one or more non-therapeutic agents, such as ondansetron, granisetron, dolasetron, palonosetron, pindolol, risperidone, or any combination of any of the foregoing.

[0115] The pharmaceutical compositions may be presented in dosage unit form, such as in the form of ampoules, vials, suppositories, dragees, tablets, or capsules.

[0116] Pharmaceutical compositions can take any suitable form (e.g., liquid, aerosol, solution, inhalant, mist, spray, or solid, powder, ointment, paste, cream, lotion, gel, patch, etc.) for administration by any desired route (e.g., pulmonary, inhalation, intranasal, oral, buccal, sublingual, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrapleural, intrathecal, transdermal, transmucosal, rectal, etc.). For example, pharmaceutical compositions of the present invention can be in the form of an aqueous solution or powder for aerosol administration by inhalation or insufflation (either by mouth or nose), in the form of a tablet or capsule for oral administration, in the form of a sterile aqueous solution or dispersion suitable for administration either by direct injection or addition to a sterile infusion fluid for intravenous infusion, or in the form of a lotion, cream, foam, patch, suspension, solution, or suppository for transdermal or transmucosal administration.

[0117] The pharmaceutical composition may be in the form of an orally acceptable dosage form, including, but not limited to, capsules, tablets, buccal forms, troches, lozenges, and oral liquids in the form of emulsions, aqueous suspensions, dispersions, or solutions. Capsules may contain a mixture of the compound of the present invention with inert fillers and / or diluents, such as pharmaceutically acceptable starches (e.g., corn, potato, or tapioca starches), sugars, artificial sweeteners, powdered cellulose, such as crystalline and microcrystalline cellulose, flour, gelatin, gums, and the like. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, can also be added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and / or emulsions are administered orally, the compound of the present invention may be suspended or dissolved in an oily phase combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

[0118] The pharmaceutical composition may be in the form of a tablet. The tablet may contain a unit dose of the compound of the present invention together with an inert diluent or carrier such as sugar or sugar alcohol, for example, lactose, sucrose, sorbitol or mannitol. The tablet may further contain a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or its derivative such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and a starch such as corn starch. The tablet may further contain a binder and a granulating agent such as polyvinylpyrrolidone, a disintegrant (e.g., an expandable cross-linked polymer such as cross-linked carboxymethylcellulose), a lubricant (e.g., a stearate salt), a preservative (e.g., a paraben), an antioxidant (e.g., BHT), a buffer (e.g., a phosphate or citrate buffer), and an effervescent agent such as a citrate / bicarbonate mixture.

[0119] Preparation of compounds The compounds described herein can be prepared as described in International Publication No. WO2021 / 163727, which is incorporated herein by reference.

[0120] As an example, some of the compounds of the invention can be prepared as follows. [ka]

[0121] Starting intermediate A-1 is oxidized, for example, by reaction with m-CPBA (meta-chlorooxybenzoic acid) in a solvent such as dichloromethane to produce intermediate I. Intermediate I is then reacted with R 1 -L 2 H to form intermediate A-3. Intermediate A-3 is first [ka] Next is R 3 -H to form the final compound. Other compounds of the invention can be prepared in an analogous manner.

[0122] Treatment method The compounds of the present invention are useful as PIKfyve kinase inhibitors.

[0123] One embodiment is a method for treating a subject having a neurological disease, comprising administering to the subject an effective amount of a compound of the present invention (or a pharmaceutical composition of the present invention). In a preferred embodiment, the subject is a human subject. The PIKfyve kinase inhibitors described herein can be used in the method for treating a neurological disease described in U.S. Patent Publication No. 2018 / 0161335 (incorporated herein by reference in its entirety). For example, the neurological disease can be a disease having neuronal cell death generated by intracellular aggregates.

[0124] In certain embodiments, the method comprises treating amyotrophic lateral sclerosis (ALS). In certain embodiments, the method comprises treating frontotemporal dementia (FTD). In certain embodiments, the method comprises treating a neurological disorder associated with abnormal endosomal trafficking. In certain embodiments, the method comprises treating a neurological disorder associated with abnormal lysosomal trafficking. In further embodiments, the method comprises inserting a (GGGGCC) n In a further embodiment, the method comprises treating a subject having a repeat expansion. In a further embodiment, the subject is haploinsufficient for C9ORF72. In a further embodiment, the method comprises treating a patient having a 50% or greater reduction in C9ORF72 protein activity. In a further embodiment, the method comprises treating a subject having a repeat expansion of (GGGGCC) n In a further embodiment, the method comprises the step of: detecting a C9ORF72 gene product containing a dipeptide repeat resulting from an expansion. n This includes gain of function or loss of function mutations due to expansion. In a further embodiment, the neurological disorder is associated with neuronal hyperexcitability.

[0125] One embodiment is a method of treating a subject having amyotrophic lateral sclerosis (ALS), comprising administering to the subject, preferably a human subject, an effective amount of a compound of the invention. Another embodiment is a method of treating a subject having frontotemporal dementia (FTD), comprising administering to the subject, preferably a human subject, an effective amount of a compound of the invention. Yet another embodiment is a method of treating a subject having Alzheimer's disease, comprising administering to the subject, preferably a human subject, an effective amount of a compound of the invention. Yet another embodiment is a method of treating a subject having Parkinson's disease, comprising administering to the subject, preferably a human subject, an effective amount of a compound of the invention. Yet another embodiment is a method of treating a subject having Huntington's disease, comprising administering to the subject, preferably a human subject, an effective amount of a compound of the invention. Yet another embodiment is a method of treating a subject having Charcot-Marie-Tooth disease (CMT), comprising administering to the subject, preferably a human subject, an effective amount of a compound of the invention.

[0126] The method may also further include administering an effective amount of a potassium channel activator, an inhibitor of a glutamate receptor (such as NMDA, AMPA, or kainite receptors) (e.g., AP5, CNQX, and NBQX), or any combination of any of the foregoing.

[0127] PIKfyve is a phosphoinositide kinase (PIK) containing a FYVE-type zinc finger domain that binds to phosphatidylinositol 3-phosphate (PI3P). PIKfyve phosphorylates PUP to produce PI(3,5)P2, which is involved in cellular processes including membrane trafficking and cytoskeletal rearrangements. Inhibition of PIKfyve by the compounds described herein is useful for treating cancer as well as Charcot-Marie-Tooth disease and certain viral infections, such as those caused by measles, Ebola virus (EboV), Marburg virus (MarV), Borna disease, and viruses selected from human immunodeficiency virus (HIV), severe acute respiratory virus (SARS), Middle East respiratory syndrome virus (MERS), JC polyomavirus (JC), BK polyomavirus (BK), herpes simplex virus (HSV), Venezuelan equine encephalitis virus (VEEV), and lymphocytic choriomeningitis virus (LCMV). The viral infection can be caused by any type of virus, including RNA viruses and DNA viruses.

[0128] One embodiment is a method of treating a viral infection in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the invention. In one embodiment, the virus is Ebola virus. In another embodiment, the virus is Middle East Respiratory Syndrome virus (MERS). In yet another embodiment, the virus is JC polyomavirus (JC). In yet another embodiment, the virus is BK polyomavirus (BK). In yet another embodiment, the virus is Herpes Simplex virus (HSV). In yet another embodiment, the virus is Marburg virus (MarV). In yet another embodiment, the virus is Venezuelan Equine Encephalitis virus (VEEV). In yet another embodiment, the virus is Lymphocytic Choriomeningitis virus (LCMV).

[0129] One embodiment is a method for treating a cell proliferative disease, cancer, or viral infection in a subject, preferably a human subject, in need of such treatment by administering to the subject an effective amount of a compound of the invention or a pharmaceutical composition comprising same.

[0130] The compounds described herein are useful for treating cancer. In one embodiment, the cancer is brain cancer, glioma, sarcoma, breast cancer, lung cancer, non-small cell lung cancer, mesothelioma, appendix cancer, genitourinary cancer, renal cell carcinoma, prostate cancer, bladder cancer, testicular cancer, penile cancer, cervical cancer, ovarian cancer, von Hippel-Lindau disease, head and neck cancer, gastrointestinal cancer, hepatocellular carcinoma, gallbladder cancer, esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, neuroendocrine tumors, thyroid tumors, pituitary tumors, adrenal tumors, hematological malignancies, or leukemia. In another embodiment, the cancer is B-cell lymphoma. In another embodiment, the cancer is melanoma.

[0131] In one embodiment, the cancer is a lymphoma. In one embodiment, the lymphoma is a B cell lymphoma. In one embodiment, the B cell lymphoma is selected from the group consisting of Hodgkin's B cell lymphoma and non-Hodgkin's B cell lymphoma. In one embodiment, the B cell lymphoma is a non-Hodgkin's B cell lymphoma selected from the group consisting of DLBCL, follicular lymphoma, marginal zone lymphoma (MZL) or mucosa-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma (overlap with chronic lymphocytic leukemia), and mantle cell lymphoma. In one embodiment, the B cell lymphoma is Burkitt's lymphoma, primary mediastinal (thymic) large B cell lymphoma, lymphoplasmacytic lymphoma that may manifest as Waldenstrom's macroglobulinemia, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), intravascular large B cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T cell / histiocyte-rich large B cell and non-Hodgkin's B-cell lymphoma selected from the group consisting of lymphoma, primary central nervous system lymphoma, primary cutaneous diffuse large B-cell lymphoma, leg type (primary cutaneous DLBCL, leg type), EBV-positive diffuse large B-cell lymphoma of the elderly, inflammation-associated diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, and plasmablastic lymphoma.

[0132] In one embodiment, the method is a method of treating lymphoma using a combination therapy comprising a compound of the present invention and a chemotherapy regimen for the treatment of lymphoma. In one embodiment, the chemotherapy regimen is a CHOP regimen. In another embodiment, the chemotherapy regimen is selected from COOP, CVP, EPOCH, Hyper-CVAD, ICE, R-CHOP, and R-CVP.

[0133] In the methods described herein, the compounds may be administered by any suitable route, such as oral, intravenous, or subcutaneous routes.

[0134] All references cited herein are incorporated by reference.

Claims

1. Compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (in the formula, R １ These are 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. R ２ Each occurrence is independent, 【Chemistry 1-1】 And here, Each R h independently consists of H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -CN, -NH2, -NHRm, or -NRm2, or two R h groups bond to form a saturated or unsaturated 5- to 7-membered ring. Each R m is independently H or a substituted or unsubstituted alkyl group. t is 0, 1, or 2. R ３ teeth, 【Chemistry 2】 And, Each R ｇ These are independently H, substituted or unsubstituted alkyl, OH, substituted or unsubstituted alkoxy, halogen, CN, or -NHR ｍ (In the formula, R ｍ (is H, or a substituted or unsubstituted alkyl group), Ring A is (i) a 5 or 6-membered heteroaryl, 5-6, 6-5, or 6-6-membered bicyclic heteroaryl, or heterocyclyl, 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)-, -NHCO-, -CONH-, -NR ｃ C(O)-, or -NR ｃ C(O)(CR ａ R ｂ ) ｍ - and L ２ is absent, -O-, -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 - and (i) X １ is CH or CR ｃ X ２ is either N or (ii) X １ N is X ２ is N, CH, or CR ｃ And, R ａ and R ｂ Each appearance is independently of hydrogen, hydroxyl, and hydroxyl (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 And, R ｃ Each occurrence is independently of hydrogen or C １－６ It is alkyl, R ｄ and R ｅ Each occurrence is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocyclyl. Each occurrence of m is independently 1 to 4. p is either 1 or 2, R ３ but 【Transformation 3】 If R ｇ (It is not hydrogen.)

2. X １ However, it is CH, and X ２ However, N is L １ However, L was absent. ２ The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is absent.

3. R １ but, 【Chemistry 4】 (Wavy line ( 【Chemistry 4-1】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein (indicated by ) is a point to be added to the rest of the compound.

4. R １ However, heterocyclyl, heteroaryl, methyl, 【Chemistry 4】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. R １ but, 【Transformation 6】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. Ring A is 【Transformation 8】 (In the formula, Each R ｋ These are independently substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, substituted or unsubstituted aryls, substituted or unsubstituted heteroaryls, substituted or unsubstituted cycloalkyls, or substituted or unsubstituted heterocyclines. Each wavy line on the right side of ring A ( 【Chemistry 9】 ) is the variable L of ring A. １ This represents the additional points to, Each wavy line on the left side of ring A represents the variable R in ring A. ２ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which represents an additional point to the compound.

7. L １ The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is absent.

8. L １ However, -NH-, -N(CH ３ )-, -O-, or -CH ２ - The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. L ２ The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is absent.

10. L ２ is -(CRaRb)m-, -OCH ２ CH ２ -, -OCH ２ -, or -OCH ２ CH ２ CH(OH)CH ２ -, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. -L ２ -R １ is -OCH ２ CH ２ CH(OH)CH ２ OH, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. R ａ and R ｂ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each occurrence is independently hydrogen, hydroxyl, or hydroxy(C1-4)alkyl.

13. portion 【Chemistry 10】 but, 【Chemistry 11】 (In the formula, R ｈ Each occurrence is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -CN, -NH ２ , - NHR ｍ , or -NR ｍ ２ is either or two R ｈ These combine to form saturated or unsaturated 5-7 membered rings. Each R ｍ These are independently H, or substituted or unsubstituted alkyl groups. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein t is 0, 1, or 2. 【Request Item 14】 【Chemistry 12】 Compounds selected from and pharmaceutically acceptable salts thereof.

15. A pharmaceutical composition for use in subjects requiring inhibition of PIKfyve, comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition for use in a subject requiring treatment of a disease or disorder related to PIKfyve, comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition for use in subjects requiring treatment of neurological disorders, comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition according to claim 17, wherein the neurological disease is amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease, Parkinson's disease, Huntington's disease, or Charcot-Marie-Tooth disease (CMT).

19. A pharmaceutical composition for use in a subject requiring treatment of a viral infection, comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition according to claim 19, wherein the viral infection is caused by Ebola virus, Middle East Respiratory Syndrome virus (MERS), JC polyomavirus (JC), BK polyomavirus (BK), herpes simplex virus (HSV), Marburg virus (MarV), Venezuelan equine encephalitis virus (VEEV), or lymphocytic choriomeningitis virus (LCMV).

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