WO2025199092A1 - Modulateurs de ship1, méthodes de traitement et utilisations associées - Google Patents

Modulateurs de ship1, méthodes de traitement et utilisations associées

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Publication number
WO2025199092A1
WO2025199092A1 PCT/US2025/020356 US2025020356W WO2025199092A1 WO 2025199092 A1 WO2025199092 A1 WO 2025199092A1 US 2025020356 W US2025020356 W US 2025020356W WO 2025199092 A1 WO2025199092 A1 WO 2025199092A1
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compound
group
alkyl
stereoisomer
pharmaceutically acceptable
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Timothy Richardson
Daniel Beck
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Purdue Research Foundation
Indiana University
Indiana University Bloomington
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Purdue Research Foundation
Indiana University
Indiana University Bloomington
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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 general field of the present disclosure is novel approaches to the treatment of Alzheimer's and other neurodegenerative disorders using novel therapeutics comprising SHIP1 phosphatase modulators.
  • AD Alzheimer’s disease
  • a ⁇ extracellular 0-amyloid
  • NFTs intra-neuronal neurofibrillary tangles
  • amyloid cascade hypothesis has come under increased scrutiny due to inadequate efficacy of drugs targeting A ⁇ peptide processing and various forms of A ⁇ . See Panza et al., “A critical appraisal of amyloid-beta-targeting therapies for Alzheimer disease,” (2019) Nat Rev Neurol 15: pp. 73-88.
  • GWAS genome-wide association studies
  • APOE ABCA7, PLCG2, and INPP5D
  • Microglia are the non-neuronal, macrophage-like cells that serve as resident immune cells in the brain. See Vaughan et al., “Neuroglial cells in the cerebral cortex of rats from young adulthood to old age: an electron microscope study,” (1974) J Neurocytol 3: pp. 405-429.
  • microglia originate from stem cells in the yolk sac and differentiate into CD45 , CX3CR1 immune cells that migrate to the central nervous system (CNS).
  • CNS central nervous system
  • Kierdorf et al. “Microglia emerge from erythromyeloid precursors via Pu. 1 - and lrf8- dependent pathways,” (2013) Nat Neurosci 16: pp. 273-280. Once resident, these cells renew slowly in humans at a rate of approximately 28 percent per year, thus providing a mechanism to renew microglia. See Reu et al., “The Lifespan and Turnover of Microglia in the Human Brain.” (2017) Cell Rep 20: pp. 779-784.
  • AD Disease associated microglia
  • (2017) Cell 169: pp. 1276-1290 Although their relevance to human microglia in AD remains a current area of intense study, they have gene signatures associated with lipid metabolism and phagocytosis hypothesized to reflect the neuroprotective role of microglia in the clearance of extracellular toxins. See Olah et al., “Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer's disease,” (2020) Nat Commun 11 : pp. 6129.
  • a two-state model of DAM induction has been proposed, in which homeostatic microglia that are associated with and support the health of neurons become activated with increased expression of DAP 12.
  • TREM2 ligands such as apolipoproteins (including, e.g., APOE) and A ⁇ induce microglial differentiation into stage-2 DAMs with increased expression of LPI. CST7. and AXL. Deczkowska et al.. “Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration,” (2016) Cell 173: pp. 1073-1081; Keren-Shaul et al. 2017.
  • TREM2 is a receptor expressed on the surface of microglia. Genetic evidence suggests that lower TREM2 expression and inactivating variants increase risk of AD. See Jonsson et al., “Variant of TREM2 associated with the risk of Alzheimer's disease,” (2013) N Engl J Med 368: pp. 107-116. TREM2 binds A ⁇ and APOE, which activates microgliosis and the clearance of extracellular debris. See Yeh et al., “TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia.” (2016) Neuron 91 : pp. 328-340.
  • the TREM2 R4/H variant reduces the affinity of TREM2 ligands and cellular activation downstream, which requires DAP 12, an adapter protein on the intracellular side of the plasma membrane that associates with numerous signal transduction mediators.
  • DAP 12 an adapter protein on the intracellular side of the plasma membrane that associates with numerous signal transduction mediators.
  • the INPP5D gene encodes the Src homology 2 (SH2) domain-containing phosphatase- 1 (SH1P1). which is a phosphatidylinositol phosphatase that plays a key role regulating pathways downstream from TREM2.
  • SH2 Src homology 2
  • SH1P1 Src homology 2 domain-containing phosphatase- 1
  • SHIP1 is a complex, multidomain protein with a phosphatase (Ptase) domain flanked by a pleckstrin-homology (PH) domain that binds phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P 3 ] and a C2 domain that binds phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P 2 ].
  • Ptase phosphatase
  • PH pleckstrin-homology
  • the C2 domain is essential for cellular function and interactions between the Ptase and C2 domains modulate enzymatic activity. See Le Coq et al., “Structural basis for interdomain communication in SHIP2 providing high phosphatase activity,” (2017) eLife 6: p. 26640.
  • SHIP1 converts PI(3,4,5)P 3 to PI(3,4)P 2 .
  • SHIP1 also contains an N-terminal SH2 domain that binds immunoreceptor tyrosine-based activation motifs (IT AMs) and a C-terminal proline rich domain that binds many other proteins including PLC ⁇ 2 and the Tec and Syk family kinases.
  • PI(3,4,5)P 3 binds and activates other PH-containing proteins such as PLC ⁇ 2, PDK1, and AKT.
  • PH PH-containing proteins
  • AKT AKT
  • SHIP1 binds ITAMs, competes with kinases, and converts PI(3,4,5)P 3 to PI(3,4)P 2 , it limits downstream signaling in multiple ways, and is therefore understood as a brake on microglia activation.
  • the present disclosure provides novel compounds that are SHIP1 inhibitors that address the need for a potent and effective treatment for Alzheimer’s disease and Alzheimer’s disease-related dementias.
  • the present disclosure also provides a pharmaceutical composition for the prevention of Alzheimer’s disease and Alzheimer's disease-related dementias.
  • the present disclosure provides one or more compounds of Formula (I): a pharmaceutically acceptable salt of the compound, a stereoisomer of the compound, or a salt of a stereoisomer of the compound, wherein: denotes a single bond or a double bond; U and X are C, V is CR V . and Y and Z are N; or X and Z are C, V is CR V .
  • R X is selected from the group consisting of wherein o is an integer 0 or 1 ;
  • R V selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 3 -C 6 cycloalkyl: wherein alkyl, alkenyl, alkynyl, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 6 alkoxy;
  • R 1 is selected from the group consisting of hydrogen, -C(O)
  • alkoxy, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR a R b , C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;nR a and R b are each independently selected from the group consisting of hydrogen C 1 -C 6 alkyl.
  • the compound may be represented by:
  • R 2 and R 3 may each be hydrogen. In any embodiment, R 2 and R 3 may be taken together to form oxo.
  • R X may be selected from the group consisting of:
  • n may be an integer 0, 1, or 2.
  • R 4 may be independently selected for each occurrence from the group consisting of fluoro, chloro, and -CH 3 .
  • R 5 may be independently selected for each occurrence from the group consisting of fluoro, chloro, and -CH 3 .
  • R V may be selected from the group consisting of hydrogen, - CH 3 , and -CH(CH 3 ) 2 .
  • R 4 and R 5 may be independently selected for each occurrence from the group consisting of fluoro, chloro, and -CH 3 .
  • the present disclosure provides a compound selected from the group consisting of:
  • the present disclosure provides a compound selected from the group consisting of:
  • the present disclosure provides a compound selected from the group consisting of: or a pharmaceutically acceptable salt of such compound, or a stereoisomer of such compound, or a pharmaceutically acceptable salt of a stereoisomer of such compound.
  • the present disclosure provides a compound selected from the group consisting of: or a pharmaceutically acceptable salt of such compound, or a stereoisomer of such compound, or a pharmaceutically acceptable salt of a stereoisomer of such compound.
  • the present disclosure provides a compound selected from the group consisting of: or a pharmaceutically acceptable salt of such compound, or a stereoisomer of such compound, or a pharmaceutically acceptable salt of a stereoisomer of such compound.
  • the present disclosure provides a pharmaceutical composition, which may comprise any compound of any aspect described herein, or a pharmaceutically acceptable salt of the compound, or a stereoisomer of the compound, or a pharmaceutically acceptable salt of a stereoisomer of the compound; further comprising a pharmaceutically acceptable excipient.
  • the composition may further comprise one or more additional neurodegenerative disorder therapeutic agents.
  • composition may further comprise one or more pharmaceutically acceptable adjuvants, binders, carriers, diluents, or fillers.
  • the present disclosure provides a method of preventing, or inhibiting the progression of a neurodegenerative disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any aspect described herein, a pharmaceutically acceptable salt of the compound, or a stereoisomer of the compound, or a pharmaceutically acceptable salt of a stereoisomer of the compound; or comprising the pharmaceutical composition of any aspect described herein.
  • the neurodegenerative disorder may be selected from the group consisting of Alzheimer’s disease, Alzheimer’s disease-related dementia, and mild cognitive impairment.
  • the Alzheimer’s disease-related dementia may be selected from the group consisting of Lewy body dementia (LBD), frontotemporal degeneration (FTD), vascular cognitive impairment and dementia (VCID), and multiple etiology dementias.
  • the subject may be a mammal. In any embodiment, the subject may be a human patient. In any embodiment, the human patient may be an adult.
  • the present disclosure provides the use of a compound of any aspect described herein for the manufacture of a medicament for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition.
  • a neurodegenerative disorder or related condition may be selected from the group consisting of Alzheimer’s disease, Alzheimer's disease-related dementia, and mild cognitive impairment.
  • the Alzheimer's disease-related dementia is selected from the group consisting of Lewy body dementia (LBD). frontotemporal degeneration (FTD). vascular cognitive impairment and dementia (VCID), and multiple etiology dementias.
  • the medicament may be formulated for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition in a mammal. In any embodiment, the medicament may be formulated for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition in a human patient. In any embodiment, the human patient may be an adult.
  • the present disclosure provides the use of a pharmaceutical composition of any aspect described herein for the manufacture of a medicament for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition.
  • a neurodegenerative disorder or related condition may be selected from the group consisting of Alzheimer’s disease, Alzheimer's disease-related dementia, and mild cognitive impairment.
  • the Alzheimer's disease-related dementia is selected from the group consisting of Lewy body dementia (LBD). frontotemporal degeneration (FTD). vascular cognitive impairment and dementia (VCID), and multiple etiology dementias.
  • the medicament may be formulated for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition in a mammal. In any embodiment, the medicament may be formulated for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition in a human patient. In any embodiment, the human patient may be an adult.
  • the disclosure provides for a composition comprising a SHIP1 inhibitor for use in combination with an antibody or antigen-binding fragment for treating Alzheimer’s disease and Alzheimer’s disease-related dementias.
  • FIG. 1 is a schematic depicting the SHIP1 complex and associated pathways.
  • FIG. 2 is a schematic depicting the malachite green enzy me assay.
  • items included in a list in the form of “at least one of A, B, and C” can mean (A); (B); (C); (A and B); (B and C); (A and C); or (A, B, and C).
  • items listed in the form of “at least one of A, B, or C” can mean (A); (B); (C); (A and B); (B and C); (A and C); or (A, B, and C).
  • SH1P1 is a complex, multi-domain protein with a phosphatase (Ptase) domain flanked by a pleckstrin- homology (PH) domain that binds phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P 3 ] and a C2 domain that binds phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P 2 ].
  • Ptase phosphatase
  • PH pleckstrin- homology
  • the C2 domain (SEQ ID NO: 1) is essential for cellular function and interactions between the Ptase and C2 domains modulate enzymatic activity. See Le Coq et al., 2017. SHIP1 converts PI(3,4,5)P 3 to PI(3,4)P 2 . SHIP1 also contains an N-terminal SH2 domain that binds immunoreceptor tyrosine-based activation motifs (ITAMs) and a C-terminal proline rich domain that binds many other proteins including PLC ⁇ 2 and the Tec and Syk family kinases. PI(3,4,5)P 3 binds and activates other PH-containing proteins such as PLC ⁇ 2, PDK1, and AKT. See Scheffzek et al. 2012.
  • SHIP1 binds receptor ITAMs, competes with kinases, and converts PI(3,4,5)P 3 to PI(3,4)P 2 , it limits downstream signaling in multiple ways, and is therefore understood as a brake on microglia activation. Therefore, our therapeutic hypothesis is that inhibition of SHIP1 early in disease would increase microglial protective functions and reduce the rate of disease progression and cognitive decline in Alzheimer’s patients.
  • the investigators of the present disclosure developed a novel class of SHIP1 modulating compounds, which are described in International Patent Application No. PCT/US2023/078035, the contents of which are incorporated by reference in their entirety herein.
  • the present disclosure provides new compounds, compositions comprising such compounds, methods of treating, preventing, or inhibiting the progression of neurodegenerative disease in a subject, and uses of such compounds and compositions.
  • the term “treating the progression of mild cognitive impairment to Alzheimer's disease” includes restraining, slowing, stopping, or reversing the progression of mild cognitive impairment to Alzheimer's disease in a patient.
  • the terms “treating” or “to treat” includes restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.
  • One or more compounds of the present disclosure can react to form pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts and common methodology for preparing them are well know n in the art. See, e.g., P. Stahl, et al. Handbook of Pharmaceutical Salts: Properties. Selection and Use (Manual of Pharmaceutical Salts: Properties. Selection and Use). 2nd revised edition (Wiley-VCH. 2011); SM Berge, et al.. "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.
  • the present disclosure provides one or more compounds of Formula (I): a pharmaceutically acceptable salt of the compound, a stereoisomer of the compound, or a salt of a stereoisomer of the compound, wherein: denotes a single bond or a double bond; U and X are C, V is CR V .
  • R X is selected from the group consisting of wherein o is an integer 0 or 1; R V selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, and C 3 -C 6 cycloalkyl; wherein alkyl, alkenyl, alkynyl, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 6
  • alkyl, alkenyl, alkynyl, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 6 alkoxy;
  • R 2 and R 3 are each hydrogen, or R 2 and R 3 are taken together to form oxo;
  • R 4 and R 5 are each independently selected for each occurrence from the group consisting of halogen, hydroxyl.
  • each alky l, alkenyl, alky nyl, alkoxy, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR a R b , C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;nR a and R b are each independently selected from the group consisting of hydrogen C 1 -C 6 alkyl, and - CH 2 -phenyl; wherein C 1 -C 6 alkyl and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 - C 6 alkoxy; or R a and R b , together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more
  • the compound may be represented by:
  • R 2 and R 3 may each be hydrogen. In any embodiment, R 2 and R 3 may be taken together to form oxo.
  • R X may be selected from the group consisting of: .
  • m may be an integer 0, 1 , or 2.
  • n may be an integer 0, 1, or 2.
  • R 4 may be independently selected for each occurrence from the group consisting of fluoro, chloro, and -CH 3 .
  • R 5 may be independently selected for each occurrence from the group consisting of fluoro, chloro, and -CH 3 .
  • R V may be selected from the group consisting of hydrogen, - CH 3 , and -CH(CH 3 ) 2 .
  • R 4 and R 5 may be independently selected for each occurrence from the group consisting of fluoro, chloro, and -CH 3 .
  • the present disclosure provides a compound selected from the group consisting of: or a pharmaceutically acceptable salt of such compound, or a stereoisomer of such compound, or a pharmaceutically acceptable salt of a stereoisomer of such compound.
  • the present disclosure provides a compound selected from the group consisting of:
  • the present disclosure provides a compound selected from the group consisting of: or a pharmaceutically acceptable salt of such compound, or a stereoisomer of such compound, or a pharmaceutically acceptable salt of a stereoisomer of such compound.
  • the present disclosure provides a compound selected from the group consisting of:
  • the present disclosure provides a compound selected from the group consisting of: or a pharmaceutically acceptable salt of such compound, or a stereoisomer of such compound, or a pharmaceutically acceptable salt of a stereoisomer of such compound.
  • the present disclosure provides a pharmaceutical composition, which may comprise any compound of any aspect described herein, or a pharmaceutically acceptable salt of the compound, or a stereoisomer of the compound, or a pharmaceutically acceptable salt of a stereoisomer of the compound; further comprising a pharmaceutically acceptable excipient.
  • the composition may further comprise one or more additional neurodegenerative disorder therapeutic agents.
  • the composition may further comprise one or more pharmaceutically acceptable adjuvants, binders, carriers, diluents, or fillers.
  • the present disclosure provides a method of preventing, or inhibiting the progression of a neurodegenerative disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any aspect described herein, a pharmaceutically acceptable salt of the compound, or a stereoisomer of the compound, or a pharmaceutically acceptable salt of a stereoisomer of the compound; or comprising the pharmaceutical composition of any aspect described herein.
  • the neurodegenerative disorder may be selected from the group consisting of Alzheimer’s disease, Alzheimer’s disease-related dementia, and mild cognitive impairment.
  • the Alzheimer’s disease-related dementia may be selected from the group consisting of Lewy body dementia (LBD), frontotemporal degeneration (FTD). vascular cognitive impairment and dementia (VCID), and multiple etiology dementias.
  • the subject may be a mammal. In any embodiment, the subject may be a human patient. In any embodiment, the human patient may be an adult.
  • the present disclosure provides the use of a compound of any aspect described herein for the manufacture of a medicament for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition.
  • a neurodegenerative disorder or related condition may be selected from the group consisting of Alzheimer’s disease, Alzheimer's disease-related dementia, and mild cognitive impairment.
  • the Alzheimer’s disease-related dementia is selected from the group consisting of Lewy body dementia (LBD), frontotemporal degeneration (FTD), vascular cognitive impairment and dementia (VCID), and multiple etiology dementias.
  • the medicament may be formulated for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition in a mammal. In any embodiment, the medicament may be formulated for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition in a human patient. In any embodiment, the human patient may be an adult.
  • the present disclosure provides the use of a pharmaceutical composition of any aspect described herein for the manufacture of a medicament for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition.
  • a neurodegenerative disorder or related condition may be selected from the group consisting of Alzheimer’s disease, Alzheimer's disease-related dementia, and mild cognitive impairment.
  • the Alzheimer’s disease-related dementia is selected from the group consisting of Lewy body dementia (LBD), frontotemporal degeneration (FTD), vascular cognitive impairment and dementia (VCID), and multiple etiology dementias.
  • the medicament may be formulated for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition in a mammal. In any embodiment, the medicament may be formulated for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition in a human patient. In any embodiment, the human patient may be an adult.
  • excipients or earners include sodium citrate or dicalcium phosphate and/or a) one or more fillers or extenders (a filler or extender may be, but is not limited to, one or more selected from starches, lactose, sucrose, glucose, mannitol, and silicic acid), b) one or more binders (binders may be selected from, but not limited to, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), c) one or more humectants (a humectant may be, but is not limited to, glycerol), d) one or more disintegrating agents (disintegrating agents may be selected from, but are not limited to, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, silicates, and sodium carbonate), e) one or more solution retarding agents (for example, but not
  • Effective or therapeutic amounts of the compositions of this disclosure include any amount sufficient to inhibit (e.g., slow or stop) the progression of a neurodegenerative disorder. In some embodiments, effective amounts of the compositions include any amount sufficient to inhibit (e.g., slow or stop) the deterioration of the cognitive function of a patient.
  • the amount of the active ingredient that may be combined with the optional carrier materials to produce a single dosage form may vary depending upon the host treated and the particular mode of administration.
  • the specific dose level for any particular patient may depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disorder or disease undergoing therapy.
  • a therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
  • V is CR V .
  • Y and Z are N;
  • X and Z are C
  • V is CR V .
  • V and U are N; or U, X and Z are C,
  • V is N
  • Y is S or O
  • V is NR V .
  • Y is N;
  • X and Z are C
  • U, V and Y are N; or
  • R X is selected from the group consisting of R V selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, and C 3 -C 6 cycloalkyk wherein alky l, alkenyl, alkynyl, and cycloalkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 6 alkoxy;
  • R 2 and R 3 are each hydrogen, or R 2 and R 3 are taken together to form oxo;
  • each alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one or more substituents each independently- selected from the group consisting of halogen, hydroxyl, -NR a R b , C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
  • R a and R b are each independently selected from the group consisting of hydrogen C 1 - C 6 alkyl, and -CH 2 -phenyl; wherein C 1 -C 6 alkyl and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 6 alkoxy; or
  • R a and R b together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; m is an integer 0. 1, 2, 3, 4, or 5; and n is an integer 0, 1, 2, 3, 4, or 5.
  • Clause 8 The compound of any one of clauses 1-7. wherein R V is selected from the group consisting of hydrogen and C 1 -C 6 alkyl.
  • Clause 10 The compound of any one of clauses 1-9, wherein m is an integer 0, 1, or 2.
  • Clause 11 The compound of any one of clauses 1-10, wherein R 4 is independently selected for each occurrence from the group consisting of fluoro, chloro, and -CH 3 .
  • Clause 13 The compound of any one of clauses 1-12, wherein R 5 is independently selected for each occurrence from the group consisting of fluoro, chloro, and -CH 3 .
  • R 2 and R 3 are each independently selected from halogen and C 1 -C 6 alkyl; m is an integer 0, 1, or 2; and n is an integer 0, 1 , or 2.
  • Clause 17 The compound of any one of clauses 14-16, wherein R 4 and R 5 are independently selected for each occurrence from the group consisting of fluoro, chloro, and -CH 3 .
  • Clause 22 A compound selected from the group consisting of: or a pharmaceutically acceptable salt of such compound, or a stereoisomer of such compound, or a pharmaceutically acceptable salt of a stereoisomer of such compound.
  • Clause 23 A pharmaceutical composition comprising a compound of any one of clauses 1-22, a pharmaceutically acceptable salt of the compound, or a stereoisomer of the compound, or a pharmaceutically acceptable salt of a stereoisomer of the compound, and a pharmaceutically acceptable excipient.
  • Clause 24 The composition of clause 23, further comprising one or more additional neurodegenerative disorder therapeutic agents.
  • Clause 25 The composition of either of clauses 23 or 24, further comprising one or more pharmaceutically acceptable adjuvants, binders, carriers, diluents, or fillers.
  • Clause 26 A method of treating, preventing, or inhibiting the progression of a neurodegenerative disorder in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of clauses 1-22, a pharmaceutically acceptable salt of the compound, or a stereoisomer of the compound, or a pharmaceutically acceptable salt of a stereoisomer of the compound; or the pharmaceutical composition of any one of clauses 23- 25.
  • Clause 27 The method of clause 26, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer’s disease, Alzheimer’s disease-related dementia, and mild cognitive impairment.
  • Clause 28 The method of clause 27, wherein the Alzheimer’s disease-related dementia is selected from the group consisting of Lewy body dementia (LBD), frontotemporal degeneration (FTD), vascular cognitive impairment and dementia (VCID), and multiple etiology dementias.
  • LBD Lewy body dementia
  • FDD frontotemporal degeneration
  • VCID vascular cognitive impairment and dementia
  • Clause 29 The method of any one of clauses 26-28, wherein the subject is a mammal.
  • Clause 30 The method of any one of clauses 26-28, wherein the subject is human patient.
  • Clause 31 The method of any one of clause 30, wherein the human patient is an adult.
  • Clause 32 Use of a compound of any of clauses 1-22 for the manufacture of a medicament for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition.
  • Clause 33 The use of clause 32, wherein the neurodegenerative disorder or related condition is selected from the group consisting of Alzheimer’s disease, Alzheimer’s disease-related dementia, and mild cognitive impairment.
  • Clause 35 The use of any one of clauses 32-34, wherein the medicament is formulated for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition in a mammal.
  • Clause 36 The use of any one of clauses 32-34, wherein the medicament is formulated for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition in a human patient.
  • Clause 37 The use of clause 36, wherein the human patient is an adult.
  • Clause 38 Use of a pharmaceutical composition of any of clauses 23-25 for the manufacture of a medicament for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition.
  • Clause 39 The use of clause 38, wherein the neurodegenerative disorder or related condition is selected from the group consisting of Alzheimer’s disease, Alzheimer’s disease-related dementia, and mild cognitive impairment.
  • Clause 40 The use of clause 39. wherein the Alzheimer’s disease-related dementia is selected from the group consisting of Lewy body dementia (LBD), frontotemporal degeneration (FTD), vascular cognitive impairment and dementia (VCID), and multiple etiology dementias.
  • LBD Lewy body dementia
  • FDD frontotemporal degeneration
  • VCID vascular cognitive impairment and dementia
  • Clause 41 The use of any one of clauses 38-40, wherein the medicament is formulated for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition in a mammal.
  • Clause 42 The use of any one of clauses 38-40, w herein the medicament is formulated for the treatment or prevention of a neurodegenerative disorder or related condition, or to inhibit progression of such neurodegenerative disorder or related condition in a human patient.
  • Clause 43 The use of clause 42, wherein the human patient is an adult.
  • Flash normal phase (NP) or reversed-phase (RP) chromatography were performed on a Teledyne ISCO NextGen 300 instrument using prepacked silica gel or Cl 8-functionalized silica gel columns available from Teledyne ISCO, or on a Teledyne ISCO CombiFlash® using prepacked silica gel columns available from Agela or Welch.
  • RP HPLC reverse-phase
  • a WatersTM AutoPurification HPLC system equipped with PDA and ELSD detectors and a WatersTM XBridge Cl 8 Prep column (10 ⁇ m, 250 mm x 19 mm).
  • High-resolution mass spectra were obtained on an Agilent 6550 Q-TOF instrument. All compounds had >95% purity as determined by LC-MS.
  • One of the following specified LC-MS methods was used to determine test compound purity:
  • Method 1 gradient table A (below); column, WatersTM ACQUITY® HSS-T3 (1.8 ⁇ m, 100 mm x 2.1 mm); mobile phase A, 0.1% trifluoroacetic acid (TFA) in H 2 O; mobile phase B, acetonitrile (ACN); flow rate. 0.3 mL/min; detection wavelength, 214 nm; column temperature, 35 °C.
  • TFA trifluoroacetic acid
  • ACN acetonitrile
  • Method 2 gradient table A; column, WatersTM ACQUITY® BEH C-18 (1.7 ⁇ m, 100 mm x 2. 1 mm) [or C-8 (1.7 ⁇ m, 100 mm x 2. 1 mm) for 11]; mobile phase A, 5 rnM NH4OAC in H 2 O; mobile phase B, ACN; flow rate, 0.3 mL/min; detection wavelength, 214 nm; column temperature. 35 °C.
  • Method 3 gradient table B; column.
  • WatersTM ACQUITY® BEH C-18 (1.7 gm, 100 mm x 2.1 mm); mobile phase A, 5 mM NH 4 OAc in H 2 O; mobile phase B, ACN; flow rate, 0.3 mL/min; detection wavelength, 214 nm; column temperature, 35 °C.
  • Method 4 gradient table C; column, WatersTM ACQUITY® BEH C-18 (1.7 ⁇ m, 50 mm x 2.1 mm); mobile phase A, 0.1% formic acid in H 2 O; mobile phase B, 0.1% formic acid in ACN; flow rate, 0.6 mL/min; detection wavelength, 254 nm; column temperature, 40 °C.
  • N-bromosuccinimide (NBS) (912 mg. 5.12 mmol, 1.2 eq). The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was diluted with H 2 O, extracted with DCM, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Reaction mixture was monitored by TLC and LCMS. Reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Crude was purified by flash chromatography using 20% EtOAc in hexane as an eluent, desired fractions were concentrated to afford l-[4-(4-methyl-l,5-diphenyl-1H-pyrazol-3-yl)piperazin-l-yl]ethan-l-one (120 mg, 256 ⁇ mol) as a brown semi solid. MS ES+ 361.17.
  • the crude material was purified by column chromatography eluted with 70% ethyl acetate in heptane.
  • the crude was purified by Prep-HPLC using TFA buffer solution to provide l-(4-methyl- 1.5-di phenyl- 1 H-pyrazol-3-yl)piperazine trifluoroacetate salt (20 mg, 62.8 ⁇ mol) as an off white solid.
  • reaction mixture was purged with N 2 for 15 minutes, palladium — triphenylphosphine (1/4) (73mg, 0.1 eq., 63.9 ⁇ mol) was added and purging continued for 5 minutes, then the reaction mixture was heated at 100 °C and stirred for 16 hours. After completion of the reaction (TLC monitoring), reaction mixture was concentrated and residue was diluted with chilled water, extracted with EtOAc, washed with water, brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to obtain crude.
  • reaction mixture was purged with N 2 for 15 minutes, RuPhos Pd G3 (66.8 mg, 0.05 eq., 79.8 ⁇ mol) was then added and purging continued for another 5 minutes.
  • the reaction mixture was heated at 130 °C and stirred for 16 hours. After completion of the reaction (TLC and LCMS monitoring), reaction mixture was concentrated and residue was diluted with chilled water, extracted with EtOAc, washed with water, brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to obtain crude.
  • reaction mixture was quenched with chilled water, extracted with EtOAc, washed with water, brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to obtain crude which was purified by PREP HPLC using ABC buffer to afford 3,3-dimethyl-l-(4-(4-methyl-l,5- diphenyl-1H-pyrazol-3-yl)piperidin-l-yl)butan-l-one (83 mg, 0.2 mmol) as a white solid.
  • reaction mixture was purged with N 2 for 15 minutes, then was added Catacxium A Pd G3 (42.9 mg, 0.05 eq.. 58.9 prnol) and purging continued for 20 minutes, then the reaction mixture was heated at 120 °C and stirred for 16 hours. After completion of the reaction (TLC & LCMS monitoring), reaction mixture was concentrated and residue was diluted with chilled water, extracted with EtOAc, washed with water, brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • reaction mixture was purged with N 2 for 15 minutes, after that palladium — triphenylphosphine (1/4) (64.6 mg, 0.05 eq., 55.9 ⁇ mol) was added and purging continued for 20 minutes, then the reaction mixture was heated at 100 °C and stirred for 16 hours. After completion of the reaction (TLC monitoring), reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • palladium — triphenylphosphine (1/4) 64.6 mg, 0.05 eq., 55.9 ⁇ mol
  • reaction mixture was diluted with cold water and extracted with EtOAc. Organic layer was combined and washed with water followed by brine. It was then dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The resulting mixture was purified by flash column chromatography on SiO 2 gel column using 0-5% EtOAc in heptanes and fractions containing the desired product were concentrated to afford 3,5- dibromo-1 -phenyl- 1H-1, 2, 4-triazole (1.9 g, 6.27 mmol) as a white solid.
  • the resulting mixture was purged with N 2 for 15 minutes, then Pd(PPh3) 4 (99.8 mg, 86.4 ⁇ mol) was added and purging continued for additional 20 minutes.
  • the reaction mixture was then heated at 80 °C under vigorous stirring for 16 hours. After completion of the reaction (TLC & LCMS monitoring) it was diluted with chilled water, extracted with EtOAc, washed with water followed by brine. The organic extract was dried over anhydrous Na 2 SO 4 . filtered and concentrated under reduced pressure.
  • the resulting mixture was purified by Si-gel flash column chromatography on 12 g Welch SiO 2 gel LS column using 30% EtOAc/ heptanes as eluant.
  • Enzymatic inhibitory potencies (IC 50 ) (see table below) were determined using PI(3,4,5)P 3 -diC 8 as a substrate at 25 °C in 50 mM HEPES buffer (pH7.4, 150 mM NaCl, 2 mM MgCl 2 ). See FIG. 2. Compounds diluted in DMSO were added to 384-well plates. Human SHIP1 1-899 multidomain enzyme solution was added. After a 20-minute incubation period, the reaction was initiated by addition of PI(3,4,5)P 3 -diC 8 . Final compound concentrations ranged from 50 nM to 950 ⁇ M.
  • CETSA Cellular Thermal Shift Assay
  • a split Nano Luciferase assay (SplitLuc CETSA) was used to demonstrate target engagement of SHIP1 inhibitors in a physiologically relevant cellular context by quantifying changes in the thermal stability of a HiBit-labeled full length SHIP1 protein in intact cells. See Martinez et al. (2016) Sci Rep 8: p. 9472; Oh-Hashi et al. (2017) Biochem Biophys Rep 12: pp. 40- 45. This assay was run in the following two formats with HMC3/HiBit-INPP5D stably transfected cells.
  • Compound dose response Run at target T m (44.2 °C for SHIP1) with compound dosing from 80 ⁇ M or 100 ⁇ M with 1 :3 serial dilutions to generate an 8-point curve. Cells were treated for 60 minutes before being heated at target T m for 3 minutes before luminescence detection. The concentration that induced a half-maximum response (AC 50 ) was calculated using a four-parameter logistic curve regression model with change at highest concentration noted when difference from control >3SD. Activities are shown in Tables 2. below.
  • pHrodo-Myelin Phagocytosis/Cell Health Assay with Microglial Cells This 384-well plate high content imaging assay was developed to quantify phagocytosis and cell health simultaneously using either BV2 or HMC3 immortalized microglial cell lines or primary microglia isolated from mouse brain. See Mason, et al., "‘Microglial Phagocytosis/Cell Health High-Content Assay,” (2023) Curr Protoc 3: e724. Briefly, cells were cultured in DMEM GlutaMax media (ThermoFisher) containing 10% FBS and Pen-Strep in 37 °C 5% CO 2 incubator.
  • DMEM GlutaMax media ThermoFisher
  • Day 1 Cells were plated (Coming Falcon 384 well Optilux Black and clear bottom plates for imaging) with BV2 at 400 cells/45pl/welk HMC3 at 600 cells/45pl/well, or primary at 2000 cell/45pl/well.
  • Day 2 Cells were treated with 10x serially diluted compounds in a dose range of 60 ⁇ M to 3 nM for 48 hrs at 37 °C.
  • Dav 3 Cells were seeded with pHrodo- myelin (for total 20 hrs) 24 hrs after starting compound treatment. The pHrodo-myelin stocks were at 1 mg/ml (protein equivalent) stored in -20 °C or -80 °C freezer.
  • Cortical tissue from C57BL/6J neonatal mice was homogenized in Dulbecco's Modified Eagle Medium (DMEM), filtered through 250 and 100 ⁇ m mesh, and cultured in Advanced DMEM/F12 supplemented with 10% fetal bovine serum, lx GlutaMAX and lx Penicillin/Streptomycin.
  • DMEM Dulbecco's Modified Eagle Medium
  • the cultures were subjected to mild trypsinization using 0.083% Trypsin-EDTA in DMEM for 30 mins to detach an intact layer of astrocytes.
  • the microglia attached to the bottom were used as described in above to measure myelin phagocytosis and cell health. Activities are shown in table 3 below. [00187] Table 3

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Abstract

L'invention concerne des composés et des compositions pharmaceutiques pour le traitement de maladies neurodégénératives et d'états apparentés, en particulier par modulation de l'activité de la phosphatase SHIP1, et des méthodes de traitement, de prévention et d'inhibition de la progression d'une maladie neurodégénérative et d'états associés l'utilisant.
PCT/US2025/020356 2024-03-20 2025-03-18 Modulateurs de ship1, méthodes de traitement et utilisations associées Pending WO2025199092A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007106721A2 (fr) * 2006-03-10 2007-09-20 Jenrin Discovery Antagonistes de recepteur cannabinoide/agonistes inverses utiles dans le traitement de l'obesite
US20080318070A1 (en) * 2005-05-24 2008-12-25 Shikoku Chemicals Corporation Water-Soluble Preflux and Usage of the Same
US20090149463A1 (en) * 2004-02-20 2009-06-11 Leifeng Cheng Therapeutic agents
US20130345268A1 (en) * 2009-02-13 2013-12-26 The Trustees Of Dartmouth College Methods and Compositions for the Treatment of RAS Associated Disorders
WO2024015759A1 (fr) * 2022-07-14 2024-01-18 The Trustees Of Indiana University Analogues de crizotinib utilisés en tant qu'inhibiteurs de ship1 utiles pour traiter les maladies d'alzheimer
WO2024092205A1 (fr) * 2022-10-27 2024-05-02 The Trustees Of Indiana University Inhibition de ship1 en tant que stratégie thérapeutique pour le traitement de la maladie d'alzheimer

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090149463A1 (en) * 2004-02-20 2009-06-11 Leifeng Cheng Therapeutic agents
US20080318070A1 (en) * 2005-05-24 2008-12-25 Shikoku Chemicals Corporation Water-Soluble Preflux and Usage of the Same
WO2007106721A2 (fr) * 2006-03-10 2007-09-20 Jenrin Discovery Antagonistes de recepteur cannabinoide/agonistes inverses utiles dans le traitement de l'obesite
US20130345268A1 (en) * 2009-02-13 2013-12-26 The Trustees Of Dartmouth College Methods and Compositions for the Treatment of RAS Associated Disorders
WO2024015759A1 (fr) * 2022-07-14 2024-01-18 The Trustees Of Indiana University Analogues de crizotinib utilisés en tant qu'inhibiteurs de ship1 utiles pour traiter les maladies d'alzheimer
WO2024092205A1 (fr) * 2022-10-27 2024-05-02 The Trustees Of Indiana University Inhibition de ship1 en tant que stratégie thérapeutique pour le traitement de la maladie d'alzheimer

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