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WO2025090928A1 - Composés pour le traitement de maladies neurodégénératives - Google Patents

Composés pour le traitement de maladies neurodégénératives Download PDF

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WO2025090928A1
WO2025090928A1 PCT/US2024/053056 US2024053056W WO2025090928A1 WO 2025090928 A1 WO2025090928 A1 WO 2025090928A1 US 2024053056 W US2024053056 W US 2024053056W WO 2025090928 A1 WO2025090928 A1 WO 2025090928A1
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trifluoromethyl
methyl
phenyl
compound
disease
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Joseph P. Vacca
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Aquinnah Pharmaceuticals Inc
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Aquinnah Pharmaceuticals Inc
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    • 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
    • C07D413/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present disclosure relates to compounds, compositions, and methods of treating or preventing neurodegen erative diseases.
  • AD Alzheimer’s disease
  • PSP Progressive Supranuclear Palsy
  • FDD Frontotemporal lobar dementia
  • CBD CorticoBasal Degeneration
  • TBI Traumatic Brain Injury
  • Hyperphosphorylation of tau causes it to aggregate in an insoluble form.
  • These aggregations of hyperphosphorylated tau protein are also referred to as PHF, or “paired helical filaments”.
  • Tauopathies are characterized by insoluble aggregates or polymers of hyperphosphorylated tau which are formed by self-polymerization of tau monomers.
  • AD Alzheimer’s disease
  • a ⁇ insoluble amyloid beta
  • neurofibrillary tangles consisting of insoluble hyperphosphorylated tau.
  • Neuronal death and progression of clinical symptoms correlates most strongly with the accumulation of tau neurofibrillary tangle.
  • current FDA approved treatments of AD only target aggregated A ⁇ (Aducanumab, Biogen/Eisai) or protofibrillar A ⁇ (Lecanemab, Biogen). Treatments aimed to suppress cytotoxic tau misfolding and/or aggregation in order to delay or halt the progression of disease are presently not available.
  • SUMMARY Provided herein are compounds designed to function as modulators (e.g., inhibitors) of cytotoxic tau misfolding and aggregation. Such compounds can be useful as therapeutic agents for treating or preventing neurodegenerative diseases, such as Alzheimer’s disease or frontotemporal dementia.
  • modulators e.g., inhibitors
  • Such compounds can be useful as therapeutic agents for treating or preventing neurodegenerative diseases, such as Alzheimer’s disease or frontotemporal dementia.
  • FIG. 1 provides images of Tau/TIA1 (which colocalize) in SY5Y cells treated with (i) DMSO and (ii) Compound 8 (333nM). Prior to treatment the Tau/TIA1 SY5Y cells were exposed to thapsigargin for 90 minutes to induce stress, as described further in Example 12.
  • FIG. 1 provides images of Tau/TIA1 (which colocalize) in SY5Y cells treated with (i) DMSO and (ii) Compound 8 (333nM). Prior to treatment the Tau/TIA1 SY5Y cells were exposed to thapsigargin for 90 minutes to induce stress, as described further in Example 12.
  • FIG. 2 provides bar charts showing Alpha-LISA quantification for (i) Tau12: Total Tau, (ii) MC1 (insoluble misfolded tau), and (iii) AT8 (Total p202/5 Tau) in PS19 (P301S) mice treated with (a) vehicle, (b) Compound 1, dose 1 (150 mg/kg), and Compound 1, dose 2 (300 mg/kg), as described further in Example 13.
  • FIG. 3 provides bar charts showing Alpha-LISA quantification for (i) Misfolded Tau, (ii) pS202,5 Tau, (iii) pT181 Tau, and (iv) Total Tau in PS19 (P301S) mice treated with Compound 8, as further described in Example 13.
  • FIG. 3 provides bar charts showing Alpha-LISA quantification for (i) Misfolded Tau, (ii) pS202,5 Tau, (iii) pT181 Tau, and (iv) Total Tau in PS19 (P301S) mice treated with Compound 8, as further described in
  • FIG. 4 provides an illustration of a high throughput screening assay used to demonstrate the effects of Compound 8 on stress granule formation, as further described in Example 15.
  • FIG. 5 provides representative images of stressed SHSY5Y-tT1 cells expressing TIA1 +ive and nuclei treated with Compound 8 or DMSO control, as further described in Example 15.
  • FIG. 7 provides a graph demonstrating the effects of pre-treatment, co-treatment, and post-treatment with Compound 8 in a modified version of a high throughput screening assay, as further described in Example 15.
  • FIG. 8 provides an illustration of human stem cell differentiation into iCNs, as further described in Example 16.
  • FIG. 9 provides representative immunofluorescent images of human stem cell-derived neurons treated with Compound 8 or DMSO followed by stress.
  • the immunofluorescent staining reveals spot-like labeling of misfolded tau (MC-1) induced by stress, as further described in Example 16.
  • FIG. 10 provides a graph demonstrating the misfolded tau (MC-1) induced by stress in human stem cell-derived neurons treated with Compound 8 or DMSO followed by stress, as further described in Example 16.
  • FIG. 11 provides an illustration of an in vivo study of PS19 mice treated with Compound 8 or vehicle, as further described in Example 17.
  • FIG. 12 provides an illustration of a biochemical analysis of tau-pathology via AlphaLISA from an in vivo study of PS19 mice treated with Compound 8 or vehicle, as further described in Example 17.
  • FIG. 13 provides a graph demonstrating the effect of Compound 8 and vehicle on tau12 from an in vivo study of PS19 mice treated with Compound 8 or vehicle, as further described in Example 17.
  • FIG. 14 provides a graph demonstrating the effect of Compound 8 and vehicle on MC-1 tau from an in vivo study of PS19 mice treated with Compound 8 or vehicle, as further described in Example 17.
  • FIG. 15 provides a graph demonstrating the effect of Compound 8 and vehicle on phosphorylated tau (AT8) from an in vivo study of PS19 mice treated with Compound 8 or vehicle, as further described in Example 17.
  • FIG. 16 provides a graph demonstrating the effect of Compound 8 and vehicle on TOC1 o.tau from an in vivo study of PS19 mice treated with Compound 8 or vehicle, as further described in Example 17.
  • FIG. 17 provides a graph of putative targets of Compound 8 from thermal shift (CETSA) and proteolysis (LiPs) performed in stressed SHSY5Y-tT1 lysates, as further described in Example 18.
  • FIG. 18 provides a graph of demonstrating that knockdown of a putative target phenocopied the effects of Compound 8 in a SHSY5Y-tT1 assay, as further described in Example 18.
  • FIG. 19 provides a graph of demonstrating that knockout of a putative target phenocopied the effects of Compound 8 in a SHSY5Y-tT1 assay, as further described in Example 18.
  • FIG. 20 provides an image of a western blot from a study where a candidate target was immunoprecipitated (IP) and probed for TIA1, as further described in Example 18.
  • IP immunoprecipitated
  • TIA1 as further described in Example 18.
  • DETAILED DESCRIPTION The present compounds and compositions are useful for treating or preventing certain neurodegenerative disorders. Some neurodegenerative disorders are characterized by cytotoxic tau misfolding and/or aggregation, which misfolding and aggregation can be inhibited in order to delay or halt the progression of such diseases. Such diseases are summarized under the term tauopathy.
  • Tauopathy refers to a disease characterized by dysfunctioning and/or toxicity of the tau protein, characterized by oligomers, aggregates or polymers of said protein. Such diseases include, but are not limited to, Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia and parkinsonism (linked to chromosome 17, FTDP-17). Tauopathies are characterized by insoluble aggregates or polymers of hyperphosphorylated tau which are formed by self-polymerization of tau monomers.
  • tau aggregation The precise molecular mechanisms involved in tau aggregation are not precisely known, but may involve a partial denaturation or misfolding of tau in conformations which have a high propensity to self- organize into higher order structures.
  • the misfolding and aggregation may be triggered by hyperphosphorylation of tau, although at present it cannot be excluded that such aberrant phosphorylation is a consequence rather than the cause of aggregation.
  • Tau is a protein with the ability to bind—and consequently stabilize and define—microtubule structure and function in neurons.
  • tau aggregation The binding of tau to microtubules is regulated by phosphorylation of tau and several tau phosphorylation sites and their corresponding kinases have been identified which control phosphorylation status of tau and consequently modulate the affinity of tau-binding to microtubules.
  • An important aspect of the tau aggregation is its associated cytotoxicity which reduces neuronal integrity and functionality and ultimately resulting in disease symptoms.
  • a direct role of tau in disease onset has been established unequivocally by the elucidation of familial mutations in tau which appear to be responsible for a very early and sometimes aggressive form of tauopathy. Such mutations comprise changes in the amino acid sequence of tau that—directly or indirectly—promote neurotoxic aggregation.
  • neurofibrillary tangles are commonly observed include: progressive supranuclear palsy, dementia pugilistica (chronic traumatic encephalopathy), frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease (Parkinson-dementia complex of Guam), tangle-predominant dementia with NFTs, similar to AD, but without plaques, ganglioglioma and gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis.
  • progressive supranuclear palsy dementia pugilistica (chronic traumatic encephalopathy), frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease (Parkinson-dementia complex of Guam)
  • tangle-predominant dementia with NFTs similar to AD, but without
  • C 1-6 alkyl is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl and hexyl.
  • each variable can be a different moiety selected from the Markush group defining the variable.
  • the two R groups can represent different moieties selected from the Markush group defined for R.
  • Suitable substituents for an optionally substituted alkyl, alkylene, heteroalkyl, heteroalkylene, cycloalkyl, heterocycloalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group include halogen, ⁇ O, —CN, —OR cc , —NR dd R ee , —S(O) kk R cc , —NR cc S(O) 2 R cc , — S(O) 2 NR dd R ee , —C( ⁇ O)OR cc , —OC( ⁇ O)OR cc , —OC( ⁇ O)R cc , —OC( ⁇ S)OR cc , —C( ⁇ S)OR cc , —O(C ⁇ S) R cc , —O(C ⁇ S) R cc , —C( ⁇ S)OR cc , —O
  • substituents refers to any of the suitable substituents for an alkyl, alkylene, heteroalkyl, heteroalkylene, cycloalkyl, heterocycloalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group, including: halogen, ⁇ O, —CN, —OR cc , —NR dd R ee , — S(O) kk R cc , —NR cc S(O) 2 R cc , —S(O) 2 NR dd R ee , —C( ⁇ O)OR cc , —OC( ⁇ O)OR cc , —OC( ⁇ O)R cc , —OC( ⁇ S)OR cc , —C( ⁇ S)OR cc , —O( ⁇ O)OR cc , —O( ⁇ O)OR cc , —OC( ⁇ O)R cc
  • alkyl refers to a radical of a straight–chain or branched, saturated hydrocarbon group having from 1 to 24 carbon atoms (“C 1 -C 24 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C 1 -C 12 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1 -C 8 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1 -C 6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1 -C 5 alkyl”).
  • an alkyl group has 1 to 4 carbon atoms (“C 1 -C 4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1 -C3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1 -C 2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2 -C 6 alkyl”).
  • C 1 -C 6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n–propyl (C 3 ), isopropyl (C 3 ), n–butyl (C 4 ), tert–butyl (C 4 ), sec–butyl (C 4 ), iso–butyl (C 4 ), n–pentyl (C 5 ), 3–pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3–methyl–2–butanyl (C 5 ), tertiary amyl (C 5 ), and n–hexyl (C 6 ).
  • alkyl groups include n–heptyl (C 7 ), n–octyl (C 8 ) and the like.
  • Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkyl group is unsubstituted C 1–10 alkyl (e.g., –CH 3 ).
  • the alkyl group is substituted C 1–6 alkyl.
  • alkylene refers to an alkyl group with one additional open valence, i.e., a bivalent group.
  • exemplary alkylene groups include, but are not limited to -CH 2 CH 2 - and CH 2 -C(CH 3 )-CH 2 -.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon–carbon double bonds, and no triple bonds (“C 2 -C 24 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2 -C 10 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C 2 -C 8 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2 -C 6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2 -C 5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2 -C 4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2 -C 3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”).
  • the one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl).
  • Examples of C 2 -C 4 alkenyl groups include ethenyl (C 2 ), 1–propenyl (C 3 ), 2–propenyl (C 3 ), 1– butenyl (C 4 ), 2–butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2 -C 6 alkenyl groups include the aforementioned C 2–4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
  • alkenyl examples include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • Each instance of an alkenyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkenyl group is unsubstituted C 2–10 alkenyl.
  • the alkenyl group is substituted C 2–6 alkenyl.
  • alkynyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon–carbon triple bonds (“C 2 -C 24 alkenyl”).
  • an alkynyl group has 2 to 10 carbon atoms (“C 2 -C 10 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C 2 -C 8 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms (“C 2 -C 6 alkynyl”).
  • an alkynyl group has 2 to 5 carbon atoms (“C 2 -C 5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2 -C 4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2 -C 3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl).
  • C 2 -C 4 alkynyl groups include ethynyl (C 2 ), 1–propynyl (C 3 ), 2–propynyl (C 3 ), 1– butynyl (C 4 ), 2–butynyl (C 4 ), and the like.
  • Each instance of an alkynyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkynyl group is unsubstituted C 2–10 alkynyl. In some embodiments, the alkynyl group is substituted C 2–6 alkynyl.
  • the term "heteroalkyl,” refers to a non-cyclic stable straight-chain or branched, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group.
  • heteroalkyl Up to two or three heteroatoms may be consecutive, such as, for example, -CH 2 -NH- OCH 3 and -CH 2 -O-Si(CH 3 ) 3 .
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as –CH 2 O, –NR C R D , or the like, it will be understood that the terms heteroalkyl and –CH 2 O or –NR C R D are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity.
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as –CH 2 O, –NR C R D , or the like.
  • heteroalkylene refers to a heteroalkyl group with one additional open valence, i.e., a bivalent group.
  • exemplary heteroalkylene groups include, but are not limited to: -CH 2 -CH 2 -O-CH 2 -, -CH 2 -O-,and -CH 2 -CH 2 -NH-CH 2 -.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6 -C 14 aryl”).
  • aromatic ring system e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array
  • an aryl group has six ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • An aryl group may be described as, e.g., a C 6 -C 10 - membered aryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • Each instance of an aryl group may be independently optionally substituted, i.e., unsubstituted (e.g., “unsubstituted aryl”) or substituted (e.g., “substituted aryl”) with one or more substituents.
  • the aryl group is unsubstituted C 6 -C 14 aryl.
  • the aryl group is substituted C 6 -C 14 aryl.
  • Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, and anthracyl.
  • heteroaryl refers to a radical of a 5–14 membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and one or more (e.g., 1–4) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl).
  • a heteroaryl group may be described as, e.g., a 5-10-membered heteroaryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • a heteroaryl group is a 5– 10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”).
  • a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”).
  • a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”).
  • the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Each instance of a heteroaryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is unsubstituted 5–14 membered heteroaryl.
  • the heteroaryl group is substituted 5–14 membered heteroaryl.
  • Exemplary heteroaryl groups include, but are not limited to, imidazolyl, pyridinyl, and quinolinyl.
  • cycloalkyl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring system that is saturated or partially unsaturated, but not aromatic, and has from 3 to 14 ring carbon atoms (“C 3 -C 14 carbocyclyl”) and zero heteroatoms in the saturated or partially unsaturated, but not aromatic, ring system.
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3 -C 8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3 -C 6 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3 -C 6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5 -C 10 cycloalkyl”).
  • a cycloalkyl group may be described as, e.g., a C 4 - C 7 -membered cycloalkyl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • Exemplary C 3 -C 10 cycloalkyl groups include, without limitation, the aforementioned C 3 -C 8 cycloalkyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro–1H–indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • the cycloalkyl group is a substituted C 3 -C 10 cycloalkyl.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexanyl, cyclohexenyl, cyclooctynyl, and bicyclo[4.4.0]decanyl.
  • Heterocycloalkyl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring system that is saturated or partially unsaturated, but not aromatic, and has from 3 to 14 ring atoms including carbon and 1 to 6 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur (e.g., –S–, –S(O)–, and – S(O) 2 –), boron, phosphorus, and silicon (“3–14 membered heterocycloalkyl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocycloalkyl group can either be monocyclic (“monocyclic heterocycloalkyl”) or polycyclic (“polycyclic heterocycloalkyl”), such as bicyclic (“bicyclic heterocycloalkyl”).
  • a heterocycloalkyl group can be a fused, bridged or spiro ring system.
  • Bicyclic heterocycloalkyl can include one or more heteroatoms in one or both rings.
  • a heterocycloalkyl group may be described as, e.g., a 3-7-membered heterocycloalkyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety.
  • Each instance of heterocycloalkyl may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocycloalkyl”) or substituted (a “substituted heterocycloalkyl”) with one or more substituents.
  • the heterocycloalkyl group is unsubstituted 3–14 membered heterocycloalkyl.
  • the heterocycloalkyl group is substituted 3– 14 membered heterocycloalkyl.
  • a heterocycloalkyl group is a 5–10 membered heterocycloalkyl having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocycloalkyl”).
  • a heterocycloalkyl group is a 5–8 membered heterocycloalkyl having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocycloalkyl”).
  • a heterocycloalkyl group is a 5–6 membered heterocycloalkyl having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocycloalkyl”).
  • the 5–6 membered heterocycloalkyl has 1–3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocycloalkyl has 1–2 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocycloalkyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • exemplary heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, 3,4-dihydro-2H-pyranyl, and octahydroindolyl.
  • “carbocyclyl” refers to a radical of a polycyclic, partially unsaturated ring system having from 6 to 20 carbon atoms and at least one fused aryl ring.
  • the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • Each instance of a carbocyclyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is unsubstituted 6-20 membered carbocyclyl.
  • the carbocyclyl group is a substituted 6-20 membered carbocyclyl.
  • Exemplary carbocyclyl groups include, but are not limited to, indenyl and tetrahydronaphthyl.
  • heterocyclyl refers to a radical of a polycyclic, partially unsaturated ring system having from 5 to 20 atoms (“5-20 membered heterocyclyl”) including carbon and 1 to 6 heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and wherein the polycyclic, partially unsaturated ring system has at least one aromatic ring (e.g., aryl or heteroaryl).
  • a heterocyclyl group has 5 to 14 ring atoms (“5-14 membered heterocyclyl”).
  • the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • Each instance of a heterocyclyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is unsubstituted 5-20 membered heterocyclyl.
  • the heterocyclyl group is a substituted 5-20 membered heterocyclyl.
  • heterocyclyl groups include, but are not limited to, 1,2,3,4- tetrahydroquinolyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, 1,4,6,7-tetrahydropyrano[4,3- b]pyrrole, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, and 5,6,7,8-tetrahydroquinolinyl.
  • cyano refers to the radical –CN.
  • halo or “halogen,” independently or as part of another substituent, mean, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.
  • haloalkyl can include alkyl structures that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl includes haloalkyl groups in which the halo is fluorine (e.g., -C 1 -C 6 alkyl-CF 3, -C 1 -C 6 alkyl-C 2 F).
  • Non- limiting examples of haloalkyl include trifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl, difluormethyl, and fluoroisopropyl.
  • alkoxy refers to an alkyl group attached to the remainder of the molecule via an oxygen linker (—O–). Alkoxy groups of the present disclosure may include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • alkoxy groups of the present disclosure are lower alkoxy groups, i.e. with between 1 and 6 carbon atoms. In certain embodiments, alkoxy groups of the present disclosure have between 1 and 4 carbon atoms.
  • hydroxy refers to the radical –OH.
  • nitro refers to –NO 2 .
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, heterocycloalkyl, carbocyclyl, or heterocyclyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring-forming substituents are attached to non-adjacent members of the base structure.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC); or preferred isomers can be prepared by asymmetric syntheses.
  • the disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • an enantiomerically pure compound can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure R–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R–compound.
  • the enantiomerically pure R– compound in such compositions can, for example, comprise, at least about 95% by weight R– compound and at most about 5% by weight S–compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure S–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S–compound.
  • the enantiomerically pure S–compound in such compositions can, for example, comprise, at least about 95% by weight S–compound and at most about 5% by weight R–compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • Compound disclosed herein may also comprise one or more isotopic substitutions. Isotopes include those atoms having the same atomic number but different mass numbers.
  • H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
  • H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
  • the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term “D” or “deuterium” indicates at least about 45% incorporation of deuterium).
  • One or more constituent atoms of the compounds of the present disclosure can be replaced or substituted with isotopes of the atoms in non-natural abundance.
  • the compound comprises one or more deuterium atoms.
  • one or more hydrogen atoms in a compound disclosed herein can be replaced or substituted by deuterium.
  • the compound comprises two or more deuterium atoms.
  • the compound comprises 1, 2, 3, 4, 5, 6, 7, 8, or 9 deuterium atoms.
  • Synthetic methods for including isotopes into organic compounds are known in the art. Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., the ability to inhibit the formation of TDP-43 inclusions), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound.
  • the compounds of the present disclosure may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
  • hydrocarbon is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom.
  • permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted.
  • the compounds are small organic or inorganic molecules, e.g., with molecular weights less than 7500 amu, preferably less than 5000 amu, and even more preferably less than 2000, 1500, 1000, 750, 600, or 500 amu.
  • one class of small organic or inorganic molecules are non-peptidyl, e.g., containing 2, 1, or no peptide and/or saccharide linkages.
  • administer refers to the placement of a composition into a subject by a method or route which results in at least partial localization of the composition at a desired site such that desired effect is produced.
  • a compound or composition described herein can be administered by any appropriate route known in the art including, but not limited to, oral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, nasal, rectal, intrathecal, and topical (including buccal and sublingual) administration.
  • the terms “decrease”, “reduced”, “reduction” , “decrease” or “inhibit” are all used herein generally to mean a decrease by a statistically significant amount.
  • the terms “reduced”, “reduction”, “decrease” or “inhibit” mean a decrease by at least 0.1% as compared to a reference level, for example a decrease by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g.
  • the terms “increased”, ”increase”, “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount.
  • the terms “increased”, “increase”, “enhance” or “activate” mean an increase by at least 0.1% as compared to a reference level, for example a decrease by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase (e.g. absent level as compared to a reference sample), or any increase between 1-100%, e.g., 10-100% as compared to a reference level.
  • a 100% increase e.g. absent level as compared to a reference sample
  • treatment delaying or preventing the onset of such a disease or disorder, reversing, alleviating, ameliorating, inhibiting, slowing down or stopping the progression, aggravation or deterioration the progression or severity of a condition associated with such a disease or disorder.
  • at least one symptom of a disease or disorder is alleviated by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%.
  • an amount of a compound or combination effective to treat a disorder refers to an amount of the compound or combination which is effective, upon single or multiple dose administration(s) to a subject, in treating a subject, or in curing, alleviating, relieving or improving a subject with a disorder (e.g., a disorder as described herein) beyond that expected in the absence of such treatment. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
  • a therapeutically effective amount can vary with the subject’s history, age, condition, sex, as well as the severity and type of the medical condition in the subject, and administration of other pharmaceutically active agents.
  • a “subject” means a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters.
  • Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon.
  • Patient or subject includes any subset of the foregoing, e.g., all of the above, but excluding one or more groups or species such as humans, primates or rodents.
  • the subject is a mammal, e.g., a primate, e.g., a human.
  • the terms, “patient” and “subject” are used interchangeably herein.
  • nucleic acid refers to a polymeric form of nucleotides, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide.
  • nucleotides either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide.
  • the terms should also be understood to include, as equivalents, analogs of either RNA or DNA made from nucleotide analogs, and, as applicable to the embodiment being described, single-stranded (such as sense or antisense) and double-stranded polynucleotides.
  • therapeutically effective amount means that amount of a compound, material, or composition comprising a compound of the present disclosure which is effective for producing some desired therapeutic effect, e.g., by inhibiting aggregation of tau, in at least a sub-population of cells in an animal and thereby blocking the biological consequences of that function in the treated cells, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • 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.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material, involved in carrying or transporting the subject antagonists from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material, involved in carrying or transporting the subject antagonists from one organ, or portion of the body, to another organ, or portion of the body.
  • 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 excipients include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, 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
  • pharmaceutically acceptable salt is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)).
  • Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • These salts may be prepared by methods known to those skilled in the art.
  • Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present disclosure.
  • R 1 is cyano, halogen, or C 1-6 alkyl
  • R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl
  • R 3 is hydrogen, cyano, or C 1-6 alkyl
  • R 4 is hydrogen or C 1-6 alkyl
  • X 1 is CH or N
  • X 2 is CR 5 or N
  • X 3 is CR 6 or N
  • R 5 is C 1-6 haloalkyl
  • R 6 is hydrogen; or R 5 and R 6 may be taken together, along with the ring to which they are attached, to form a 9-membered bicyclic heteroaryl
  • R 7 is hydrogen or C 1-6 haloalkyl.
  • R 1 is cyano, halogen, or C 1-3 alkyl. In certain embodiments, R 1 is cyano, fluoro, or CH 3 . In certain embodiments, R 1 is cyano. In certain embodiments, R 1 is halogen. In certain embodiments, R 1 is fluoro. In certain embodiments, R 1 is C 1-6 alkyl. In certain embodiments, R 1 is C 1-3 alkyl. In certain embodiments, R 1 is CH 3 . In certain embodiments, R 2 is selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 3-6 cycloalkyl.
  • R 2 is selected from the group consisting of hydrogen, -CH 2 CH 3 , CF 3 , -O-CH 3 , and cyclopropyl.
  • R 2 is hydrogen.
  • R 2 is C 1-6 alkyl.
  • R 2 is C 1-3 alkyl.
  • R 2 is -CH 2 CH 3 .
  • R 2 is C 1-6 haloalkyl.
  • R 2 is C 1-3 haloalkyl.
  • R 2 is CF 3 .
  • R 2 is C 1-6 alkoxy. In certain embodiments, R 2 is C 1-3 alkoxy.
  • R 2 is -O- CH 3 . In certain embodiments, R 2 is C 3-6 cycloalkyl. In certain embodiments, R 2 is cyclopropyl. In certain embodiments, R 3 is hydrogen, cyano, or C 1-3 alkyl. In certain embodiments, R 3 is hydrogen, cyano, or CH 3 . In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is cyano. In certain embodiments, R 3 is C 1-6 alkyl. In certain embodiments, R 3 is C 1-3 alkyl. In certain embodiments, R 3 is CH 3 . In certain embodiments, R 1 is halogen, R 2 is C 1-6 haloalkyl, and R 3 is hydrogen.
  • R 1 is halogen, R 2 is C 1-3 haloalkyl, and R 3 is hydrogen. In certain embodiments, R 1 is fluoro, R 2 is C 1-3 haloalkyl, and R 3 is hydrogen. In certain embodiments, R 1 is halogen, R 2 is CF 3 , and R 3 is hydrogen. In certain embodiments, R 1 is fluoro, R 2 is CF 3 , and R 3 is hydrogen. In certain embodiments, R 1 is cyano, R 2 is C 1-6 haloalkyl, and R 3 is hydrogen. In certain embodiments, R 1 is cyano, R 2 is C 1-3 haloalkyl, and R 3 is hydrogen.
  • R 1 is cyano, R 2 is CF 3 , and R 3 is hydrogen.
  • R 1 is halogen, R 2 is C 1-6 alkoxy, and R 3 is hydrogen.
  • R 1 is halogen, R 2 is C 1-3 alkoxy, and R 3 is hydrogen.
  • R 1 is fluoro, R 2 is C 1-3 alkoxy, and R 3 is hydrogen.
  • R 1 is halogen, R 2 is -O- CH 3 , and R 3 is hydrogen.
  • R 1 is fluoro, R 2 is -O-CH 3 , and R 3 is hydrogen.
  • R 1 is halogen, R 2 is hydrogen, and R 3 is hydrogen.
  • R 1 is fluoro, R 2 is hydrogen, and R 3 is hydrogen.
  • R 1 is halogen, R 2 is C 1-6 alkyl, and R 3 is hydrogen.
  • R 1 is halogen, R 2 is C 1-3 alkyl, and R 3 is hydrogen.
  • R 1 is fluoro, R 2 is C 1-3 alkyl, and R 3 is hydrogen.
  • R 1 is halogen, R 2 is - CH 2 CH 3 , and R 3 is hydrogen.
  • R 1 is fluoro, R 2 is -CH 2 CH 3 , and R 3 is hydrogen.
  • R 1 is halogen, R 2 is C 3-6 cycloalkyl, and R 3 is hydrogen. In certain embodiments, R 1 is fluoro, R 2 is C 3-6 cycloalkyl, and R 3 is hydrogen. In certain embodiments, R 1 is halogen, R 2 is cyclopropyl, and R 3 is hydrogen. In certain embodiments, R 1 is fluoro, R 2 is cyclopropyl, and R 3 is hydrogen. In certain embodiments, R 1 is halogen, R 2 is hydrogen, and R 3 is cyano. In certain embodiments, R 1 is fluoro, R 2 is hydrogen, and R 3 is cyano.
  • R 1 is halogen, R 2 is hydrogen, and R 3 is C 1-6 alkyl. In certain embodiments, R 1 is halogen, R 2 is hydrogen, and R 3 is C 1-3 alkyl. In certain embodiments, R 1 is fluoro, R 2 is hydrogen, and R 3 is C 1-3 alkyl. In certain embodiments, R 1 is halogen, R 2 is hydrogen, and R 3 is CH 3 . In certain embodiments, R 1 is fluoro, R 2 is hydrogen, and R 3 is CH 3 . In certain embodiments, R 1 is C 1-6 alkyl, R 2 is hydrogen, and R 3 is hydrogen. In certain embodiments, R 1 is C 1-3 alkyl, R 2 is hydrogen, and R 3 is hydrogen.
  • R 1 is CH 3 , R 2 is hydrogen, and R 3 is hydrogen. In certain embodiments, R 1 is halogen, R 2 is hydrogen, and R 3 is hydrogen. In certain embodiments, R 1 is fluoro, R 2 is hydrogen, and R 3 is hydrogen. In certain embodiments, R 4 is hydrogen or C 1-3 alkyl. In certain embodiments, R 4 is hydrogen, CH 3 , or -CH 2 CH 2 CH 3 . In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is C 1-6 alkyl. In certain embodiments, R 4 is C 1-3 alkyl. In certain embodiments, R 4 is CH 3 . In certain embodiments, R 4 is -CH 2 CH 2 CH 3 . In certain embodiments, X 1 is CH.
  • X 1 is N. In certain embodiments, X 2 is CR 5 . In certain embodiments, X 2 is N. In certain embodiments, X 3 is CR 6 . In certain embodiments, X 2 is N. In certain embodiments, X 1 is CH, X 2 is N, and X 3 is CR 6 . In certain embodiments, X 1 is CH, X 2 is CR 5 , and X 3 is N. In certain embodiments, X 1 is N, X 2 is CR 5 , and X 3 is N. In certain embodiments, X 1 is N, X 2 is CR 5 , and X 3 is N. In certain embodiments, X 1 is N, X 2 is CR 5 , and X 3 is CR 6 .
  • X 1 is CH, X 2 is CR 5 , and X 3 is CR 6 .
  • R 5 is C 1-3 haloalkyl.
  • R 5 is CF 3 .
  • R 6 is hydrogen.
  • R 5 and R 6 are taken together, along with the ring to which they are attached, to form a 9-membered bicyclic heteroaryl.
  • R 5 and R 6 are taken together, along with the ring to which they are attached, to form indolyl.
  • X 1 is CH, X 2 is N, and X 3 is CR 6 , wherein R 6 is hydrogen.
  • X 1 is N, X 2 is CR 5 , and X 3 is N, wherein R 5 is C 1-3 haloalkyl. In certain embodiments, X 1 is N, X 2 is CR 5 , and X 3 is N, wherein R 5 is CF 3 . In certain embodiments, X 1 is N, X 2 is CR 5 , and X 3 is CR 6 , wherein R 5 is C 1-6 haloalkyl and R 6 is hydrogen. In certain embodiments, X 1 is N, X 2 is CR 5 , and X 3 is CR 6 , wherein R 5 is C 1- 3 haloalkyl and R 6 is hydrogen.
  • X 1 is N, X 2 is CR 5 , and X 3 is CR 6 , wherein R 5 is CF 3 and R 6 is hydrogen.
  • X 1 is CH, X 2 is CR 5 , and X 3 is CR 6 , wherein R 5 is C 1-6 haloalkyl and R 6 is hydrogen.
  • X 1 is CH, X 2 is CR 5 , and X 3 is CR 6 , wherein R 5 is C 1-3 haloalkyl and R 6 is hydrogen.
  • X 1 is CH, X 2 is CR 5 , and X 3 is CR 6 , wherein R 5 is CF 3 and R 6 is hydrogen.
  • X 1 is CH, X 2 is CR 5 , and X 3 is CR 6 , wherein R 5 and R 6 are taken together, along with the ring to which they are attached, to form a 9-membered bicyclic heteroaryl.
  • X 1 is CH, X 2 is CR 5 , and X 3 is CR 6 , wherein R 5 and R 6 are taken together, along with the ring to which they are attached, to form indolyl.
  • R 7 is hydrogen or C 1-3 haloalkyl. In certain embodiments, R 7 is hydrogen or CF 3 . In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is C 1- 6 haloalkyl. In certain embodiments, R 7 is C 1-3 haloalkyl. In certain embodiments, R 7 is CF 3 .
  • the compound e.g., a compound of formula (I) is selected from the compounds disclosed in Table 1.
  • the compound of formula (I) is a compound selected from the group consisting of: 1-((5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)piperidine-4- carboxamide; 1-((5-(p-tolyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)piperidine-4- carboxamide; 1-((5-(4-fluoro-2-methylphenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3- (trifluoromethyl)phenyl)piperidine-4-carboxamide; 1-((5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3- (trifluoromethyl)phenyl)piperidine-4-carbox
  • the compound of formula (Ia) is a compound selected from the group consisting of: 1-((5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)piperidine-4- carboxamide; 1-((5-(4-fluoro-2-methylphenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3- (trifluoromethyl)phenyl)piperidine-4-carboxamide; 1-((5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3- (trifluoromethyl)phenyl)piperidine-4-carboxamide; 1-((5-(2-cyano-4-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3- (trifluoromethyl)
  • the compound of formula (Ib) is a compound selected from the group consisting of: 1-((5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)piperidine-4- carboxamide; 1-((5-(4-fluoro-2-methylphenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3- (trifluoromethyl)phenyl)piperidine-4-carboxamide; 1-((5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3- (trifluoromethyl)phenyl)piperidine-4-carboxamide; 1-((5-(2-cyano-4-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3- (trifluoromethyl)
  • compositions and Routes of Administration comprising a compound disclosed herein (e.g., a compound of Formula (I), (Ia), or (Ib), or a stereoisomer and/or pharmaceutically acceptable salt thereof); and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and a compound of formula (I):
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and a compound of formula (Ia): or a stereoisomer and/or a pharmaceutically acceptable salt thereof, wherein the variables R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , R 5 , R 6 , and R 7 are as defined herein.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and a compound of formula (Ia): or a stereoisomer and/or a pharmaceutically acceptable salt thereof, wherein the variables R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , R 5 , R 6 , and R 7 are as defined herein.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (Ib):
  • the amount and concentration of a compound disclosed herein e.g., a compound of formula (I), (Ia), or (Ib), or a stereoisomer and/or pharmaceutically acceptable salt thereof) in the pharmaceutical compositions, as well as the quantity of the pharmaceutical composition administered to a subject, can be selected based on clinically relevant factors, such as medically relevant characteristics of the subject (e.g., age, weight, gender, other medical conditions, and the like), the solubility of the compound(s) in the pharmaceutical composition, the potency and activity of the compounds, and the manner of administration of the pharmaceutical compositions.
  • medically relevant characteristics of the subject e.g., age, weight, gender, other medical conditions, and the like
  • solubility of the compound(s) in the pharmaceutical composition e.g., the potency and activity of the compounds, and the manner of administration of the pharmaceutical compositions.
  • the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. While it is possible for a compound of the present disclosure to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition), where the compound is combined with one or more pharmaceutically acceptable diluents, excipients or carriers.
  • the compounds according to the present disclosure may be formulated for administration in any convenient way for use in human or veterinary medicine.
  • the compound included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting.
  • the compounds of the present disclosure which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically acceptable dosage forms such as described below or by other conventional methods known to those of skill in the
  • another aspect of the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds described above (e.g., a compound of formula (I), (Ia), or (Ib), or a stereoisomer and/or pharmaceutically acceptable salt thereof), formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), lozenges, dragees, capsules, pills, tablets (e.g., those targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) transmucosally; (9) nasally; or
  • compounds can be implanted into a patient or injected using a drug delivery system. See, for example, Urquhart, et al., (1994) Ann Rev Pharmacol Toxicol 24:199-236; Lewis, ed. “Controlled Release of Pesticides and Pharmaceuticals” (Plenum Press, New York, 1981); U.S. Patent No. 3,773,919; and U.S. Patent No. 353,270,960.
  • Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the pharmaceutical compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • compositions of the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
  • compositions or pharmaceutical compositions include the step of bringing into association a compound of the present disclosure with the carrier and, optionally, one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient.
  • a compound of the present disclosure may also be administered as a bolus, electuary, or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cety
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present disclosure may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using polymer matrices, liposomes and/or microspheres to provide the desired release profile. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • opacifying agents include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the abovedescribed excipients.
  • Liquid dosage forms for oral administration of the compounds of the present disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the present disclosure for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the present disclosure with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the heart, lung, bladder, urethra, ureter, rectum, or intestine. Furthermore, compositions can be formulated for delivery via a dialysis port.
  • Ophthalmic formulations are also contemplated as being within the scope of this disclosure.
  • Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion.
  • injection includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and intrastemal injection and infusion.
  • the compositions are administered by intravenous infusion or injection.
  • 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.
  • compositions of this disclosure suitable for parenteral administration comprise one or more compounds of the present disclosure in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • the compounds of the present disclosure When the compounds of the present disclosure are administered as pharmaceuticals, to a subject in need thereof, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% of active ingredient in combination with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition containing, for example, 0.1 to 99.5% of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the addition of the active compound of the present disclosure to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration.
  • an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed.
  • feed premixes and complete rations are described in reference books (such as "Applied Animal Nutrition", W.H.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals.
  • a variety of biocompatible polymers including hydrogels), including both biodegradable and non- degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • the subject is a mammal.
  • the mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but are not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of disorders associated with neurodegenerative disease or disorder, cancer, or viral infections. In addition, the methods described herein can be used to treat domesticated animals and/or pets.
  • a subject can be male or female.
  • a subject can be one who has been previously diagnosed with or identified as suffering from or having a neurodegenerative disease or disorder.
  • Methods of Treatment without wishing to be bound by a theory, pharmaceutical compositions or compounds of formula (I), (Ia), or (Ib) can be used to delay the progression of neurodegenerative illnesses where the pathology incorporates tauopathy.
  • neurodegenerative disease refers to a neurological disease characterized by loss or degeneration of neurons.
  • the term “neurodegenerative disease” includes diseases caused by the involvement of genetic factors or the cell death (apoptosis) of neurons attributed to abnormal protein accumulation and so on. Additionally, neurodegenerative diseases include neurodegenerative movement disorders and neurodegenerative conditions relating to memory loss and/or dementia. Neurodegenerative diseases include tauopathies and ⁇ - synucleopathies.
  • Exemplary neurodegenerative diseases include, but are not limited to, Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with dementia (ALSD), Huntington's disease (HD), Huntington’s chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranu
  • ⁇ -synucleopathy refers to a neurodegenerative disorder or disease involving aggregation of ⁇ -synuclein or abnormal ⁇ -synuclein in nerve cells in the brain (Ostrerova, N., et al. (1999) J Neurosci 19:5782:5791; Rideout, H.J., et al. (2004) J Biol Chem 279:46915-46920).
  • ⁇ -Synucleopathies include, but are not limited to, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Pick's disease, Down's syndrome, multiple system atrophy, amylotrophic lateral sclerosis (ALS), Hallervorden-Spatz syndrome, and the like.
  • tauopathy refers to a neurodegenerative disease associated with the pathological aggregation of tau protein in the brain. Tauopathies include, but are not limited to, Alzheimer’s disease, Pick's disease, corticobasal degeneration, Argyrophilic grain disease (AGD), progressive supranuclear palsy, Frontotemporal dementia, Frontotemporal lobar degeneration, or Pick's complex.
  • a neurodegenerative disease in a subject in need thereof, the methods generally comprising administering to the subject an effective amount of a compound disclosed herein (e.g., a compound of Formula (I), (Ia), or (Ib), or a stereoisomer and/or pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition disclosed herein.
  • a compound disclosed herein e.g., a compound of Formula (I), (Ia), or (Ib), or a stereoisomer and/or pharmaceutically acceptable salt thereof
  • a method of treating or preventing a neurodegenerative disease in a subject in need thereof comprising administering to the subject an effective amount of a compound of formula (I): or a stereoisomer and/or a pharmaceutically acceptable salt thereof, wherein the variables R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , R 5 , R 6 , and R 7 are as defined herein.
  • a method of treating or preventing a neurodegenerative disease in a subject in need thereof the method comprising administering to the subject an effective amount of a compound of formula (Ia):
  • a method of treating or preventing a neurodegenerative disease in a subject in need thereof comprising administering to the subject an effective amount of a compound of formula (Ib): or a stereoisomer and/or a pharmaceutically acceptable salt thereof, wherein the variables R 2 , R 3 , and R 4 are as defined herein.
  • a method of treating or preventing a neurodegenerative disease in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I):
  • R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , R 5 , R 6 , and R 7 are as defined herein.
  • a method of treating or preventing a neurodegenerative disease in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (Ia): or a stereoisomer and/or a pharmaceutically acceptable salt thereof, wherein the variables R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , R 5 , R 6 , and R 7 are as defined herein.
  • a method of treating or preventing a neurodegenerative disease in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (Ib):
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Huntington’s chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia
  • FTD frontotemporal dementia
  • FTLD-U FTD caused by mutations in the progranulin protein or tau protein
  • IBMPFD frontotemporal dementia
  • the neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, progressive supranuclear palsy, dementia pugilistica (chronic traumatic encephalopathy), frontotemporal dementia, parkinsonism linked to chromosome 17, Lytico-Bodig disease (Parkinson-dementia complex of Guam), tangle-predominant dementia with NFTs, ganglioglioma and gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis.
  • the neurodegenerative disease is Alzheimer’s disease or frontotemporal dementia.
  • LCMS Liquid Chromatography/Mass
  • Example 1 Preparation of 1-((5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3- (trifluoromethyl)phenyl)piperidine-4-carboxamide (Compound 1) Step 1: Synthesis of tert-butyl 4-((3-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10 g, 43 mmol) and 3-(trifluoromethyl)aniline (8.44 g, 52 mmol) in DMF (60 mL) were added DIEA (16.83 g, 13.02 mmol) and HATU (19.8 g, 52 mmol) at room temperature, and the mixture was stirred at 50°C for 16 hours.
  • DIEA (16.83 g, 13.02 mmol
  • HATU (19.8 g,
  • Step 2 Synthesis of N-(3-(trifluoromethyl)phenyl)piperidine-4-carboxamide hydrochloride To a solution of tert-butyl 4-((3-(trifluoromethyl)phenyl)carbamoyl)piperidine-1- carboxylate (15 g, 40.1 mmol) in EtOAc (30 mL) was added HCl (50 mL, 2M in EtOAc), and the mixture was stirred at 25 °C for 16 hours.
  • Step 3 Synthesis of (Z)-2-chloro-N'-hydroxyacetimidamide
  • 2-Chloroacetonitrile (20 g, 265 mmol) and hydroxylamine hydrochloride (18.4 g, 265 mmol) were dissolved in water (66 ml), and the colorless solution was cooled to 10 ⁇ 15°C with an ice-bath.
  • Na 2 CO 3 (14.0 g, 132 mmol) was added portionwise to the mixture keeping the temperature below 30°C. The mixture was then stirred for 1 hour at 30°C. After completion, NaCl was added and the mixture was extracted four with EtOAc (150 ml x 4).
  • Step 4 Synthesis of (Z)-2-chloro-N'-((4-fluorobenzoyl)oxy)acetimidamide
  • acetone 50 mL
  • 4-fluorobenzoyl chloride 8.77 g, 55.3 mmol
  • Step 5 Synthesis of 3-(chloromethyl)-5-(4-fluorophenyl)-1,2,4-oxadiazole
  • a solution of (Z)-2-chloro-N'-((4-fluorobenzoyl)oxy)acetimidamide in HOAc (60 mL) was stirred at 120°C for 4 hours. After completion, the solvent was removed under reduced pressure. The residue was diluted with H 2 O and extracted with EtOAc for 3 times. The combined organic phases were washed with brine, dried over Na 2 SO 4 , and filtered.
  • Step 6 Synthesis of 1-((5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3- (trifluoromethyl)phenyl)piperidine-4-carboxamide
  • 3-(chloromethyl)-5-(4-fluorophenyl)-1,2,4-oxadiazole 3.6 g, 16.9 mmol
  • N-(3-(trifluoromethyl)phenyl)piperidine-4-carboxamide hydrochloride 7.83 g, 25.3 mmol
  • MeCN 15 mL
  • DIEA 8.74 g, 67.6 mmol
  • Example 2 Preparation of 1-((5-(2-cyano-4-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-N- (3-(trifluoromethyl)phenyl)piperidine-4-carboxamide (Compound 2); 1-((5-(4-fluoro-3- (trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3- (trifluoromethyl)phenyl)piperidine-4-carboxamide (Compound 3); 1-((5-(4-fluoro-2- methylphenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)piperidine-4- carboxamide (Compound 4); and 1-((5-(p-tolyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3- (trifluoromethyl)phenyl)piperidine-4
  • Step 1 Synthesis of methyl 3-cyclopropyl-4-fluorobenzoate
  • Step 2 Synthesis of 3-cyclopropyl-4-fluorobenzoic acid
  • Step 3 Synthesis of 3-cyclopropyl-4-fluorobenzoyl chloride
  • oxalyl chloride 775 mg, 6.1052 mmol
  • Step 4 Synthesis of (Z)-2-chloro-N'-((3-cyclopropyl-4-fluorobenzoyl)oxy)acetimidamide
  • acetone 10 mL
  • 3-cyclopropyl-4-fluorobenzoyl chloride 600 mg crude
  • Step 5 Synthesis of 3-(chloromethyl)-5-(3-cyclopropyl-4-fluorophenyl)-1,2,4-oxadiazole
  • (Z)-2-chloro-N'-((3-cyclopropyl-4-fluorobenzoyl)oxy)acetimidamide (720 mg crude) in AcOH (5 mL) was stirred at 120 °C for 4 h. After completion, the solvent was removed under reduced pressure.
  • Step 6 Synthesis of 1-((5-(3-cyclopropyl-4-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3- (trifluoromethyl)phenyl)piperidine-4-carboxamide
  • 3-(chloromethyl)-5-(3-cyclopropyl-4-fluorophenyl)-1,2,4-oxadiazole 180 mg crude, 0.7124 mmol
  • N-(3-(trifluoromethyl)phenyl)piperidine-4-carboxamide hydrochloride (329.9 mg, 1.0686 mmol) in MeCN (5 mL) was added DIEA (368 mg, 2.8496 mmol), and the mixture was stirred at 70 °C for 16 hours.
  • Example 4 Preparation of 1-((5-(3-ethyl-4-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-N- (3-(trifluoromethyl)phenyl)piperidine-4-carboxamide (Compound 7)
  • Step 2 Synthesis of methyl 3-ethyl-4-fluorobenzoate
  • methyl 4-fluoro-3-vinylbenzoate (1.16 g, 6.438 mmol) in EtOAc (10 mL)
  • PtO 2 0.116 g, 0.51 mmol
  • the mixture was stirred at 25 °C for 16 h.
  • the mixture was filtered and the solvent was removed under reduced pressure.
  • Step 3 Synthesis of 3-ethyl-4-fluorobenzoic acid
  • methyl 3-ethyl-4-fluorobenzoate 1.28 g crude
  • LiOH 0.66 g, 27.7 mmol
  • the mixture was stirred at 25 °C for 16 hours.
  • the acetic acid was added to adjust pH to 4 ⁇ 6, and the mixture was extracted with EtOAc(25 mL) for 3 times.
  • the combined organic layers was washed with brine, dried over Na 2 SO 4 and filtered.
  • Step 4 Synthesis of 3-ethyl-4-fluorobenzoyl chloride To a solution of 3-ethyl-4-fluorobenzoic acid (820 mg crude) in DCM (10 mL) was added oxalyl chloride (1.238 g, 9.7524 mmol) and the mixture was stirred at 25 °C for 4 h. After completion, the solvent was removed under reduced pressure to afford 3-ethyl-4-fluorobenzoyl chloride (900 mg crude) as a yellow oil, which was used for next step directly.
  • oxalyl chloride 1.238 g, 9.7524 mmol
  • Step 5 Synthesis of (Z)-2-chloro-N'-((3-ethyl-4-fluorobenzoyl)oxy)acetimidamide
  • acetone 10 mL
  • K 2 CO 3 1.348 g, 9.7524 mmol
  • Step 7 Synthesis of 1-((5-(3-ethyl-4-fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-N-(3- (trifluoromethyl)phenyl)piperidine-4-carboxamide
  • 3-(chloromethyl)-5-(3-ethyl-4-fluorophenyl)-1,2,4-oxadiazole (344 mg crude) and N-(3-(trifluoromethyl)phenyl)piperidine-4-carboxamide hydrochloride (662 mg, 2.1441 mmol) in MeCN (5 mL) was added DIEA (739 mg, 5.7176 mmol), and the mixture was stirred at 70 °C for 16 hours.
  • Step 2 Synthesis of 2-methyl-N-(3-(trifluoromethyl)phenyl)piperidine-4-carboxamide
  • 2-methyl-N-(3-(trifluoromethyl)phenyl)isonicotinamide 24 g, 0.0853 mol
  • EtOAc 500 mL
  • Pd/C 2.7 g
  • the mixture was stirred at 50°C for 48 h under H 2 (3 MPa).
  • the mixture was filtered and the solvent was removed under reduced pressure to afford 2-methyl-N-(3-(trifluoromethyl)phenyl)piperidine-4-carboxamide (20 g, 81.59% yield) as a white solid.
  • Step 4 Synthesis of 1-((5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2- methyl-N-(3-(trifluoromethyl)phenyl)piperidine-4-carboxamide
  • a solution of (Z)-2-chloro-N'-((4-fluoro-3-(trifluoromethyl)benzoyl)oxy)acetimidamide 32 g crude, 0.1068 mol) in HOAc (250 mL) was stirred at 120°C for 6 hours.
  • Step 5 Synthesis of 1-((5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-2- methyl-N-(3-(trifluoromethyl)phenyl)piperidine-4-carboxamide
  • 3-(chloromethyl)-5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4- oxadiazole (16 g, 0.0568 mol)
  • 2-methyl-N-(3-(trifluoromethyl)phenyl)piperidine-4- carboxamide 17.9 g, 0.0624 mol
  • MeCN 300 mL
  • DIEA 22 g, 0.1704 mol
  • Example 6 Preparation of 1-((5-(4-cyano-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3- yl)methyl)-2-methyl-N-(3-(trifluoromethyl)phenyl)piperidine-4-carboxamide (Compound 9); 1-((5-(4-fluoro-3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-methyl-N-(3- (trifluoromethyl)phenyl)piperidine-4-carboxamide (Compound 10); and 1-((5-(4- fluorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-2-methyl-N-(3- (trifluoromethyl)phenyl)piperidine-4-carboxamide (Compound 11) Compounds 9-11 were prepared analogously to Compound 8, as described in Example 5. Characterization data for Compounds 9-11 is shown below in Table 3. Table 3. Characterization Data for Compound
  • Compound 12 and Compound 13 can be obtained by SFC separation of compound Compound 8 (Column: UniChiral YMC-CMD -10H (size: 50mm I.D. ⁇ 250mm L); Mobile phase: 90%n-Hexane/10%Ethanol(V/V); Flow rate: 120 mL/min), to deliver Compound 13 (peak 2, 9.538 min) and Compound 12 (peak 1, 8.354 min), respectively.
  • Step 2 Synthesis of N-(3-(trifluoromethyl)phenyl)-2-vinylisonicotinamide
  • 2-bromo-N-(3-(trifluoromethyl)phenyl)isonicotinamide (1 g, 0.0029 mol)
  • 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.89 g, 0.0058 mol)
  • Step 3 Synthesis of cis-2-ethyl-N-(3-(trifluoromethyl)phenyl)piperidine-4-carboxamide
  • N-(3-(trifluoromethyl)phenyl)-2-vinylisonicotinamide 800 mg, 2.7373 mmol
  • EtOAc 100 mL
  • PtO 2 0.12 g, 0.5284 mmol
  • Example 9 Preparation of cis-1-((5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3- yl)methyl)-2-propyl-N-(3-(trifluoromethyl)phenyl)piperidine-4-carboxamide (Compound 15)
  • Compound 15 was prepared analogously to Compound 14, as described in Example 8. Characterization data for Compound 15 is shown below in Table 4. Table 4. Characterization Data for Compound 15
  • Step 2 Synthesis of cis-methyl 1-((5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3- yl)methyl)-2-methylpiperidine-4-carboxylate
  • 3-(chloromethyl)-5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4- oxadiazole (1 g, 0.0036 mol)
  • cis-methyl-2-methylpiperidine-4-carboxylate (0.62 g, 0.0039 mol)
  • MeCN 20 mL
  • DIEA 1.4 g, 0.0108 mol
  • Step 3 Synthesis of cis-1-((5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)- 2-methylpiperidine-4-carboxylic acid
  • Step 4 Synthesis of cis-1-((5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)- N-(1H-indol-5-yl)-2-methylpiperidine-4-carboxamide
  • cis-1-((5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3- yl)methyl)-2-methylpiperidine-4-carboxylic acid 80 mg, 0.2065 mmol
  • 1H-indol-5-amine 27 mg, 0.2065 mmol
  • NMI 59 mg, 0.7228 mmol
  • TCFH 70 mg, 0.2478 mmol
  • Example 11 Preparation of cis-1-((5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol- 3-yl)methyl)-2-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxamide (Compound 17); cis-1-((5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3- yl)methyl)-2-methyl-N-(2-(trifluoromethyl)pyridin-4-yl)piperidine-4-carboxamide (Compound 18); cis-1-((5-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3- yl)methyl)-2-methyl-N-(2-(trifluoromethyl)pyrimidin-4-yl)piperidine-4-carboxamide (Compound 19); and cis-1
  • Example 12 SH-SY5Y-tT1 Cell Assay Exemplary compounds disclosed herein were evaluated for efficacy in inhibiting stress granules compounded of tau and TIA1 in cellular imaging-based assays.
  • Human neuroblastoma SH-SY5Y cells (ATCC, cat# CRL-2266) were engineered to stably express a tetracycline repressor protein (Blasticidin resistance, designated as TREx-SY5Y cells, customer cell line development by ThermoFisher).
  • Trex-SY5Y cells were sequentially stably transfected with pcDNA5/TO[tauP301S::eGFP] (Hygromycin B resistance) then pT-REx- DEST30[TIA1::mKate2] (Neomycin resistance).
  • the resulting line was designated “SH-SY5Y- tT1”, in which exposure to tet induces expression of human tau with a P301S mutation fused to eGFP and human TIA1 fused to mKate2.
  • exposure to stress by treatment with arsenite or thapsigargin
  • SGs cytoplasmic tau/TIA1 stress granules
  • A indicates an IC 50 of less than 500 nM
  • B indicates an IC 50 range from 500 nM to 1000 nM
  • C indicates an IC 50 range from 1000 nM to 2000 nM
  • D indicates an IC 50 greater than 2000 nM.
  • Table 7 Stress Granules Per Cell- Thapsigargin: Average IC 50 (nM). Example 13.
  • PS19 Mouse Model for Investigation of In Vivo Efficacy The PS19 transgenic mouse line (strain name: C57BL/6;C3-Tg(Prnp-MAPT*P301S) PS19Vle/J) constitutively expresses human 1N4R tau protein carrying the familial FTD-causing mutation P301S (Yoshiyama et al., Neuron, 2007, 53(3), 337–351).
  • heterozygous (+/-) PS19 mice develop tau pathologies; by 8 to 9 months, these pathologies include a) neurofibrillary tangles of misfolded and phosphorylated tau in the neocortex, hippocampus, amygdala and brain stem; b) neuron loss in the hippocampus and the entorhinal cortex (EC); c) microgliosis in the white and grey matter of the hippocampus, amygdala and EC; d) decreased synaptophysin immunoreactivity in the hippocampus.
  • 4R tau includes the alternatively spliced exon 10 and thus contains 4 repeated microtubule domains.
  • AD pathology consists of both 4R and 3R tau isoforms (the latter lacking exon 10) (Wang & Mandelkow, Nature Reviews Neuroscience, 2016, 17(1), 5–21).
  • the PS19 mouse model is an excellent platform for characterization of therapeutics targeting 4R tauopathies, and may be an appropriate model for conditions exhibiting 3R tauopathy (such as AD and Pick’s disease) or secondary tau pathology (such as Huntington’s disease (HD) and in Parkinson’s disease and related Lewy body dementias) (Fernández-Nogales et al., Nature Medicine, 2014, 20(8), 881–885; Pan et al., Journal of Molecular Neuroscience : MN, 2021, 71(11), 2179–2191).
  • 3R tauopathy such as AD and Pick’s disease
  • secondary tau pathology such as Huntington’s disease (HD) and in Parkinson’s disease and related Lewy body dementias
  • PS19 model has been used extensively to understand the etiology of tauopathies and for investigation of the in vivo efficacy of anti-tauopathy therapeutics (Makani et al., Acta Neuropathologica Communications, 2016, 4(106), 1-12).
  • PS19 mice used in in vivo efficacy studies are aged greater than 7 months of age and were treated with Compounds 1 and 8 daily (QD) by oral gavage (PO) for 28 days.
  • QD Compounds 1 and 8 daily
  • PO oral gavage
  • Frontocortical (F.Ctx) tissue is biochemically partitioned (Apicco et al., Nature Neuroscience, 2018, 21(1), 72–82; Ramsden et al., The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, 2005, 25(46), 10637–10647) and the resulting fractions assayed for total tau (tau12), misfolded tau (MC-1) and phosphorylated tau (AT8 and pT181).
  • AlphaLISA Detection of Pathological Tau Species Reduction of pathogenic tau species was quantified by AlphaLISA immunodetection assay (PerkinElmer, Revvity).
  • AlphaLISA for quantitative detection of analytes in multiple biological samples and across many disease conditions see the following publications (Baldo et al., ENeuro, 2018, 5(4), 1-16; Bielefeld- Sevigny, Assay and Drug Development Technologies, 2009, 7(1), 90–92; Cauchon et al., Analytical Biochemistry, 2009, 388(1), 134–139; Dehdashti et al., Current Alzheimer Research, 2013, 10(7), 679–687; Medda et al., Journal of Biomolecular Screening, 2016, 21(8), 804–815; Szekeres et al., Journal of Biomolecular Screening, 2008, 13(2), 101–111).
  • LY3303560 humanized MC-1 Zagotenemab
  • iADRS Alzheimer's Disease Rating Scale
  • Tau phosphorylated at Serine 202/Threonine 205 (AT8) and at Threonine 181 (pT181) is increased in affected brains and plasma of AD patients (Koss et al., Acta Neuropathologica, 2016, 132(6), 875–895; Murray et al., Global neuropathologic severity of Alzheimer’s disease and locus coeruleus vulnerability influences plasma phosphorylated tau levels, 2022, 17(1), 85).
  • Plasma and CSF pT181 tau correlates with predictive positive tau positron emission tomography (PET) in the diagnosis of AD; and plasma pT181 tau levels are diagnostic of AD (versus non-AD neurodegenerative conditions) and predictive progression from mild-cognitive impairment (MC-I) to AD (Janelidze et al., Nature Medicine, 2020, 26(3), 379–386). Due to these findings, biofluid pT181 levels have been used as pharmacodynamic markers in several clinical trials, including in those of the FDA-approved anti-amyloid immunotherapeutic Lecanamab (Biogen) (van Dyck et al., The New England Journal of Medicine, 2023, 388(1), 9-21).
  • MC-1 and phosphorylated (AT8, pT181) tau were selected as these are recognized pharmacodynamic markers that correlate with improvement in response to treatment (in either transgenic mice or AD patients), and significant reduction in one or more of these biomarkers in the PS19 mouse study, provides good evidence for assessment and efficacy in patients.
  • pathological tau was reduced (FIG. 2 and FIG. 3).
  • Example 14 DMPK Characteristics Compound 8 exhibited good potency, efficacy, and DMPK characteristics, as shown in the table below. Table 8.
  • Example 15 High Throughput Screening Assay Compound 8 inhibits stress granule formation.
  • Cartoon schematic showing the high- throughput screening (HTS) assay is shown in FIG. 4.
  • Representative image of stressed SHSY5Y-tT1 cells expressing TIA1 +ive and nuclei is shown in FIG. 5.
  • Red-punctate formation in the presence of stress is indicative of TIA1 +ive stress granule formation.
  • Tau pathology (positive for MC1 and AT8) forms in these stress granules.
  • Compound 8 greatly reduces the number of TIA1 stress granules relative to DMSO control (B), and correspondingly reduces Tau pathology in these cells (see panel 4).
  • Compound 8 is a prophylactic and therapeutic compound.
  • compound was treated before (2h), at the same time (co-), or after (2h) stress.
  • Compound 8 significantly reduced the number of stress granules relative to DMSO control (FIG. 7). Stress granules were reduced within an hour of compound administration.
  • Example 16 In Vitro Efficacy Compound 8 prevents stress granule formation in human stem cell-derived neurons. Human stem cells were differentiated into iCNs (FIG. 8).
  • Example 18 Target Identification Identification of putative targets of Compound 8: Thermal shift (CETSA) and limited proteolysis (LiPs) was performed in stressed SHSY5Y-tT1 lysates and doses of Compound 8.

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Abstract

Des composés, des compositions et des méthodes de traitement ou de prévention de maladies neurodégénératives sont présentement décrits.
PCT/US2024/053056 2023-10-25 2024-10-25 Composés pour le traitement de maladies neurodégénératives Pending WO2025090928A1 (fr)

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US20100234377A1 (en) * 2007-04-05 2010-09-16 Evotec Ag Piperazine compounds for the inhibition of haematopoietic prostaglandin d synthase

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DATABASE PUBCHEM COMPOUND 21 July 2010 (2010-07-21), XP093311787, Database accession no. CID 46367706 *
DATABASE PUBCHEM COMPOUND 21 July 2010 (2010-07-21), XP093311788, Database accession no. CID 46367671 *
DATABASE PUBCHEM COMPOUND 21 July 2010 (2010-07-21), XP093311795, Database accession no. CID 46323988 *

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