WO2022256299A1 - 7-morpholino-5-(3-phenyl-1 h-pyrazol-1 -yl)-furo[3,2-b]pyridine derivatives and similar compounds as pikfyve kinase inhibitors for the treatment of e.g. amyotrophic lateral sclerosis (als) - Google Patents

7-morpholino-5-(3-phenyl-1 h-pyrazol-1 -yl)-furo[3,2-b]pyridine derivatives and similar compounds as pikfyve kinase inhibitors for the treatment of e.g. amyotrophic lateral sclerosis (als) Download PDF

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WO2022256299A1
WO2022256299A1 PCT/US2022/031550 US2022031550W WO2022256299A1 WO 2022256299 A1 WO2022256299 A1 WO 2022256299A1 US 2022031550 W US2022031550 W US 2022031550W WO 2022256299 A1 WO2022256299 A1 WO 2022256299A1
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compound
alkyl
mmol
pyrazol
disease
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French (fr)
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Mark D. Rosen
Weiling Liang
Jr. Robert A. Galemmo
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Verge Analytics, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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

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 phosphorylation of phosphatidylinositol, 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 PIKfyve functions of endolysosomal transport, endomembrane homeostasis, and biogenesis of endosome carrier vesicles (ECV)/multivesicular bodies (MVB) from early endosomes. Further, PIKfyve is required for endocy tic- 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.
  • Mutations in PIKfyve are associated with corneal fleck dystrophy, an autosomal dominant disorder characterized by numerous white flecks in all layers of the corneal stroma.
  • 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, polymicrogyria (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, frontotemporal dementia, diseases of neuronal nuclear inclusions of polyglutamine 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, frontotemporal 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.
  • tauopathies including but not limited to Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementias, and chronic traumatic encephalopathy
  • TBI traumatic brain injury
  • ALS cerebral ischemia
  • FTD frontotemporal dementia
  • 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.
  • Embodiment 1 is a compound of Formula (I): wherein Y 1 is N or C-R 1 ; Y 2 is N or C-R 2 ; X is N, or CH; provided that when Y 1 is N, Y 2 is C-R 2 and when Y 2 is N, Y 1 is C-R 1 ; R 1 is H, or C 3-8 aryl, C 3-8 heteroaryl, C 3-8 cycloalkyl, or C 3-8 heterocyclyl, each optionally substituted with from 1 to 3 R s ; R 2 is H, or C 3-8 aryl, C 3-8 heteroaryl, C 3-8 cycloalkyl, or C 3-8 heterocyclyl, each optionally substituted with from 1 to 3 R s ; R 3 is H, halo, OH, C 1-4 alkyl, NR p R q , C 1-4 alkyl-NR p R q , C 1-4 alkyl-OH, C 1-4 alkyl
  • Embodiment 2 is the compound of embodiment 1, wherein Y 1 is N, Y 2 is C-R 2 .
  • Embodiment 3 is the compound of embodiment 1, wherein Y 2 is N, Y 1 is C-R 1 .
  • Embodiment 4 is the compound of embodiment 1, wherein Y 1 is C-R 1 and Y 2 is C-R 2 .
  • Embodiment 5 is the compound of embodiment 1, wherein Y 1 is C-R 1 and Y 2 is C-R 2 , and wherein one of R 1 and R 2 is not H.
  • Embodiment 6 is the compound of embodiment 1, wherein X is N.
  • Embodiment 7 is the compound of embodiment 1, wherein X is N, and one of Y 1 and Y 2 is N.
  • Embodiment 8 is the compound of embodiment 1, wherein X is N, Y 1 is C-R 1 , and Y 2 is C-R 2 .
  • Embodiment 9 is the compound of embodiment 1, wherein X is N, Y 1 is C-R 1 , and Y 2 is C-R 2 , and wherein one of R 1 and R 2 is not H.
  • Embodiment 10 is the compound of embodiment 1, wherein X is CH.
  • Embodiment 11 is the compound of embodiment 1, wherein X is CH, and one of Y 1 and Y 2 is N.
  • Embodiment 12 is the compound of embodiment 1, wherein X is CH, and Y 1 and Y 2 are N.
  • Embodiment 13 is the compound of any one of embodiments 1 - 12, wherein Y 1 is C-R 1 and R 1 is H, or phenyl or C 3-8 heteroaryl each optionally substituted with from 1 to 3 R s .
  • Embodiment 14 is the compound of any one of embodiments 1 - 13, wherein R 1 is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, or cyclopentenyl, each optionally substituted with 1 or 2 R s .
  • Embodiment 15 is the compound of any one of embodiments 1 - 13, wherein R 1 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 R s .
  • Embodiment 16 is the compound of any one of embodiments 1 - 15, wherein Y 2 is C-R 2 and R 2 is H, or phenyl or C 3-8 heteroaryl each optionally substituted with from 1 to 3 R s .
  • Embodiment 17 is the compound of any one of embodiments 1 - 16, wherein R 2 is phenyl, pyridinyl, pyrimidinyl, pyrazolyl or cyclopentenyl, each optionally substituted with 1 or 2 R s .
  • Embodiment 18 is the compound of any one of embodiments 1 - 16, wherein R 2 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 R s .
  • Embodiment 19 is the compound of any one of embodiments 1 - 18, wherein R 3 is H, C 1-4 alkyl-NR p R q , C 1-4 alkyl-OH, C 1-4 alkyl-OC 1-4 alkyl, C(O)OH, or C(O)-OC 1-4 alkyl.
  • Embodiment 20 is the compound of any one of embodiments 1 - 18, wherein R 3 is (CH 2 )NH 2 , (CH 2 )N(CH 3 ) 2 , (CH 2 )OH, (CH 2 )OCH 3 , C(O)OH, or C(O)OCH 2 CH 3 .
  • Embodiment 21 is the compound of any one of embodiments 1 - 20, wherein R 4 is phenyl, pyridinyl, pyrimidinyl, or pyrazolyl, each optionally substituted with from 1 to 2 R s .
  • Embodiment 22 is the compound of any one of embodiments 1 - 20, wherein R 4 is pyrazolylmethyl , imidazolylmethyl, morpholinomethyl, piperidinylmethyl, dioxanylmethy, dioxanylethyl, dioxanylethylenyl, dioxanylpropyl, dioxanylpropylenyl, cyclohexenyl, cyclopentenyl, dihydropyridinyl, each optionally substituted with from 1 to 2 R s .
  • Embodiment 23 is the compound of any one of embodiments 1 - 22, wherein R s is H, F, Cl, Br, NH2, OH, oxo, OC 1-6 alkyl, or C 1-6 alkyl.
  • Embodiment 24 is the compound of any one of embodiments 1 - 22, wherein R s is H, F, Cl, OH, oxo, methyl, ethyl, or propyl.
  • Embodiment 25 is the compound of any one of embodiments 1 - 22, wherein R s is H or methyl.
  • Embodiment 26 is the compound of any one of embodiments 1 - 25, wherein R 4 is C(O)R y , -C(O)NR x R y , NR x C(O)R y , C 1-4 alkylNR x C(O)R y , or C(O)C 1-4 alkylNR x C(O)R y ..
  • Embodiment 27 is the compound of any one of embodiments 1 - 26, wherein R x is H, or methyl or ethyl, optionally substituted with one R o .
  • Embodiment 28 is the compound of any one of embodiments 1 - 26, wherein R x is H or methyl.
  • Embodiment 29 is the compound of any one of embodiments 1 - 26, wherein R y is C 1-4 alkyl-R r , C 1-4 alkyl, -O-C 1-4 alkyl, -SO 2 -C 1-4 alkyl, C 1-4 alkyl-SO 2 - R r , cycloalkyl, , (C 1-4 alkyl)cycloalkyl, heterocyclyl, (C 1-4 alkyl)heterocyclyl, O-heterocyclyl, C 3-8 aryl, (C 1-4 alkyl)C 3-8 aryl, C 3-8 heteroaryl, ( C 1-4 alkyl) C 3-8 heteroaryl, each optionally substituted with 1 to 3 R o substituents.
  • R y is C 1-4 alkyl-R r , C 1-4 alkyl, -O-C 1-4 alkyl, -SO 2 - R r , cycloalkyl, , (C
  • Embodiment 30 is the compound of any one of embodiments 1 - 26, wherein R y is C 1-4 alkyl, optionally substituted with one, two, or three R o substituents.
  • Embodiment 31 is the compound of any one of embodiments 1 - 26, wherein R y is methyl, ethyl, propyl, or isopropyl, each optionally substituted with one, two, or three R o substituents.
  • Embodiment 32 is the compound of any one of embodiments 1 - 26, wherein R y is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropanyl, (dimethylamino)ethyl, or (dimethylamino)butyl.
  • Embodiment 33 is the compound of any one of embodiments 1 - 26, wherein R y is methoxy.
  • Embodiment 34 is the compound of any one of embodiments 1 - 26, wherein R y is -SO2-methyl.
  • Embodiment 35 is the compound of any one of embodiments 1 - 26, wherein R y is cycloalkyl or -C 1-2 alkyl(cycloalkyl), each optionally substituted with one, two, or three R o substituents.
  • Embodiment 36 is the compound of any one of embodiments 1 - 24, wherein R y is monocyclic cycloalkyl, or (C 1-4 alkyl)monocyclic cycloalkyl, optionally substituted with one, two, or three R o substituents.
  • Embodiment 37 is the compound of any one of embodiments 1 - 24, wherein R y is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, or cyclopentenyl, each optionally substituted with one, two, or three R o substituents.
  • Embodiment 38 is the compound of any one of embodiments 1 - 26, wherein R y is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2- cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, cyclohexenylpropyl, or cyclopentenylpropyl.
  • Embodiment 39 is the compound of any one of embodiments 1 - 26, wherein R y is heterocyclyl or -O- heterocyclyl, optionally substituted with one, two, or three R° substituents.
  • Embodiment 40 is the compound of any one of embodiments 1 - 26, wherein R y is tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxanyl, pyrazolyl, dihydropyridinyl, or oxetanyloxy, each optionally substituted with one, two, or three R° substituents.
  • Embodiment 41 is the compound of any one of embodiments 1 - 26, wherein wherein R y is tetrahydrofuranylmethyl, tetrahydropyranylmethyl, oxetanylmethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, dioxanylmethyl, pyrazolylmethyl, dihydropyridinylmethyl, or oxetanyloxymethyl, tetrahydrofuranylpropyl, tetrahydropyranylpropyl, oxetanylpropyl, azetidinylpropyl, pyrrolidinylpropyl, piperidinylpropyl, morpholinylpropyl, piperazinylpropyl, dioxanylpropyl, pyrazolylpropyl, dihydropyridinylpropyl, or
  • Embodiment 42 is the compound of any one of embodiments 1 - 26, wherein R x and R y taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with C 1-4 alkyl.
  • Embodiment 43 is the compound of any one of embodiments 1 - 26, wherein R x and R y taken together with the nitrogen to which they are attached form a heterocycloalkyl, optionally substituted with C 1-4 alkyl.
  • Embodiment 44 is the compound of any one of embodiments 1 - 26, wherein R x and R y taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with methyl.
  • Embodiment 45 is the compound of any one of embodiments 1 - 26, wherein R x and R y are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxa-l-azaspiro[3.3]heptanyl, or 2-oxa- 6-azaspiro[3.3]heptanyl, each optionally substituted with methyl.
  • Embodiment 46 is the compound of any one of embodiments 1 - 45, wherein each R° substituent is independently C 1-4 alkyl, -OH, oxo, -O C 1-4 alkyl, or -NR p R q .
  • Embodiment 47 is the compound of any one of embodiments 1 - 45, wherein at least one R° substituent is C 1-4 alkyl.
  • Embodiment 48 is the compound of any one of embodiments 1 - 45, wherein at least one R° substituent is -OH.
  • Embodiment 49 is the compound of any one of embodiments 1 - 45, wherein at least one R° substituent is -NR p R q .
  • Embodiment 50 is the compound of any one of embodiments 1 - 45, wherein at least one R° substituent is oxo.
  • Embodiment 51 is the compound of any one of embodiments 1 - 50, wherein R p and R q are each independently H or methyl.
  • Embodiment 52 is the compound of any one of embodiments 1 - 50, wherein R p and R q taken together with the nitrogen to which they are attached form a heterocyclyl.
  • Embodiment 53 is the compound of any one of embodiments 1 - 50, wherein R p and R q taken together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl 6-oxa-l-azaspiro[3.3]heptanyl, or 2-oxa- 6-azaspiro[3.3]heptanyl.
  • Embodiment 54 is the compound of any one of embodiments 1 - 53, wherein R 5 is H, methyl, ethyl, propyl, Cl, Br, or -OH.
  • Embodiment 55 is the compound of any one of embodiments 1 - 53, wherein R 5 is H or methyl.
  • Embodiment 56 is the compound of any one of embodiments 1 - 53, wherein R 5 is H.
  • Embodiment 57 is a compound selected from Table 1, and/or pharmaceutically acceptable salts thereof.
  • Embodiment 58 is the compound of any one of embodiments 1 - 57, wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.
  • Embodiment 59 is a pharmaceutical composition comprising a compound and/or a pharmaceutically acceptable salt or prodrug of any one of embodiments 1-58 and a pharmaceutically acceptable excipient.
  • Embodiment 60 is a method of inhibiting PIKfyve kinase in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of embodiments 1 to 58, or a pharmaceutical composition of embodiment 59.
  • Embodiment 61 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 to 58, or a pharmaceutical composition of embodiment 59.
  • Embodiment 62 is the method of embodiment 61, wherein the disease is associated with PIKfyve activity.
  • Embodiment 63 is the method of embodiment 61, wherein the disease is amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth (CMT; including type 4J (CMT4J)), and Yunis-Varon syndrome, autophagy, polymicrogyria (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 polyglutamine and intranuclear inclusion bodies, disease of Marinesco and Hirano bodies, tauopathy, Alzheimer’s disease, neurodegeneration, spongiform neurodegeneration, peripheral neuropathy, leukoencephalopathy, inclusion
  • ALS am
  • Embodiment 64 is the method of embodiment 59, wherein the disease is ALS, FTD, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or CMT.
  • Embodiment 65 is the method of embodiment 59, wherein the disease is ALS.
  • Embodiment 66 is the method of embodiment 61, 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 67 is the method of embodiment 61, 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 a lysosomal storage disease
  • Embodiment 68 is the method of embodiment 61, 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 69 is a compound of any one of embodiments 1 to 58 for use as a medicament.
  • Embodiment 70 is the compound of embodiment 69, wherein the compound is for use in treating a neurological disease treatable by inhibition of PIKfyve kinase.
  • Embodiment 71 is the use of a compound of any one of embodiments 1 to 58 in the manufacture of a medicament for treating a disease in a subject in which PIKfyve contributes to the pathology and/or symptoms of the disease.
  • a dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -C(0)NH 2 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.
  • C 1-6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
  • references to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%.
  • the term “about” includes the indicated amount ⁇ 5%.
  • the term “about” includes the indicated amount ⁇ 1%.
  • to the term “about X” includes description of “X”.
  • the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise.
  • reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
  • C 1-x alkyl refers to an alkyl group with from 1 to x carbon atoms.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • 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., C 6-20 aryl), 6 to 18 carbon ring atoms (i.e., C 6-18 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl) or 6 to 10 carbon ring atoms (i.e., C 6-10 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 heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl. [0086] “Amino” means a -NH 2 . [0087] “Alkoxy” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
  • 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., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.
  • Cx-ycycloalkyl refers to a cycloalkyl group with from x to y carbon atoms in the ring, where x and y are integers.
  • Carboxy means –COOH.
  • 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., -CH 2 Cl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CF(CH 3 ) 2 , and the like.
  • C x-y means the number of carbon atoms in the alkyl group ranges from x to y.
  • fluoroalkyl When the alkyl is substituted with only fluoro, it can be referred to in this disclosure as fluoroalkyl.
  • Heterocyclyl means a saturated or unsaturated monovalent monocyclic or bi-cyclic group (fused bi-cyclic or bridged bi-cyclic) 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.
  • 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-1H-oxazolo[3,4-a]pyrazin-3(5H)-one- yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-yl, 3-oxa-8-azabicyclo[3.2.1]octane-yl, and the like.
  • heterocyclyl When the heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.
  • Cx-yheterocyclyl refers to a heterocyclyl group with from x to y carbon atoms in the ring, where x and y are integers.
  • Heterocyclylalkyl and “heterocycloalkyl” mean an –(alkylene)-R radical where R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.
  • Heteroaryl 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, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrazolopyridinyl, indazolyl, furopyrimidinyl, and the like.
  • Cx-yheteroaryl refers to a heteroaryl group with from x to y carbon atoms, where x and y are integers.
  • 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, /Moluenesulfonic 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. It is understood that the pharmaceutically acceptable salts are non-toxic.
  • heterocyclyl group optionally substituted with an alkyl group means that the alkyl 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;
  • Treating” or “treatment” of a disease includes:
  • preventing the disease e.g., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, e.g., arresting or reducing the development of the disease or its clinical symptoms; or
  • 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 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 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 recrystallization, or chromatography, or any combination thereof.
  • Stereoisomers may also be obtained by stereoselective synthesis.
  • Certain compounds of Formula (I) can 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 or prodrug 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.
  • Prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt or prodrug 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 or prodrug thereof.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, U 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). Isotopic substitution with 2 H, U C, 13 C, 14 C, 15 C, 12 N, 13 N,
  • the compounds disclosed herein have some or all of the 3 ⁇ 4 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. [0115] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • Y 1 is N or C-R 1 ;
  • Y 2 is N or C-R 2 ;
  • X is N, or CH; provided that when Y 1 is N, Y 2 is C-R 2 and when Y 2 is N, Y 1 is C-R 1 ;
  • R 1 is H, or C 3-8 aryl, C 3-8 heteroaryl, C 3-8 cycloalkyl, or C 3-8 heterocyclyl, each optionally substituted with from 1 to 3 R s ;
  • R 2 is H, or C 3-8 aryl, C 3-8 heteroaryl, C 3-8 cycloalkyl, or C 3-8 heterocyclyl, each optionally substituted with from 1 to 3 R s ;
  • R 3 is H, halo, OH, C 1-4 alkyl, NR p R q , C 1-4 alkyl-NR p R q , C 1-4 alkyl-OH, C 1-4 alkyl-OC 1-4 alkyl, OC 1-4 alkyl, C(O)-C 1-4 alkyl, C(O)-C 1-4 alkyl-NR p R q , C(O)OH, C(O)-OC 1-4 alkyl, or C(O)-OC 1-4 alkyl-NR p R
  • R 5 is H, Ci-6alkyl, halo, -OH, or -OCi-6alkyl.
  • Y 1 is N or C-R 1 ;
  • Y 2 is N or C-R 2 ;
  • X is N, or CH; provided that when Y 1 is N, Y 2 is C-R 2 and when Y 2 is N, Y 1 is C-R 1 ;
  • R 1 is H, or C 3-8 aryl, C 3-8 heteroaryl, C 3-8 cycloalkyl, or C 3-8 heterocyclyl, each optionally substituted with from 1 to 3 R s ;
  • R 2 is H, or C 3-8 aryl, C 3-8 heteroaryl, C 3-8 cycloalkyl, or C 3-8 heterocyclyl, each optionally substituted with from 1 to 3 R s ;
  • R 4 is C 3-8 aryl, C 3-8 heteroaryl, C 3-8 cycloalkyl, or C 3-8 heterocyclyl, each optionally substituted with from 1 to 3 R s , or -C(0)NR x R y ;
  • R s is H, halo, amino, OH, OCi-6alkyl, Ci-6alkyl;
  • R x is H or C 1-4 alkyl, optionally substituted with R°;
  • R y is H, Ci-ralkyl, -O-Ci-ralkyl, -SOi-Ci-ralkyl, Ci-ralkyl-SOi- R r , cycloalkyl, -C 1-4 alkyl(cycloalkyl), heterocyclyl, -O-heterocyclyl, each optionally substituted with 1 to 3 R° substituents; or R x and R y taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with C 1-4 alkyl; each R r is C 1-4 alkyl or -NR p R q ; each R° substituent is independently C 1-4 alkyl, -OH, -OC 1-4 alkyl, halo, cyano, or -NR p R q ; R p and R q are each independently H or C 1-4 alkyl; or R p and R q taken together with the nitrogen to which they are attached form a heterocyclyl;
  • R 5 is H, Ci-6alkyl, halo, -OH, or -OCi-6alkyl.
  • Y 1 is N, Y 2 is C-R 2 . In some embodiments, Y 2 is N, Y 1 is C-R 1 . In some embodiments, Y 1 is C-R 1 and Y 2 is C-R 2 . In some embodiments, Y 1 is C-R 1 and Y 2 is C-R 2 , and one of R 1 and R 2 is not H.
  • X is N. In some embodiments, X is N, and one of Y 1 and Y 2 is N.
  • X is N, Y 1 is C-R 1 , and Y 2 is C-R 2 . In some embodiments, X is N, Y 1 is C-R 1 , and Y 2 is C-R 2 , and one of R 1 and R 2 is not H. In some embodiments, X is CH. In some embodiments, X is CH, and one of Y 1 and Y 2 is N. In some embodiments, X is CH, and Y 1 and Y 2 are N. [0120] In some embodiments, Y 1 is C-R 1 and R 1 is H, or phenyl or C 3-8 heteroaryl each optionally substituted with from 1 to 3 R s .
  • R 1 is phenyl, pyridinyl, pyrimidinyl, pyrazolyl , or cyclopentenyl, each optionally substituted with 1 or 2 R s . In some embodiments, R 1 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 R s . [0121] In some embodiments, Y 2 is C-R 2 and R 2 is H, or phenyl or C 3-8 heteroaryl each optionally substituted with from 1 to 3 R s .
  • R 2 is phenyl, pyridinyl, pyrimidinyl, pyrazolyl or cyclopentenyl, each optionally substituted with 1 or 2 R s .
  • R 2 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 R s .
  • R 3 is H, C 1-4 alkyl-NR p R q , C 1-4 alkyl-OH, C 1-4 alkyl-OC 1-4 alkyl, C(O)OH, or C(O)-OC 1-4 alkyl. In other embodiments.
  • R 3 is (CH 2 )NH 2 , (CH 2 )N(CH 3 ) 2 , (CH2)OH, (CH2)OCH3, C(O)OH, or C(O)OCH2CH3.
  • R 4 is phenyl, pyridinyl, pyrimidinyl, or pyrazolyl each optionally substituted with from 1 to 2 R s .
  • R 4 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 R s .
  • R s is H, F, Cl, Br, NH2, OH, oxo, OC1-6alkyl, or C1-6alkyl.
  • R s is H, F, Cl, OH, oxo, methyl, ethyl, or propyl. In some embodiments, R s is H or methyl.
  • R 4 is pyrazolylmethyl , imidazolylmethyl, morpholinomethyl, piperidinylmethyl, dioxanylmethy, dioxanylethyl, dioxanylethylenyl, dioxanylpropyl, dioxanylpropylenyl, cyclohexenyl, cyclopentenyl, dihydropyridinyl, each optionally substituted with from 1 to 2 R s .
  • R 4 is C(O)R y , -C(O)NR x R y , NR x C(O)R y , C 1-4 alkylNR x C(O)R y , or C(O)C 1-4 alkylNR x C(O)R y . In some embodiments, R 4 is -C(O)NR x R y . [0127] In some embodiments, R x is H, or methyl or ethyl, optionally substituted with one R o . In some embodiments, R x is H or methyl.
  • R y is C 1-4 alkyl-R r , C 1-4 alkyl, -0-C 1-4 alkyl, -S02-C 1-4 alkyl, Ci- 4alkyl-S02- R r , cycloalkyl, , (C 1-4 alkyl)cycloalkyl, heterocyclyl, (C 1-4 alkyl)heterocyclyl, O- heterocyclyl, C 3-8 aryl, (C 1-4 alkyl)C 3-8 aryl, C 3-8 heteroaryl, (C 1-4 alkyl)C 3-8 heteroaryl, each optionally substituted with 1 to 3 R° substituents.
  • R y is C 1-4 alkyl, -O-C 1- 4 alkyl, -S0 2 -C 1-4 alkyl, C 1-4 alkyl-SO 2 -R r , cycloalkyl, -C 1-4 alkyl(cycloalkyl), heterocyclyl, -O- heterocyclyl, each optionally substituted with 1 to 3 R° substituents.
  • R y is C 1-4 alkyl, optionally substituted with one, two, or three R° substituents.
  • R y is methyl, ethyl, propyl, or isopropyl, each optionally substituted with one, two, or three R° substituents.
  • R y is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropanyl, (dimethylamino)ethyl, or (dimethylamino)butyl.
  • R y is methoxy.
  • R y is -SO 2 -methyl.
  • R y is cycloalkyl, or (C 1-4 alkyl)monocyclic cycloalkyl, or -C 1- 2 alkyl(cycloalkyl), each optionally substituted with one, two, or three R° substituents.
  • R y is monocyclic cycloalkyl, or (C 1-4 alkyl)monocyclic cycloalkyl, optionally substituted with one, two, or three R° substituents.
  • R y is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, or cyclopentenyl, each optionally substituted with one, two, or three R° substituents.
  • R y is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1 -cyclopropyl ethyl, 2-cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, cyclohexenylpropyl, or cyclopentenylpropyl.
  • R y is heterocyclyl or -O- heterocyclyl, optionally substituted with one, two, or three R° substituents.
  • R y is tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxanyl, pyrazolyl, dihydropyridinyl, or oxetanyloxy, each optionally substituted with one, two, or three R° substituents.
  • R y is tetrahydrofuranylmethyl, tetrahydropyranylmethyl, oxetanylmethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, dioxanylmethyl, pyrazolylmethyl, dihydropyridinylmethyl, or oxetanyloxymethyl, tetrahydrofuranylpropyl, tetrahydropyranylpropyl, oxetanylpropyl, azetidinylpropyl, pyrrolidinylpropyl, piperidinylpropyl, morpholinylpropyl, piperazinylpropyl, dioxanylpropyl, pyrazolylpropyl, dihydropyridinylpropyl, or oxetanyloxy propyl, each optionally substituted with
  • R x is H and R y is methyl, ethyl, isopropyl, cyclopropyl, methoxy, or cyclopentyl. In some embodiments, R x is H and R y is isopropyl. [0133] In some embodiments, R x and R y taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with C 1-4 alkyl. In some embodiments, R x and R y taken together with the nitrogen to which they are attached form a heterocycloalkyl, optionally substituted with C 1-4 alkyl.
  • R x and R y taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with methyl. In some embodiments, R x and R y are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxa-l-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl, each optionally substituted with methyl.
  • each R r is C 1-4 alkyl or -NR p R q . In some embodiments, R r is methyl, ethyl, propyl, or isopropyl or -NR p R q .
  • each R° substituent is independently C 1-4 alkyl, -OH, oxo, -O C 1-4 alkyl, or -NR p R q .
  • at least one R° substituent is C 1-4 alkyl.
  • at least one R° substituent is -OH.
  • at least one R° substituent is -NR p R q .
  • at least one R° substituent is oxo.
  • R p and R q are each independently H or methyl.
  • R p and R q taken together with the nitrogen to which they are attached form a heterocyclyl.
  • R p and R q taken together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl 6-oxa-l-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl.
  • R 5 is H, methyl, ethyl, propyl, Cl, Br, or -OH. In some embodiments, R 5 is H or methyl.
  • the compound of Formula (I) or the pharmaceutically acceptable salt thereof is a compound of Formula (I): as defined herein, wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.
  • one or more hydrogen atoms attached to carbon atoms of R 1 is replaced by deuterium atoms.
  • R 2 , R 3 , R 4 , and/or R 5 are replaced by deuterium atoms.
  • one or more hydrogen atoms attached to carbon atoms of R°, R s , R p , R q , R r , R x , and/or R y are replaced by deuterium atoms.
  • one or more C 1-4 alkyl group has one or more hydrogen atoms attached to carbon atoms replaced by deuterium atoms.
  • one or more methyl groups have one or more hydrogen atoms attached to the carbon atom replaced by deuterium atoms.
  • the compound of Formula (I) comprises a -D in place of at least one -H, or a -CD3 substituent in place of at least one CFb.
  • 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 subject, 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 or prodrug 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 re- constitution 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 drug- delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug- delivery 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 g 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
  • 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 non- ionic 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 compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly.
  • the combination agent is an anticancer agent, such as an alkylating agent, a corticosteroid, a platinum drug, a purine analog, an anti-metabolite, or particular agents such as cyclophosphamide, chlorambucil, bendamustine, prednisone, dexamethasone, carboplatin, cisplatin, cladribine, fludarabine, capecitabine, gemcitabine, methotrexate, pralatrexate, bleomycin, doxorubicin, vincristine, or rituximab.
  • an anticancer agent such as an alkylating agent, a corticosteroid, a platinum drug, a purine analog, an anti-metabolite, or particular agents such as cyclophosphamide, chlorambucil, bendamustine, prednisone,
  • 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 subject 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 non- domesticated 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 mammal e.g., a human
  • a non-human mammal e.g., a domesticated animal (e.g., laboratory animals, household pets, or livestock), a non- domesticated animal (e.g., wildlife), a dog, a cat, a rodent, a mouse, a hamster, a cow, a bird, a chicken, a fish, a pig
  • 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 physiology 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. [0158] 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, intrasternal, 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 disclosure relates to a method of inhibiting PIKfyve kinase in a subject in need thereof comprising administering to the subject an effective amount of a compound.
  • 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 a neurological disease.
  • the disease is associated with a FIG4 deficiency.
  • a method for treating a subject with a neurological disease or disorder associated with PIKfyve kinase activity comprising administering to the subject an effective amount of a compound or pharmaceutical composition as described herein.
  • 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, polymicrogyria (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, frontotemporal 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, Guilla
  • ALS amyotroph
  • 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 the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
  • 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.
  • reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated under reduce pressure. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine (120 mg, 0.35 mmol) as a yellow solid.
  • the reaction was stirred at 100 o C under N 2 for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide N-(methyl-d3)-N-((1-methyl-3-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)-1H-pyrazol-5-yl)methyl)methanamine-d3 (54 mg, 0.107 mmol) as an off-white solid.
  • the reaction mixture was diluted with water (30 mL) and a large amount of solid was precipitated. After filtration, the filter cake was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 2-(1-methyl-1H-pyrazol-3-yl)-7-morpholino-5-(3-phenyl-1H-pyrazol-1- yl)furo[3,2-b]pyridine (17 mg, 0.040 mmol) as a white solid.
  • the reaction mixture was stirred at 110 o C under N 2 for 1 h. The completion of the reaction was monitored by TLC.
  • the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated.
  • the resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 50% EtOAc/PE to provide 5-chloro-7-morpholino-2-(pyridin-2-yl)furo[3,2- b]pyridine (419 mg, 1.33 mmol) as a yellow solid.
  • reaction mixture was stirred at 150 o C under N2 overnight. The completion of the reaction was monitored by TLC.
  • the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure.
  • the resulting residue was purified by preparative TLC with a elution of 50% EtOAc/PE to provide 5-(3-(cyclopent-1- en-1-yl)-1H-pyrazol-1-yl)-7-morpholino-2-(pyridin-2-yl)furo[3,2-b]pyridine (10 mg, 0.024 mmol) as a white solid.
  • the reaction mixture was stirred at 90 o C under N 2 overnight. The completion of the reaction was monitored by TLC.
  • the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated under reduce pressure.
  • the resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide 2-(2-methoxypyridin-3-yl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridine (46 mg, 0.1 mmol) as a yellow solid.
  • the reaction was stirred at 120 o C for 30 min. The completion of the reaction was monitored by TLC.
  • the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure.
  • the resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide 3-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)pyridin-2(1H)-one (8 mg, 0.018 mmol) as a yellow solid.
  • the reaction was stirred at 90 o C under N2 for 1 h. The completion of the reaction was monitored by TLC.
  • the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated.
  • the resulting residue was purified by silica gel column chromatography with a gradient elution of 30% EtOAc/PE to 50% EtOAc/PE to provide 5-chloro-7-morpholino-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4- yl)furo[3,2-b]pyridine (430 mg, 1.11 mmol) as a yellow solid.
  • the reaction was stirred at 90 o C under N2 for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated.
  • the completion of the reaction was monitored by TLC.
  • the reaction mixture was quenched with aqueous NaHCO3 solution to adjust pH to 8.
  • the aqueous solution was extracted with DCM (3 X 20 mL).
  • the combined organic phase was concentrated under reduced pressure.
  • the resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 7-morpholino-2-(1H-pyrazol-4-yl)-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridine (200 mg, 0.47 mmol) as a yellow solid.
  • the reaction was stirred at 80 o C under N2 overnight. The completion of the reaction was monitored by TLC.
  • the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated.
  • the resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 40% EtOAc/PE to provide 5-chloro-7-morpholino-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4- yl)furo[3,2-b]pyridine (320 mg, 0.82 mmol) as a yellow oil.
  • the reaction was stirred at 105 o C under N2 overnight. The completion of the reaction was monitored by TLC.
  • the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated under reduce pressure.
  • the reaction mixture was stirred at rt for 1 h. The completion of the reaction was monitored by TLC.
  • the aqueous solution was extracted with DCM (2 x 20 mL).
  • the combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure.
  • the resulting residue was slurry in Et 2 O to provide 3-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol- 1-yl)propan-1-ol (205 mg, 0.44 mmol) as a yellow solid.
  • the reaction mixture was stirred at 100 o C overnight. The completion of the reaction was monitored by TLC.
  • the reaction mixture was diluted with water and was extracted with DCM (2 x 20 mL). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated under reduce pressure.
  • the resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide 2,2- dimethyl-3-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2-yl)-1H- pyrazol-1-yl)propyl acetate (20 mg, 0.037 mmol) as a white solid.
  • reaction mixture was stirred at rt for 3 h. The completion of the reaction was monitored by TLC.
  • the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 15 mL). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated under reduce pressure.
  • reaction mixture was stirred at 110 o C under N 2 overnight. The completion of the reaction was monitored by TLC.
  • the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure.
  • the resulting residue was purified by silica gel column chromatography with a gradient elution of 30% EtOAc/PE to 50% EtOAc/PE to provide (7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)methanol (65 mg, 0.17 mmol) as an off-white solid.
  • reaction was stirred at rt overnight. The completion of the reaction was monitored by TLC.
  • the reaction mixture was quenched with NH 4 Cl solution (10 mL) and extracted with DCM/MeOH (50:1, 3 x 10 mL). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated under reduced pressure.
  • reaction mixture was stirred at rt overnight. The completion of the reaction was monitored by TLC.
  • the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the resulting residue was purified by silica gel column chromatography with a gradient elution of 5% EtOAc/PE to 20% EtOAc/PE to provide ((2,3-dimethoxypropoxy)methyl)benzene (2.19 g, 10.4 mmol) as a yellow oil.
  • the combined organic phase was dried over anhydrous Na 2 SO 4 and used directly for the next step without further work-up.
  • pyrazole 200 mg, 2.94 mmol
  • the reaction mixture was stirred at rt overnight and the reaction was monitored by TLC.
  • the reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 10 mL).
  • reaction mixture was stirred at -78 o C under N2 for 0.5 h.
  • a solution of 7-morpholino-5-(3-(m-tolyl)-1H- pyrazol-1-yl)furo[3,2-b]pyridine-2-carbaldehyde (GP17.1, 500 mg, 1.30 mmol) in THF (5 mL) dropwise.
  • the completion of the reaction was monitored by TLC.
  • the reaction mixture was quenched with NH4Cl solution (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure.
  • reaction mixture was stirred at rt overnight. The completion of the reaction was monitored by TLC.
  • the reaction mixture was quenched with NH 4 Cl aqueous solution (200 mL) and followed by 1M HCl aqueous solution to adjust pH to 2.
  • the aqueous solution was extracted with EtOAc (3 x 100 mL).
  • the combined organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to provide crude oxetane-3-carboxylic acid (600 mg, 5.88 mmol).
  • TBDPSCl (11.3 g, 40 mmol). TLC showed the starting material was consumed. After that, TBSCl (6.2 g, 40 mmol) was added to the above mixture. The reaction mixture was heated to 50 o C for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated.
  • the reaction mixture was stirred at rt for 1 h. To the above mixture was added 2-((tert-butyldimethylsilyl)oxy)-3-((tert- butyldiphenylsilyl)oxy)propanal (GP27.2, 143 mg, 0.32 mmol). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated.
  • PIKfyve Full length human recombinant PIKFYVE expressed in baculovirus expression system as N-terminal GST-fusion protein (265 kDa) was obtained from Carna 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.
  • PI3P fluorescently-labeled phosphatidylinositol 3-phosphate
  • PS phospho-L-serine
  • Kinase protein was pre-diluted in an assay buffer comprising 25 mM HEPES, pH 7.5, 1 mM DTT, 2.5 mM MgCl 2 , and 2.5 mM MnCl 2 , and 0.005% Triton X-100, and dispensed into a 384-well plate (10 ⁇ L 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 ⁇ L of 2x PI3P/PS substrate supplemented with ATP.
  • the final concentration of enzyme was 2 nM, the final concentration of ATP was 10 mM, and the final concentration of PI3P/PS substrate was 1 ⁇ M (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.
  • PSR product to sum ratio
  • P inh (PSR 0%inh - PSR compound )/(PSR 0%inh - PSR 100%inh )*100 in which PSRcompound is the product/sum ratio in the presence of compound, PSR0%inh is the product/sum ratio in the absence of compound, and the PSR 100%inh is the product/sum ratio in the absence of the enzyme.
  • IC 50 of test compounds 50%-inhibition
  • %-inh cdata (Pinh versus compound concentration) were fitted by a four-parameter sigmoid dose- response model using XLfit software (IDBS). Table 3

Abstract

The present invention relates to compounds of formula (I) that are inhibitors of PlKfyve kinase and are therefore useful for the treatment of e.g. neurological diseases, such as e.g. amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, ADHD, schizophrenia, depression, or bipolar disorder. An exemplary compound is e.g. 7-morpholino-5-(3-phenyl-lH- pyrazol-l-yl)-2-(lH-pyrazol-4-yl)furo[3, 2-b]pyridine (compound 10) Data on the PlKfyve kinase inhibition are provided, e.g.:

Description

-MORPHOLINO-5-(3-PHENYL-1 H-PYRAZOL-1 -YL)-FURO[3,2-B]PYRIDINE DERIVATIVES AND SIMILAR COMPOUNDS AS PIKFYVE KINASE INHIBITORS FOR THE TREATMENT OF E.G. AMYOTROPHIC
LATERAL SCLEROSIS (ALS)
Cross Reference to Related Applications
[0001] This application claims priority to U.S. Provisional Application No.63/195, 236, filed on June 1, 2021, the disclosure of which is hereby incorporated by reference in their entireties.
Field of Invention
[0002] 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.
Background
[0003] Phosphoinositide kinases (PIKs) catalyze the phosphorylation of phosphatidylinositol, 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.
[0004] 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. Inhibition of PIKfyve activity increases levels of PI3P, stimulating autophagy and improving motor neuron health. Phosphorylated inositides produced by PIKfyve are localized in various cellular membranes and organelles, consistent with the various PIKfyve functions of endolysosomal transport, endomembrane homeostasis, and biogenesis of endosome carrier vesicles (ECV)/multivesicular bodies (MVB) from early endosomes. Further, PIKfyve is required for endocy tic- vacuolar pathway and nuclear migration. Thus, PIKfyve helps maintain proper morphology of the endosome and lysosome.
[0005] In mammalian cells, PI3P levels are regulated by the reciprocal activities of PIKfyve and the phosphatase FIG4 phosphoinositide 5-phosphatase (FIG4). Zolov etal. , “In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P,” Proc. Natl. Acad. Sci. USA 2012, 109(43), 17472-17477. Normally, FIG4 is localized on the cytoplasmic surface of endolysosomal vesicles in a complex. 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. Mutations in PIKfyve are associated with corneal fleck dystrophy, an autosomal dominant disorder characterized by numerous white flecks in all layers of the corneal stroma.
[0006] 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, polymicrogyria (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, frontotemporal dementia, diseases of neuronal nuclear inclusions of polyglutamine 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.
[0007] 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, frontotemporal 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. Other therapeutic targets for intervention with 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 [0008] Embodiment 1 is a compound of Formula (I):
Figure imgf000005_0001
wherein Y1 is N or C-R1; Y2 is N or C-R2; X is N, or CH; provided that when Y1 is N, Y2 is C-R2 and when Y2 is N, Y1 is C-R1; R1 is H, or C3-8aryl, C3-8heteroaryl, C3-8cycloalkyl, or C3-8heterocyclyl, each optionally substituted with from 1 to 3 Rs; R2 is H, or C3-8aryl, C3-8heteroaryl, C3-8cycloalkyl, or C3-8heterocyclyl, each optionally substituted with from 1 to 3 Rs; R3 is H, halo, OH, C1-4 alkyl, NRpRq, C1-4 alkyl-NRpRq, C1-4 alkyl-OH, C1-4 alkyl-O C1-4 alkyl, OC1-4 alkyl, C(O)-C1-4 alkyl, C(O)-C1-4 alkyl-NRpRq, C(O)OH, C(O)-OC1-4 alkyl, or C(O)-OC1-4 alkyl-NRpRq; R4 is C3-8aryl, C3-8heteroaryl, C3-8cycloalkyl, C3-8heterocyclyl, C1-4 alkyl, C1-4 alkylP(O))(ORx)2, (C1-4 alkyl)C3-8 aryl, (C1-4 alkyl)C3-8 heteroaryl, (C1-4 alkyl)C3-8 cycloalkyl, or (C1-4 alkyl)C3-8 heterocyclyl, each optionally substituted with from 1 to 3 Rs, or R4 is C(O)Ry, -C(O)NRxRy, NRxC(O)Ry, C1-4 alkylNRxC(O)Ry, or C(O)C1-4 alkylNRxC(O)Ry; Rs is halo, amino, oxo, OH, C3-8 heterocyclyl, OC1-6alkyl, C1-6alkyl, C1-6alkenyl, C1- 6alkyl-OH, C1-6 alkyl-O-C1-4 alkyl, C1-6 alkyl-O-C1-4 alkyl-O-C1-4 alkyl, (C1-4 alkyl)C3-8 aryl, (C1-4 alkyl)C3-8 heteroaryl, (C1-4 alkyl)C3-8 cycloalkyl, (C1-4 alkyl)C3-8 heterocyclyl or C1-6 alkyl-NRpRq; Rx is H or C1-4alkyl, optionally substituted with Ro; Ry is H, C1-4alkyl-Rr, C1-4alkyl, -O-C1-4alkyl, -SO2-C1-4alkyl, C1-4alkyl-SO2- Rr, cycloalkyl, (-C1-4alkyl)cycloalkyl, heterocyclyl, (-C1-4alkyl)heterocyclyl, O-heterocyclyl, C3-8 aryl, (-C1-4alkyl)C3-8 aryl, C3-8 heteroaryl, (-C1-4alkyl)C3-8 heteroaryl, each optionally substituted with 1 to 3 Ro substituents; or Rx and Ry taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with C1-4alkyl; each Rr is C1-4alkyl or -NRpRq; each Ro substituent is independently C1-4alkyl, oxo, -OH, -OC1-4alkyl, halo, cyano, heterocyclyl, or -NRpRq; Rp and Rq are each independently H or C1-4alkyl; or Rp and Rq taken together with the nitrogen to which they are attached form a heterocyclyl; R5 is H, C1-6alkyl, halo, -OH, or -OC1-6alkyl. [0009] Embodiment 2 is the compound of embodiment 1, wherein Y1 is N, Y2 is C-R2. [0010] Embodiment 3 is the compound of embodiment 1, wherein Y2 is N, Y1 is C-R1. [0011] Embodiment 4 is the compound of embodiment 1, wherein Y1 is C-R1 and Y2 is C-R2. [0012] Embodiment 5 is the compound of embodiment 1, wherein Y1 is C-R1 and Y2 is C-R2, and wherein one of R1 and R2 is not H. [0013] Embodiment 6 is the compound of embodiment 1, wherein X is N. [0014] Embodiment 7 is the compound of embodiment 1, wherein X is N, and one of Y1 and Y2 is N. [0015] Embodiment 8 is the compound of embodiment 1, wherein X is N, Y1 is C-R1, and Y2 is C-R2. [0016] Embodiment 9 is the compound of embodiment 1, wherein X is N, Y1 is C-R1, and Y2 is C-R2, and wherein one of R1 and R2 is not H. [0017] Embodiment 10 is the compound of embodiment 1, wherein X is CH. [0018] Embodiment 11 is the compound of embodiment 1, wherein X is CH, and one of Y1 and Y2 is N. [0019] Embodiment 12 is the compound of embodiment 1, wherein X is CH, and Y1 and Y2 are N. [0020] Embodiment 13 is the compound of any one of embodiments 1 - 12, wherein Y1 is C-R1 and R1 is H, or phenyl or C3-8heteroaryl each optionally substituted with from 1 to 3 Rs. [0021] Embodiment 14 is the compound of any one of embodiments 1 - 13, wherein R1 is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, or cyclopentenyl, each optionally substituted with 1 or 2 Rs. [0022] Embodiment 15 is the compound of any one of embodiments 1 - 13, wherein R1 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 Rs. [0023] Embodiment 16 is the compound of any one of embodiments 1 - 15, wherein Y2 is C-R2 and R2 is H, or phenyl or C3-8heteroaryl each optionally substituted with from 1 to 3 Rs. [0024] Embodiment 17 is the compound of any one of embodiments 1 - 16, wherein R2 is phenyl, pyridinyl, pyrimidinyl, pyrazolyl or cyclopentenyl, each optionally substituted with 1 or 2 Rs. [0025] Embodiment 18 is the compound of any one of embodiments 1 - 16, wherein R2 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 Rs. [0026] Embodiment 19 is the compound of any one of embodiments 1 - 18, wherein R3 is H, C1-4 alkyl-NRpRq, C1-4 alkyl-OH, C1-4 alkyl-OC1-4 alkyl, C(O)OH, or C(O)-OC1-4 alkyl. [0027] Embodiment 20 is the compound of any one of embodiments 1 - 18, wherein R3 is (CH2)NH2, (CH2)N(CH3)2, (CH2)OH, (CH2)OCH3, C(O)OH, or C(O)OCH2CH3. [0028] Embodiment 21 is the compound of any one of embodiments 1 - 20, wherein R4 is phenyl, pyridinyl, pyrimidinyl, or pyrazolyl, each optionally substituted with from 1 to 2 Rs. [0029] Embodiment 22 is the compound of any one of embodiments 1 - 20, wherein R4 is pyrazolylmethyl , imidazolylmethyl, morpholinomethyl, piperidinylmethyl, dioxanylmethy, dioxanylethyl, dioxanylethylenyl, dioxanylpropyl, dioxanylpropylenyl, cyclohexenyl, cyclopentenyl, dihydropyridinyl, each optionally substituted with from 1 to 2 Rs. [0030] Embodiment 23 is the compound of any one of embodiments 1 - 22, wherein Rs is H, F, Cl, Br, NH2, OH, oxo, OC1-6alkyl, or C1-6alkyl. [0031] Embodiment 24 is the compound of any one of embodiments 1 - 22, wherein Rs is H, F, Cl, OH, oxo, methyl, ethyl, or propyl. [0032] Embodiment 25 is the compound of any one of embodiments 1 - 22, wherein Rs is H or methyl. [0033] Embodiment 26 is the compound of any one of embodiments 1 - 25, wherein R4 is C(O)Ry, -C(O)NRxRy, NRxC(O)Ry, C1-4 alkylNRxC(O)Ry, or C(O)C1-4 alkylNRxC(O)Ry.. [0034] Embodiment 27 is the compound of any one of embodiments 1 - 26, wherein Rx is H, or methyl or ethyl, optionally substituted with one Ro. [0035] Embodiment 28 is the compound of any one of embodiments 1 - 26, wherein Rx is H or methyl. [0036] Embodiment 29 is the compound of any one of embodiments 1 - 26, wherein Ry is C1-4 alkyl-Rr, C1-4alkyl, -O-C1-4alkyl, -SO2-C1-4alkyl, C1-4alkyl-SO2- Rr, cycloalkyl, , (C1-4 alkyl)cycloalkyl, heterocyclyl, (C1-4 alkyl)heterocyclyl, O-heterocyclyl, C3-8 aryl, (C1-4 alkyl)C3-8 aryl, C3-8 heteroaryl, ( C1-4 alkyl) C3-8 heteroaryl,, each optionally substituted with 1 to 3 Ro substituents. [0037] Embodiment 30 is the compound of any one of embodiments 1 - 26, wherein Ry is C1-4alkyl, optionally substituted with one, two, or three Ro substituents. [0038] Embodiment 31 is the compound of any one of embodiments 1 - 26, wherein Ry is methyl, ethyl, propyl, or isopropyl, each optionally substituted with one, two, or three Ro substituents. [0039] Embodiment 32 is the compound of any one of embodiments 1 - 26, wherein Ry is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropanyl, (dimethylamino)ethyl, or (dimethylamino)butyl. [0040] Embodiment 33 is the compound of any one of embodiments 1 - 26, wherein Ry is methoxy. [0041] Embodiment 34 is the compound of any one of embodiments 1 - 26, wherein Ry is -SO2-methyl. [0042] Embodiment 35 is the compound of any one of embodiments 1 - 26, wherein Ry is cycloalkyl or -C1-2alkyl(cycloalkyl), each optionally substituted with one, two, or three Ro substituents. [0043] Embodiment 36 is the compound of any one of embodiments 1 - 24, wherein Ry is monocyclic cycloalkyl, or (C1-4 alkyl)monocyclic cycloalkyl, optionally substituted with one, two, or three Ro substituents. [0044] Embodiment 37 is the compound of any one of embodiments 1 - 24, wherein Ry is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, or cyclopentenyl, each optionally substituted with one, two, or three Ro substituents. [0045] Embodiment 38 is the compound of any one of embodiments 1 - 26, wherein Ry is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2- cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, cyclohexenylpropyl, or cyclopentenylpropyl. [0046] Embodiment 39 is the compound of any one of embodiments 1 - 26, wherein Ry is heterocyclyl or -O- heterocyclyl, optionally substituted with one, two, or three R° substituents. [0047] Embodiment 40 is the compound of any one of embodiments 1 - 26, wherein Ry is tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxanyl, pyrazolyl, dihydropyridinyl, or oxetanyloxy, each optionally substituted with one, two, or three R° substituents.
[0048] Embodiment 41 is the compound of any one of embodiments 1 - 26, wherein wherein Ry is tetrahydrofuranylmethyl, tetrahydropyranylmethyl, oxetanylmethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, dioxanylmethyl, pyrazolylmethyl, dihydropyridinylmethyl, or oxetanyloxymethyl, tetrahydrofuranylpropyl, tetrahydropyranylpropyl, oxetanylpropyl, azetidinylpropyl, pyrrolidinylpropyl, piperidinylpropyl, morpholinylpropyl, piperazinylpropyl, dioxanylpropyl, pyrazolylpropyl, dihydropyridinylpropyl, or oxetanyloxypropyl, each optionally substituted with one, two, or three R° substituents.
[0049] Embodiment 42 is the compound of any one of embodiments 1 - 26, wherein Rx and Ry taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with C1-4alkyl.
[0050] Embodiment 43 is the compound of any one of embodiments 1 - 26, wherein Rx and Ry taken together with the nitrogen to which they are attached form a heterocycloalkyl, optionally substituted with C1-4alkyl.
[0051] Embodiment 44 is the compound of any one of embodiments 1 - 26, wherein Rx and Ry taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with methyl.
[0052] Embodiment 45 is the compound of any one of embodiments 1 - 26, wherein Rx and Ry are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxa-l-azaspiro[3.3]heptanyl, or 2-oxa- 6-azaspiro[3.3]heptanyl, each optionally substituted with methyl.
[0053] Embodiment 46 is the compound of any one of embodiments 1 - 45, wherein each R° substituent is independently C1-4alkyl, -OH, oxo, -O C1-4alkyl, or -NRpRq.
[0054] Embodiment 47 is the compound of any one of embodiments 1 - 45, wherein at least one R° substituent is C1-4alkyl.
[0055] Embodiment 48 is the compound of any one of embodiments 1 - 45, wherein at least one R° substituent is -OH. [0056] Embodiment 49 is the compound of any one of embodiments 1 - 45, wherein at least one R° substituent is -NRpRq.
[0057] Embodiment 50 is the compound of any one of embodiments 1 - 45, wherein at least one R° substituent is oxo.
[0058] Embodiment 51 is the compound of any one of embodiments 1 - 50, wherein Rp and Rq are each independently H or methyl.
[0059] Embodiment 52 is the compound of any one of embodiments 1 - 50, wherein Rp and Rq taken together with the nitrogen to which they are attached form a heterocyclyl.
[0060] Embodiment 53 is the compound of any one of embodiments 1 - 50, wherein Rp and Rq taken together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl 6-oxa-l-azaspiro[3.3]heptanyl, or 2-oxa- 6-azaspiro[3.3]heptanyl.
[0061] Embodiment 54 is the compound of any one of embodiments 1 - 53, wherein R5 is H, methyl, ethyl, propyl, Cl, Br, or -OH.
[0062] Embodiment 55 is the compound of any one of embodiments 1 - 53, wherein R5 is H or methyl.
[0063] Embodiment 56 is the compound of any one of embodiments 1 - 53, wherein R5 is H. [0064] Embodiment 57 is a compound selected from Table 1, and/or pharmaceutically acceptable salts thereof.
[0065] Embodiment 58 is the compound of any one of embodiments 1 - 57, wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.
[0066] Embodiment 59 is a pharmaceutical composition comprising a compound and/or a pharmaceutically acceptable salt or prodrug of any one of embodiments 1-58 and a pharmaceutically acceptable excipient.
[0067] Embodiment 60 is a method of inhibiting PIKfyve kinase in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of embodiments 1 to 58, or a pharmaceutical composition of embodiment 59.
[0068] Embodiment 61 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 to 58, or a pharmaceutical composition of embodiment 59.
[0069] Embodiment 62 is the method of embodiment 61, wherein the disease is associated with PIKfyve activity. [0070] Embodiment 63 is the method of embodiment 61, wherein the disease is amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth (CMT; including type 4J (CMT4J)), and Yunis-Varon syndrome, autophagy, polymicrogyria (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 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 disorder, depression, bipolar disorder I, or bipolar disorder II.
[0071] Embodiment 64 is the method of embodiment 59, wherein the disease is ALS, FTD, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or CMT.
[0072] Embodiment 65 is the method of embodiment 59, wherein the disease is ALS.
[0073] Embodiment 66 is the method of embodiment 61, wherein the disease is a tauopathy such as Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, or chronic traumatic encephalopathy.
[0074] Embodiment 67 is the method of embodiment 61, 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.
[0075] Embodiment 68 is the method of embodiment 61, 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.
[0076] Embodiment 69 is a compound of any one of embodiments 1 to 58 for use as a medicament.
[0077] Embodiment 70 is the compound of embodiment 69, wherein the compound is for use in treating a neurological disease treatable by inhibition of PIKfyve kinase.
[0078] Embodiment 71 is the use of a compound of any one of embodiments 1 to 58 in the manufacture of a medicament for treating a disease in a subject in which PIKfyve contributes to the pathology and/or symptoms of the disease. Detailed Description
[0079] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings.
[0080] A dash
Figure imgf000012_0001
that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(0)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.
[0081] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms.
For example, “C1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.
[0082] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In certain embodiments, the term “about” includes the indicated amount ± 5%. In certain embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
[0083] “Alkyl” means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like. C1-xalkyl refers to an alkyl group with from 1 to x carbon atoms. [0084] “Alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
[0085] “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. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 18 carbon ring atoms (i.e., C6-18 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl) or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl. [0086] “Amino” means a -NH2. [0087] “Alkoxy” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like. [0088] “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., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like. Cx-ycycloalkyl refers to a cycloalkyl group with from x to y carbon atoms in the ring, where x and y are integers. [0089] “Carboxy” means –COOH. [0090] “Halo” means fluoro, chloro, bromo, or iodo; in one embodiment fluoro or chloro. [0091] “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., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, and the like. In ” meoalkyl, “Cx-y” means the number of carbon atoms in the alkyl group ranges from x to y. When the alkyl is substituted with only fluoro, it can be referred to in this disclosure as fluoroalkyl. [0092] “Heterocyclyl” means a saturated or unsaturated monovalent monocyclic or bi-cyclic group (fused bi-cyclic or bridged bi-cyclic) 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. More specifically the term 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-1H-oxazolo[3,4-a]pyrazin-3(5H)-one- yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-yl, 3-oxa-8-azabicyclo[3.2.1]octane-yl, and the like. When the heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic. Cx-yheterocyclyl refers to a heterocyclyl group with from x to y carbon atoms in the ring, where x and y are integers. [0093] “Heterocyclylalkyl” and “heterocycloalkyl” mean an –(alkylene)-R radical where R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like. [0094] “Heteroaryl” 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, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrazolopyridinyl, indazolyl, furopyrimidinyl, and the like. Cx-yheteroaryl refers to a heteroaryl group with from x to y carbon atoms, where x and y are integers.
[0095] “Mammal” as used herein means domesticated animals (such as dogs, cats, and horses), and humans. In one embodiment, mammal is a human.
[0096] The term “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, /Moluenesulfonic 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. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington ’s Pharmaceutical Sciences , 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference. [0097] “Oxo” means an =(0) group and “carbonyl” means a >C(0) group.
[0098] “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “heterocyclyl group optionally substituted with an alkyl group” means that the alkyl 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.
[0099] The phrases “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.
[0100] The phrase “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.
[0101] The phrase “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. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose;
(2) starches, such as corn 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, corn 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 hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
[0102] “Treating” or “treatment” of a disease includes:
(1) preventing the disease, e.g., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, e.g., arresting or reducing the development of the disease or its clinical symptoms; or
(3) relieving the disease, e.g., causing regression of the disease or its clinical symptoms. [0103] 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 and the age, weight, etc., of the mammal to be treated.
[0104] 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 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 recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.
[0105] Certain compounds of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt or prodrug thereof can 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. For example, pyrazole tautomers as shown below are equivalent structures. The depiction of one such structure is intended to encompass both structures.
Figure imgf000016_0001
[0106] Additionally, as used herein the term 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.
[0107] Pharmaceutically acceptable salts of the compounds of Formula (I) (or any of the embodiments thereof described herein) are within the scope of this disclosure. In addition, the compounds described herein include hydrates and solvates of the compounds or pharmaceutically acceptable salts thereof.
[0108] 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 or prodrug 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) (or any of the embodiments thereof described herein) 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., h\ A-di m ethyl am i nocarbonyl ) or phosphonates (e.g., -0P(=0)(0H)2 ) 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 or prodrug thereof are also within the scope of this disclosure.
[0109] 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 or prodrug thereof.
[0110] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, UC, 13C and/or 14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As 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.
[0111] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure.
[0112] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 2H, UC, 13C, 14C, 15C, 12N, 13N,
15 contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
[0113] In certain embodiments, the compounds disclosed herein have some or all of the ¾ atoms replaced with 2H 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.
[0114] 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. [0115] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
[0116] In one aspect of is a compound of Formula (I):
Figure imgf000018_0001
wherein
Y1 is N or C-R1;
Y2 is N or C-R2;
X is N, or CH; provided that when Y1 is N, Y2 is C-R2 and when Y2 is N, Y1 is C-R1;
R1 is H, or C3-8aryl, C3-8heteroaryl, C3-8cycloalkyl, or C3-8heterocyclyl, each optionally substituted with from 1 to 3 Rs; R2 is H, or C3-8aryl, C3-8heteroaryl, C3-8cycloalkyl, or C3-8heterocyclyl, each optionally substituted with from 1 to 3 Rs; R3 is H, halo, OH, C1-4 alkyl, NRpRq, C1-4 alkyl-NRpRq, C1-4 alkyl-OH, C1-4 alkyl-OC1-4 alkyl, OC1-4 alkyl, C(O)-C1-4 alkyl, C(O)-C1-4 alkyl-NRpRq, C(O)OH, C(O)-OC1-4 alkyl, or C(O)-OC1-4 alkyl-NRpRq; R4 is C3-8aryl, C3-8heteroaryl, C3-8cycloalkyl, C3-8heterocyclyl, C1-4 alkyl, C1-4 alkylP(O))(ORx)2, (C1-4 alkyl)C3-8 aryl, (C1-4 alkyl)C3-8 heteroaryl, (C1-4 alkyl)C3-8 cycloalkyl, or (C1-4 alkyl)C3-8 heterocyclyl, each optionally substituted with from 1 to 3 Rs, or R4 is C(O)Ry, -C(O)NRxRy, NRxC(O)Ry, C1-4 alkylNRxC(O)Ry, or C(O)C1-4 alkylNRxC(O)Ry; Rs is halo, amino, oxo, OH, C3-8 heterocyclyl, OC1-6alkyl, C1-6alkyl, C1-6alkenyl, C1- 6alkyl-OH, C1-6 alkyl-O-C1-4 alkyl, C1-6 alkyl-O-C1-4 alkyl-O-C1-4 alkyl, (C1-4 alkyl)C3-8 aryl, (C1-4 alkyl)C3-8 heteroaryl, (C1-4 alkyl)C3-8 cycloalkyl, (C1-4 alkyl)C3-8 heterocyclyl or C1-6 alkyl-NRpRq; Rx is H or C1-4alkyl, optionally substituted with Ro; Ry is H, C1-4alkyl-Rr, C1-4alkyl, -O-C1-4alkyl, -SO2-C1-4alkyl, C1-4alkyl-SO2- Rr, cycloalkyl, (-C1-4alkyl)cycloalkyl, heterocyclyl, (-C1-4alkyl)heterocyclyl, O-heterocyclyl, C3-8 aryl, (-C1-4alkyl)C3-8 aryl, C3-8 heteroaryl, (-C1-4alkyl) C3-8 heteroaryl, each optionally substituted with 1 to 3 Ro substituents; or Rx and Ry taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with C1-4alkyl; each Rr is C1-4alkyl or -NRpRq; each Ro substituent is independently C1-4alkyl, oxo, -OH, -OC1-4alkyl, halo, cyano, heterocyclyl, or -NRpRq; Rp and Rq are each independently H or C1-4alkyl; or Rp and Rq taken together with the
nitrogen to which they are attached form a heterocyclyl; R5 is H, Ci-6alkyl, halo, -OH, or -OCi-6alkyl.
[0117] In another aspect is a compound of Formula (la):
Figure imgf000020_0001
wherein
Y1 is N or C-R1;
Y2 is N or C-R2;
X is N, or CH; provided that when Y1 is N, Y2 is C-R2 and when Y2 is N, Y1 is C-R1;
R1 is H, or C3-8aryl, C3-8heteroaryl, C3-8cycloalkyl, or C3-8heterocyclyl, each optionally substituted with from 1 to 3 Rs;
R2 is H, or C3-8aryl, C3-8heteroaryl, C3-8cycloalkyl, or C3-8heterocyclyl, each optionally substituted with from 1 to 3 Rs;
R4 is C3-8aryl, C3-8heteroaryl, C3-8cycloalkyl, or C3-8heterocyclyl, each optionally substituted with from 1 to 3 Rs, or -C(0)NRxRy;
Rs is H, halo, amino, OH, OCi-6alkyl, Ci-6alkyl;
Rx is H or C1-4alkyl, optionally substituted with R°;
Ry is H, Ci-ralkyl, -O-Ci-ralkyl, -SOi-Ci-ralkyl, Ci-ralkyl-SOi- Rr, cycloalkyl, -C1-4alkyl(cycloalkyl), heterocyclyl, -O-heterocyclyl, each optionally substituted with 1 to 3 R° substituents; or Rx and Ry taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with C1-4alkyl; each Rr is C1-4alkyl or -NRpRq; each R° substituent is independently C1-4alkyl, -OH, -OC1-4alkyl, halo, cyano, or -NRpRq; Rp and Rq are each independently H or C1-4alkyl; or Rp and Rq taken together with the nitrogen to which they are attached form a heterocyclyl;
R5 is H, Ci-6alkyl, halo, -OH, or -OCi-6alkyl. [0118] In some embodiments, Y1 is N, Y2 is C-R2. In some embodiments, Y2 is N, Y1 is C-R1. In some embodiments, Y1 is C-R1 and Y2 is C-R2. In some embodiments, Y1 is C-R1 and Y2 is C-R2, and one of R1 and R2 is not H. [0119] In some embodiments, X is N. In some embodiments, X is N, and one of Y1 and Y2 is N. In some embodiments, X is N, Y1 is C-R1, and Y2 is C-R2. In some embodiments, X is N, Y1 is C-R1, and Y2 is C-R2, and one of R1 and R2 is not H. In some embodiments, X is CH. In some embodiments, X is CH, and one of Y1 and Y2 is N. In some embodiments, X is CH, and Y1 and Y2 are N. [0120] In some embodiments, Y1 is C-R1 and R1 is H, or phenyl or C3-8heteroaryl each optionally substituted with from 1 to 3 Rs. In some embodiments, R1 is phenyl, pyridinyl, pyrimidinyl, pyrazolyl , or cyclopentenyl, each optionally substituted with 1 or 2 Rs. In some embodiments, R1 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 Rs. [0121] In some embodiments, Y2 is C-R2 and R2 is H, or phenyl or C3-8heteroaryl each optionally substituted with from 1 to 3 Rs. In some embodiments, R2 is phenyl, pyridinyl, pyrimidinyl, pyrazolyl or cyclopentenyl, each optionally substituted with 1 or 2 Rs. In some embodiments, R2 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 Rs. [0122] In some embodiments, R3 is H, C1-4 alkyl-NRpRq, C1-4 alkyl-OH, C1-4 alkyl-OC1-4 alkyl, C(O)OH, or C(O)-OC1-4 alkyl. In other embodiments. R3 is (CH2)NH2, (CH2)N(CH3)2, (CH2)OH, (CH2)OCH3, C(O)OH, or C(O)OCH2CH3. [0123] In some embodiments, R4 is phenyl, pyridinyl, pyrimidinyl, or pyrazolyl each optionally substituted with from 1 to 2 Rs. In some embodiments, R4 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 Rs. [0124] In some embodiments, Rs is H, F, Cl, Br, NH2, OH, oxo, OC1-6alkyl, or C1-6alkyl. In some embodiments, Rs is H, F, Cl, OH, oxo, methyl, ethyl, or propyl. In some embodiments, Rs is H or methyl. [0125] In some embodiments, R4 is pyrazolylmethyl , imidazolylmethyl, morpholinomethyl, piperidinylmethyl, dioxanylmethy, dioxanylethyl, dioxanylethylenyl, dioxanylpropyl, dioxanylpropylenyl, cyclohexenyl, cyclopentenyl, dihydropyridinyl, each optionally substituted with from 1 to 2 Rs. [0126] In some embodiments, R4 is C(O)Ry, -C(O)NRxRy, NRxC(O)Ry, C1-4 alkylNRxC(O)Ry, or C(O)C1-4 alkylNRxC(O)Ry. In some embodiments, R4 is -C(O)NRxRy. [0127] In some embodiments, Rx is H, or methyl or ethyl, optionally substituted with one Ro. In some embodiments, Rx is H or methyl. [0128] In some embodiments, Ry is C1-4alkyl-Rr, C1-4alkyl, -0-C1-4alkyl, -S02-C1-4alkyl, Ci- 4alkyl-S02- Rr, cycloalkyl, , (C1-4 alkyl)cycloalkyl, heterocyclyl, (C1-4 alkyl)heterocyclyl, O- heterocyclyl, C3-8aryl, (C1-4 alkyl)C3-8 aryl, C3-8 heteroaryl, (C1-4 alkyl)C3-8 heteroaryl,, each optionally substituted with 1 to 3 R° substituents. In some embodiments, Ry is C1-4alkyl, -O-C1- 4alkyl, -S02-C1-4alkyl, C1-4alkyl-SO2-Rr, cycloalkyl, -C1-4alkyl(cycloalkyl), heterocyclyl, -O- heterocyclyl, each optionally substituted with 1 to 3 R° substituents. In some embodiments, Ry is C1-4alkyl, optionally substituted with one, two, or three R° substituents. In some embodiments,
Ry is methyl, ethyl, propyl, or isopropyl, each optionally substituted with one, two, or three R° substituents. In some embodiments, Ry is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropanyl, (dimethylamino)ethyl, or (dimethylamino)butyl. In some embodiments, Ry is methoxy. In some embodiments, Ry is -SO2-methyl.
[0129] In some embodiments, Ry is cycloalkyl, or (C1-4 alkyl)monocyclic cycloalkyl, or -C1- 2alkyl(cycloalkyl), each optionally substituted with one, two, or three R° substituents. In some embodiments, Ry is monocyclic cycloalkyl, or (C1-4 alkyl)monocyclic cycloalkyl, optionally substituted with one, two, or three R° substituents. In some embodiments, Ry is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, or cyclopentenyl,, each optionally substituted with one, two, or three R° substituents. In some embodiments, Ry is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1 -cyclopropyl ethyl, 2-cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, cyclohexenylpropyl, or cyclopentenylpropyl.
[0130] In some embodiments, Ry is heterocyclyl or -O- heterocyclyl, optionally substituted with one, two, or three R° substituents. In some embodiments, Ry is tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxanyl, pyrazolyl, dihydropyridinyl, or oxetanyloxy, each optionally substituted with one, two, or three R° substituents.
[0131] In some embodiments, Ry is tetrahydrofuranylmethyl, tetrahydropyranylmethyl, oxetanylmethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, dioxanylmethyl, pyrazolylmethyl, dihydropyridinylmethyl, or oxetanyloxymethyl, tetrahydrofuranylpropyl, tetrahydropyranylpropyl, oxetanylpropyl, azetidinylpropyl, pyrrolidinylpropyl, piperidinylpropyl, morpholinylpropyl, piperazinylpropyl, dioxanylpropyl, pyrazolylpropyl, dihydropyridinylpropyl, or oxetanyloxy propyl, each optionally substituted with one, two, or three R° substituents.
[0132] In some embodiments, Rx is H and Ry is methyl, ethyl, isopropyl, cyclopropyl, methoxy, or cyclopentyl. In some embodiments, Rx is H and Ry is isopropyl. [0133] In some embodiments, Rx and Ry taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with C1-4alkyl. In some embodiments, Rx and Ry taken together with the nitrogen to which they are attached form a heterocycloalkyl, optionally substituted with C1-4alkyl. In some embodiments, Rx and Ry taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with methyl. In some embodiments, Rx and Ry are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxa-l-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl, each optionally substituted with methyl.
[0134] In some embodiments, each Rr is C1-4alkyl or -NRpRq. In some embodiments, Rr is methyl, ethyl, propyl, or isopropyl or -NRpRq.
[0135] In some embodiments, each R° substituent is independently C1-4alkyl, -OH, oxo, -O C1-4 alkyl, or -NRpRq. In some embodiments, at least one R° substituent is C1-4alkyl. In some embodiments, at least one R° substituent is -OH. In some embodiments, at least one R° substituent is -NRpRq. In some embodiments, at least one R° substituent is oxo.
[0136] In some embodiments, Rp and Rq are each independently H or methyl.
[0137] In some embodiments, Rp and Rq taken together with the nitrogen to which they are attached form a heterocyclyl. In some embodiments, Rp and Rq taken together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl 6-oxa-l-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl.
[0138] In some embodiments, R5 is H, methyl, ethyl, propyl, Cl, Br, or -OH. In some embodiments, R5 is H or methyl.
[0139] In some embodiments, the compound of Formula (I) or the pharmaceutically acceptable salt thereof is a compound of Formula (I):
Figure imgf000023_0001
as defined herein, wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms. [0140] In some embodiments, one or more hydrogen atoms attached to carbon atoms of R1,
R2, R3, R4, and/or R5 are replaced by deuterium atoms.
[0141] In some embodiments, one or more hydrogen atoms attached to carbon atoms of R°, Rs, Rp, Rq, Rr, Rx, and/or Ry are replaced by deuterium atoms.
[0142] In some embodiments, one or more C1-4alkyl group has one or more hydrogen atoms attached to carbon atoms replaced by deuterium atoms. In some embodiments, one or more methyl groups have one or more hydrogen atoms attached to the carbon atom replaced by deuterium atoms.
[0143] In some embodiments, the compound of Formula (I) comprises a -D in place of at least one -H, or a -CD3 substituent in place of at least one CFb.
Table 1
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
and pharmaceutically acceptable salts thereof.
Methods of Treating, Administration, and Pharmaceutical Compositions [0144] In general, 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. In one embodiment, the dosage level will be about 0.1 to about 250 mg/kg per day. In another embodiment 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. Within this range 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. For oral administration, 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 subject, the potency of the compound being utilized, the route and form of administration, and other factors. [0145] In general, compounds of this disclosure 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. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
[0146] Pharmaceutical 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 or prodrug form.
[0147] 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. Alternatively, the compositions described herein can be lyophilized or in powder form for re- constitution 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 drug- delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
[0148] The pharmaceutical compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration.
[0149] The pharmaceutical compositions described herein can be formulated for administration as an injection. Non-limiting examples of 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. [0150] For parenteral administration, the compounds can be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently nontoxic, and non-therapeutic. A vehicle can be 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).
[0151] Sustained-release preparations can also be prepared. Examples of sustained-release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and g ethyl -L-glutamate, non- degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPO™ (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.
[0152] Pharmaceutical formulations of the 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 non- ionic surfactants or polyethylene glycol.
[0153] 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. In some embodiments, the combination of the drugs together are safer or more effective than either drug alone. In some embodiments 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. When a compound of the present disclosure is used contemporaneously with one or more other drugs, in some embodiments, the agents are administered together in a single pharmaceutical composition in unit dosage form. Accordingly, 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. In some embodiments, 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. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly. For example, the combination agent is an anticancer agent, such as an alkylating agent, a corticosteroid, a platinum drug, a purine analog, an anti-metabolite, or particular agents such as cyclophosphamide, chlorambucil, bendamustine, prednisone, dexamethasone, carboplatin, cisplatin, cladribine, fludarabine, capecitabine, gemcitabine, methotrexate, pralatrexate, bleomycin, doxorubicin, vincristine, or rituximab. In some embodiments, the combination agent is a drug for reduction of symptoms of ALS. In some embodiments, 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.
[0154] The compounds, pharmaceutical compositions, and methods of the present disclosure can be useful for treating a subject 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 non- domesticated 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. In preferred embodiments, compounds, pharmaceutical compositions, and methods of the present disclosure are used for treating a human.
[0155] 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. [0156] In practicing the methods described herein, 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 physiology 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.
[0157] 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. [0158] 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.
[0159] 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.
[0160] 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. [0161] One of ordinary skill in the art would understand that the amount, duration, and frequency of administration of a pharmaceutical composition or compound described herein to a subject in need thereof depends on several factors including, for example but not limited to, the health of the subject, the specific disease or condition of the patient, the grade or level of a specific disease or condition of the patient, the additional therapeutics the subject is being or has been administered, and the like.
[0162] The methods, compounds, and pharmaceutical compositions described herein can be for administration to a subject in need thereof. Often, 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, intrasternal, intratumoral, or intraperitoneally. Additionally, 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. [0163] 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.
[0164] 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. In one aspect, the disclosure relates to a method of inhibiting PIKfyve kinase in a subject in need thereof comprising administering to the subject an effective amount of a compound. In one aspect, 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. In some aspects, the disease is a neurological disease. In some embodiments, the disease is associated with a FIG4 deficiency. In some embodiments is a method for treating a subject with a neurological disease or disorder associated with PIKfyve kinase activity, comprising administering to the subject an effective amount of a compound or pharmaceutical composition as described herein. [0165] In some embodiments, 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, polymicrogyria (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, frontotemporal 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 disorder, depression, bipolar disorder I, or bipolar disorder II.
[0166] In some embodiments, 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.
[0167] In some embodiments, the neurological disease is a tauopathy such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, or chronic traumatic encephalopathy.
[0168] In some embodiments, 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.
[0169] In some embodiments, 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.
[0170] 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.
EXAMPLES
[0171] The following preparations of compounds of Formula (I) and intermediates are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.
[0172] 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, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this disclosure can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
[0173] Unless specified to the contrary, 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.
[0174] Compounds of Formula (I) and subformulae and species described herein, including those where the substituent groups as defined herein, can be prepared as illustrated and described below.
[0175] Unless otherwise noted, all reagents were used without further purification. 'H NMR spectra were obtained in CDC13, DMSO-d6, or CD3OD at room temperature on a Bruker 300 MHz instrument. When more than one conformer was detected, the chemical shifts for the most abundant one is reported. Chemical shifts of ¾ NMR spectra were recorded in parts per million (ppm) on the d scale from an internal standard of residual solvent. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. LC-MS conditions were as described below:
[0176] LCMS Column: Agilent Zorbax XDB C18 4.6x50 mm, 3.5mih a. Mobile phase: Solvent A: Water (with 0.1% formic acid); Solvent B: MeOH b. Flow rate: 1.0 mL/min, Run time: 2 min gradient (20%-90% B), then 3 min @90% B, Temperature: 30 °C
[0177] HPLC Column: Agilent SB-C18 4.6x 150 mm, 3.5μm a. Mobile phase: Solvent A: water (with 0.02% TFA); Solvent B: MeOH b. Flow rate: 1.0 mL/min, c. Run time: 0.5 min @10% B, 9.5 min gradient (10%-90% B), then 10 min
@90% B, d. Temperature: 30 °C
[0178] Preparative LC Column: Phenomenex Luna 5u 100A, 21.2x250mm, 5pm a. Mobile phase: Solvent A: Water; Solvent B: MeOH b. Flow rate: 10 mL/min, c. Run time: 1 min @20% B, 30 min gradient (20%-80% B), then 10 min @90%
B, d. Temperature: Ambient
[0179] The following abbreviations are used in the text:
Figure imgf000044_0001
Figure imgf000045_0004
[0180] General procedure 1
[0181] Preparation of Compound 6: N-isopropyl-7-morpholino-5-(3-phenyl-lH-pyrazol- l-yl)furo[3,2-b]pyridine-2-carboxamide
Figure imgf000045_0001
Figure imgf000045_0002
p
[0182] Synthesis of 7 -morpholinofuro[ 3,2-b ] pyridine
Figure imgf000045_0003
[0183] A solution of 7-chlorofuro[3,2-b]pyridine (1 g, 6.49 mmol), K2CO3 (3.6 g, 25.97 mmol), morpholine (30 mL) in water (10 mL) was stirred at 100 °C overnight. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide 7-morpholinofuro[3,2-b]pyridine (1.1 g, 5.39 mmol) as a colorless oil. LC-MS (ESI+): m/z 205 (MH+).1HNMR (300 MHz, CDCl3) δ 8.27 (d, J = 5.4 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.53 (d, J = 5.4 Hz, 1H), 3.94-3.90 (m, 4H), 3.67-3.61 (m, 4H). [0184] Synthesis of 7-morpholinofuro[3,2-b]pyridine 4-oxide
Figure imgf000046_0001
[0185] To a solution of 7-morpholinofuro[3,2-b]pyridine (1.1 g, 5.39 mmol) in DCM (10 mL) was added m-CPBA (3.3 g, 19.6 mmol). The mixture was stirred at rt overnight. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 5% MeOH/DCM to 10% MeOH/DCM to provide 7-morpholinofuro[3,2-b]pyridine 4-oxide (0.32 g, 1.45 mmol) as a white solid. LC-MS (ESI+): m/z 220 (MH+).1HNMR (300 MHz, CDCl3) δ 8.07 (d, J = 5.4 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 3.6 Hz, 1H), 6.49 (d, J = 6.9 Hz, 1H), 3.94-3.90 (m, 4H), 3.60-3.54 (m, 4H). [0186] Synthesis of 5-chloro-7-morpholinofuro[3,2-b]pyridine
Figure imgf000046_0002
[0187] A solution of 7-morpholinofuro[3,2-b]pyridine 4-oxide (0.32 g, 1.45 mmol) in POCl3 (8 mL) and toluene (8 mL) was heated to 80 oC for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution until the pH = 8. The aqueous solution was extracted with EtOAc (3 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure to provide crude 5-chloro-7-morpholinofuro[3,2-b]pyridine (170 mg, 0.71 mmol). The crude product was used directly for the next step without further purification. LC-MS (ESI+): m/z 239 (MH+) [0188] Synthesis of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000047_0001
[0189] A suspension of crude 5-chloro-7-morpholinofuro[3,2-b]pyridine (170 mg, 0.71 mmol), 3-phenyl-1H-pyrazole (123 mg, 0.86 mmol), Cs2CO3 (466 mg, 1.43 mmol) and Cu2O (31 mg, 0.21 mmol) in DMF (10 mL) was heated to 110 oC overnight. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine (120 mg, 0.35 mmol) as a yellow solid. LC-MS (ESI+): m/z 347 (MH+) [0190] Synthesis of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2- carboxylic acid [0191] To a solution of 7-m
Figure imgf000047_0002
orpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine (120 mg, 0.35 mmol) in anhydrous THF (20 mL) at -78 oC under N2 was added n-BuLi (0.3 mL, 2.5 M, 0.70 mmol) dropwise. The reaction mixture was stirred at that temperature for 1 h. To the above solution was added dry ice (150 mg, 3.5 mmol) in one potion. The resulting reaction mixture was stirred at that temperature for 2 h. The completion of the reaction was monitored by TLC. The reaction was quenched with water and the pH was adjusted to 5 using 1 N HCl solution. The mixture was extracted with DCM (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure to provide crude 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2-carboxylic acid (20 mg, 0.05 mmol) as a yellow solid. LC-MS (ESI+): m/z 391 (MH+). [0192] Synthesis of N-isopropyl-7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2- b]pyridine-2-carboxamide
Figure imgf000048_0001
[0193] A solution of crude 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2- carboxylic acid (20 mg, 0.05 mmol), propan-2-amine (5 mg, 0.077 mmol), EDCl (25 mg, 0.12 mmol) and HOBT (17 mg, 0.12 mmol) in DCM was stirred at rt overnight. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly and purified by preparative TLC with a elution of MeOH/DCM (1:15) to provide N-isopropyl-7-morpholino- 5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2-carboxamide (5.5 mg, 0.012 mmol) as a white solid. LC-MS (ESI+): m/z 432 (MH+).1HNMR (300 MHz, CDCl3) δ 9.54 (d, J = 8.4 Hz, 1H), 9.06 (d, J = 2.7 Hz, 1H), 8.26 (d, J = 5.7 Hz, 1H), 7.91 (d, J = 6.9 Hz, 2H), 7.48-7.26 (m, 3H), 6.82 (d, J = 3.0 Hz, 1H), 6.61 (d, J = 6.0 Hz, 1H), 4.33-4.27 (m, 1H), 3.95-3.92 (m, 4H), 3.71-3.68 (m, 4H), 1.33 (d, J = 6.6 Hz, 6H). [0194] General procedure 2: [0195] Compound 55: Synthesis of N-(methyl-d3)-N-((1-methyl-3-(7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-5-yl)methyl)methanamine-d3
Figure imgf000049_0001
[0196] Synthesis of N-((3-bromo-1-methyl-1H-pyrazol-5-yl)methyl)-N-(methyl- d3)methanamine-d3
Figure imgf000049_0002
[0197] To a solution of 3-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (GP 2.1, 1.0 g, 5.29 mmol) in MeOH (30 mL) at rt was added bis(methyl-d3)amine hydrochloride (931 mg, 10.58 mmol), NaBH3CN (931 mg, 10.58 mmol) and 2 drops of AcOH. The solution was stirred at rt overnight. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL) and extracted with MeOH/DCM (1:15, 3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide N-((3-bromo-1-methyl-1H- pyrazol-5-yl)methyl)-N-(methyl-d3)methanamine-d3 (683 mg, 5.42 mmol) as a yellow oil. LC- MS (ESI+): m/z 224/226 (MH+).1HNMR (300 MHz, CDCl3) δ 6.21 (s, 1H), 3.85 (s, 3H), 3.43 (s, 2H). [0198] Synthesis of 5-chloro-7-morpholino-2-(tributylstannyl)furo[3,2-b]pyridine
Figure imgf000050_0001
[0199] To a solution of 5-chloro-7-morpholinofuro[3,2-b]pyridine (GP 1.4, 0.8 g, 3.38 mmol) in THF (40 mL) at -78 oC under N2 was added n-BuLi (1.6 mL, 2.5 M, 4.05 mmol). After stirred at -78 oC for 1 h, to the solution was added a solution of tributylchlorostannane (1.32 g, 4.05 mmol) in THF (10 mL). The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 5- chloro-7-morpholino-2-(tributylstannyl)furo[3,2-b]pyridine (1.6 g, 3.03 mmol) as a yellow solid. 1HNMR (300 MHz, CDCl3) δ 6.92 (s, 1H), 6.45 (s, 1H), 3.91-3.88 (m, 4H), 3.63-3.60 (m, 4H), 1.67-1.52 (m, 6H), 1.40-1.21 (m, 6H), 1.20-1.10 (m, 6H), 0.95-0.85 (m, 9H). [0200] Synthesis of N-((3-(5-chloro-7-morpholinofuro[3,2-b]pyridin-2-yl)-1-methyl-1H- pyrazol-5-yl)methyl)-N-(methyl-d3)methanamine-d3
Figure imgf000050_0002
[0201] To a solution of 5-chloro-7-morpholino-2-(tributylstannyl)furo[3,2-b]pyridine (GP 2.3, 1.2 g, 2.27 mmol) in 1,4-dioxane (50 mL) at rt was added N-((3-bromo-1-methyl-1H-pyrazol-5- yl)methyl)-N-(methyl-d3)methanamine-d3 (GP 2.2, 560 mg, 2.50 mmol) and Pd(PPh3)4 (262 mg, 0.227 mmol). The reaction was stirred at 90 oC under N2 for 1 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 8% MeOH/DCM to provide N-((3-(5-chloro-7-morpholinofuro[3,2-b]pyridin-2- yl)-1-methyl-1H-pyrazol-5-yl)methyl)-N-(methyl-d3)methanamine-d3 (130 mg, 0.34 mmol) as a white solid. LC-MS (ESI+): m/z 382/384 (MH+).1HNMR (300 MHz, CDCl3) δ 7.02 (s, 1H), 6.57 (s, 2H), 3.99-3.91 (m, 7H), 3.69-3.63 (m, 4H), 3.47 (s, 2H). [0202] Synthesis of N-(methyl-d3)-N-((1-methyl-3-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-5-yl)methyl)methanamine-d3
Figure imgf000051_0001
[0203] To a solution of N-((3-(5-chloro-7-morpholinofuro[3,2-b]pyridin-2-yl)-1-methyl-1H- pyrazol-5-yl)methyl)-N-(methyl-d3)methanamine-d3 (GP 2.4, 50 mg, 0.13 mmol) in 1,4- dioxane (10 mL) was added 3-(m-tolyl)-1H-pyrazole (30 mg, 0.16 mmol), Cs2CO3 (60 mg, 0.20 mmol), t-Buxphos (20 mg, 0.042 mmol) and Pd2(dba)3 (20 mg, 0.013 mmol). The reaction was stirred at 100 oC under N2 for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide N-(methyl-d3)-N-((1-methyl-3-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)-1H-pyrazol-5-yl)methyl)methanamine-d3 (54 mg, 0.107 mmol) as an off-white solid. LC-MS (ESI+): m/z 504 (MH+).1HNMR (300 MHz, CD3OD) δ 8.76 (d, J = 2.7 Hz, 1H), 7.88 (s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.44-7.35 (m, 2H), 7.31-7.25 (m, 3H), 7.14 (d, J = 2.7 Hz, 1H), 4.62 (s, 2H), 4.19-4.15 (m, 4H), 4.11 (s, 3H), 3.99-3.96 (m, 4H), 2.44 (s, 3H). [0204] General procedure 3: [0205] Compound 2: Synthesis of 2-(1-methyl-1H-pyrazol-3-yl)-7-morpholino-5-(3- phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000052_0001
[0206] Synthesis of 5-chloro-2-iodo-7-morpholinofuro[3,2-b]pyridine
Figure imgf000052_0002
[0207] To a solution of 5-chloro-7-morpholinofuro[3,2-b]pyridine (GP 1.4,100 mg, 0.42 mmol) in THF (40 mL) at -78 oC under N2 was added LDA (0.3 mL, 2.0M, 0.63 mmol). After stirred at -78 oC for 1 h, to the solution was added a solution of NIS (113 mg, 0.51 mmol) in THF (20 mL). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (20 mL). The aqueous solution was extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 20% EtOAc/PE to provide 5-chloro-2-iodo-7- morpholinofuro[3,2-b]pyridine (38 mg, 0.10 mmol) as a yellow solid. LC-MS (ESI+): m/z 365/367 (MH+).1HNMR (300 MHz, CDC13) δ 7.02 (s, 1H), 6.45 (s, 1H), 3.91-3.87 (m, 4H), 3.60-3.56 (m, 4H). [0208] Synthesis of 5-chloro-2-(1-methyl-1H-pyrazol-3-yl)-7-morpholinofuro[3,2-b]pyridine
Figure imgf000052_0003
Figure imgf000052_0004
GP3.2 [0209] To a solution of 5-chloro-2-iodo-7-morpholinofuro[3,2-b]pyridine (GP3.1, 250 mg, 0.68 mmol) in 1,4-dioxane/H2O (4/1, 18 mL) was added 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (160 mg, 0.82 mmol), K3CO3 (284 mg, 2.06 mmol) and PdCl2(PPh3)2 (50 mg, 0.069 mmol). The reaction was stirred at 90 oC under N2 for 1 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 4% MeOH/DCM to provide 5-chloro-2-(1-methyl-1H-pyrazol-3- yl)-7-morpholinofuro[3,2-b]pyridine (205 mg, 0.64 mmol) as a white solid. LC-MS (ESI+): m/z 319/321 (MH+).1HNMR (300 MHz, CDCl3) δ 7.43 (d, J = 2.1 Hz, 1H), 7.04 (s, 1H), 6.60 (d, J = 2.1 Hz, 1H), 6.52 (s, 1H), 4.23 (s, 3H), 3.99-3.94 (m, 4H), 3.67-3.64 (m, 4H). [0210] Synthesis of 2-(1-methyl-1H-pyrazol-3-yl)-7-morpholino-5-(3-phenyl-1H-pyrazol-1- yl)furo[3,2-b]pyridine
Figure imgf000053_0001
[0211] A suspension of 5-chloro-2-(1-methyl-1H-pyrazol-3-yl)-7-morpholinofuro[3,2- b]pyridine (GP3.2, 60 mg, 0.19 mmol), 3-phenyl-1H-pyrazole (82 mg, 0.57 mmol) and Cs2CO3 (250 mg, 0.76 mmol) in DMAc (4 mL) was stirred at 140 oC under microwave for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (30 mL) and a large amount of solid was precipitated. After filtration, the filter cake was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 2-(1-methyl-1H-pyrazol-3-yl)-7-morpholino-5-(3-phenyl-1H-pyrazol-1- yl)furo[3,2-b]pyridine (17 mg, 0.040 mmol) as a white solid. LC-MS (ESI+): m/z 427 (MH+). 1HNMR (300 MHz, CDCl3) δ 8.62 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 1.2 Hz, 2H), 7.47-7.42 (m, 4H), 7.37-7.32 (m, 1H), 7.10 (s, 1H), 6.78 (d, J = 2.4 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 4.11 (s, 3H), 4.01-3.96 (m, 4H), 3.79-3.69 (m, 4H). [0212] General Procedure 4 [0213] Compound 37: Synthesis of 5-(3-(cyclopent-1-en-1-yl)-1H-pyrazol-1-yl)-7- morpholino-2-(pyridin-2-yl)furo[3,2-b]pyridine
Figure imgf000054_0001
[0214] Synthesis of 5-chloro-7-morpholino-2-(pyridin-2-yl)furo[3,2-b]pyridine
Figure imgf000054_0002
[0215] To a solution of 5-chloro-2-iodo-7-morpholinofuro[3,2-b]pyridine (GP 3.1, 500 mg, 1.37 mmol) in DMF (50 mL) at rt was added 2-(tributylstannyl)pyridine (758 mg, 2.10 mmol), CuI (78 mg, 0.41 mmol) and PdCl2(PPh3)2 (100 mg, 0.14 mmol). The reaction mixture was stirred at 110 oC under N2 for 1 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 50% EtOAc/PE to provide 5-chloro-7-morpholino-2-(pyridin-2-yl)furo[3,2- b]pyridine (419 mg, 1.33 mmol) as a yellow solid. LC-MS (ESI+): m/z 316/318 (MH+). [0216] Synthesis of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole
Figure imgf000054_0003
[0217] To a solution of 3-bromo-1H-pyrazole (500 mg, 3.4 mmol) in DCM (40 mL) at rt was added DHP (429 mg, 5.1 mmol) and TsOH (32 mg, 0.17 mmol). The reaction mixture was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 2% EtOAc/PE to 4% EtOAc/PE to provide 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (678 g, 2.95 mmol) as a colorless oil. LC-MS (ESI+): m/z 231/233 (MH+).1HNMR (300 MHz, CDCl3) δ 7.50 (s, 1H), 6.32 (s, 1H), 5.34-5.30 (m, 1H), 4.06-4.03 (m, 1H), 3.72-3.63 (m, 1H), 2.09-2.00 (m, 3H), 1.74-1.62 (m, 3H). [0218] Synthesis of 3-(cyclopent-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole
Figure imgf000055_0001
[0219] To a solution of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (GP4.2, 100 mg, 0.43 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) at rt was added K2CO3 (180 mg, 1.30 mmol), 2- (cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (126 mg, 0.65 mmol) and Pd(PPh3)4 (50 mg, 0.04 mmol). The reaction was stirred at 80 oC under N2 for 1 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated. The resulting residue was purified by silica gel column chromatography with a gradient elution of 2% EtOAc/PE to 4% EtOAc/PE to provide 3- (cyclopent-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (90 mg, 0.41 mmol). LC-MS (ESI+): m/z 219 (MH+).1HNMR (300 MHz, CDCl3) δ 7.53 (s, 1H), 6.37 (s, 1H), 6.14 (s, 1H), 5.34-5.30 (m, 1H), 4.06-4.03 (m, 1H), 3.72-3.63 (m, 1H), 2.75-2.70 (m, 2H), 2.50-2.45 (m, 2H), 2.05-1.95 (m, 5H), 1.74-1.62 (m, 3H). [0220] Synthesis of 3-(cyclopent-1-en-1-yl)-1H-pyrazole
Figure imgf000055_0002
[0221] To a solution of 3-(cyclopent-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (GP4.3, 90 mg, 0.41 mmol) in DCM (2 mL) was added TFA (0.3 mL). The reaction mixture was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with aqueous NaHCO3 solution to adjust pH = 8. The resulting mixture was extracted with DCM (3 X 10 mL). The combined organic phase was concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 2% EtOAc/PE to 10% EtOAc/PE to provide 3-(cyclopent-1-en-1-yl)-1H- pyrazole (45 mg, 0.34 mmol) as a light-yellow solid. LC-MS (ESI+): m/z 135 (MH+).1HNMR (300 MHz, CDCl3) δ 7.53 (s, 1H), 6.34 (s, 1H), 6.14 (s, 1H), 2.75-2.70 (m, 2H), 2.55-2.45 (m, 2H), 2.05-1.95 (m, 2H). [0222] Synthesis of 5-(3-(cyclopent-1-en-1-yl)-1H-pyrazol-1-yl)-7-morpholino-2-(pyridine-2- yl)furo[3,2-b]pyridine
Figure imgf000056_0001
[0223] To a solution of 5-chloro-7-morpholino-2-(pyridine-2-yl)furo[3,2-b]pyridine (GP4.1, 100 mg, 0.32 mmol) in DMAc (10 mL) was added 3-(cyclopent-1-en-1-yl)-1H-pyrazole (GP4.4, 85 mg, 0.63 mmol), Pd2(dba)3 (145 mg, 0.16 mmol), t-Buxphos (135 mg, 0.32 mmol) and Cs2CO3 (155 mg, 1.76 mmol). The reaction mixture was stirred at 150 oC under N2 overnight. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by preparative TLC with a elution of 50% EtOAc/PE to provide 5-(3-(cyclopent-1- en-1-yl)-1H-pyrazol-1-yl)-7-morpholino-2-(pyridin-2-yl)furo[3,2-b]pyridine (10 mg, 0.024 mmol) as a white solid. LC-MS (ESI+): m/z 414 (MH+).1HNMR (300 MHz, CDCl3) δ 8.70 (t, J = 2.4 Hz, 1H), 8.54 (s, 1H), 7.81 (d, J = 3.9 Hz, 2H), 7.61 (s, 1H), 7.50 (s, 1H), 7.38-7.28 (m, 1H), 6.54 (t, J = 2.4 Hz, 1H), 6.29 (s, 1H), 4.02-3.98 (m, 4H), 3.79-3.76 (m, 4H), 2.86-2.82 (m, 2H), 2.55-2.52 (m, 2H), 2.09-2.00 (m, 2H). [0224] General Procedure 5 [0225] Compound 56: Synthesis of 2-(2-methoxypyridin-3-yl)-7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000057_0001
[0226] Synthesis of 5-chloro-2-(2-methoxypyridin-3-yl)-7-morpholinofuro[3,2-b]pyridine
Figure imgf000057_0002
[0227] To a solution of 5-chloro-2-iodo-7-morpholinofuro[3,2-b]pyridine (GP3.1, 120 mg, 0.33 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) at rt was added Na2CO3 (105 mg, 0.99 mmol), (2- methoxypyridin-3-yl)boronic acid (76 mg, 0.65 mmol) and Pd(PPh3)4 (38 mg, 0.03 mmol). The reaction mixture was stirred at 80 oC under N2 for 1 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 33% EtOAc/PE to provide 5-chloro-2-(2-methoxypyridin-3-yl)-7-morpholinofuro[3,2-b]pyridine (120 mg, 0.35 mmol) as a yellow solid. LC-MS (ESI+): m/z 346/348 (MH+).1HNMR (300 MHz, CDCl3) δ 8.22-8.20 (m, 1H), 8.11-8.08 (m, 1H), 7.61 (s, 1H), 7.06-7.02 (m, 1H), 6.54 (s, 1H), 4.13 (s, 3H), 3.96-3.91 (m, 4H), 3.68-3.60 (m, 4H). [0228] Synthesis of 2-(2-methoxypyridin-3-yl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridine
Figure imgf000057_0003
[0229] To a solution of 5-chloro-2-(2-methoxypyridin-3-yl)-7-morpholinofuro[3,2-b]pyridine (GP5.1, 60 mg, 0.17 mmol) in 1,4-dioxane (5 mL) was added 3-(m-tolyl)-1H-pyrazole (55 mg, 0.34 mmol), Pd2(dba)3 (80 mg, 0.09 mmol), t-Buxphos (75 mg, 0.17 mmol) and Cs2CO3 (115 mg, 0.34 mmol). The reaction mixture was stirred at 90 oC under N2 overnight. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide 2-(2-methoxypyridin-3-yl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridine (46 mg, 0.1 mmol) as a yellow solid. LC-MS (ESI+): m/z 468 (MH+).1HNMR (300 MHz, CDCl3) δ 8.62 (d, J = 2.7 Hz, 1H), 8.22-8.20 (m, 1H), 8.15-8.12 (m, 1H), 7.78 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.08-7.03 (m, 1H), 6.78 (d, J = 2.7 Hz, 1H), 4.15 (s, 3H), 4.02- 3.98 (m, 4H), 3.80-3.77 (m, 4H), 2.44 (s, 3H). [0230] General Procedure 6 [0231] Compound 57: Synthesis of 3-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)pyridin-2(1H)-one
Figure imgf000058_0001
[0232] Synthesis of 3-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)pyridin-2(1H)-one
Figure imgf000058_0002
[0233] To a solution of 2-(2-methoxypyridin-3-yl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol- 1-yl)furo[3,2-b]pyridine (Compound 56, 23 mg, 0.05 mmol) in DMF (2 mL) at rt was added LiCl (7 mg, 0.2 mmol) and TsOH (16 mg, 0.2 mmol). The reaction was stirred at 120 oC for 30 min. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide 3-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)pyridin-2(1H)-one (8 mg, 0.018 mmol) as a yellow solid. LC-MS (ESI+): m/z 454 (MH+).1HNMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.11-8.08 (m, 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.48-7.45 (m, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 6.78 (d, J = 2.7 Hz, 1H), 6.53-6.48 (m, 1H), 4.02-3.99 (m, 4H), 3.80-3.78 (m, 4H), 2.44 (s, 3H). [0234] General procedure 7 [0235] Compound 61: Synthesis of N,N-bis(methyl-d3)-2-(4-(7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethan-1-amine hydrogen chloride
Figure imgf000059_0001
[0236] Synthesis of 5-chloro-7-morpholino-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4- yl)furo[3,2-b]pyridine
Figure imgf000059_0002
GP7.1 [0237] To a solution of 5-chloro-2-iodo-7-morpholinofuro[3,2-b]pyridine (GP3.1, 600 mg, 1.65 mmol) in 1,4-dioxane/H2O (4/1, 30 mL) was added 1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (550 mg, 1.98 mmol), K2CO3 (682 mg, 5.0 mmol) and PdCl2(PPh3)2 (116 mg, 0.16 mmol). The reaction was stirred at 90 oC under N2 for 1 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated. The resulting residue was purified by silica gel column chromatography with a gradient elution of 30% EtOAc/PE to 50% EtOAc/PE to provide 5-chloro-7-morpholino-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4- yl)furo[3,2-b]pyridine (430 mg, 1.11 mmol) as a yellow solid. LC-MS (ESI+): m/z 389/391 (MH+).1HNMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 7.88 (s, 1H), 6.75 (s, 1H), 6.50 (s, 1H), 5.47- 5.43 (m, 1H), 4.13-4.08 (m, 1H), 3.94-3.91 (m, 4H), 3.77-3.70 (m, 1H), 3.63-3.61 (m, 4H), 2.15- 2.05 (m, 3H), 1.75-1.62 (m, 3H). [0238] Synthesis of 7-morpholino-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-5-(3-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000060_0001
[0239] To a solution of 5-chloro-7-morpholino-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol- 4-yl)furo[3,2-b]pyridine (GP7.1, 410 mg, 1.06 mmol) in 1,4-dioxane (40 mL) was added 3-(m- tolyl)-1H-pyrazole (334 mg, 2.11 mmol), Cs2CO3 (689 mg, 2.11 mmol), t-BuXphos (450 mg, 1.06 mmol) and Pd2(dba)3 (484 mg, 0.53 mmol). The reaction was stirred at 90 oC under N2 for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide 7-morpholino-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-5-(3- (m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine (600 mg, 1.17 mmol) as a yellow solid. LC-MS (ESI+): m/z 511 (MH+).1HNMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.77 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.41 (s, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 6.81 (s, 1H), 6.76 (d, J = 2.4 Hz, 1H), 5.47-5.43 (m, 1H), 4.15-4.10 (m, 1H), 3.99-3.96 (m, 4H), 3.76-3.71 (m, 5H), 2.43 (s, 3H), 2.16-2.05 (m, 3H), 1.75-1.62 (m, 3H). [0240] Synthesis of 7-morpholino-2-(1H-pyrazol-4-yl)-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridine
Figure imgf000061_0001
[0241] To a solution of 7-morpholino-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-5-(3- (m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine (GP7.2, 600 mg, 1.17 mmol) in DCM (15 mL) at rt was added TFA (5 mL). The solution was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with aqueous NaHCO3 solution to adjust pH to 8. The aqueous solution was extracted with DCM (3 X 20 mL). The combined organic phase was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 7-morpholino-2-(1H-pyrazol-4-yl)-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridine (200 mg, 0.47 mmol) as a yellow solid. LC-MS (ESI+): m/z 427 (MH+). [0242] Synthesis of 2-(1-(2-bromoethyl)-1H-pyrazol-4-yl)-7-morpholino-5-(3-(m-tolyl)-1H- pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000061_0002
[0243] A suspension of 7-morpholino-2-(1H-pyrazol-4-yl)-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridine (GP7.3, 190 mg, 0.445 mmol), 1,2-dibromoethane (832 mg, 4.45 mmol) and K2CO3 (420 mg, 1.29 mmol) in DMF (20 mL) was heated to 60 oC for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide 2-(1-(2-bromoethyl)-1H-pyrazol-4-yl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridine (150 mg, 0.28 mmol) as a yellow solid. LC-MS (ESI+): m/z 533/535 (MH+).1HNMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.77 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.42 (s, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 6.81 (s, 1H), 6.76 (d, J = 2.4 Hz, 1H), 4.58 (t, J = 6.0 Hz, 2H), 3.99-3.96 (m, 4H), 3.82-3.75 (m, 6H), 2.41 (s, 3H). [0244] Synthesis of N,N-bis(methyl-d3)-2-(4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethan-1-amine hydrogen chloride
Figure imgf000062_0001
[0245] A suspension of 2-(1-(2-bromoethyl)-1H-pyrazol-4-yl)-7-morpholino-5-(3-(m-tolyl)- 1H-pyrazol-1-yl)furo[3,2-b]pyridine (GP7.4, 140 mg, 0.26 mmol), bis(methyl-d3)amine hydrochloride (35 mg, 0.40 mmol) and K2CO3 (73 mg, 0.53 mmol) in DMF (7 mL) was heated to 60 oC for 4 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 5% MeOH/DCM to provide N,N-bis(methyl-d3)-2-(4-(7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethan-1-amine (50 mg, 0.10 mmol) as a white solid. LC-MS (ESI+): m/z 504 (MH+). [0246] To a solution of N,N-bis(methyl-d3)-2-(4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethan-1-amine (the ‘free base’, 50 mg, 0.10 mmol) in DCM (5 mL) was added Et2O/HCl (0.5 mL). The solution was stirred at rt for 10 min. The reaction mixture was concentrated directly. The resulting residue was slurry in Et2O to provide N,N-bis(methyl-d3)-2-(4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)-1H-pyrazol-1-yl)ethan-1-amine hydrochloride (50 mg, 0.09 mmol) as a yellow solid. LC-MS (ESI+): m/z 504 (MH+).1HNMR (300 MHz, CD3OD) δ 8.74 (d, J = 2.7 Hz, 1H), 8.58 (s, 1H), 8.22 (s, 1H), 7.88 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.32-7.20 (m, 3H), 7.13 (d, J = 2.7 Hz, 1H), 4.73 (t, J = 5.7 Hz, 2H), 4.21-4.11 (m, 4H), 4.01-3.91 (m, 4H), 3.76 (t, J = 5.7 Hz, 2H), 2.44 (s, 3H). [0247] General procedure 8 [0248] Compound 10: Synthesis of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)-2-(1H- pyrazol-4-yl)furo[3,2-b]pyridine and Compound 11: Synthesis of 3-(4-(7-morpholino-5-(3- phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)propan-1-ol
Figure imgf000063_0001
[0249] Synthesis of 5-chloro-7-morpholino-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4- yl)furo[3,2-b]pyridine
Figure imgf000063_0002
[0250] To a solution of 5-chloro-2-iodo-7-morpholinofuro[3,2-b]pyridine (GP3.1, 360 mg, 0.99 mmol) in 1,4-dioxane/H2O (10/1, 20 mL) was added 1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (303 mg, 1.086 mmol), K2CO3 (410 mg, 2.96 mmol) and PdCl2(PPh3)2 (70 mg, 0.079 mmol). The reaction was stirred at 80 oC under N2 overnight. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 40% EtOAc/PE to provide 5-chloro-7-morpholino-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4- yl)furo[3,2-b]pyridine (320 mg, 0.82 mmol) as a yellow oil. LC-MS (ESI+): m/z 389/391 (MH+).1HNMR (300 MHz, CDCl3) δ 8.00 (s, 1H), 7.87 (s, 1H), 6.74 (s, 1H), 6.50 (s, 1H), 5.47- 5.43 (m, 1H), 4.13-4.08 (m, 1H), 3.94-3.91 (m, 4H), 3.77-3.71 (m, 1H), 3.64-3.61 (m, 4H), 2.15- 2.05 (m, 3H), 1.75-1.62 (m, 3H). [0251] Synthesis of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)-2-(1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazol-4-yl)furo[3,2-b]pyridine
Figure imgf000064_0001
[0252] To a solution of 5-chloro-7-morpholino-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol- 4-yl)furo[3,2-b]pyridine (GP8.1, 320 mg, 0.82 mmol) in 1,4-dioxane (15 mL) at rt was added 3- phenyl-1H-pyrazole (178 mg, 1.23 mmol), Pd2(dba)3 (151 mg, 0.17 mmol), t-Buxphos (140 mg, 0.33 mmol) and Cs2CO3 (805 mg, 2.50 mmol). The reaction was stirred at 105 oC under N2 overnight. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 33% EtOAc/PE to provide 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)-2-(1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)furo[3,2-b]pyridine (280 mg, 0.56 mmol) as a yellow solid. LC-MS (ESI+): m/z 497 (MH+).1HNMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.00 (s, 1H), 7.96-7.90 (m, 2H), 7.47-7.32 (m, 5H), 6.81-6.77 (m, 2H), 5.47-5.43 (m, 1H), 4.13-4.08 (m, 1H), 3.94-3.91 (m, 4H), 3.77-3.71 (m, 5H), 2.15-2.05 (m, 3H), 1.75-1.62 (m, 3H). [0253] Synthesis of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)-2-(1H-pyrazol-4-yl)furo[3,2- b]pyridine
Figure imgf000065_0001
[0254] To a solution of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)-2-(1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazol-4-yl)furo[3,2-b]pyridine (GP8.2, 280 mg, 0.56 mmol) in MeOH (3 mL) was added a solution of Et2O/HCl (3 mL). The reaction mixture was stirred at rt for 1 h and then concentrated directly. The resulting residue was slurry in Et2O to provide 7-morpholino-5-(3- phenyl-1H-pyrazol-1-yl)-2-(1H-pyrazol-4-yl)furo[3,2-b]pyridine hydrochloride (250 mg, 0.61 mmol) as a white solid. LC-MS (ESI+): m/z 413 (MH+).1HNMR (300 MHz, CD3OD) δ 8.74 (s, 1H), 8.35 (s, 2H), 8.02 (d, J = 6.6 Hz, 2H), 7.65-7.42 (m, 3H), 7.27 (s, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 4.15-4.10 (m, 4H), 3.96-3.90 (m, 4H). [0255] Synthesis of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)-2-(1-(3-((tetrahydro-2H- pyran-2-yl)oxy)propyl)-1H-pyrazol-4-yl)furo[3,2-b]pyridine
Figure imgf000065_0002
[0256] A suspension of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)-2-(1H-pyrazol-4- yl)furo[3,2-b]pyridine hydrochloride (Compound 10, 350 mg, 0.78 mmol), 2-(3- bromopropoxy)tetrahydro-2H-pyran (209 mg, 0.94 mmol) and Cs2CO3 (1.02 g, 3.12 mmol) in DMF (10 mL) was heated to 60 oC for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The residue was purified by silica gel column chromatography with a gradient elution of PE to EtOAc to provide 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)-2-(1-(3- ((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H-pyrazol-4-yl)furo[3,2-b]pyridine (180 mg, 0.32 mmol) as a white solid. LC-MS (ESI+): m/z 555 (MH+).1HNMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 7.96-7.94 (m, 2H), 8.87 (s, 1H), 8.82 (s, 1H), 7.47-7.35 (m, 4H), 6.77 (s, 2H), 4.60-4.58 (m, 1H), 4.34 (t, J = 6.6 Hz, 2H), 3.98-3.96 (m, 4H), 3.89-3.79 (m, 2H), 3.76-3.74 (m, 4H), 3.53-3.40 (m, 2H), 2.23-2.19 (m, 2H), 1.84-1.74 (m, 2H), 1.62-1.58 (m, 4H). [0257] Synthesis of 3-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)- 1H-pyrazol-1-yl)propan-1-ol
Figure imgf000066_0001
[0258] To a solution of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)-2-(1-(3-((tetrahydro-2H- pyran-2-yl)oxy)propyl)-1H-pyrazol-4-yl)furo[3,2-b]pyridine (GP8.3, 180 mg, 0.32 mmol) in MeOH (6 mL) at rt was added a solution of Et2O/HCl (3 mL). The reaction mixture was stirred at rt for 1 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with NaHCO3 aqueous solution until the pH = 8. The aqueous solution was extracted with DCM (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was slurry in Et2O to provide 3-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol- 1-yl)propan-1-ol (205 mg, 0.44 mmol) as a yellow solid. LC-MS (ESI+): m/z 471 (MH+).1HNMR (300 MHz, CDCl3) δ 8.60 (d, J = 2.4 Hz, 1H), 7.95-7.93 (m, 2H), 7.87 (s, 1H), 7.81 (s, 1H), 7.47-7.42 (m, 3H), 7.37-7.35 (m, 1H), 6.79-6.77 (m, 2H), 4.38 (t, J = 6.4 Hz, 2H), 3.99-3.96 (m, 4H), 3.76-3.73 (m, 4H), 3.68 (t, J = 5.4 Hz, 2H), 2.30 (t, J = 5.4 Hz, 1H), 2.15- 2.11 (m, 2H). [0259] General procedure 9 [0260] Compound 17: Synthesis of 2,2-dimethyl-3-(4-(7-morpholino-5-(3-phenyl-1H- pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)propan-1-ol
Figure imgf000067_0001
[0261] Synthesis of 3-bromo-2,2-dimethylpropyl acetate
Figure imgf000067_0002
[0262] To a solution of 3-bromo-2,2-dimethylpropan-1-ol (300 mg, 1.80 mmol), DMAP (22 mg, 0.18 mmol) and Et3N (546 mg, 5.40 mmol) in DCM (10 mL) under N2 at 0 oC was added a solution of Ac2O in DCM (3 mL) dropwise. The reaction mixture was stirred at rt for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with DCM (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide crude 3-bromo- 2,2-dimethylpropyl acetate (380 mg, 1.83 mmol) as a light yellow oil.1HNMR (300 MHz, CDCl3) δ 3.94 (s, 2H), 3.35 (s, 2H), 2.08 (s, 3H), 1.06 (s, 6H). [0263] Synthesis of 2,2-dimethyl-3-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2- b]pyridine-2-yl)-1H-pyrazol-1-yl)propyl acetate
Figure imgf000068_0001
[0264] To a solution of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)-2-(1H-pyrazol-4- yl)furo[3,2-b]pyridine (Compound 10, 35 mg, 0.085 mmol) in DMF (10 mL) at rt was added 3- bromo-2,2-dimethylpropyl acetate (GP9.1, 35 mg, 0.17 mmol) and Cs2CO3 (325 mg, 0.17 mmol). The reaction mixture was stirred at 100 oC overnight. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water and was extracted with DCM (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide 2,2- dimethyl-3-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2-yl)-1H- pyrazol-1-yl)propyl acetate (20 mg, 0.037 mmol) as a white solid. LC-MS (ESI+): m/z 541 (MH+). [0265] Synthesis of 2,2-dimethyl-3-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2- b]- 66 -yridine-2-yl)-1H-pyrazol-1-yl)propan-1-ol
Figure imgf000068_0002
[0266] To a solution of 2,2-dimethyl-3-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol-1- yl)furo[3,2-b]- 66 -yridine-2-yl)-1H-pyrazol-1-yl)propyl acetate (GP9.2, 20 mg, 0.037 mmol) in MeOH/H2O (3:1, 4 mL) was added NaOH solid (3 mg, 0.074 mmol). The reaction mixture was stirred at rt overnight. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by preparative HPLC to provide 2,2-dimethyl-3-(4-(7- morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)propan-1-ol (17 mg, 0.034 mmol) as a white solid. LC-MS (ESI+): m/z 499 (MH+).1HNMR (300 MHz, CDCl3) δ 8.61 (d, J = 2.4 Hz, 1H), 7.95-7.93 (m, 2H), 7.87 (s, 1H), 7.74 (s, 1H), 7.44-7.42 (m, 3H), 7.37-7.35 (m, 1H), 6.80-6.77 (m, 2H), 4.08 (s, 2H), 4.01- 3.95 (m, 4H), 3.74-3.70 (m, 4H), 3.38-3.31 (m, 1H), 3.26-3.20 (m, 2H), 0.99 (s, 6H). [0267] General procedure 10 [0268] Compound 18: Synthesis of 2-methyl-4-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol- 1-yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)butan-2-ol
Figure imgf000069_0001
[0269] Synthesis of 2-methyl-4-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)-1H-pyrazol-1-yl)butan-2-ol
Figure imgf000069_0002
[0270] A suspension of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)-2-(1H-pyrazol-4- yl)furo[3,2-b]pyridine (Compound 10, 25 mg, 0.06 mmol), 4-bromo-2-methylbutan-2-ol (20 mg, 0.12 mmol) and Cs2CO3 (39 mg, 0.12 mmol) in DMF (10 mL) was heated to 50 oC and stirred for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The residue was purified by preparative TLC with a elution of DCM/MeOH (15:1) to provide 2-methyl-4-(4- (7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)butan-2- ol (20 mg, 0.04 mmol) as a white solid. LC-MS (ESI+): m/z 499 (MH+).1HNMR (300 MHz, CDCl3) δ 8.61 (d, J = 2.4 Hz, 1H), 7.95-7.93 (m, 2H), 7.85 (s, 1H), 7.80 (s, 1H), 7.47-7.42 (m, 3H), 7.37-7.32 (m, 1H), 6.77 (s, 2H), 4.38 (t, J = 6.9 Hz, 2H), 4.01- 3.97 (m, 4H), 3.80-3.74 (m, 4H), 2.12 (t, J = 7.5 Hz, 2H), 2.03 (s, 1H), 1.31 (s, 6H). [0271] General procedure 11 [0272] Compound 19: Synthesis of 7-morpholino-2-(1-(3-morpholinopropyl)-1H-pyrazol- 4-yl)-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000070_0001
[0273] Synthesis of 2-(1-(3-bromopropyl)-1H-pyrazol-4-yl)-7-morpholino-5-(3-phenyl-1H- pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000070_0002
[0274] A suspension of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)-2-(1H-pyrazol-4- yl)furo[3,2-b]pyridine (Compound 10, 30 mg, 0.07 mmol), 1,3-dibromopropane (147 mg, 0.73 mmol) and Cs2CO3 (47 mg, 0.15 mmol) in DMF (2 mL) was heated to 50 oC and stirred for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC with a elution of DCM/MeOH (15:1) to provide 2-(1-(3- bromopropyl)-1H-pyrazol-4-yl)-7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine (20 mg, 0.04 mmol) as a white solid. LC-MS (ESI+): m/z 533/535 (MH+). [0275] Synthesis of 7-morpholino-2-(1-(3-morpholinopropyl)-1H-pyrazol-4-yl)-5-(3-phenyl- 1H-pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000071_0001
[0276] To a solution of 2-(1-(3-bromopropyl)-1H-pyrazol-4-yl)-7-morpholino-5-(3-phenyl- 1H-pyrazol-1-yl)furo[3,2-b]pyridine (GP11.1, 20 mg, 0.04 mmol) in THF was added morpholine (33 mg, 0.4) and NaI (1 mg, 0.008 mmol). The reaction mixture was stirred at rt overnight. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The residue was purified by preparative TLC with a elution of DCM/MeOH (20:1) to provide 7-morpholino- 2-(1-(3-morpholinopropyl)-1H-pyrazol-4-yl)-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine (15 mg, 0.028 mmol) as a white solid. LC-MS (ESI+): m/z 540 (MH+).1HNMR (300 MHz, CDCl3) δ 8.61 (d, J = 2.4 Hz, 1H), 7.95-7.93 (m, 2H), 7.86 (s, 1H), 7.79 (s, 1H), 7.47-7.42 (m, 3H), 7.37-7.32 (m, 1H), 6.77 (s, 2H), 4.27 (t, J = 6.9 Hz, 2H), 3.97 -3.90 (m, 4H), 3.80-3.60 (m, 8H), 2.44-2.34 (m, 6H), 2.11 (t, J = 6.9 Hz, 2H). [0277] General procedure 12 [0278] Compound 29: Synthesis of N,N-bis(methyl-d3)-2-(4-(7-morpholino-5-(3-phenyl- 1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethan-1-amine
Figure imgf000071_0002
[0279] Synthesis of 2-(1-(2-bromoethyl)-1H-pyrazol-4-yl)-7-morpholino-5-(3-phenyl-1H- pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000072_0001
[0280] A suspension of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)-2-(1H-pyrazol-4- yl)furo[3,2-b]pyridine (Compound 10, 120 mg, 0.27 mmol), 1,2-dibromoethane (505 mg, 2.7 mmol) and Cs2CO3 (351 mg, 1.08 mmol) in DMF (5 mL) was heated to 50 oC and stirred for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide 2-(1-(2-bromoethyl)-1H-pyrazol-4-yl)-7-morpholino-5-(3-phenyl- 1H-pyrazol-1-yl)furo[3,2-b]pyridine (95 mg, 0.18 mmol) as a yellow solid. LC-MS (ESI+): m/z 519 (MH+).1HNMR (300 MHz, CDCl3) δ 8.61 (d, J = 2.7 Hz, 1H), 7.95-7.93 (m, 3H), 7.86 (s, 1H), 7.47-7.42 (m, 3H), 7.37-7.32 (m, 1H), 6.82 (s, 1H), 6.78 (d, J = 2.7 Hz, 1H), 4.58 (t, J = 6.3 Hz, 2H), 4.01- 3.96 (m, 4H), 3.82-3.74 (m, 6H). [0281] Synthesis of N,N-bis(methyl-d3)-2-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethan-1-amine
Figure imgf000072_0002
[0282] To a solution of 2-(1-(2-bromoethyl)-1H-pyrazol-4-yl)-7-morpholino-5-(3-phenyl-1H- pyrazol-1-yl)furo[3,2-b]pyridine (GP12.1, 95 mg, 0.18 mmol) in DMF (3 mL) was added bis(methyl-d3)amine hydrochloride (161 mg, 1.83 mmol) and Cs2CO3 (596 mg, 1.83 mmol). The reaction mixture was stirred at rt for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 15 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 2% MeOH/DCM to 5% MeOH/DCM to provide N,N-bis(methyl-d3)- 2-(4-(7-morpholino-5-(3-phenyl-lH-pyrazol-l-yl)furo[3,2-b]pyridin-2-yl)-lH-pyrazol-l- yl)ethan-l -amine (34 mg, 0.069 mmol) as a white solid. LC-MS (ESI+): m/z 490 (MH+).
1HNMR (300 MHz, DMSO-d6) d 8.64 (d, J= 2.4 Hz, 1H), 8.38 (s, 1H), 8.03-7.96 (m, 3H), 7.49- 7.44 (m, 2H), 7.40-7.33 (m, 2H), 7.05-7.03 (m, 2H), 4.27 (t, J= 6.6 Hz, 2H), 3.87-3.83 (m, 4H), 3.71-3.68 (m, 4H), 2.69 (t, J= 6.6 Hz, 2H).
[0283] General Procedure 13
[0284] Compound 47: Synthesis of (S)-2-methyl-4-(4-(7-morpholino-5-(3-phenyl-lH- pyrazol-l-yl)furo[3,2-b]pyridin-2-yl)-lH-pyrazol-l-yl)butan-2-yl 2-amino-3- methylbutanoate hydrochloride
Figure imgf000073_0001
[0285] Synthesis of (S)-2-methyl-4-(4-(7-morpholino-5-(3-phenyl-lH-pyrazol-l-yl)furo[3,2-
Figure imgf000073_0002
GP13.1
[0286] To a solution of 2-methyl-4-(4-(7-morpholino-5-(3-phenyl-lH-pyrazol-l-yl)furo[3,2- b]pyridin-2-yl)-lH-pyrazol-l-yl)butan-2-ol (Compound 18, 100 mg, 0.20 mmol) in anhydrous DCM (5 mL) at it was added DMAP (73.5 mg, 0.60 mmol), DIC (75.9 mg, 0.60 mmol) and scandium trifluoromethanesulfonate (60 mg, 0.12 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 2% MeOH/DCM to 10% MeOH/DCM to provide (S)-2-methyl-4-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-1H- pyrazol-1-yl)butan-2-yl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (65 mg, 0.09 mmol) as a white solid. LC-MS (ESI+): m/z 698 (MH+).1HNMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 7.95-7.93 (m, 2H), 7.85-7.84 (m, 2H), 7.47-7.42 (m, 3H), 7.37-7.32 (m, 1H), 6.78 (s, 2H), 4.29 (t, J = 7.5 Hz, 2H), 4.00-3.96 (m, 4H), 3.76-3.74 (m, 4H), 2.52-2.35 (m, 2H), 2.16-2.10 (m, 1H), 1.57 (s, 3H), 1.49 (s, 3H), 1.46 (s, 9H), 1.00 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H). [0287] Synthesis of (S)-2-methyl-4-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-
Figure imgf000074_0001
Compound 47 [0288] To a solution of (S)-2-methyl-4-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)butan-2-yl 2-((tert-butoxycarbonyl)amino)-3- methylbutanoate (20 mg, 0.03 mmol) in DCM (1 mL) at rt was added a solution of Et2O/HCl (0.5 mL). The solution was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly. The resulting residue was slurry in DCM to provide (S)-2-methyl-4-(4-(7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)-1H-pyrazol-1-yl)butan-2-yl 2-amino-3-methylbutanoate hydrochloride (15 mg, 0.024 mmol) as a yellow solid. LC-MS (ESI+): m/z 598 (MH+).1HNMR (300 MHz, CD3OD) δ 8.74 (d, J = 2.7 Hz, 1H), 8.53 (s, 1H), 8.13 (s, 1H), 8.04 (d, J = 6.9 Hz, 2H), 7.51-7.43 (m, 3H), 7.27 (s, 1H), 7.17-7.15 (m, 2H), 4.45- 4.40 (m, 2H), 4.21-4.11 (m, 4H), 4.04-3.94 (m, 4H), 3.89-3.88 (m, 1H), 2.54-2.26 (m, 3H), 1.64 (s, 3H), 1.60 (s, 3H), 1.10 (d, J = 6.9 Hz, 6H). [0289] General Procedure 14 [0290] Compound 51: Synthesis of (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(4-(4-(7- morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-1H-pyrazol-1- yl)butoxy)tetrahydro-2H-pyran-3,4,5-triol
Figure imgf000075_0001
GP14.1
[0292] To a solution of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-hydroxytetrahydro-2H-pyran- 3,4,5-triyl triacetate (500 mg, 1.44 mmol) in anhydrous DCM (5 mL) at rt was added K2CO3 (595 mg, 4.31 mmol) and CCbCN (415 mg, 2.87 mmol). The reaction mixture was stirred at rt for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated under reduce pressure to provide crude (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6- (2,2,2-trichloro-l-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (300 mg, 0.86 mmol) as a colorless oil. 1HNMR (300 MHz, CDCb) d 8.71 (s, 1H), 6.57-6.54 (m, 1H), 5.57-5.22 (m, 1H), 5.19-5.12 (m, 2H), 4.31-4.02 (m, 3H), 2.08-2.02 (m, 12H).
[0293] Synthesis of (2R,3R,4S,5R, 6R)-2-(acetoxymethyl)-6-(4-bromobutoxy)tetrahydro-2H- pyran-3,4,5-triyl triacetate
Figure imgf000075_0002
GP14.2
[0294] To a solution of crude (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(2,2,2-trichloro-l- iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (GP14.2, 250 mg, 0.01 mmol) in anhydrous DCM (5 mL) at rt was added 4-bromobutan-l-ol (97 mg, 0.01 mmol), 4A molecular sieve and TMSOTf (10 drops). The reaction mixture was stirred at rt overnight. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide crude (2R,3R,4S,5R,6R)-2- (acetoxymethyl)-6-(4-bromobutoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (250 mg, 0.52 mmol) as a colorless oil. LC-MS (ESI+): m/z 483/485 (MH+).
[0295] Synthesis of (2R,3R,4S,5R, 6R)-2-(acetoxymethyl)-6-(4-(4-(7-morpholino-5-(3-phenyl- lH-pyrazol-l-yl)furo[3,2-b]pyridin-2-yl)-lH-pyrazol-l-yl)butoxy)tetrahydro-2H-pyran-3,4,5- triyl triacetate
Figure imgf000076_0001
GP14.3
[0296] To a solution of crude (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4- bromobutoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (GP'14.2, 100 mg, 0.2 mmol) in anhydrous DMF (10 mL) at rt was added 7-morpholino-5-(3-phenyl-lH-pyrazol-l-yl)-2-(lH- pyrazol-4-yl)furo[3,2-b]pyridine (50 mg, 0.12 mmol) and Cs2CO3 (260 mg, 0.8 mmol). The solution was stirred at 50 °C for 4 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by preparative TLC with a elution of 8% MeOH/DCM to provide (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-(4-(7-morpholino-5-(3- phenyl-lH-pyrazol-l-yl)furo[3,2-b]pyridin-2-yl)-lH-pyrazol-l-yl)butoxy)tetrahydro-2H-pyran- 3,4,5-triyl triacetate (6 mg, 0.007 mmol) as a white solid. LC-MS (ESI+): m/z 815 (MEL).
[0297] Synthesis of (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(4-(4-(7-morpholino-5-(3-phenyl- lH-pyrazol-l-yl)furo[3,2-b]pyridin-2-yl)-lH-pyrazol-l-yl)butoxy)tetrahydro-2H-pyran-3,4,5- triol
Figure imgf000076_0002
Compound 51
[0298] To a solution of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-(4-(7-morpholino-5-(3- phenyl-lH-pyrazol-l-yl)furo[3,2-b]pyridin-2-yl)-lH-pyrazol-l-yl)butoxy)tetrahydro-2H-pyran- 3,4,5-triyl triacetate (GP14.3, 6 mg, 0.007 mmol) in MeOH (1 mL) at rt was added NaOMe (1.5 mg, 0.028 mmol). The reaction mixture was stirred at rt for 0.5 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly under reduce pressure. The resulting residue was purified by preparative TLC with a elution of 12% MeOH/DCM to provide (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(4-(4-(7-morpholino-5-(3-phenyl-lH-pyrazol- l-yl)furo[3,2-b]pyridin-2-yl)-lH-pyrazol-l-yl)butoxy)tetrahydro-2H-pyran-3,4,5-triol (2.6 mg, 0.004 mmol) as a white solid. LC-MS (ESI+): m/z 647 (MH+).1HNMR (300 MHz, CD3OD) d 8.54 (d, J= 2.4 Hz, 1H), 8.27 (d, J= 8.4 Hz, 1H), 7.98 (s, 1H), 7.94-7.92 (m, 2H), 7.44-7.42 (m, 2H), 7.38-7.36 (m, 2H), 6.90-6.89 (m, 2H), 4.80-4.79 (m, 1H), 4.29-4.27 (m, 2H), 3.97-3.94 (m, 4H), 3.79-3.76 (m, 4H), 3.65-3.45 (m, 4H), 3.42-3.35 (m, 2H), 3.29-3.27 (m, 2H), 2.04-1.95 (m, 2H), 1.70-1.60 (m, 2H).
[0299] General procedure 15
[0300] Compound 46: Synthesis of N-(2,2-difluoro-3-hydroxypropyl)-7-morpholino-5-(3- phenyl-lH-pyrazol-l-yl)furo[3,2-b]pyridine-2-carboxamide
Figure imgf000077_0001
GP15.1
[0302] To a solution of 5-chloro-7-morpholinofuro[3,2-b]pyridine (GP1.4, 1.0 g, 4.20 mmol) in THF (40 mL) at -78 °C under N2 was added n-BuLi (2.5 mL, 2.5M, 6.30 mmol). After stirred at -78 oC for 1 h, to a solution was added anhydrous DMF (2 mL). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with NH4Cl aqueous solution (40 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 5-chloro-7-morpholinofuro[3,2-b]pyridine-2-carbaldehyde (1.0 g, 4.20 mmol) as a yellow solid. LC-MS (ESI+): m/z 267/269 (MH+).1HNMR (300 MHz, CDCl3) δ 9.88 (s, 1H), 7.57 (s, 1H), 6.64 (s, 1H), 3.93-3.90 (m, 4H), 3.69-3.67 (m, 4H).
Figure imgf000078_0001
GP15.2 [0304] To a solution of 5-chloro-7-morpholinofuro[3,2-b]pyridine-2-carbaldehyde (GP15.1, 5.2 g, 19.55 mmol) in MeOH/DCM (1:1, 100 mL) at 0 oC was added NaBH4 (1.48 g, 39.1 mmol). After stirred at 0 oC for 1 h, TLC showed the reaction was completed. The reaction mixture was quenched with NH4Cl aqueous solution (100 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 50% EtOAc/PE to provide (5-chloro-7- morpholinofuro[3,2-b]pyridin-2-yl)methanol (4.5 g, 16.8 mmol) as a white solid. LC-MS (ESI+): m/z 269/271 (MH+).1HNMR (300 MHz, CDCl3) δ 6.73 (s, 1H), 6.58 (s, 1H), 4.77 (d, J = 4.8 Hz, 2H), 3.91-3.87 (m, 4H), 3.71-3.61 (m, 4H), 2.28-2.24 (m, 1H). [0305] Synthesis of (7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)methanol
Figure imgf000078_0002
GP15.3 [0306] To a solution of (5-chloro-7-morpholinofuro[3,2-b]pyridine-2-yl)methanol (GP15.2, 100 mg, 0.37 mmol) in 1,4-dioxane (10 mL) was added 3-phenyl-1H-pyrazole (107 g, 0.74 mmol), Pd2(dba)3 (102 g, 0.11 mmol), t-Buxphos (95 mg, 0.22 mmol) and Cs2CO3 (182 mg, 0.56 mmol). The reaction mixture was stirred at 110 oC under N2 overnight. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 30% EtOAc/PE to 50% EtOAc/PE to provide (7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)methanol (65 mg, 0.17 mmol) as an off-white solid. LC-MS (ESI+): m/z 377 (MH+).1HNMR (300 MHz, CD3OD) δ 8.54 (s, 1H), 7.92 (d, J = 7.2 Hz, 2H), 7.46-7.33 (m, 4H), 6.88 (d, J = 2.7 Hz, 1H), 6.78 (s, 1H), 4.71 (s, 2H), 3.93-3.90 (m, 4H), 3.77-3.73 (m, 4H). [0307] Synthesis of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2- carbaldehyde
Figure imgf000079_0001
GP15.4 [0308] To a solution of (7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)methanol (GP15.3, 75 mg, 0.20 mmol) in DCM/THF (1:1, 10 mL) at rt was added Dess- Martin (128 mg, 0.30 mmol). The reaction was stirred at rt for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with NaHCO3 aqueous solution (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure to provide crude 7- morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2-carbaldehyde (67 mg, 0.18 mmol) as a white solid. The crude product used directly for the next step without further purification. LC-MS (ESI+): m/z 375 (MH+).1HNMR (300 MHz, CDCl3) δ 9.90 (s, 1H), 8.62 (s, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.61 (d, J = 2.7 Hz, 2H), 7.46-7.33 (m, 3H), 6.80 (d, J = 2.4 Hz, 1H), 3.98-3.94 (m, 4H), 3.88-3.78 (m, 4H). [0309] Synthesis of 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2- carboxylic acid
Figure imgf000080_0001
GP15.5 [0310] To a solution of crude 7-morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine- 2-carbaldehyde (GP15.4, 50 mg, 0.13 mmol) in t-BuOH/THF/CH3CN (1:1:1, 9 mL) at 0 oC was added NaH2P4 (60 mg, 0.39 mmol), NaClO2 (23 mg, 0.26 mmol), 2-Methyl-2-butene (36 mg, 0.52 mmol) and water (1 mL). The reaction was stirred at 0 oC for 1 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with ice water and the pH was adjusted to 4 using 1N HCl aqueous solution. A large amount of white solid was precipitated after acidification. After filtration, the filter cake was dried to provide 7- morpholino-5-(3-phenyl-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2-carboxylic acid (70 mg, 0.18 mmol) as a white solid. LC-MS (ESI+): m/z 391 (MH+).1HNMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.06-7.98 (m, 2H), 7.64 (s, 1H), 7.49-7.45 (m, 3H), 7.41-7.36 (m, 1H), 7.07 (s, 1H), 3.92-3.86 (m, 4H), 3.79-3.72 (m, 4H). [0311] Synthesis of N-(2,2-difluoro-3-hydroxypropyl)-7-morpholino-5-(3-phenyl-1H-pyrazol- 1-yl)furo[3,2-b]pyridine-2-carboxamide
Figure imgf000080_0002
Compound 46 [0312] To a solution of 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2- carboxylic acid (GP15.5, 50 mg, 0.13 mmol) in DCM (10 mL) at rt was added 3-amino-2,2- difluoropropan-1-ol (21 mg, 0.19 mmol), EDCl (50 mg, 0.26 mmol) and DMAP (31 mg, 0.26 mmol). The reaction was stirred at rt overnight. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with NH4Cl solution (10 mL) and extracted with DCM/MeOH (50:1, 3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide N-(2,2-difluoro-3-hydroxypropyl)-7-morpholino-5-(3-phenyl-1H- pyrazol-1-yl)furo[3,2-b]pyridine-2-carboxamide (36 mg, 0.074 mmol) as a yellow solid. LC-MS (ESI+): m/z 484 (MH+).1HNMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.60 (s, 2H), 7.48-7.43 (m, 2H), 7.39-7.34 (m, 1H), 6.9-6.80 (m, 2H), 4.03-3.93 (m, 5H), 3.86- 3.78 (m, 2H), 3.74-3.71 (m, 4H), 3.50-3.49 (m, 2H). [0313] General Procedure 16 [0314] Compound 64: Synthesis of N-(2,3-dimethoxypropyl)-7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2-carboxamide
Figure imgf000081_0001
GP16.1 [0316] To a solution of 3-(benzyloxy)propane-1,2-diol (2.0 g, 11 mmol) in DMF (10 mL) at 0 oC was added NaH (1.06 g, 60%, 26.4 mmol). After stirred at 0 oC for 1 h, to the above mixture was added CH3I (4.68 g, 33 mmol) dropwise. The reaction mixture was stirred at rt overnight. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 5% EtOAc/PE to 20% EtOAc/PE to provide ((2,3-dimethoxypropoxy)methyl)benzene (2.19 g, 10.4 mmol) as a yellow oil.1HNMR (300 MHz, CDCl3) δ 7.58-7.26 (m, 5H), 4.55 (s, 2H), 3.60-3.50 (m, 5H), 3.67 (s, 3H), 3.23 (s, 3H). [0317] Synthesis of 2,3-dimethoxypropan-1-ol
Figure imgf000082_0001
[0318] To a solution of ((2,3-dimethoxypropoxy)methyl)benzene (GP16.1, 2.19 g, 10.4 mmol) in MeOH (100 mL) at rt was added Pd/C (200 mg). The reaction mixture was stirred under the hydrogen atmosphere for 2 days. The completion of the reaction was monitored by TLC. After filtration, the filtrate was concentrated directly to provide crude 2,3- dimethoxypropan-1-ol (1.08 g, 9.0 mmol) as colorless oil.1HNMR (300 MHz, CDCl3) δ 3.82- 3.75 (m, 1H), 3.68-3.62 (m, 1H), 3.58-3.53 (m, 2H), 3.50 (s, 3H), 3.46-3.42 (m, 1H), 3.40 (s, 3H), 2.16-2.12 (m, 1H). [0319] Synthesis of 2,3-dimethoxypropyl 4-methylbenzenesulfonate
Figure imgf000082_0002
[0320] To a solution of crude 2,3-dimethoxypropan-1-ol (GP16.2, 500 mg, 4.17 mmol) in DCM (20 mL) at rt was added Et3N (463 mg, 4.59 mmol) and 4-methylbenzene-1-sulfonyl chloride (872 mg, 4.59 mmol). The reaction mixture was stirred at rt for 4 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly under reduced pressure. The resulting residue was purified by preparative TLC with a elution of 33% EtOAc/PE to provide 2,3-dimethoxypropyl 4-methylbenzenesulfonate (378 mg, 1.38 mmol) as a colorless oil. LC-MS (ESI+): m/z 297 (M+Na).1HNMR (300 MHz, CDCl3) δ 7.82 (d, J = 7.2 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 4.19-4.13 (m, 1H), 4.09-4.04 (m, 1H), 3.62-3.52 (m, 1H), 3.49-3.62 (m, 2H), 3.39 (s, 3H), 3.31 (s, 3H), 2.47 (s, 3H). [0321] Synthesis of 2-(2,3-dimethoxypropyl)isoindoline-1,3-dione
Figure imgf000082_0003
[0322] To a solution of 2,3-dimethoxypropyl 4-methylbenzenesulfonate (GP16.3, 378 mg, 1.38 mmol) in DMF (20 mL) at rt was added potassium 1,3-dioxoisoindolin-2-ide (280 mg, 1.52 mmol). The reaction mixture was stirred at 80 oC for 4 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC with a elution of 50% EtOAc/PE to provide 2-(2,3-dimethoxypropyl)isoindoline-1,3-dione (207 mg, 0.83 mmol) as a colorless oil. LC-MS (ESI+): m/z 272 (M+Na). [0323] Synthesis of 2,3-dimethoxypropan-1-amine
Figure imgf000083_0001
[0324] To a solution of 2-(2,3-dimethoxypropyl)isoindoline-1,3-dione (GP16.4, 207 mg, 0.83 mmol) in EtOH (50 mL) at rt was added NH2NH2.H2O (104 mg, 2.08 mmol). The reaction mixture was stirred at 80 oC for 1 h. The completion of the reaction was monitored by TLC. After filtration, the filtrate was concentrated directly under reduced pressure to provide crude 2,3-dimethoxypropan-1-amine (100 mg, 0.92 mmol) which was used directly for the next step without further purification. [0325] Synthesis of N-(2,3-dimethoxypropyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridine-2-carboxamide
Figure imgf000083_0002
[0326] GP16.6 was prepared by the same method used for GP1.6 with 3-(m-tolyl)-1H- pyrazole substituted for 3-phenyl-1H-pyrazole. To a solution of crude 7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2-carboxylic acid (GP16.6, 100 mg, 0.25 mmol) in DCM (20 mL) at rt was added 2,3-dimethoxypropan-1-amine (GP16.5, 35 mg, 0.29 mmol), EDCl (120 mg, 0.63 mmol) and DMAP (75 mg, 0.63 mmol). The reaction mixture was stirred at rt overnight. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 3% MeOH/DCM to provide N-(2,3-dimethoxypropyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridine-2-carboxamide (58.6 mg, 0.17 mmol) as a yellow solid. LC-MS (ESI+): m/z 506 (MH+).1HNMR (300 MHz, CDCl3) δ 8.60 (d, J = 3.0 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 7.36-7.31 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.02-6.96 (m, 1H), 6.78 (d, J = 3.0 Hz, 1H), 3.99-3.88 (m, 5H), 3.75-3.72 (m, 4H), 3.62-3.55 (m, 4H), 3.49 (s, 3H), 3.43 (s, 3H), 2.44 (s, 3H). [0327] General Procedure 17 [0328] Compound 60: Synthesis of 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propan-1-one
Figure imgf000084_0001
[0329] Synthesis of 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2- yl)ethanol
Figure imgf000084_0002
[0330] GP17.1 was prepared by the same method used for GP15.4 with 3-(m-tolyl)-1H- pyrazole substituted for 3-phenyl-1H-pyrazole. To a solution of 7-morpholino-5-(3-(m-tolyl)- 1H-pyrazol-1-yl)furo[3,2-b]pyridine-2-carbaldehyde (GP17.1, 550 mg, 1.42 mmol) in anhydrous THF (40 mL) at 0 oC under N2 was added CH3MgBr (2.5 mL, 2.84 mmol) dropwise. The solution was stirred at 0 oC for 1 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with NH4Cl aqueous solution (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure to provide crude 1-(7-morpholino-5-(3-(m-tolyl)-1H- pyrazol-1-yl)furo[3,2-b]- 82 -yridine-2-yl)ethanol (550 mg, 1.36 mmol). LC-MS (ESI+): m/z 405 (MH+).1HNMR (300 MHz, CDCl3) δ 8.58 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.42 (s, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 6.73 (s, 1H), 5.04-5.02 (m, 1H), 3.97-3.93 (m, 4H), 3.73-3.70 (m, 4H), 2.44 (s, 3H), 1.65 (d, J = 6.6 Hz, 3H). [0331] Synthesis of 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2- yl)ethan-1-one
Figure imgf000085_0001
[0332] To a solution of crude 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)ethanol (GP17.2, 550 mg, 1.36 mmol) in CH3CN (50 mL) was added IBX (648 mg, 2.31 mmol). The solution was stirred at 70 oC for 1 h. The completion of the reaction was monitored by TLC. After filtration, the filtrate was concentrated directly under reduce pressure to provide crude 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]- 83 -yridine-2- yl)ethan-1-one (650 mg, 1.62 mmol). LC-MS (ESI+): m/z 405 (MH+).1HNMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 7.77 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.57-7.55 (m, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 3.99-3.96 (m, 4H), 3.81-3.78 (m, 4H), 2.62 (s, 3H), 2.44 (s, 3H). [0333] Synthesis of €-1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)-3-(tetrahydro-2H-pyran-4-yl)prop-2-en-1-one
Figure imgf000085_0002
[0334] To a solution of 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)ethan-1-one (GP17.3, 18 mg, 0.045 mmol) in anhydrous THF (10 mL) at 0 oC under N2 was added TiCl4 (115 mg, 0.61 mmol). After stirred at that temperature for 25 min, to the above solution was added Et3N (1.83 g, 41 mmol) in one potion. After stirred for another 20 min, a solution of tetrahydro-2H-pyran-4-carbaldehyde (50 mg, 0.44 mmol) in anhydrous THF (2 mL) was added to the above mixture dropwise. After addition, the reaction mixture was allowed to warm to room temperature. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with NH4Cl aqueous solution (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The residue was purified by preparative TLC with a elution of DCM/MeOH (15:1) to provide (E)-1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)prop-2-en-1-one (20 mg, 0.04 mmol) as a white solid. LC-MS (ESI+): m/z 499 (MH+). [0335] Synthesis of 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)- 3-(tetrahydro-2H-pyran-4-yl)propan-1-ol
Figure imgf000086_0001
[0336] To a solution of (E)-1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)prop-2-en-1-one (GP17.4, 20 mg, 0.04 mmol) in THF/EtOH (1:1, 2 mL) was added a catalytic amount of PtO2. The reaction mixture was stirred under the hydrogen atmosphere for 1 h. The completion of the reaction was monitored by LC- MS. After filtration, the filtrate was concentrated to provide crude 1-(7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propan-1-ol (10 mg, 0.02 mmol) which was used directly for the next step without further purification. LC-MS (ESI+): m/z 503 (MH+). [0337] Synthesis of 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)- 3-(tetrahydro-2H-pyran-4-yl)propan-1-one
Figure imgf000086_0002
[0338] To a solution of crude 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propan-1-ol (GP17.5, 10 mg, 0.02 mmol) in CH3CN (50 mL) was added IBX (10 mg, 0.035 mmol). The solution was stirred at 70 oC for 1 h. The completion of the reaction was monitored by TLC. After filtration, the filtrate was concentrated under reduce pressure. The residue was purified by preparative TLC with a elution of DCM/MeOH (20:1) to provide 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propan-1-one (5 mg, 0.01 mmol) as a yellow solid. LC-MS (ESI+): m/z 501 (MH+).1HNMR (300 MHz, CDCl3) δ 8.59 (d, J = 2.7 Hz, 1H), 7.76- 7.71 (m, 2H), 7.57- 7.54 (m, 2H), 7.36-7.31 (m, 1H), 7.20-7.17 (m, 1H), 6.79 (d, J = 2.7 Hz, 1H), 4.01-3.95 (m, 6H), 3.80-3.77 (m, 4H), 3.43-3.35 (m, 2H), 2.99-2.94 (m, 2H), 2.44 (s, 3H), 1.77-1.64 (m, 5H), 1.36-1.32 (m, 2H). [0339] General procedure 18 [0340] Compound 52: Synthesis of 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridine-2-yl)butane-1,3-dione
Figure imgf000087_0001
[0341] Synthesis of 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2- yl)butane-1,3-dione
Figure imgf000087_0002
[0342] To a solution of 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[-3,2- b]pyridineyridin-2-yl)ethanone (GP17.3, 40 mg, 0.10 mmol) in anhydrous THF (10 mL) at rt under N2 was added t-BuOK (11 mg, 0.10 mmol). After stirred at rt for 40 min, to the mixture was added Ac2O (11 mg, 0.10 mmol) in one potion. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with NH4Cl aqueous solution (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 50% EtOAc/PE to provide 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)butane-1,3- dione (12 mg, 0.027 mmol) as a yellow solid. LC-MS (ESI+): m/z 445 (MH+).1HNMR (300 MHz, CDCl3) δ 8.57 (d, J = 2.4 Hz, 1H), 7.76-7.70 (m, 2H), 7.45 (s, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.18-7.16 (d, J = 7.5 Hz, 1H), 6.79 (s, 1H), 6.76 (d, J = 2.4 Hz, 1H), 5.73 (d, J = 2.4 Hz, 1H), 5.24 (d, J = 2.1 Hz, 1H), 3.96-3.93 (m, 4H), 3.74-3.71 (m, 4H), 2.43 (s, 3H), 2.32 (s, 3H). [0343] General Procedure 19 [0344] Compound 21: Synthesis of 2-((1H-pyrazol-1-yl)methyl)-7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000088_0001
[0345] Synthesis of 2-((1H-pyrazol-1-yl)methyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridine
Figure imgf000088_0002
[0346] GP19.1 was prepared by the same method used for GP15.3 with 3-(m-tolyl)-1H- pyrazole substituted for 3-phenyl-1H-pyrazole. To a solution of (7-morpholino-5-(3-(m-tolyl)- 1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)methanol (GP19.1, 50 mg, 0.13 mmol) in DCM (10 mL) at 0 oC was added MsCl (22 mg, 0.19 mmol) and Et3N (32 mg, 0.32 mmol). The reaction mixture was stirred at 0 oC for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with ice water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic phase was dried over anhydrous Na2SO4 and used directly for the next step without further work-up. After filtration, to the DCM organic phase was added pyrazole (200 mg, 2.94 mmol) in one potion. The reaction mixture was stirred at rt overnight and the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The resulting residue was purified by preparative TLC with a elution of 25% EtOAc/PE to provide 2-((1H-pyrazol-1-yl)methyl)-7-morpholino-5-(3-(m-tolyl)- 1H-pyrazol-1-yl)furo[3,2-b]pyridine (50 mg, 0.11 mmol) as a white solid. LC-MS (ESI+): m/z 441 (MH+).1HNMR (300 MHz, CD3OD) δ 8.52 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 7.75-7.70 (m, 1H), 7.70-7.68 (m, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.38 (s, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.19-7.16 (m, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.79 (s, 1H), 6.38 (t, J = 2.1 Hz, 1H), 5.58 (s, 2H), 3.90-3.87 (m, 4H), 3.71-3.68 (m, 4H), 2.41 (s, 3H). [0347] General Procedure 20 [0348] Compound 40: Synthesis of N-((7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)methyl)isobutyramide
Figure imgf000089_0001
[0349] Synthesis of 2-(bromomethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridine
Figure imgf000089_0002
GP20.1 [0350] To a solution of (7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)methanol (G19.1, 1 g, 2.56 mmol) in THF (70 mL) at rt was added PBr3 (690 mg, 2.58 mmol). The solution was stirred at rt for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with NaHCO3 aqueous solution (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure to provide 2-(bromomethyl)-7-morpholino-5- (3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine (1.0 g, 2.21 mmol). LC-MS (ESI+): m/z 453/455 (MH+).1HNMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 7.76-7.71 (m, 2H), 7.46 (s, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 6.94 (s, 1H), 6.77 (d, J = 2.7 Hz, 1H), 4.59 (s, 2H), 3.97-3.95 (m, 4H), 3.77-3.75 (m, 4H), 2.43 (s, 3H). [0351] Synthesis of 2-(azidomethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridine
Figure imgf000090_0001
GP20.2 [0352] To a solution of 2-(bromomethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridine (GP20.1, 50 mg, 0.11 mmol) in anhydrous DMF (10 mL) was added NaN3 (22 mg, 0.33 mmol). The reaction mixture was stirred at 60 oC for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 6 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 2-(azidomethyl)-7- morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine (50 mg, 0.12 mmol). LC-MS (ESI+): m/z 416 (MH+). [0353] Synthesis of (7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)methanamine
Figure imgf000090_0002
GP20.3 [0354] To a solution of 2-(azidomethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridine (GP20.2, 50 mg, 0.12 mmol) in EtOAc (5 mL) was added a catalytic amount of Pd/C. The reaction mixture was stirred under hydrogen atmosphere for 1 h. The completion of the reaction was monitored by TLC. After filtration, the filtrate was concentrated directly to provide crude (7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)methanamine (54 mg, 0.14 mmol). The crude product was used directly for the next step without further purification. LC-MS (ESI+): m/z 390 (MH+).1HNMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 7.77-7.71 (m, 2H), 7.41 (s, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.17 (d, J = 6.6 Hz, 1H), 6.75 (s, 1H), 6.67 (s, 1H), 4.02 (s, 2H), 3.97-3.95 (m, 4H), 3.77-3.75 (m, 4H), 2.44 (s, 3H). [0355] Synthesis of N-((7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)methyl)isobutyramide
Figure imgf000091_0001
[0356] To a solution of crude (7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)methanamine (GP20.3, 44 mg, 0.11 mmol) in DMF (5 mL) at 0 oC was added a catalytic amount of DMAP and Na2CO3 (22 mg, 0.21 mmol). After stirred at 0 oC for 10 min, to the above mixture was added isobutyryl chloride (17 mg, 0.16 mmol). The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by preparative TLC with a elution of DCM/MeOH (15:1) to provide N-((7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)methyl)isobutyramide (10 mg, 0.022 mmol) as a white solid. LC-MS (ESI+): m/z 460 (MH+).1HNMR (300 MHz, CDCl3) δ 8.56 (d, J = 2.7 Hz, 1H), 7.76-7.73 (m, 2H), 7.70 (s, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 2.7 Hz, 1H), 6.68 (s, 1H), 5.83 (brs, 1H), 4.63 (d, J = 5.7 Hz, 2H), 3.95-3.91 (m, 4H), 3.71- 3.68 (m, 4H), 2.46-2.39 (m, 4H), 1.25-1.20 (d, J = 6.9 Hz, 6H). [0357] General Procedure 21 [0358] Compound 38: Synthesis of diethyl ((7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)methyl)phosphonate
Figure imgf000091_0002
[0359] Synthesis of diethyl ((7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin- 2-yl)methyl)phosphonate
Figure imgf000092_0001
[0360] To a solution of 2-(bromomethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridine (GP20.1, 700 mg, 1.54 mmol) in toluene (20 mL) at rt was added triethyl phosphite (2.3 g, 13.8 mmol). The reaction mixture was stirred at 100 oC overnight. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly. The resulting residue was purified by silica gel column chromatography with a gradient elution of 30% EtOAc/PE to 50% EtOAc/PE to provide diethyl ((7-morpholino-5-(3-(m-tolyl)- 1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)methyl)phosphonate (450 mg, 0.88 mmol) as a white solid. LC-MS (ESI+): m/z 511 (MH+).1HNMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 7.76-7.70 (m, 2H), 7.41 (s, 1H), 7.35-7.30 (m, 1H), 7.17-7.15 (m, 1H), 6.76 (d, J = 2.7 Hz, 2H), 4.19-4.09 (m, 4H), 3.95- 3.92 (m, 4H), 3.73-3.70 (m, 4H), 3.43 (s, 1H), 3.36 (s, 1H), 2.43 (s, 3H), 1.34-1.23 (m, 6H). [0361] General Procedure 22 [0362] Compound 44: Synthesis of (S,E)-2-(2-(1,4-dioxan-2-yl)vinyl)-7-morpholino-5-(3- (m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000092_0002
[0363] Synthesis of (R)-1,4-dioxane-2-carbaldehyde
Figure imgf000092_0003
[0364] To a solution of (S)-(1,4-dioxan-2-yl)methanol (550 mg, 4.23 mmol) in CH3CN (50 mL) at rt was added IBX (2 g, 7.14 mmol). The reaction mixture was stirred at 75 oC for 1 h. The completion of the reaction was monitored by TLC. After filtration, the filtrate was concentrated under reduce pressure to provide crude (R)-1,4-dioxane-2-carbaldehyde (130 mg, 1.12 mmol) as a colorless oil. [0365] Synthesis of (S,E)-2-(2-(1,4-dioxan-2-yl)vinyl)-7-morpholino-5-(3-(m-tolyl)-1H- pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000093_0001
[0366] To a solution of diethyl ((7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)methyl)phosphonate (Compound 38, 100 mg, 0.44 mmol) in anhydrous THF (10 mL) at 0 oC under N2 was added NaH (53 mg, 1.32 mmol). After stirred at that temperature for 25 min, to the above mixture was added a solution of crude (R)-1,4-dioxane-2-carbaldehyde (GP22.1, 45 mg, 0.39 mmol) in THF in one potion. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (20 mL) and extracted with DCM (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by preparative HPLC to provide (S,E)-2-(2-(1,4-dioxan-2-yl)vinyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridine (15 mg, 0.32 mmol) as a white solid. LC-MS (ESI+): m/z 473 (MH+). 1HNMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 7.76-7.73 (m, 2H), 7.70 (s, 1H), 7.42- 7.33 (m, 1H), 7.26-7.15 (m, 1H), 6.76-6.65 (m, 3H), 6.30-6.29 (m, 1H), 4.35- 4.25 (m, 1H), 3.97-3.94 (m, 4H), 3.89-3.86 (m, 3H), 3.81-3.68 (m, 6H), 3.46- 3.42 (m, 1H), 2.43 (s, 3H). [0367] General Procedure 23 [0368] Compound 45: Synthesis of (S)-2-(2-(1,4-dioxan-2-yl)ethyl)-7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000093_0002
[0369] Synthesis of (S)-2-(2-(1,4-dioxan-2-yl)ethyl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol- 1-yl)furo[3,2-b]pyridine
Figure imgf000094_0001
[0370] To a solution of (S,E)-2-(2-(1,4-dioxan-2-yl)vinyl)-7-morpholino-5-(3-(m-tolyl)-1H- pyrazol-1-yl)furo[3,2-b]pyridine (Compound 44, 15 mg, 0.32 mmol) in EtOAc (5 mL) was added a catalytic amount of Pd/C. The reaction mixture was stirred under hydrogen atmosphere for 3 h. The completion of the reaction was monitored by LC-MS. After filtration, the filtrate was concentrated directly to provide (S)-2-(2-(1,4-dioxan-2-yl)ethyl)-7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine (16 mg, 0.32 mmol) as a white solid. LC-MS (ESI+): m/z 475 (MH+).1HNMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 7.77-7.71 (m, 2H), 7.38 (s, 1H), 7.35-7.30 (m, 1H), 7.18- 7.13 (m, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.52 (s, 1H), 3.96-3.93 (m, 4H), 3.81- 3.63 (m, 10H), 3.38-3.35 (m, 1H), 2.99-2.83 (m, 2H), 2.43 (s, 3H), 1.83- 1.81 (m, 2H). [0371] General procedure 24 [0372] Compound 62: Synthesis of N-methyl-N-(4-(7-morpholino-5-(3-(m-tolyl)-1H- pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-4-oxobutyl)acetamide
Figure imgf000094_0002
[0373] Synthesis of tert-butyl methyl(prop-2-yn-1-yl)carbamate
Figure imgf000094_0003
[0374] To a solution of tert-butyl prop-2-yn-1-ylcarbamate (1 g, 6.45 mmol) in THF (50 mL) at 0 oC was added NaH (310 mg, 12.38 mmol). The reaction mixture was stirred at 0 oC under N2 for 1 h. To the above mixture was added CH3I (1.8 g, 12.9 mmol) dropwise. The reaction mixture was allowed to warm to rt and stirred overnight. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide crude tert-butyl methyl(prop-2-yn-1- yl)carbamate (1.1 g, 7.1 mmol) as a yellow oil. [0375] Synthesis of tert-butyl (4-hydroxy-4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)but-2-yn-1-yl)(methyl)carbamate
Figure imgf000095_0001
[0376] To a solution of tert-butyl methyl(prop-2-yn-1-yl)carbamate (GP24.1, 200 mg, 1.29 mmol) in THF (20 mL) at -78 oC under N2 was added n-BuLi (2.5M, 0.67 mmol). The reaction mixture was stirred at -78 oC under N2 for 1 h. To the above mixture was added a solution of 7- morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine-2-carbaldehyde (GP17.1, 250 mg, 0.65 mmol) in THF (2 mL) dropwise. The completion of the reaction was monitored by TLC. The reaction was quenched with NH4Cl solution (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20 % EtOAc/PE to 33% EtOAc/PE to provide tert- butyl (4-hydroxy-4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)but- 2-yn-1-yl)(methyl)carbamate (110 mg, 0.20 mmol). LC-MS (ESI+): m/z 558 (MH+). [0377] Synthesis of tert-butyl (4-hydroxy-4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)butyl)(methyl)carbamate
Figure imgf000095_0002
[0378] To a solution of tert-butyl (4-hydroxy-4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)but-2-yn-1-yl)(methyl)carbamate (GP24.2, 110 mg, 0.20 mmol) in EtOAc (2 mL) was added a catalytic amount of Pd/C. The reaction mixture was stirred under hydrogen atmosphere for 1 h. The completion of the reaction was monitored by LC-MS. After filtration, the filtrate was concentrated directly to provide crude tert-butyl (4-hydroxy-4-(7- morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)butyl)(methyl)carbamate (100 mg, 0.18 mmol). The crude product was used directly for the next step without further purification. LC-MS (ESI+): m/z 562 (MH+). [0379] Synthesis of tert-butyl methyl(4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)-4-oxobutyl)carbamate
Figure imgf000096_0001
[0380] To a solution of tert-butyl (4-hydroxy-4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)butyl)(methyl)carbamate (GP24.3, 100 mg, 0.18 mmol) in CH3CN (50 mL) at rt was added IBX (80 mg, 0.28 mmol). The reaction mixture was stirred at 70 oC for 2 h. The completion of the reaction was monitored by TLC. After filtration, the filter cake was washed with EtOAc (3 x 10 mL). The combined filtrate was concentrated under reduced pressure to provide crude tert-butyl methyl(4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)-4-oxobutyl)carbamate (100 mg, 0.18 mmol). LC-MS (ESI+): m/z 560 (MH+). [0381] Synthesis of 4-(methylamino)-1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)butan-1-one
Figure imgf000096_0002
[0382] To a solution of tert-butyl methyl(4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)-4-oxobutyl)carbamate (GP24.4, 100 mg, 0.18 mmol) in DCM (3 mL) at rt was added TFA (0.3 mL). The solution was stirred at rt for 1 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with NaHCO3 solution to adjust the pH to 8. The aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC with a elution of EtOAc to provide 4-(methylamino)-1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)butan-1-one (40 mg, 0.087 mmol). LC-MS (ESI+): m/z 460 (MH+). [0383] Synthesis of N-methyl-N-(4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)-4-oxobutyl)acetamide
Figure imgf000097_0001
[0384] To a solution of 4-(methylamino)-1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)butan-1-one (GP24.5, 40 mg, 0.087 mmol) in DCM (3 mL) at rt was added Ac2O (0.1 mL). The reaction was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with DCM (2 x 5 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduce pressure. The resulting residue was purified by preparative TLC using a elution of EtOAc to provide N-methyl-N-(4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)-4-oxobutyl)acetamide (9 mg, 0.018 mmol). LC-MS (ESI+): m/z 502 (MH+).1HNMR (300 MHz, CDCl3) δ 8.61 (d, J = 2.7 Hz, 1H), 7.78-7.73 (m, 2H), 7.60-7.56 (m, 2H), 7.36-7.28 (m, 1H), 7.20-7.17 (m, 1H), 6.80 (d, J = 2.7 Hz, 1H), 4.01-3.98 (m, 4H), 3.82- 3.79 (m, 4H), 3.50-3.48 (m, 2H), 3.05-2.99 (m, 5H), 2.46 (s, 3H), 2.12-2.02 (m, 5H). [0385] General procedure 25 [0386] Compound 65: Synthesis of 1-(4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)-4-oxobutyl)pyrrolidin-2-one
Figure imgf000097_0002
Compound 65 [0387] Synthesis of 4-chloro-1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)but-2-yn-1-ol
Figure imgf000098_0001
[0388] To a solution of 3-chloroprop-1-yne (290 mg, 3.87 mmol) in THF (20 mL) at -78 oC under N2 was added n-BuLi (2.5M, 0.67 mmol). The reaction mixture was stirred at -78 oC under N2 for 0.5 h. To the above solution was added a solution of 7-morpholino-5-(3-(m-tolyl)-1H- pyrazol-1-yl)furo[3,2-b]pyridine-2-carbaldehyde (GP17.1, 500 mg, 1.30 mmol) in THF (5 mL) dropwise. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with NH4Cl solution (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtrated and concentrated under reduce pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20 % EtOAc/PE to 33% EtOAc/PE to provide 4-chloro-1-(7-morpholino-5- (3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)but-2-yn-1-ol (400 mg, 0.86 mmol). LC- MS (ESI+): m/z 463 (MH+). [0389] Synthesis of 4-azido-1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)but-2-yn-1-ol
Figure imgf000098_0002
[0390] To a solution of 4-chloro-1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)but-2-yn-1-ol (GP25.1, 400 mg, 0.76 mmol) in DMF (5 mL) at rt was added NaN3 (148 mg, 2.27 mmol). The reaction mixture was stirred at rt overnight. The completion of the reaction was monitored by TLC. The reaction was quenched with water and extracted with EtOAc (2 x 30 mL). The combined organic phase was combined and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide crude 4-azido-1-(7- morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)but-2-yn-1-ol (300 mg, 0.81 mmol). LC-MS (ESI+): m/z 470 (MH+). [0391] Synthesis of 4-amino-1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)butan-1-ol
Figure imgf000099_0001
[0392] To a solution of 4-azido-1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)but-2-yn-1-ol (GP25.2, 300 mg, 0.81 mmol) in EtOAc (6 mL) was added a catalytic amount of Pd/C. The reaction mixture was stirred under hydrogen atmosphere overnight. The completion of the reaction was monitored by HPLC. After filtration, the filtrate was concentrated directly to provide crude 4-amino-1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol- 1-yl)furo[3,2-b]pyridin-2-yl)butan-1-ol (330 mg, 0.74 mmol). The crude product was used directly for the next step without further purification. LC-MS (ESI+): m/z 448 (MH+). [0393] Synthesis of 4-chloro-N-(4-hydroxy-4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)butyl)butanamide
Figure imgf000099_0002
[0394] To a solution of 4-amino-1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)butan-1-ol (GP25.3, 330 mg, 0.74 mmol) and Et3N (150 mg, 1.48 mmol) in DCM (50 mL) was added a solution of 4-chlorobutanoyl chloride (103 mg, 0.74 mmol) in DCM (1 mL) dropwise. The reaction mixture was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 10% MeOH/DCM to provide 4-chloro-N-(4-hydroxy-4-(7-morpholino-5-(3- (m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)butyl)butanamide (100 mg, 0.20 mmol) as a brown solid. LC-MS (ESI+): m/z 552/554 (MH+). [0395] Synthesis of 4-chloro-N-(4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)-4-oxobutyl)butanamide
Figure imgf000100_0001
[0396] To a solution of 4-chloro-N-(4-hydroxy-4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)butyl)butanamide (GP25.4, 100 mg, 0.20 mmol) in CH3CN (50 mL) at rt was added IBX (112 mg, 0.40 mmol). The reaction mixture was stirred at 70 oC for 2 h. The completion of the reaction was monitored by TLC. After filtration, the filter cake was washed with EtOAc (3 x 10 mL). The combined filtrate was concentrated under reduced pressure to provide crude 4-chloro-N-(4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin- 2-yl)-4-oxobutyl)butanamide (33 mg, 0.074 mmol). LC-MS (ESI+): m/z 550/552 (MH+). [0397] Synthesis of 1-(4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)-4-oxobutyl)pyrrolidin-2-one
Figure imgf000100_0002
[0398] To a solution of 4-chloro-N-(4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)-4-oxobutyl)butanamide (GP25.5, 33 mg, 0.074 mmol) in THF (50 mL) at rt was added NaH (20 mg, 0.148 mmol). The solution was stirred at rt for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 ml) and extracted with EtOAc (2 x 30 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduce pressure. The resulting mixture was purified by preparative TLC with an elution of 7% MeOH/DCM to provide 1-(4-(7-morpholino- 5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)-4-oxobutyl)pyrrolidin-2-one (15 mg, 0.03 mmol) as a white solid. LC-MS (ESI+): m/z 514 (MH+).1HNMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 7.76-7.71 (m, 2H), 7.55 (d, J = 5.1 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 6.6 Hz, 1H), 6.77 (d, J = 2.7 Hz, 1H), 3.98-3.95 (m, 4H), 3.80-3.77 (m, 4H), 3.46-3.38 (m, 4H), 3.00 (t, J = 7.2 Hz, 2H), 2.44 (s, 3H), 2.34 (t, J = 7.8 Hz, 2H), 2.07-2.00 (m, 4H). [0399] General procedure 26 [0400] Compound 63: Synthesis of 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1- yl)furo[3,2-b]pyridin-2-yl)-3-(oxetan-3-yl)propane-1,3-dione
Figure imgf000101_0001
[0401] Synthesis of oxetane-3-carboxylic acid
Figure imgf000101_0002
[0402] To a solution of oxetan-3-ylmethanol (1.0 g, 11.36 mmol) in CH3CN/H2O (2:1, 30 mL) at rt was added RuCl3 (234 mg, 1.14 mmol) and NaIO4 (4.8 g, 22.72 mmol). The reaction mixture was stirred at rt overnight. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with NH4Cl aqueous solution (200 mL) and followed by 1M HCl aqueous solution to adjust pH to 2. The aqueous solution was extracted with EtOAc (3 x 100 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide crude oxetane-3-carboxylic acid (600 mg, 5.88 mmol).1HNMR (300 MHz, DMSO-d6) δ 12.8 (brs, 1H), 4.71-4.66 (m, 2H), 4.64-4.58 (m, 2H), 3.85-3.75 (m, 1H). [0403] Synthesis of (1H-benzo[d][1,2,3]triazol-1-yl)(oxetan-3-yl)methanone
Figure imgf000102_0001
[0404] To a solution of oxetane-3-carboxylic acid (GP26.1, 600 mg, 5.88 mmol) in DCM (25 mL) was added EDCl (1.3 g, 6.79 mmol) and 1H-benzo[d][1,2,3]triazole (770 mg, 6.47 mmol). The solution was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated directly under reduced pressure. The resulting residue was purified by column silica gel chromatography with a gradient elution of 10 % EtOAc/PE to 30 % EtOAc/PE to provide (1H-benzo[d][1,2,3]triazol-1-yl)(oxetan-3-yl)methanone (840 mg, 4.13 mmol) as a white solid.1HNMR (300 MHz, DMSO-d6) δ 8.28-8.25 (m, 2H), 7.84-7.79 (m, 1H), 7.66-7.61 (m, 1H), 5.32-5.10 (m, 1H), 4.95-4.67 (m, 4H). [0405] Synthesis of 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)- 3-(oxetan-3-yl)propane-1,3-dione
Figure imgf000102_0002
[0406] To a solution of 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)ethanone (GP17.3, 30 mg, 0.15 mmol) in THF (10 mL) at rt was added NaH (8 mg, 0.19 mmol). The reaction mixture was stirred at rt for 1 h. To the above mixture was added a solution of (1H-benzo[d][1,2,3]triazol-1-yl)(oxetan-3-yl)methanone (GP26.2, 60 mg, 0.15 mmol) in THF (2 mL) dropwise. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by preparative TLC to provide 1-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin- 2-yl)-3-(oxetan-3-yl)propane-1,3-dione (6 mg, 0.012 mmol) as a white solid. LC-MS (ESI+): m/z 487 (MH+).1HNMR (300 MHz, CDCl3) δ 8.59 (d, J = 1.5 Hz, 1H), 7.76-7.70 (m, 2H), 7.53 (s, 1H), 7.40-7.30 (m, 2H), 7.25-7.15 (m, 1H), 6.78 (d, J = 2.7 Hz, 1H), 6.11 (s, 1H), 5.30 (s, 1H), 4.81-4.75 (m, 1H), 4.57 (t, J = 11.8 Hz, 1H), 4.10-3.95 (m, 4H), 3.90-3.80 (m, 1H), 3.78- 3.70 (m, 4H), 3.00-2.85 (m, 1H), 2.44 (s, 3H), 2.05-1.95 (m, 1H). [0407] General procedure 27 [0408] Compound 53: Synthesis of (E)-2-(3,4-dimethoxybut-1-en-1-yl)-7-morpholino-5- (3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000103_0001
[0409] Synthesis of 2,2,3,3,9,9-hexamethyl-8,8-diphenyl-5-vinyl-4,7-dioxa-3,8-disiladecane
Figure imgf000103_0002
[0410] To a solution of but-3-ene-1,2-diol (3 g, 34 mmol) in DMF (10 mL) at 0 oC was added imidazole (5.56 g, 68 mmol) under N2. To the solution was added TBDPSCl (11.3 g, 40 mmol). TLC showed the starting material was consumed. After that, TBSCl (6.2 g, 40 mmol) was added to the above mixture. The reaction mixture was heated to 50 oC for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 20% EtOAc/PE to provide 2,2,3,3,9,9-hexamethyl-8,8- diphenyl-5-vinyl-4,7-dioxa-3,8-disiladecane (10 g, 22.7 mmol). [0411] Synthesis of 2-((tert-butyldimethylsilyl)oxy)-3-((tert-butyldiphenylsilyl)oxy)propanal
Figure imgf000104_0001
[0412] To a solution of 2,2,3,3,9,9-hexamethyl-8,8-diphenyl-5-vinyl-4,7-dioxa-3,8- disiladecane (GP27.1, 2 g, 45 mmol) in THF/H2O (3:1, 28 mL) at 0 oC was added a catalytic amount of OsO4. The solution was stirred at 0 oC for 1 h. To the solution was added a solution of NaIO4 (3 g, 14.1 mmol) in water (5 mL) dropwise. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel column chromatography with a gradient elution of 5% EtOAc/PE to 10% EtOAc/PE to provide 2-((tert-butyldimethylsilyl)oxy)- 3-((tert-butyldiphenylsilyl)oxy)propanal (1.1 g, 2.5 mmol). [0413] Synthesis of (E)-2-(3-((tert-butyldimethylsilyl)oxy)-4-((tert-butyldiphenylsilyl)oxy)but- 1-en-1-yl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000104_0002
[0414] To a solution of diethyl ((7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)methyl)phosphonate (Compound 38, 110 mg, 0.22 mmol) in THF (10 mL) at rt was added NaH (26 mg, 0.66 mmol) under N2. The reaction mixture was stirred at rt for 1 h. To the above mixture was added 2-((tert-butyldimethylsilyl)oxy)-3-((tert- butyldiphenylsilyl)oxy)propanal (GP27.2, 143 mg, 0.32 mmol). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 20% EtOAc/PE to provide (E)-2-(3-((tert- butyldimethylsilyl)oxy)-4-((tert-butyldiphenylsilyl)oxy)but-1-en-1-yl)-7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine (110 mg, 0.14 mmol). LC-MS (ESI+): m/z 799 (MH+). [0415] Synthesis of (E)-4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2- yl)but-3-ene-1,2-diol
Figure imgf000105_0001
[0416] To a solution of (E)-2-(3-((tert-butyldimethylsilyl)oxy)-4-((tert- butyldiphenylsilyl)oxy)but-1-en-1-yl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridine (GP27.3, 110 mg, 0.14 mmol) in THF (10 mL) at rt was added TBAF (36 mg, 0.14 mmol). The reaction mixture was stirred at rt for 1 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide (E)-4-(7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridin-2-yl)but-3-ene-1,2-diol (40 mg, 0.09 mmol). LC-MS (ESI+): m/z 447 (MH+). [0417] Synthesis of (E)-2-(3,4-dimethoxybut-1-en-1-yl)-7-morpholino-5-(3-(m-tolyl)-1H- pyrazol-1-yl)furo[3,2-b]pyridine
Figure imgf000105_0002
[0418] To a solution of (E)-4-(7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2- b]pyridin-2-yl)but-3-ene-1,2-diol (GP27.4, 20 mg, 0.045 mmol) in DMF (5 mL) at rt was added NaH (26 mg, 0.66 mmol). The reaction mixture was stirred at rt for 1 h. To the above mixture was added CH3I (12 mg, 0.09 mmol). The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified preparative TLC with a elution of 50% EtOAc/PE to provide (E)-2-(3,4- dimethoxybut-1-en-1-yl)-7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)furo[3,2-b]pyridine (3 mg, 0.006 mmol) as a yellow solid. LC-MS (ESI+): m/z 475 (MH+).1HNMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 7.76-7.71 (m, 2H), 7.43-7.33 (m, 1H), 7.30-7.26 (m, 1H), 7.18- 7.16 (m, 1H), 6.76-6.62 (m, 3H), 6.36-6.33 (m, 1H), 4.03-4.01 (m, 1H), 3.98- 3.95 (m, 4H), 3.74-3.71 (m, 4H), 3.55-3.53 (m, 2H), 3.44-3.41 (m, 6H), 2.43 (s, 3H). [0419] General procedure 28 [0420] Synthesis of Compound 67: (1-(2-(1-methyl-1H-pyrazol-4-yl)-7- morpholinofuro[3,2-b]pyridin-5-yl)-3-(m-tolyl)-1H-pyrazol-5-yl)methanol
Figure imgf000106_0001
[0421] Synthesis of 5-chloro-7-morpholino-2-(trimethylsilyl)furo[3,2-b]pyridine
Figure imgf000106_0002
[0422] 2.0 g of GP1.4 was converted to GP28.1 using TMS-Cl/n-BuLi/dryTHF/-78 oC/2 h. After work-up and purification, 1.6 g of GP28.1 was obtained. [0423] Synthesis of 7-morpholino-5-(3-(m-tolyl)-1H-pyrazol-1-yl)-2-(trimethylsilyl)furo[3,2- b]pyridine
Figure imgf000106_0003
[0424] 1.6 g of GP28.1 was converted to GP28.2 using a mixture of t-BuXphos, Cs2CO3, 3- (m-tolyl)-1H-pyrazole, Pd2(dba)3 in dioxane at 100 oC for 18h. After work-up and purification, 1.4 g of GP28.2 was obtained. [0425] Synthesis of 1-(7-morpholino-2-(trimethylsilyl)furo[3,2-b]pyridin-5-yl)-3-(m-tolyl)-1H- pyrazole-5-carbaldehyde
Figure imgf000107_0001
[0426] 1.1 g of GP28.2 was converted to GP28.3 using dry DMF and LDA in THF at -78 oC over 2 h. After work-up, 1.1 g of crude product GP28.3 was obtained. [0427] Synthesis of (1-(7-morpholino-2-(trimethylsilyl)furo[3,2-b]pyridin-5-yl)-3-(m-tolyl)- 1H-pyrazol-5-yl)methanol
Figure imgf000107_0002
[0428] 1.1 g of crude GP28.3 was converted to GP28.4 with NaBH4 in THF at ambient temperature over 30 min. After work-up and purification, 810 mg of GP28.4 was obtained. [0429] Synthesis of (1-(2-iodo-7-morpholinofuro[3,2-b]pyridin-5-yl)-3-(m-tolyl)-1H-pyrazol- 5-yl)methanol
Figure imgf000107_0003
[0430] 100 mg of GP28.4 was converted to GP28.5 using KF, NIS in MeCN at 55 oC over 2 h. TLC showed a new major spot and LC-MS showed the desired product. After work-up and purification, 30 mg of 28.5 was obtained. [0431] Synthesis of [2-[2-(1-methylpyrazol-4-yl)-7-morpholino-furo[3,2-b]pyridin-5-yl]-5-(m-tolyl)pyrazol- 3-yl]methanol
Figure imgf000108_0001
[0432] 30 mg of GP28.5 was converted to Compound 67 by reaction with 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with PdCl2(PPh3)2, K2CO3 in dioxane/H2O at 90 oC over 3 h. TLC showed a new major spot and LC-MS showed the desired product. After work-up and purification, 16 mg of Compound 67 was obtained as a pale-yellow solid. LCMS (M+H)+: 471.29; HPLC purity: 99.3%; 1HNMR (300 MHz, CDCl3) δ 7.85 (s, 1H), 7.76 (s, 1H), 7.72-7.67 (m, 2H), 7.36-7.30 (m, 2H), 7.16 (d, J = 7.5 Hz, 1H), 6.77 (s, 1H), 6.69 (s, 1H), 6.63 (t, J = 7.2 Hz, 1H), 4.73 (d, J = 7.2 Hz, 2H), 4.00-3.91 (m, 7H), 3.79-3.77 (m, 4H). [0433] General Procedure 29 [0434] Synthesis of Compound 72: 5-[5-(methoxymethyl)-3-(m-tolyl)pyrazol-1-yl]-2-(1- methylpyrazol-4-yl)-7-morpholino-furo[3,2-b]pyridine
Figure imgf000108_0002
[0435] 20 mg of Compound 67 was converted to Compound 72 using MeI and NaH in dryTHF. The reaction was stirred at ambient temperature overnight. After work-up and purification, 8.0 mg of Compound 72 was obtained as a white solid. LCMS (M+H)+: 485.38; HPLC purity: 99.7%.1HNMR (300 MHz, CDCl3) δ 7.85 (s, 1H), 7.76-7.69 (m, 3H), 7.33-7.30 (m, 2H), 7.16 (d, J = 6.6 Hz, 1H), 6.79 (d, J = 6.6 Hz, 2H), 5.03 (s, 2H), 4.08-3.96 (m, 7H), 3.73- 3.71 (m, 4H), 3.50 (s, 3H), 2.42 (s, 3H). [0436] General Procedure 30 [0437] Synthesis of Compound 80: ethyl 1-(2-(1-methyl-1H-pyrazol-4-yl)-7- morpholinofuro[3,2-b]pyridin-5-yl)-3-(m-tolyl)-1H-pyrazole-5-carboxylate
Figure imgf000109_0001
[0438] Synthesis of 1-(7-morpholino-2-(trimethylsilyl)furo[3,2-b]pyridin-5-yl)-3-(m-tolyl)-1H- pyrazole-5-carboxylic acid
Figure imgf000109_0002
[0439] 20 mg of GP28.3 was converted to GP30.1 using NaH2PO4/NaClO2 with 2-Methyl-2- butene in a mixture of t-BuOH/MeCN/H2O at ambient temperature for 2 h. TLC showed a new major spot and LC-MS showed the desired product. After work-up and purification, 15 mg of GP30.1 was obtained. [0440] Synthesis of ethyl 1-(7-morpholino-2-(trimethylsilyl)furo[3,2-b]pyridin-5-yl)-3-(m- tolyl)-1H-pyrazole-5-carboxylate [0441] 500 mg of GP30.1 was converted to GP30.2 using Iodoethane and K2CO3 in acetonitrile at room temperature over 18 h. After work-up and purification, 475 mg of GP30.2 was obtained. [0442] Synthesis of ethyl 1-(2-iodo-7-morpholinofuro[3,2-b]pyridin-5-yl)-3-(m-tolyl)-1H- pyrazole-5-carboxylate
Figure imgf000110_0001
[0443] 475 mg of GP30.2 was converted to GP30.3 using N-iodosuccinamide and potassium fluoride in acetonitrile after heating at 50 oC for 2 h. After work-up, 420 mg of GP30.3 was obtained. [0444] Synthesis of ethyl 1-(2-(1-methyl-1H-pyrazol-4-yl)-7-morpholinofuro[3,2-b]pyridin-5- yl)-3-(m-tolyl)-1H-pyrazole-5-carboxylate
Figure imgf000110_0002
[0445] 50 mg of GP30.3 was converted to Compound 80 by the reaction of (1-methyl-1H- pyrazol-4-yl)boronic acid in the presence of Pd (PPh3)2Cl2 and K2CO3 in dioxane while heating at 90 oC for 18 h. After work-up and purification, 8.5 mg of Compound 80 was obtained as a yellow solid. LCMS (M+H)+: 512.76; HPLC purity: 96.4%; 1HNMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.76-7.74 (m, 2H), 7.68-7.66 (m, 1H), 7.36- 7.31 (m, 1H), 7.22-7.18 (m, 2H), 6.88 (s, 1H), 6.76 (s, 1H), 4.30 (q, J = 6.9 Hz, 2H), 4.02- 3.93 (m, 7H), 3.72-3.69 (m, 4H), 2.40 (s, 3H), 1.27 (t, J = 6.9 Hz, 3H). [0446] General Procedure 31 [0447] Synthesis of Compound 86: 2-[2-(l-methylpyrazol-4-yl)-7-morpholino-furo[3,2- b] pyr idin-5-yl] -5-(m-tolyl)pyrazole-3-carboxylic acid
Figure imgf000111_0001
[0448] 75 mg of Compound 80 was converted to Compound 86 by stirring with Li OH in
H20/Me0H at room temperature overnight. After work-up and purification, 60 mg of Compound 86 was obtained as an off-white solid. LCMS (M+H)+: 485.38; HPLC purity: 98.3%; 1HNMR (300 MHz, DMSO-d6) d 13.98 (brs, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.78 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.44 (s, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 3.93 (s, 3H), 3.85-3.82 (m, 4H), 3.72-3.69 (m, 4H), 2.32 (s, 3H).
[0449] Compounds in Table 2 are prepared using methods identified in the table, or using methods analogous to those described herein.
Table 2
Figure imgf000111_0002
Figure imgf000112_0001
Figure imgf000113_0001
- Ill -
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
[0450] Biological Example 1: Inhibition of PIKfyve [0451] Full length human recombinant PIKFYVE expressed in baculovirus expression system as N-terminal GST-fusion protein (265 kDa) was obtained from Carna 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. [0452] The 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 MgCl2, and 2.5 mM MnCl2, and 0.005% Triton X-100, and dispensed into a 384-well plate (10 µL 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 µL of 2x PI3P/PS substrate supplemented with ATP. The final concentration of enzyme was 2 nM, the final concentration of ATP was 10 mM, and the final concentration of PI3P/PS substrate was 1 µM (PI3P). The kinase reactions were allowed to proceed for 3 h at room temperature. Following incubation, the reactions were quenched by addition of 50 mL of termination buffer (100 mM HEPES, pH 7.5, 0.01% Triton X-100, 20 mM EDTA). 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 = (PSR0%inh - PSRcompound)/(PSR0%inh - PSR100%inh)*100 in which PSRcompound is the product/sum ratio in the presence of compound, PSR0%inh is the product/sum ratio in the absence of compound, and the PSR100%inh is the product/sum ratio in the absence of the enzyme. To determine the IC50 of test compounds (50%-inhibition) the %-inh cdata (Pinh versus compound concentration) were fitted by a four-parameter sigmoid dose- response model using XLfit software (IDBS). Table 3
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001

Claims

What is claimed is: 1. A compound of Formula (I):
Figure imgf000132_0001
wherein Y1 is N or C-R1; Y2 is N or C-R2; X is N, or CH; provided that when Y1 is N, Y2 is C-R2 and when Y2 is N, Y1 is C-R1; R1 is H, or C3-8aryl, C3-8heteroaryl, C3-8cycloalkyl, or C3-8heterocyclyl, each optionally substituted with from 1 to 3 Rs; R2 is H, or C3-8aryl, C3-8heteroaryl, C3-8cycloalkyl, or C3-8heterocyclyl, each optionally substituted with from 1 to 3 Rs; R3 is H, halo, OH, C1-4 alkyl, -NRpRq, C1-4 alkyl-NRpRq, C1-4 alkyl-OH, C1-4 alkyl-OC1-4 alkyl, OC1-4 alkyl, C(O)-C1-4 alkyl, C(O)-C1-4 alkyl-NRpRq, C(O)OH, C(O)-OC1-4 alkyl, or C(O)-OC1-4 alkyl-NRpRq; R4 is C3-8 aryl, C3-8 heteroaryl, C3-8 cycloalkyl, C3-8 heterocyclyl, C1-4 alkyl, C1-4 alkylP(O))(ORx)2, (C1-4 alkyl)C3-8 aryl, (C1-4 alkyl)C3-8 heteroaryl, (C1-4 alkyl)C3-8 cycloalkyl, or (C1-4 alkyl)C3-8 heterocyclyl each optionally substituted with from 1 to 3 Rs, or C(O)Ry, C(O)NRxRy , NRxC(O)Ry, C1-4 alkylNRxC(O)Ry, or C(O)C1-4 alkylNRxC(O)Ry; Rs is halo, amino, oxo, OH, C3-8 heterocyclyl, OC1-6alkyl, C1-6alkyl, C1-6alkenyl, C1-6alkyl-OH, C1-6 alkyl-O-C1-4 alkyl, C1-6 alkyl-O-C1-4 alkyl-O-C1-4 alkyl, (C1-4 alkyl)C3-8 aryl, (C1-4 alkyl)C3-8 heteroaryl, (C1-4 alkyl) C3-8 cycloalkyl, (C1-4 alkyl) C3-8 heterocyclyl or C1-6 alkyl-NRpRq; Rx is H or C1-4alkyl, optionally substituted with Ro; Ry is H, C1-4alkyl-Rr, C1-4alkyl, -O-C1-4alkyl, -SO2-C1-4alkyl, C1-4alkyl-SO2-Rr, cycloalkyl, (-C1-4alkyl)cycloalkyl, heterocyclyl, (-C1-4alkyl)heterocyclyl, O-heterocyclyl, C3-8 aryl, (-C1-4alkyl)C3-8 aryl, C3-8 heteroaryl, (-C1-4alkyl)C3-8 heteroaryl, each optionally substituted with 1 to 3 Ro substituents; or Rx and Ry taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with C1-4alkyl; each Rr is C1-4alkyl or -NRpRq; each Ro substituent is independently C1-4alkyl, oxo, -OH, -OC1-4alkyl, halo, cyano, heterocyclyl, or -NRpRq; Rp and Rq are each independently H or C1-4alkyl; or Rp and Rq taken together with the nitrogen to which they are attached form a heterocyclyl; R5 is H, C1-6alkyl, halo, -OH, or -OC1-6alkyl.
2. The compound of claim 1, wherein Y1 is N, Y2 is C-R2.
3. The compound of claim 1, wherein Y2 is N, Y1 is C-R1.
4. The compound of claim 1, wherein Y1 is C-R1 and Y2 is C-R2.
5. The compound of claim 1, wherein Y1 is C-R1 and Y2 is C-R2, and wherein one of R1 and R2 is not H.
6. The compound of claim 1, wherein X is N.
7. The compound of claim 1, wherein X is N, and one of Y1 and Y2 is N.
8. The compound of claim 1, wherein X is N, Y1 is C-R1, and Y2 is C-R2.
9. The compound of claim 1, wherein X is N, Y1 is C-R1, and Y2 is C-R2, and wherein one of R1 and R2 is not H.
10. The compound of claim 1, wherein X is CH.
11. The compound of claim 1, wherein X is CH, and one of Y1 and Y2 is N.
12. The compound of claim 1, wherein X is CH, and Y1 and Y2 are N.
13. The compound of any one of claims 1 - 12, wherein Y1 is C-R1 and R1 is H, or phenyl or C3-8heteroaryl each optionally substituted with from 1 to 3 Rs.
14. The compound of any one of claims 1 - 13, wherein R1 is phenyl pyridinyl, pyrimidinyl, pyrazolyl, or cyclopentenyl, each optionally substituted with 1 or 2 Rs.
15. The compound of any one of claims 1 - 13, wherein R1 is phenyl pyridinyl, or pyrazolyl each optionally substituted with 1 Rs.
16. The compound of any one of claims 1 - 15, wherein Y2 is C-R2 and R2 is H, or phenyl or C3-8heteroaryl each optionally substituted with from 1 to 3 Rs.
17. The compound of any one of claims 1 - 16, wherein R2 is phenyl, pyridinyl, pyrimidinyl, pyrazolyl or cyclopentenyl, each optionally substituted with 1 or 2 Rs.
18. The compound of any one of claims 1 - 16, wherein R2 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 Rs.
19. The compound of any one of claims 1 - 18, wherein R3 is H, C1-4 alkyl-NRpRq, C1-4 alkyl- OH, C1-4 alkyl-OC1-4 alkyl, C(O)OH, or C(O)-OC1-4 alkyl.
20. The compound of any one of claims 1 - 18, wherein R3 is (CH2)NH2, (CH2)N(CH3)2, (CH2)OH, (CH2)OCH3, C(O)OH, or C(O)OCH2CH3.
21. The compound of any one of claims 1 - 20, wherein R4 is phenyl, pyridinyl, pyrimidinyl, or pyrazolyl, each optionally substituted with from 1 to 2 Rs.
22. The compound of any one of claims 1 - 20, wherein R4 is pyrazolylmethyl , imidazolylmethyl, morpholinomethyl, piperidinylmethyl, dioxanylmethy, dioxanylethyl, dioxanylethylenyl, dioxanylpropyl, dioxanylpropylenyl, cyclohexenyl, cyclopentenyl, dihydropyridinyl, each optionally substituted with from 1 to 2 Rs.
23. The compound of any one of claims 1 - 22, wherein Rs is H, Cl, Br, F, NH2, oxo, OH, OC1-6alkyl, or C1-6alkyl.
24. The compound of any one of claims 1 - 22, wherein Rs is H, Cl, F, OH, oxo, methyl, ethyl, or propyl.
25. The compound of any one of claims 1 - 22, wherein Rs is H or methyl.
26. The compound of any one of claims 1 - 25, wherein R4 is C(O)Ry, -C(O)NRxRy , NRxC(O)Ry, C1-4 alkylNRxC(O)Ry, or C(O)C1-4 alkylNRxC(O)Ry.
27. The compound of any one of claims 1 - 26, wherein Rx is H, or methyl or ethyl, optionally substituted with one Ro.
28. The compound of any one of claims 1 - 26, wherein Rx is H or methyl.
29. The compound of any one of claims 1 - 26, wherein Ry is C1-4alkyl-Rr, C1-4alkyl, -O-C1-4 alkyl, -SO2-C1-4alkyl,C1-4alkyl-SO2- Rr, cycloalkyl, , (C1-4 alkyl)cycloalkyl, heterocyclyl, (C1-4 alkyl)heterocyclyl, O-heterocyclyl, C3-8 aryl, (C1-4 alkyl)C3-8 aryl, C3-8 heteroaryl, (C1-4 alkyl)C3-8 heteroaryl,, each optionally substituted with 1 to 3 Ro substituents.
30. The compound of any one of claims 1 - 26, wherein Ry is C1-4alkyl, optionally substituted with one, two, or three Ro substituents.
31. The compound of any one of claims 1 - 26, wherein Ry is methyl, ethyl, propyl, or isopropyl, each optionally substituted with one, two, or three Ro substituents.
32. The compound of any one of claims 1 - 26, wherein Ry is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropanyl, (dimethylamino)ethyl, or (dimethylamino)butyl.
33. The compound of any one of claims 1 - 26, wherein Ry is methoxy.
34. The compound of any one of claims 1 - 26, wherein Ry is -SO2-methyl.
35. The compound of any one of claims 1 - 26, wherein Ry is cycloalkyl or -C1- 2alkyl(cycloalkyl), each optionally substituted with one, two, or three Ro substituents.
36. The compound of any one of claims 1 - 26, wherein Ry is monocyclic cycloalkyl, or (C1-4 alkyl)monocyclic cycloalkyl, optionally substituted with one, two, or three Ro substituents.
37. The compound of any one of claims 1 - 26, wherein Ry is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, or cyclopentenyl, each optionally substituted with one, two, or three R° substituents.
38. The compound of any one of claims 1 - 26, wherein Ry is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1 -cyclopropyl ethyl, 2-cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, cyclohexenylpropyl, or cyclopentenylpropyl.
39. The compound of any one of claims 1 - 26, wherein Ry is heterocyclyl or -O- heterocyclyl, optionally substituted with one, two, or three R° substituents.
40. The compound of any one of claims 1 - 26, wherein Ry is tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxanyl, pyrazolyl, dihydropyridinyl, or oxetanyloxy, each optionally substituted with one, two, or three R° substituents.
41. The compound of any one of claims 1 - 26, wherein Ry is tetrahydrofuranylmethyl, tetrahydropyranylmethyl, oxetanylmethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, dioxanylmethyl, pyrazolylmethyl, dihydropyridinylmethyl, or oxetanyloxymethyl, tetrahydrofuranylpropyl, tetrahydropyranylpropyl, oxetanylpropyl, azetidinylpropyl, pyrrolidinylpropyl, piperidinylpropyl, morpholinylpropyl, piperazinylpropyl, dioxanylpropyl, pyrazolylpropyl, dihydropyridinylpropyl, or oxetanyloxypropyl, each optionally substituted with one, two, or three R° substituents.
42. The compound of any one of claims 1 - 26, wherein Rx and Ry taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with C1-4alkyl.
43. The compound of any one of claims 1 - 26, wherein Rx and Ry taken together with the nitrogen to which they are attached form a heterocycloalkyl, optionally substituted with Ci- 4alkyl.
44. The compound of any one of claims 1 - 26, wherein Rx and Ry taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with methyl.
45. The compound of any one of claims 1 - 26, wherein Rx and Ry are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxa-l-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl, each optionally substituted with methyl.
46. The compound of any one of claims 1 - 45, wherein each R° substituent is independently C1-4alkyl, -OH, oxo, -OC1-4alkyl, or -NRpRq.
47. The compound of any one of claims 1 - 45, wherein at least one R° substituent is Ci-
4alkyl.
48. The compound of any one of claims 1 - 45, wherein at least one R° substituent is -OH.
49. The compound of any one of claims 1 - 45, wherein at least one R° substituent is -NRpRq.
50. The compound of any one of claims 1 - 45, wherein at least one R° substituent is oxo.
51. The compound of any one of claims 1 - 50, wherein Rp and Rq are each independently H or methyl.
52. The compound of any one of claims 1 - 50, wherein Rp and Rq taken together with the nitrogen to which they are attached form a heterocyclyl.
53. The compound of any one of claims 1 - 50, wherein Rp and Rq taken together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl 6-oxa-l-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl.
54. The compound of any one of claims 1 - 53, wherein R5 is H, methyl, ethyl, propyl, Cl,
Br, or -OH.
55. The compound of any one of claims 1 - 53, wherein R5 is H or methyl.
56. The compound of any one of claims 1 - 53, wherein R5 is H.
57. A compound selected from Table 1, and/or pharmaceutically acceptable salts thereof.
58. The compound of any one of claims 1 - 57, wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.
59. A pharmaceutical composition comprising a compound and/or a pharmaceutically acceptable salt or prodrug of any one of claims 1-57 and a pharmaceutically acceptable excipient.
60. A method of inhibiting PIKfyve kinase in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of claims 1 to 57, or a pharmaceutical composition of claim 58.
61. 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 claims 1 to 57, or a pharmaceutical composition of claim 58.
62. The method of claim 60, wherein the disease is associated with PIKfyve activity.
63. The method of claim 60, wherein the disease is amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth (CMT; including type 4J (CMT4J)), and Yunis-Varon syndrome, autophagy, polymicrogyria (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 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 disorder, depression, bipolar disorder I, or bipolar disorder II.
64. The method of claim 60, wherein the disease is ALS, FTD, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or CMT.
65. The method of claim 60, wherein the disease is ALS.
66. The method of claim 60, wherein the disease is a tauopathy such as Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, or chronic traumatic encephalopathy.
67. The method of claim 60, 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.
68. The method of claim 60, 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.
69. A compound of any one of claims 1 to 57 for use as a medicament.
70. The compound of claim 68, wherein the compound is for use in treating a neurological disease treatable by inhibition of PIKfyve kinase.
71. Use of a compound of any one of claims 1 to 57 in the manufacture of a medicament for treating a disease in a subject in which PIKfyve contributes to the pathology and/or symptoms of the disease.
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