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WO2024226890A1 - Composés de pyrazole 3h-imidazo(4,5-b)pyridine et leurs utilisations - Google Patents

Composés de pyrazole 3h-imidazo(4,5-b)pyridine et leurs utilisations Download PDF

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WO2024226890A1
WO2024226890A1 PCT/US2024/026398 US2024026398W WO2024226890A1 WO 2024226890 A1 WO2024226890 A1 WO 2024226890A1 US 2024026398 W US2024026398 W US 2024026398W WO 2024226890 A1 WO2024226890 A1 WO 2024226890A1
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substituted
compound
mmol
tolyl
morpholino
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Weiling Liang
Jr. Robert A. Galemmo
Brian C. Shook
Andrés E. DULCEY
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Verge Analytics Inc
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Verge Analytics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure provides compounds that are phosphoinositide kinase inhibitors, in particular FYVE-type finger-containing phosphoinositide kinase (“PIKfyve”) inhibitors and are therefore useful for the treatment of central nervous system diseases. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
  • PIKfyve FYVE-type finger-containing phosphoinositide kinase
  • Phosphoinositide kinases catalyze the phosphory lation of phosphatidy linositol, which is a component of eukaryotic cell membranes, and related phospholipids called phosphoinositides. Phosphoinositides are involved in the regulation of diverse cellular processes, including cellular proliferation, survival, cytoskeletal organization, vesicle trafficking, glucose transport, and platelet function. Fruman et al., “Phosphoinositide Kinases,” Ann. Review. Biochem. 1998, 67, 481-507. Phosphorylated derivatives of phosphatidylinositol regulate cytoskeletal functions, membrane trafficking, and receptor signaling by recruiting protein complexes to cell and endosomal membranes.
  • PIKs Phosphoinositide kinases
  • FYVE-type finger-containing phosphoinositide kinase (PIKfyve; also known as phosphatidylinositol-3-phosphate 5-kinase type III or PIPKIII) is a ubiquitously expressed PIK with both lipid and protein kinase activity. In its capacity as a lipid kinase, the enzyme phosphorylates the D-5 position in endosomal phosphatidylinositol and phosphatidylinositol-3- phosphate (PI3P) to generate the corresponding 5-phosphate phospholipid analogs. Shisheva et al., Cell Biol. Int. 2008, 32(6), 591.
  • PI3P is found in cell membranes with roles in protein trafficking, protein degradation, and autophagy. Nascimbeni et al., FEBSJ. 2017, 284. 1267- 1278.
  • PIKfyve regulates endomembrane homeostasis and plays a role in the biogenesis of endosome carrier vesicles from early endosomes. The enlarged endosome/lysosome structure was observed in cells expressing PIKfyve dominant negative or siRNA. Ikonomov et al., J. Biol. Chem. 2001, 276(28), 26141-26147; Rutherford et al. , J. Cell Sci. 2006, 119, 3944-3957.
  • Phosphorylated inositides produced by PIKfyve are localized in various cellular membranes and organelles, consistent with the various PIKfy ve functions of endolysosomal transport, endomembrane homeostasis, and biogenesis of endosome carrier vesicles (ECV)/multivesicular bodies (MVB) from early endosomes. Further, PIKfyve is required for endocytic-vacuolar pathway and nuclear migration. Thus, PIKfyve helps maintain proper morphology of the endosome and lysosome.
  • FIG4 phosphoinositide 5-phosphatase
  • Inhibition of PIKfyve would mimic overexpression of FIG4, thereby increasing levels of PI3P, stimulating autophagy, and improving motor neuron health.
  • Numerous diseases are correlated with FIG4 deficiencies, such as deleterious FIG4 mutations or diminished FIG4 function, and are therefore suitable as target diseases for treatment with PIKfyve inhibitors, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth (including type 4J (CMT4J)), and Yunis- Varon syndrome.
  • ALS amyotrophic lateral sclerosis
  • PLS primary lateral sclerosis
  • CMT4J Charcot-Marie-Tooth
  • Yunis- Varon syndrome including type 4J (CMT4J)
  • Exemplary diseases associated with FIG4 deficiencies are amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth (including type 4J (CMT4J)), Yunis-Varon syndrome, poly microgyri a (including polymicrogyria with seizures), temporo- occipital polymicrogyria, Pick’s disease, Parkinson's disease, Parkinson's disease with Lewy bodies, dementia with Lewy bodies.
  • ALS amyotrophic lateral sclerosis
  • PLS primary lateral sclerosis
  • CMT4J Charcot-Marie-Tooth
  • Yunis-Varon syndrome Yunis-Varon syndrome
  • poly microgyri a including polymicrogyria with seizures
  • temporo- occipital polymicrogyria Pick’s disease
  • Parkinson's disease Parkinson's disease with Lewy bodies, dementia with Lewy bodies.
  • Lewy body disease fronto-temporal dementia, diseases of neuronal nuclear inclusions of poly glutamine and intranuclear inclusion bodies, disease of Marinesco and Hirano bodies, Alzheimer’s disease, neurodegeneration, spongiform neurodegeneration, autophagy, peripheral neuropathy, leukoencephalopathy, motor neuropathy, sensory neuropathy. Bharadwaj et al., Hum. Mol. Genet. 2016, 25(4). 682-692.
  • PIKfyve inhibitors are useful in a range of neurological disorders, such as tauopathies (including but not limited to Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementias, and chronic traumatic encephalopathy), traumatic brain injury’ (TBI), cerebral ischemia, ALS, fronto-temporal dementia (FTD), Guillain-Barre Syndrome, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, CMT.
  • lysosomal storage diseases including but not limited to Fabry's disorder, Gaucher's disorder, Niemann Pick C, Tay-Sachs, and Mucolipidosis type IV), as well as several types of neuropathies.
  • PIKfyve inhibitors include Huntington's disease and psychiatric disorders (such as ADHD, schizophrenia, mood disorders including but not limited to major depressive disorder, bipolar disorder I, and bipolar disorder II).
  • Gardiner et al. “Prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among large population-based cohorts,"’ JAMA Neurol. 2019, 76(6), 650-656; PCT Publ. No. WO2016/210372; US Publ. No. US2018/0161335. Summary
  • Embodiment 1 is a compound of Formula (I):
  • W is N, CH, or CR 4 ‘;
  • R is H, oxo, alkyl, alkenyl, heteroaryl, heterocyclyl, or carboxamide, each substituted with 0, 1, or 2 R x groups and each R x is oxo, hydroxyl, cyano, substituted or unsubstituted alkyd, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, substituted or unsubstituted ester, substituted or unsubstituted sulfonyl, substituted or unsubstituted amide, substituted or unsubstituted carboxamide, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkoxyalkyl;
  • R 1 is H, alkyl, cycloalkyl, heterocyclyl, amino, alkoxy, alkoxyalkyl, amide, carboxamide, or sulfonyl, each substituted with 0, 1, or 2 R y groups and each R y is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted amino, substituted or unsubstituted ester, substituted or unsubstituted sulfonyl, substituted or unsubstituted amide, substituted or unsubstituted carboxamide, substituted or unsubstituted urea, substituted or unsubstituted carb
  • R 4 and R 4 * are aryl, lieteroar l. or heterocyclyl, each substituted with 0, 1, or 2 R z groups and each R z is alkyl, cycloalkyl, haloalkyl. alkoxy, haloalkoxy, halo, or -CN, provided that only one of R 4 and R 4 * is present;
  • R 5 is H, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy carbonyl, substituted or unsubstituted ester, or substituted or unsubstituted carboxamide;
  • R 6 is absent, H, or alkyl
  • R 7 and R 8 are each independently H, Ci-6 alkyl or R 7 and R 8 join together to form a fused or bridging ring system;
  • — represents a single or double bond; x is 0, 1 or 2;
  • R 9 is absent or oxo; and pharmaceutically acceptable salts, solvates, and prodrugs thereof; provided that when R 6 is absent, R 7 and R 8 are
  • R 4 is /n-tolyl, then R is not substituted or unsubstituted piperidinyl; substituted or unsubstituted pyrrolidinyl; -CH 2 OH; -CH 2 (substituted or unsubstituted heterocyclyl); or C(O)NR*R** wherein R* and R** join to form a substituted or unsubstituted heterocyclic group.
  • Embodiment 2 is the compound of embodiment 1 , wherein R is H, oxo, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted Ci-6 alkenyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted monocyclic heterocyclyl. or R a R b NC(O)-; and each R a and R b is independently H, Ci-6 alkyL Ci-shaloalkyl, Ci-6 cycloalkyl, or CH 3 C(O)-.
  • Embodiment 3 is the compound of embodiment 2, wherein each R a and R b is independently H, cyclopropyl, cyclobutyl, methyl, ethyl, CH 3 C(O)-, -CD 3 , or -CFs.
  • Embodiment 4 is the compound of embodiment 1 or 2, wherein R is H, oxo, methyl, ethyl, propyl, isopropyl, isobutyl, propenyl, pyridyl, pyrimidinyl, pyrazolyl, dioxanyl, oxetanyl, morpholino, 3,6-dihydro-2H-pyranyl, or R a R b NC(O)-.
  • Embodiment 5 is the compound of embodiment 1 or 2, wherein R is H.
  • Embodiment 6 is the compound of any one of embodiments 1-5, wherein R x is monocyclic heteroaryl, monocyclic heterocyclyl, Ci-6 alkyl. Ci-s cycloalkyl, R a R b N, R a O-, R c , R a R b N-(Ci-6 alkyl)-, R a O-(Ci-6 alkyl)-, or R C O-(CI-6 alkyl)-; and R c is H, methyl, ethyl, HOC(O)CH 2 -, CH 3 OC(O)CH 2 -, (CH 3 ) 3 COC(O)CH 2 -, (CH 3 ) 3 COC(O)NH-, H 2 NC(O)CH 2 -,
  • Embodiment 7 is the compound of any one of embodiments 1-5, wherein R x is methyl, cyclopropyl, cyclobutyl, pyridyl, pyrazolyl, morpholino, piperidinyl, piperazinyl, R a R b N, R a O-, R c , R a R b N-ethyl, R c O-ethyl-, R c O-methyl-, or R c O-isopentyl.
  • R x is methyl, cyclopropyl, cyclobutyl, pyridyl, pyrazolyl, morpholino, piperidinyl, piperazinyl, R a R b N, R a O-, R c , R a R b N-ethyl, R c O-ethyl-, R c O-methyl-, or R c O-isopentyl.
  • Embodiment 8 is the compound of any one of embodiments 1-7, wherein R 1 is H, Ci-6 alkyl, C i-6 cycloalkyl, monocyclic heterocyclyl, R a O-, R a O-(Ci-6 alkyd), R a R b NC(O)-, or alkyl- SO2-.
  • Embodiment 9 is the compound of any one of embodiments 1-7, wherein R 1 is H, propyl, ethyl, methyl, isobutyl, cyclobutyl, cyclopropyl. azetidinyL oxetanyl. piperidinyl, tetrahydropyran, tetrahydrofuran, thietane 1,1 dioxide, hexahydropyrimidin-2-one, R a O-, R a O- ethyl, R a O-methyl, R a R b NC(O)-, CH3CH2SO2-, (CH 3 ) 2 CHSO 2 -, or cyclopropyl-SCh-.
  • Embodiment 10 is the compound of any one of embodiments 1-9, wherein R y is C1-6 alkyl, C1-6 alkenyl. C1-6 haloalkyl, C1-6 cycloalkyl, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocyclyl, halo, -CN, -OH, R a O-, CH3SO2-.
  • R d is methyl, oxo, CHsC(O)-, CH 3 OC(O)-, CH 3 SO 2 -, -F, (CH 3 ) 3 CO-, (CD 3 ) 3 CO-, R a O-, -CN, NH 2 , (CH 3 ) 3 COC(O)-, H 2 NC(O)-, CH 3 HNC(O)-.
  • Embodiment 11 is the compound of any one of embodiments 1-9, wherein R y is methyl, cyclopropyl, cyclobutyl, pyridinyl, phenyl, piperidinyl, pyrrolidinyl, oxetanyl, pyrrolidinone, imidazolidin-2-one, oxazolidin-2-one, lH-l,2,4-triazol-5-one, tetrahydropyran, dioxanyl, azetidinyl, -CN, -F,
  • Embodiment 12 is the compound of any one of embodiments 1-11, wherein R 4 is H, phenyl, pyrazolyl, thiazolyl, thienyl, oxabicyclo[2.1.1]hexanyl, and norbomanyl, each substituted by 0, 1. or 2 R z wherein each R z is -CN, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 cycloalkyl, deuterated alkyl, or C1-6 haloalkoxy.
  • Embodiment 13 is the compound of embodiment 12, wherein R 4 is H, phenyl, pyrazolyl, thiazolyl, thienyl, oxabicyclo[2. l. l]hexanyl, or norbomanyl.
  • Embodiment 14 is the compound of embodiment 12 or 13, wherein each R z is -Cl, -F, - CN, -CF 3 , -CDS, -OCF 3 , methyl, ethyl, cyclopropyl, methoxy, difluoromethoxy, or difluoromethyl.
  • Embodiment 15 is the compound of any one of embodiments 1-14, wherein each R 5 is - C(O)NR a R b , -C(O)OR a , unsubstituted C1-6 alkyl, or C1-6 alkyl substituted with 1 or 2 -OR a or - NH 2 , -NH-R a , -NR a R b groups.
  • Embodiment 16 is the compound of any one of embodiments 1-14, wherein each R 5 is H, hydroxymethyl, hydroxyethyl, methoxymethyl, H 2 N-methyl, CH 3 NH-methyl, or (CH 3 ) 2 N- methyl, trideuteriomethoxymethyl, -C(O)NR a R b , -C(O)OR a .
  • Embodiment 17 is the compound of any one of embodiments 1-16, wherein R 6 is absent.
  • Embodiment 18 is the compound of any one of embodiments 1-176, wherein R is not substituted with an R x group.
  • Embodiment 19 is the compound of any one of embodiments 1-17, wherein R is substituted with 1 R x group.
  • Embodiment 20 is the compound of any one of embodiments 1-17, wherein R is substituted with 2 R x groups.
  • Embodiment 21 is the compound of any one of embodiments 1-20, wherein R 1 is not substituted with an R y group.
  • Embodiment 22 is the compound of any one of embodiments 1-20, wherein R 1 is substituted with 1 R y group.
  • Embodiment 23 is the compound of any one of embodiments 1-20, wherein R 1 is substituted with 2 R y groups.
  • Embodiment 24 is the compound of any one of embodiments 10-23, wherein R y is not substituted with an R d group.
  • Embodiment 25 is the compound of any one of embodiments 10-23, wherein R y is substituted with 1 R d group.
  • Embodiment 26 is the compound of any one of embodiments 10-23, wherein R y is substituted with 2 R d groups.
  • Embodiment 27 is the compound of any one of embodiments 1-26, wherein R 4 is not substituted with an R z group.
  • Embodiment 28 is the compound of any one of embodiments 1-26, wherein R 4 is substituted with 1 R z group.
  • Embodiment 29 is the compound of any one of embodiments 1-26, wherein R 4 is substituted with 2 R z groups.
  • Embodiment 30 is the compound of any one of embodiments 1-29, wherein W is CH.
  • Embodiment 31 is the compound of any one of embodiments 1-30, wherein R 7 and R 8 are each H.
  • Embodiment 32 is the compound of any one of embodiments 1-30, wherein R 7 and R 8 join together to form a 1 or 2 carbon bridged rin g system.
  • Embodiment 33 is the compound of embodiment 1, having the structure of Formula (Ic) and pharmaceutically acceptable salts, solvates, and prodrugs thereof.
  • Embodiment 34 is the compound of embodiment 33, wherein R is H.
  • Embodiment 35 is the compound of embodiment 33, wherein R 4 is m-tolyl or m- chlorophenyl.
  • Embodiment 36 is the compound of embodiment 33, wherein R 1 is H, methyl, ethyl or isopropyl substituted with 1 R y group and R y is substituted with 1 or 2 R d groups.
  • Embodiment 37 is the compound of embodiment 33, having the structure of Formula (Ic- pharmaceutically acceptable salts, solvates, and prodrugs thereof wherein n is 0, 1 or 2; and each R x is independently halo, cyano, C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy.
  • Embodiment 38 is the compound of embodiment 37, wherein n is 1 or 2; and each R x is independently F, Cl, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, fluoroethoxy, difluoroethoxy, or trifluoroethoxy.
  • Embodiment 39 is the compound of embodiment 37, wherein R 1 is H, methyl, ethyl or isopropyl substituted with 1 R y group and R y is substituted with 1 or 2 R d groups.
  • Embodiment 40 is a compound selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof or a compound selected from
  • Embodiment 41 is a compound and/or a pharmaceutically acceptable salt of any one of embodiments 1-40, wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.
  • Embodiment 42 is a pharmaceutical composition comprising a compound and/or a pharmaceutically acceptable salt of any one of embodiments 1-41 and a pharmaceutically acceptable excipient.
  • Embodiment 43 is a method of inhibiting PIKf ve kinase in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of embodiments 1-41, or a pharmaceutical composition of embodiment 42.
  • Embodiment 44 is a method of treating a neurological disease associated with PIKfyve activity in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of embodiments 1-51, or a pharmaceutical composition of embodiment 52.
  • Embodiment 45 is the method of embodiment 44, wherein the neurological disease is amyotrophic lateral sclerosis (ALS), primary' lateral sclerosis (PLS), Charcot-Marie-Tooth (CMT; including ty pe 4J (CMT4J)), and Yunis-Varon syndrome, autophagy, polymicrogyria (including polymicrogyria with seizures), temporo-occipital polymicrogyria.
  • ALS amyotrophic lateral sclerosis
  • PLS primary' lateral sclerosis
  • CMT Charcot-Marie-Tooth
  • Yunis-Varon syndrome autophagy
  • polymicrogyria including polymicrogyria with seizures
  • temporo-occipital polymicrogyria is the method of embodiment 44, wherein the neurological disease is amyotrophic lateral sclerosis (ALS), primary' lateral sclerosis (PLS), Charcot-Marie-Tooth (CMT; including ty
  • Parkinson’s disease Parkinson’s disease with Lewy 7 bodies, dementia with Lewy bodies, Lewy' body disease, fronto-temporal dementia, diseases of neuronal nuclear inclusions of polyglutamine and intranuclear inclusion bodies, disease of Marinesco and Hirano bodies, tauopathy, Alzheimer’s disease, neurodegeneration, spongiform neurodegeneration, peripheral neuropathy, leukoencephalopathy, inclusion body disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, traumatic brain injury' (TBI), cerebral ischemia, Guillain-Barre Syndrome, chronic inflammatory' demyelinating polyneuropathy, multiple sclerosis, a lysosomal storage disease, Fabry’s disorder, Gaucher's disorder, Niemann Pick C disease, Tay-Sachs disease, and Mucolipidosis type IV, neuropathy. Huntington’s disease, a psychiatric disorder, ADHD, schizophrenia, a mood disorder, major depressive
  • Embodiment 46 is the method of embodiment 44, wherein the disease is ALS, FTD, Alzheimer’s disease. Parkinson’s disease. Huntington’s disease, or CMT.
  • Embodiment 47 is the method of embodiment 44, wherein the disease is ALS.
  • Embodiment 48 is the method of embodiment 44, wherein the disease is a tauopathy such as Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, or chronic traumatic encephalopathy.
  • a tauopathy such as Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, or chronic traumatic encephalopathy.
  • Embodiment 49 is the method of embodiment 44, wherein the disease is a lysosomal storage disease such as Fabry’s disorder, Gaucher's disorder, Niemann Pick C disease, Tay- Sachs disease, or Mucolipidosis type IV.
  • Fabry Fabry’s disorder
  • Gaucher's disorder Gaucher's disorder
  • Niemann Pick C disease Tay- Sachs disease
  • Mucolipidosis type IV Mucolipidosis type IV.
  • Embodiment 50 is the method of embodiment 44, wherein the disease is a psychiatric disorder such as ADHD, schizophrenia, or mood disorders such as major depressive disorder, depression, bipolar disorder I, or bipolar disorder II.
  • a psychiatric disorder such as ADHD, schizophrenia, or mood disorders such as major depressive disorder, depression, bipolar disorder I, or bipolar disorder II.
  • Embodiment 51 is a compound of any one of embodiments 1-41 for use as a medicament.
  • Embodiment 52 is the compound of embodiment 51, wherein the compound is for use in treating a neurological disease treatable by inhibition of PIKlyve kinase.
  • Embodiment 53 is the use of a compound of any one of embodiments 1-41 in the manufacture of a medicament for treating a neurological disease in a subject in which PIKl ve contributes to the pathology and/or symptoms of the disease.
  • the term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary’ skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system.
  • “about” or “approximately” can mean within one or more than one standard deviation per the practice in the art.
  • “about” or “approximately” can mean a range of up to 10% (i.e., ⁇ 10%) or more depending on the limitations of the measurement system.
  • about 5 mg can include any number between 4.5 mg and 5.5 mg.
  • the terms can mean up to an order of magnitude or up to 5-fold of a value.
  • the meaning of “about” or “approximately” should be assumed to be within an acceptable error range for that particular value or composition.
  • Reference to "about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • B, and/or C is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
  • the terms “or a combination thereof’ and “or combinations thereof’ as used herein refers to any and all permutations and combinations of the listed terms preceding the term.
  • “A, B, C, or combinations thereof’ is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, ACB, CBA, BCA, BAC, or CAB.
  • a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -C(O)NH2 is attached through the carbon atom.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line or a dashed line drawn through a line in a Formula indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.
  • Cu-v indicates that the following group has from u to v carbon atoms.
  • Ci-6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to ten carbon atoms or a branched saturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl. butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to ten carbon atoms or a branched saturated divalent hydrocarbon radical of three to ten carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1 -methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Alkenyl means a linear unsaturated or partially unsaturated monovalent hydrocarbon radical of two to ten carbon atoms or a branched unsaturated or partially unsaturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., ethylenyl, propylenyl. 2-propylenyl, butenyl (including all isomeric forms), pentenyl (including all isomeric forms), and the like.
  • C2- x alkenyl refers to an alkenyl group with from 2 to x carbon atoms.
  • Alkylsulfonyl means a-SChR radical where R is alkyl as defined above, e.g., methylsulfonyl, ethyl sulfonyl, and the like.
  • amino means a -NH2.
  • Substituted amino means -NR*R**, where the R* and R** substituents are alkyl or substituted alkyl as defined herein.
  • Alkoxy means a -OR radical where R is alky l as defined above, e g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or /m-butoxy. and the like.
  • Alkoxyalkyl means a linear monovalent hydrocarbon radical of one to ten carbon atoms or a branched monovalent hydrocarbon radical of three to ten carbons substituted with an alkoxy group, (in one embodiment one or two alkoxy groups), as defined above, e.g., 2- methoxyethyl, 1-, 2-. or 3 -methoxy propyl. 2-ethoxyethyl, and the like.
  • Alkoxy carbonyl means a -C(O)OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
  • Acyl means a -C(O)R radical where R is alkyl, haloalky 1, or cycloalkyl, e.g., acetyd, propionyl, cyclopropylcarbonyl, and the like.
  • R is alky l
  • the radical is also referred to herein as alkylcarbonyl.
  • Aryl refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems.
  • aryl has 6 to 20 ring carbon atoms (i.e., C6-20 ary l), 6 to 18 carbon ring atoms (i.e., Ce-18 ary l), 6 to 12 carbon ring atoms (i.e., C6-12 aryl) or 6 to 10 carbon ring atoms (i.e., Ce-io aryl).
  • Examples of aryl groups include phenyl, naphthyl, fluorenyl and anthryl.
  • Aryl does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroary l, the resulting ring system is heteroary l. If one or more aryl groups are fused with a heterocycly 1, the resulting ring system is heterocyclyl.
  • Cycloalkyl means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms wherein one or two carbon atoms may be replaced by an oxo group, e.g., cyclopropy 1, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.
  • Carboxy means -C(O)OH.
  • Carboxamide means - C(O)NR*R**.
  • Carboxamide means -OC(O)NR*R**.
  • Halo means fluoro, chloro, bromo, or iodo; in one embodiment fluoro or chloro.
  • Haloalkyl means alkyl radical as defined above, which is substituted with one or one to five halogen atoms (in one embodiment fluorine or chlorine,) including those substituted with different halogens, e.g., -CH2CI. -CF3. -CHF2. -CH2CF3, -CF2CF3, -CF(CH3)2, and the like. When the alkyl is substituted with only fluoro, it can be referred to in this disclosure as fluoroal kyl.
  • Haloalkoxy means a -OR radical where R is haloalkyl as defined above e.g., -OCF3, -OCHF2, and the like.
  • R is haloalkyl where the alkyl is substituted with only fluoro, it can be referred to in this disclosure as fluoroalkoxy.
  • “Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2- hydroxy ethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2- hydroxybutyl, 3-hydroxybutyl. 4-hydroxybutyl, 2,3-dihydroxypropyl, l-(hydroxymethyl)-2- hydroxyethyl, 2.3-dihydroxybutyl.
  • Heterocyclyl means a saturated or unsaturated monovalent monocyclic or bi-cyclic group (fused bi-cyclic or bridged bi-cyclic or spiro compounds) of 4 to 10 ring atoms in which one or two ring atoms are heteroatom selected from N, O. and S(O) n , where n is an integer from 0 to 2, the remaining ring atoms being C. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -CO- group.
  • heterocyclyl includes, but is not limited to, oxetanyl, pyrrolidino, piperidino, homopiperidino, 2- oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, hexahydropyrrolo[1.2-a]pyrazin-6(2H)-one-yl, tetrahydro-lH-oxazolo[3.4-a]pyrazin-3(5H)-one- yl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine-yl, 3-oxa-8-azabicyclo[3.2.1]octane-yl, 6- oxa-l-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, and the like.
  • C x-y heterocyclyl refers to a heterocyclyl group with from x to y carbon atoms in the ring, where x and y are integers.
  • Heterocyclylalkyl or “heterocycloalkyl” means a -(alkylene)-R radical where R is heterocyclyl ring as defined above e g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.
  • Heterocycloamino means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(O) n , where n is an integer from 0 to 2, the remaining ring atoms being C provided that at least one of the ring atoms is N.
  • one or two ring carbon atoms in the heterocycloamino ring can optionally be replaced by a -CO- group.
  • the heterocycloamino ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.
  • Heterocycloaminoalkyr means a -(alkylene)-R radical where R is heterocycloamino as described above.
  • Heteroaryf means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms where one or more, (in one embodiment one, two, or three), ring atoms are heteroatom selected from N, O, and S, the remaining ring atoms being carbon.
  • Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pynmidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.
  • Cx-yheteroaryl refers to a heteroaryl group with from x to y carbon atoms, where x and y are integers.
  • Rea means -NRC(O)NR*R**.
  • Triazaindene and “triazaindenyl” refers to 3f/-imidazo(4.5-6)pyridine. unless specified otherwise.
  • mammal as used herein means domesticated animals (such as dogs, cats, and horses), and humans. In one embodiment, mammal is a human.
  • salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, /Moluenesul fonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary , and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • heterocyclyl group optionally substituted with an alkyl group means that the al kyl may but need not be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with alkyl.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular. subarachnoid, intraspinal and intrastemal injection and infusion.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository' waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydro
  • a “therapeutically effective amount” means the amount of a compound of Formula (I) (or any of the embodiments thereof described herein), that, when administered to a mammal for treating a disease, is sufficient to treat the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity 7 and the age, weight, etc., of the mammal to be treated.
  • the compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. All chiral, diastereomeric, racemic forms, as individual forms and mixtures thereof, are within the scope of this disclosure, unless the specific stereochemistry 7 or isomeric form is specifically indicated.
  • Compounds of the present disclosure containing an asymmetrically substituted atom may be isolated in optically active, optically enriched, optically pure, or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recry stallization, or chromatography, or any combination thereof.
  • Stereoisomers may' also be obtained by stereoselective synthesis.
  • Certain compounds of Formula (I) may exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof, are within the scope of this disclosure.
  • pyrazole tautomers as shown below are equivalent structures. The depiction of one such structure is intended to encompass both structures.
  • alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as heteroaryl, heterocyclyl are substituted, they include all the positional isomers.
  • the present disclosure also includes the prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt thereof.
  • the term prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula (I) (or any of the embodiments thereof described herein) when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo.
  • Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups in vivo or by routine manipulation.
  • Prodrugs of compounds of Formula (I) include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified.
  • Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., A/A imethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like.
  • Prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt thereof are also within the scope of this disclosure.
  • the present disclosure also includes polymorphic forms (amorphous as well as crystalline) and deuterated forms of compounds of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt thereof.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, n C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846.514 and 6,334,997.
  • deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Isotopic substitution with 2 H, n C, 13 C. 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 CL 37 C1, 79 Br, 81 Br, and 125 I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention
  • the compounds disclosed herein have some or all of the atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21 ; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32. [0119] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • W is N, CH, or CR 4 *
  • R is H, oxo, alkyl, alkenyl, heteroaryl, heterocyclyl, or carboxamide, each substituted with 0, 1, or 2 R x groups and each R x is oxo, hydroxyl, cyano, substituted or unsubstituted alky l, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, substituted or unsubstituted ester, substituted or unsubstituted sulfonyl, substituted or unsubstituted amide, substituted or unsubstituted carboxamide, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkoxyalkyl;
  • R 1 is H, alkyl, cycloalkyl, heterocyclyl, amino, alkoxy, alkoxyalkyl, amide, carboxamide, or sulfonyl, each substituted with 0, 1, or 2 R y groups and each R y is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted amino, substituted or unsubstituted ester, substituted or unsubstituted sulfonyl, substituted or unsubstituted amide, substituted or unsubstituted carboxamide, substituted or unsubstituted urea, substituted or unsubstituted carb
  • R 4 and R 4 * are aryl, heteroaryl, or heterocyclyl, each substituted with 0, 1, or 2 R z groups and each R z is alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halo, or -CN, provided that only one of R 4 and R 4 * is present; or when R 3 and R 4 are bonded to the same carbon, then R 3 and R 4 join to form a monocyclic or bicyclic cycloalkyl;
  • R 5 is H, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy carbonyl, substituted or unsubstituted ester, or substituted or unsubstituted carboxamide;
  • R 6 is absent, H, or alkyl;
  • R 7 and R 8 are each independently H, Ci-6 alkyl or R 7 and R 8 join together to form a fused or bridging ring system;
  • — represents a single or double bond; x is 0, 1 or 2;
  • R 9 is absent or oxo; and pharmaceutically acceptable salts, solvates, and prodrugs thereof; provided that when R 6 is absent, R 7 and R 8 are
  • R 4 is m-tolyl. then R is not substituted or unsubstituted piperidinyl; substituted or unsubstituted pyrrolidinyl; -CH2OH; -CH 2 (substituted or unsubstituted heterocyclyl); or C(O)NR*R** wherein R* and R** join to form a substituted or unsubstituted heterocyclic group.
  • W is CH. In some embodiments, W is N. In some embodiments, W is CR 4 *.
  • R is H, oxo, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted monocyclic heterocyclyl, or R a R b NC(O)-.
  • R is H, oxo, methyl, ethyl, propyl, isopropyl, isobutyl, propenyl, pyridyl, pyrimidinyl, pyrazolyl, dioxanyl, oxetanyl, morpholino, 3,6-dihydro-2H- pyranyl, or R a R b NC(O)-.
  • R is H and R 6 is absent.
  • R is not R a R b NC(O)-.
  • R x is monocyclic heteroaryl, monocyclic heterocyclyl, Ci-6 alkyl, Ci-6 cycloalkyl, R a R b N, R a O-, R c , R a R b N-(Ci-6 alkyl)-, R a O-(Ci-6 alkyl)-, or R C O-(CI-6 alkyl)-.
  • R x is methyl, cyclopropyl, cyclobutyl, pyridyl, pyrazolyl, morpholino.
  • R is not substituted with an R x group. In some embodiments, R is substituted with 1 R x group. In some embodiments, R is substituted with 2 R x groups.
  • each R a and R b is independently H, Ci-6 alkyl, Ci-e haloalkyl, Ci-6 cycloalkyl, or CHsC(O)-.
  • each R a and R b is independently H, cyclopropyl, cyclobutyl, methyl, ethyl, CH3C(O)-, -CD3, or -CF3.
  • each R c is H, methyl, ethyl, HOC(O)CH2-. CHsOC(O)CH2-, (CH 3 )3COC(O)CH 2 -, (CH 3 )3COC(O)NH-, H 2 NC(O)CH 2 -, CH 3 NHC(O)CH2-, (CH 3 ) 2 NC(O)CH2-, NC-ethyl, H 2 N-, H 2 N-ethyl, CH 3 NH-ethyl, or (CH 3 ) 2 N-ethyl.
  • R 1 is H, C1-6 alkyl, C1-6 cycloalkyl, monocyclic heterocyclyl, R a O-, R a O-(Ci-6 alkyl), R a R b NC(O)-, or alkyl-SCh-.
  • R 1 is H, propyl, ethyl, methyl, isobutyl, cyclobutyl, cyclopropyl, azetidinyl. oxetanyl.
  • R y is Ci-6 alkyl, Ci-6 alkenyl, Ci-6 haloalkyl, Ci-6 cycloalkyl, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocyclyl, halo, -CN, -OH, R a O-, CH3SO2- CH 3 C(O)-, R a OC(O)-, R a R b NC(O)-, H 2 NC(O)NH-,R a R b N-, or methylallyl, each further substituted with 0, 1, or 2 R d groups. In some embodiments.
  • R y is methyl, cyclopropyl, cyclobutyl, pyridinyl, phenyl, piperidinyl. pyrrolidinyl, oxetanyl. pyrrolidinone, imidazolidin-2- one, oxazolidin-2-one, lH-l,2,4-triazol-5-one, tetrahydropyran, dioxanyl, azetidinyl, -CN, -F, - CF3, -OH, R a O-, CH3SO2-, CH 3 C(O)-, HOC(O)-, R a R b NC(O)-, H 2 NC(O)NH-, R a R b N-, or methylallyl
  • R 1 is not substituted with an R y group. In some embodiments. R 1 is substituted with 1 R y group. In some embodiments, R 1 is substituted with 2 R y groups.
  • R d is methyl, oxo, CHsC(O)-, CHsOC(O)-, CH3SO2-, -F, (CH 3 )3CO-, (CD 3 ) 3 CO-, R a O-, -CN, -NH2, (CH 3 )3COC(O)-, H 2 NC(O)-, CH 3 HNC(O)-.
  • R y is not substituted with an R d group. In some embodiments. R y is substituted with 1 R d group. In some embodiments, R y is substituted with 2 R d groups.
  • R 4 is H, phenyl, pyrazolyl, thiazolyl, thienyl, oxabicyclo[2.1.1]hexanyl, and norbomanyl, each substituted by 0, 1, or 2 R z .
  • R 4 is H, phenyl, pyrazolyl, thiazolyl, thienyl, oxabicyclo[2.1.1]hexanyl, or norbomanyl.
  • each R z is -CN, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 cycloalkyl, deuterated alkyd, or C1-6 haloalkoxy.
  • R z is -Cl, -F, -CN, -CF3, -CD3, -OCF3, methyl, ethyl, cyclopropyl, methoxy, difluoromethoxy, or difluoromethyl.
  • R 4 is not substituted with an R z group. In some embodiments. R 4 is substituted with 1 R z group. In some embodiments, R 4 is substituted with 2 R z groups.
  • R 4 is tolyl. In some embodiments, R 4 is m-tolyl. In some embodiments, R 4 is chlorophenyl. In some embodiments, R 4 is m-chlorophenyl.
  • R 5 is -C(O)NR a R b , -C(O)OR a , unsubstituted C1-6 alkyl, or C1-6 alkyl substituted with 1 or 2 OR a or alkylamino groups.
  • R 5 is H, hydroxymethyl, hydroxyethyl, methoxymethyl, H 2 N-methyl, CHsNH-methyl. or (CH3) 2 N- methyl, trideuteriomethoxymethyl, -C(O)NR a R b , -C(O)OR a .
  • R 6 is absent.
  • R 7 and R 8 are each H. In some embodiments one of R 7 and R 8 is H. In some embodiments one of R 7 and R 8 is methyl. In some embodiments R 7 and R 8 join together to form a fused or bridging ring system. In some embodiments R 7 and R 8 join together to form a fused ring system. In some embodiments R 7 and R 8 join together to form a bridging ring system. In some embodiments when R 7 and R 8 join together to form a fused ring system the additional ring is a 4, 5, 6, or 7 membered ring. In some embodiments R 7 and R 8 join together to form a bridged ring system wherein the bridge comprises 1, 2, or 3 carbon atoms.
  • R is H
  • R 4 is m-tolyl or m-chlorophenyl
  • R 1 is H, methyl, ethyl or isopropyl substituted with 1 R y group and R y is substituted with 1 or 2 R d groups.
  • n 0, 1 or 2; and each R x is independently halo, cyano, C1-3 alky l, C1-3 haloalkyl, C3-6 cycloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy.
  • n is 1 or 2; and each R x is independently F, Cl, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, fluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, fluoroethoxy, difluoroethoxy, or trifluoroethoxy.
  • R 1 is H, methyl, ethyl or isopropyl substituted with 1 R y group and R y is substituted with 1 or 2 R d groups.
  • ring is a 5- or 6- membered heterocyclic ring comprises optionally a C, N or O in addition to the N at the fusion point for the rings, and is optionally substituted with an oxo group, an alky l group, halo, CN, or alkoxy group.
  • the compound of Formula (I) is selected from:
  • the compound of Formula (I) is selected from the compounds of Table 1.
  • the compounds of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Therapeutically effective amounts of compounds of Formula (I) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
  • the dosage level will be about 0. 1 to about 250 mg/kg per day.
  • the dosage level will be about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0. 1 to about 50 mg/kg per day.
  • the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day.
  • the compositions may be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.
  • the actual amount of the compound of this disclosure, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subj ect, the potency of the compound being utilized, the route and form of administration, and other factors.
  • compositions will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g.. transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration.
  • routes e.g.. oral, systemic (e.g.. transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration.
  • parenteral e.g., intramuscular, intravenous, or subcutaneous
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • compositions can be formulated using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries.
  • the formulation can be modified depending upon the route of administration chosen.
  • the pharmaceutical compositions can also include the compounds described herein in a free base form or a pharmaceutically acceptable salt form.
  • Methods for formulation of the pharmaceutical compositions can include formulating any of the compounds described herein with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.
  • Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives.
  • the compositions described herein can be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drugdelivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drugdelivery systems e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration.
  • compositions described herein can be formulated for administration as an injection.
  • formulations for injection can include a sterile suspension, solution, or emulsion in oily or aqueous vehicles.
  • Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils, synthetic fatty acid esters, or liposomes.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension.
  • the suspension can also contain suitable stabilizers.
  • Injections can be formulated for bolus injection or continuous infusion.
  • the compounds can be formulated in a unit dosage injectable form (e.g.. solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle.
  • a pharmaceutically acceptable parenteral vehicle e.g.. water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin.
  • Nonaqueous vehicles such as fixed oils and ethyl oleate can also be used.
  • Liposomes can be used as carriers.
  • the vehicle can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).
  • sustained-release preparations can also be prepared.
  • sustained-release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and y ethyl-L-glutamate, non- degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTM (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.
  • LUPRON DEPOTM i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate
  • poly-D-(-)-3-hydroxybutyric acid i.e., injectable microspheres composed of lactic acid
  • compositions described herein can be prepared for storage by mixing a compound with a pharmaceutically acceptable carrier, excipient, and/or a stabilizer.
  • This formulation can be a lyophilized formulation or an aqueous solution.
  • Acceptable carriers, excipients, and/or stabilizers can be nontoxic to recipients at the dosages and concentrations used.
  • Acceptable carriers, excipients, and/or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and/or nonionic surfactants or polyethylene glycol.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid and methionine
  • preservatives polypeptides
  • proteins such as serum albumin or gelatin
  • hydrophilic polymers amino acids
  • Compounds of the present disclosure may be used in methods of treating in combination with one or more other combination agents (e.g., one, two, or three other drugs) that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present disclosure are useful.
  • the combination of the drugs together are safer or more effective than either drug alone.
  • the compound disclosed herein and the one or more combination agents have complementary activities that do not adversely affect each other.
  • Such molecules can be present in combination in amounts that are effective for the purpose intended.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure.
  • the agents are administered together in a single pharmaceutical composition in unit dosage form.
  • the pharmaceutical compositions of the present disclosure also include those that contain one or more other active ingredients, in addition to a compound of the present disclosure.
  • the weight ratio of the compound of the present disclosure to the second active agent may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • combination therapy includes therapies in which the compound of the present disclosure and one or more other drugs are administered separately, and in some cases, the two or more agents are administered on different, overlapping schedules.
  • the combination agent is a drug for reduction of symptoms of ALS.
  • the combination agent is selected from an NAD supplement (such as nicotinamide riboside, offered under the trade names Basis® or Tru Niagen®). vitamin B12 (oral or injection), glycopyrrolate, atropine, scopolamine, baclofen, tizanidine. mexiletine. an SSRI. a benzodiazepine, Neudexta. riluzole, and edaravone, and combinations thereof.
  • the compounds, pharmaceutical compositions, and methods of the present disclosure can be useful for treating a subj ect such as, but not limited to, a mammal, a human, a non-human mammal, a domesticated animal (e.g., laboratory animals, household pets, or livestock), a nondomesticated animal (e.g., wildlife), a dog, a cat, a rodent, a mouse, a hamster, a cow, a bird, a chicken, a fish, a pig, a horse, a goat, a sheep, or a rabbit.
  • a subj ect such as, but not limited to, a mammal, a human, a non-human mammal, a domesticated animal (e.g., laboratory animals, household pets, or livestock), a nondomesticated animal (e.g., wildlife), a dog, a cat, a rodent, a mouse, a hamster, a cow, a bird,
  • the compounds, pharmaceutical compositions, and methods described herein can be useful as a therapeutic, for example a treatment that can be administered to a subject in need thereof.
  • a therapeutic effect can be obtained in a subject by reduction, suppression, remission, or eradication of a disease state, including, but not limited to, a symptom thereof.
  • a therapeutic effect in a subject having a disease or condition, or pre-disposed to have or is beginning to have the disease or condition can be obtained by a reduction, a suppression, a prevention, a remission, or an eradication of the condition or disease, or pre-condition or pre-disease state.
  • therapeutically effective amounts of the compounds or pharmaceutical compositions described herein can be administered to a subject in need thereof, often for treating and/or preventing a condition or progression thereof.
  • a pharmaceutical composition can affect the physiol ogy of the subject, such as the immune system, inflammatory response, or other physiologic affect.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors.
  • Treat and/or treating can refer to any indicia of success in the treatment or amelioration of the disease or condition. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treat can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely. [0161] Prevent, preventing, and the like can refer to the prevention of the disease or condition in the patient. For example, if an individual at risk of contracting a disease is treated with the methods of the present disclosure and does not later contract the disease, then the disease has been prevented, at least over a period of time, in that individual.
  • a therapeutically effective amount can be the amount of a compound or pharmaceutical composition or an active component thereof sufficient to provide a beneficial effect or to otherwise reduce a detrimental non-beneficial event to the individual to whom the composition is administered.
  • a therapeutically effective dose can be a dose that produces one or more desired or desirable (e.g., beneficial) effects for which it is administered, such administration occurring one or more times over a given period of time. An exact dose can depend on the purpose of the treatment and can be ascertainable by one skilled in the art using known techniques.
  • the compounds or pharmaceutical compositions described herein that can be used in therapy can be formulated and dosages established in a fashion consistent with good medical practice taking into account the disorder to be treated, the condition of the individual patient, the site of delivery' of the compound or pharmaceutical composition, the method of administration and other factors known to practitioners.
  • the compounds or pharmaceutical compositions can be prepared according to the description of preparation described herein.
  • compositions or compounds described herein can be for administration to a subject in need thereof.
  • administration of the compounds or pharmaceutical compositions can include routes of administration, non-limiting examples of administration routes include intravenous, intraarterial, subcutaneous, subdural, intramuscular, intracranial, intrastemal, intratumoral, or intraperitoneally.
  • a pharmaceutical composition or compound can be administered to a subject by additional routes of administration, for example, by inhalation, oral, dermal, intranasal, or intrathecal administration.
  • Pharmaceutical compositions or compounds of the present disclosure can be administered to a subject in need thereof in a first administration, and in one or more additional administrations.
  • the one or more additional administrations can be administered to the subject in need thereof minutes, hours, days, weeks, or months following the first administration. Any one of the additional administrations can be administered to the subject in need thereof less than 21 days, or less than 14 days, less than 10 days, less than 7 days, less than 4 days or less than 1 day after the first administration.
  • the one or more administrations can occur more than once per day, more than once per week, or more than once per month.
  • the compounds or pharmaceutical compositions can be administered to the subject in need thereof in cycles of 21 days. 14 days, 10 days, 7 days, 4 days, or daily over a period of one to seven days.
  • the compounds, pharmaceutical compositions, and methods provided herein can be useful for the treatment of a plurality of diseases or conditions or preventing a disease or a condition in a subject, or other therapeutic applications for subjects in need thereof.
  • the disclosure relates to a method for treating a neurological disease mediated by PIKfyve activity in a subject in need thereof, comprising administering an effective amount of a compound or a pharmaceutical composition as described herein to the subject.
  • the disease is associated with a FIG4 deficiency.
  • the neurological disease is amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth (CMT; including type 4J (CMT4J)), and Yunis-Varon syndrome, autophagy 7 , polymicrogyria (including polymicrogyria with seizures), temporo-occipital polymicrogyria.
  • ALS amyotrophic lateral sclerosis
  • PLS primary lateral sclerosis
  • CMT Charcot-Marie-Tooth
  • Yunis-Varon syndrome autophagy 7
  • polymicrogyria including polymicrogyria with seizures
  • temporo-occipital polymicrogyria temporo-occipital polymicrogyria.
  • Parkinson’s disease Parkinson’s disease with Lewy bodies, dementia with Lewy bodies, Lewy body disease, fronto-temporal dementia, diseases of neuronal nuclear inclusions of polyglutamine and intranuclear inclusion bodies, disease of Marinesco and Hirano bodies, tauopathy, Alzheimer's disease, neurodegeneration, spongiform neurodegeneration, peripheral neuropathy, leukoencephalopathy, motor neuropathy, sensory neuropathy, inclusion body disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, traumatic brain injury (TBI), cerebral ischemia, Guillain-Barre Syndrome, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, a lysosomal storage disease, Fabry ’s disorder, Gaucher's disorder, Niemann Pick C disease, Tay-Sachs disease, and Mucolipidosis type IV, neuropathy, Huntington's disease, a psychiatric disorder, ADHD, schizophrenia, a mood
  • the neurological disease is ALS, FTD, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or CMT. In some embodiments, the neurological disease is ALS.
  • the neurological disease is a tauopathy such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, or chronic traumatic encephalopathy.
  • the neurological disease is a lysosomal storage disease such as Fabry's disorder, Gaucher's disorder, Niemann Pick C disease, Tay-Sachs disease, or Mucolipidosis type IV.
  • the neurological disease is a psychiatric disorder such as ADHD, schizophrenia, or mood disorders such as major depressive disorder, depression, bipolar disorder I, or bipolar disorder II.
  • the disclosure further provides any compounds disclosed herein for use in a method of treatment of the human or animal body by therapy. Therapy may be by any mechanism disclosed herein, such as inhibiting, reducing, or reducing progression of the diseases disclosed herein.
  • the disclosure further provides any compound disclosed herein for prevention or treatment of any condition disclosed herein.
  • the disclosure also provides any compound or pharmaceutical composition thereof disclosed herein for obtaining any clinical outcome disclosed herein for any condition disclosed herein.
  • the disclosure also provides use of any compound disclosed herein in the manufacture of a medicament for preventing or treating any disease or condition disclosed herein.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds.
  • the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C, or from about 0 °C to about 125 °C or at about room (or ambient) temperature, e.g., about 20 °C.
  • trimethoxymethane 970 mL
  • TSOH-H2O 3.7 g, 0.021 mol
  • reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4. filtrated and concentrated. The resulting residue was purified by silica gel column chromatography with a gradient elution of 5% EtOAc/PE to 25% EtOAc/PE to provide ethyl l-(6-((2-methoxyethyl)amino)-4-morpholino- 5-nitropyridin-2-yl)-3-(m-tolyl)-lH-pyrazole-5-carboxylate (395 mg, 0.77 mmol) as a yellow oil.
  • reaction mixture was diluted with water (30 mL) and extracted with DCM (3 x 20 mL). The combined organic phases were washed with saturated aqueous NaCl solution (2 x 20 mL), dried over anhydrous NazSO-i. filtrated and concentrated. The resulting residue was purified by slurry in MeOH to provide l-(3-(2-methoxyethyl)-7- morpholino-3H-imidazo[4,5-b]pyridin-5-yl)-N-methyl-3-(m-tolyl)-lH-pyrazole-5-carboxamide (36 mg, 0.077 mmol) as an off-white solid.
  • reaction mixture was diluted with water (30 mL) and extracted with DCM (3 x 20 mL). The combined organic phases were washed with saturated aqueous NaCl solution (2 x 20 mL), dried over anhydrous Na2SC>4, filtrated and concentrated.
  • N2-(2,4-dimethoxybenzyl)-4-morpholino-6-(3-(m- tolyl)-lH- pyrazol-l-yl)pyridine-2,3-diamine 107.0 g, 0.21 mol
  • trimethoxymethane 970 mL
  • TSOH-H2O 3.7 g, 0.021 mol
  • the reaction mixture was heated to reflux and stirred for 2 h. After completion of the reaction as indicated by TLC and LC-MS analysis, the reaction mixture was concentrated directly. The resulting residual was slurry in EtOAc/PE (1/5.
  • reaction mixture was diluted wi th water (20 mL) and extracted with DCM (3 x 10 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduce pressure. The resulting residue was purified by preparative TLC with an elution of 50% EtOAc/PE to provide l-((5-(3-(3-(difluoromethoxy)phenyl)-lH-pyrazol-l-yl)-7-morpholino-3H- imidazo[4,5-b]pyridin-3-yl)methyl)cyclopropanecarbonitrile (39 mg, 0.079 mmol) as a white solid.
  • reaction mixture was diluted with water (20 mL).
  • the aqueous solution was extracted with EtOAc (3 x 10 mL).
  • the combined organic phases were washed with saturated aqueous NaCl solution (2 x 20 mL), dried over anhydrous Na2SO4, filtrated and concentrated.
  • reaction mixture was stirred at rt for 3 h. After completion of the reaction as indicated by TLC analysis, the reaction mixture was quenched with water (50 mL) and extracted with DCM (3 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduce pressure. The resulting residue was used for the next step without further purification.
  • reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated.
  • reaction mixture was stirred at that temperature for 1 h. After completion of the reaction as indicated by TLC and LC-MS analysis, the reaction mixture was quenched with NH4CI solution and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduce pressure.
  • PIKFYVE Full length human recombinant PIKFYVE expressed in baculovirus expression system as N-termmal GST-fusion protein (265 kDa) was obtained from Cama Biosciences (Kobe, Japan).
  • the kinase substrate was prepared by mixing and sonicating fluorescently-labeled phosphatidylinositol 3-phosphate (PI3P) with phospho-L-serine (PS) at a 1 : 10 ratio in 50 mM HEPES buffer pH7.5.
  • kinase reactions were assembled in 384-well plates (Greiner) in a total volume of 20 mL as follows.
  • Kinase protein was pre-diluted in an assay buffer comprising 25 mM HEPES, pH 7.5, 1 mM DTT, 2.5 mM MgCh, and 2.5 mM MnCh, and 0.005% Triton X-100, and dispensed into a 384-well plate (10 pL per well).
  • Test compounds were serially pre-diluted in DMSO and added to the protein samples by acoustic dispensing (Labcyte Echo). The concentration of DMSO was equalized to 1% in all samples. All test compounds were tested at 12 concentrations.
  • Apilimod was used as a reference compound and was tested in identical manner in each assay plate.
  • Control samples (0%-inhibition, in the absence of inhibitor, DMSO only) and 100%-inhibition (in the absence of enzyme) were assembled in replicates of four and were used to calculate %-inhibition in the presence of compounds.
  • the reactions were initiated by addition of 10 pL of 2x PI3P/PS substrate supplemented with ATP.
  • the final concentration of enzyme was 2 nM
  • the final concentration of ATP was 10 mM
  • the final concentration of PI3P/PS substrate was 1 pM (PI3P).
  • the kinase reactions were allowed to proceed for 3 h at room temperature.
  • Terminated plates were analyzed on a microfluidic electrophoresis instrument (Caliper LabChip® 3000, Caliper Life Sciences/Perkin Elmer). The change in the relative fluorescence intensity of the PI(3)P substrate and PI(3,5)P product peaks was measured. The activity' in each test sample was determined as the product to sum ratio (PSR): P/(S+P), where P is the peak height of the product, and S is the peak height of the substrate. Percent inhibition (Pinh) was determined using the following equation:
  • Pinh (PSR.0°/oinh - PSRcompound)/(PSRo%inh - PSR100%inh)* 100 in which PSRcompound is the product/sum ratio in the presence of compound.
  • PSRo%inh is the product/sum ratio in the absence of compound, and the PSRioo%inh is the product/sum ratio in the absence of the enzyme.
  • ICso of test compounds 50%-inhibition
  • the %-inh cdata (Pinh versus compound concentration) were fitted by a four-parameter sigmoid doseresponse model using XLfit software (IDBS).
  • HEK 293T Immortalized human embryonic kidney 293T
  • plasmids containing TDP-43 Q331K mutation were transfected with plasmids containing TDP-43 Q331K mutation, resulting in an increase in cell death that is biologically relevant to ALS patients.
  • Cell death is measured as reductions in the amount of ATP, an indicator of metabolically active cells, that is quantified by a luminescence Cell-Titer- Glo® (CTG) reagent.
  • CCG luminescence Cell-Titer- Glo®
  • HEK293T cells were passaged using 0.25% Trypsin-EDTA and plated at a density of 10,000 cells/well in 96- well tissue culture plates (inner 60 wells). The following day, the cells were transfected with TDP43-Q331K plasmid using Lipofectamine 3000 and treatment with compound was performed (9-point dose response curve, half-log serial dilution with lOuM as the highest concentration with 6 replicates). After 48 hours of incubation, CellTiter-Glo reagent was added, and the lysates were transferred to opaque white flat-bottom polystyrene plates. Compound induced rescue of HEK cells with mutant TDP43 related viability deficit was measured using the CellTiter-Glo assay.
  • Dose-response curve graphs were generated using GraphPad Prism. ECso values for compound treatment were determined using a four-parameter variable slope dose-response curve fitted to the Hill equation. Data point(s) of high concentration compound-induced toxicity resulting in decreased cellular viability was excluded.

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Abstract

La présente invention concerne des composés qui sont des inhibiteurs de kinases PIKfyve utiles pour le traitement de maladies neurologiques pouvant être traitées par inhibition de PIKfyve. L'invention concerne également des compositions pharmaceutiques contenant de tels composés, et des procédés de traitement utilisant de tels composés.
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