WO2018195075A1 - Composés, compositions et procédés d'utilisation associés - Google Patents

Composés, compositions et procédés d'utilisation associés Download PDF

Info

Publication number
WO2018195075A1
WO2018195075A1 PCT/US2018/027969 US2018027969W WO2018195075A1 WO 2018195075 A1 WO2018195075 A1 WO 2018195075A1 US 2018027969 W US2018027969 W US 2018027969W WO 2018195075 A1 WO2018195075 A1 WO 2018195075A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
disease
cancer
alkyl
mixture
Prior art date
Application number
PCT/US2018/027969
Other languages
English (en)
Inventor
Duane A. Burnett
Joseph P. Vacca
Original Assignee
Aquinnah Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aquinnah Pharmaceuticals, Inc. filed Critical Aquinnah Pharmaceuticals, Inc.
Publication of WO2018195075A1 publication Critical patent/WO2018195075A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to compounds, compositions and methods for modulating inclusion formation and stress granules in cells, and for treatment of neurodegenerative diseases, musculoskeletal diseases, cancer, ophthalmological diseases, and viral infections.
  • TDP-43 protein was identified as one of the major components of protein inclusions that typify the
  • ALS Amyotrophic Lateral Sclerosis
  • FTLD-U Frontotemporal Lobar Dementia with ubiquitin inclusions
  • TDP-43 biology appear to be sufficient to cause neurodegenerative disease, as studies have indicated that mutations in TDP-43 occur in familial ALS (Barmada, S.J., et al. (2010) J N euro sci 30:639-649; Gitcho, M.A., et al. (2008) Ann Neurol 63(4): 535-538; Johnson, B.S., et al. (2009) / Biol Chem 284:20329-20339; Ling, S.C., et al. (2010) Proc Natl Acad Sci U.S.A.
  • TDP-43 has been found to play a role in the stress granule machinery (Colombrita, C, et al. (2009) J Neurochem 111(4): 1051-1061; Liu-Yesucevitz, L., et al. (2010) PLoS One 5(10):el3250). Analysis of the biology of the major proteins that accumulate in other neurodegenerative diseases has lead to major advances in our understanding of the pathophysiology of TDP-43 inclusions as well as the development of new drug discovery platforms.
  • the invention provides a compound of Formula (I):
  • the invention provides methods for treatment of a neurodegenerative disease or disorder, a musculoskeletal disease or disorder, a cancer, an ophthalmological disease or disorder (e.g., a retinal disease or disorder), and/or a viral infection in a subject, the method comprising administering a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) to a subject in need thereof.
  • a compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • the invention provides methods of diagnosing a neurodegenerative disease in a subject, the method comprising administering a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) to the subject.
  • a compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • the compound of Formula (I) can be modified with a label.
  • the invention provides methods of modulating stress granules comprising contacting a cell with a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)).
  • a compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • TDP-43 inclusion formation comprising contacting a cell with a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)).
  • the invention provides a method of screening for modulators of TDP- 43 aggregation comprising contacting a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) with the cell that expresses TDP-43 and develops spontaneous inclusions.
  • a compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • ALS Amyotrophic lateral sclerosis
  • Lou Gehrig's disease or Charcot disease is a fatal neurodegenerative disease that occurs with an incidence of approximately 1/100,000 (Mitchell, J.D. and Borasio, G.D., (2007) Lancet 369:2031-41).
  • ALS presents with motor weakness in the distal limbs that rapidly progresses proximally (Mitchell, J.D. and Borasio, G.D., (2007) Lancet 369:2031-41; Lambrechts, D.E., et al. (2004) Trends Mol Med 10:275-282).
  • TDP- 43 is the major protein that accumulates in affected motor neurons in sporadic ALS (Neumann, M., et al. (2006) Science 314: 130-133). The causes of sporadic ALS are not known, but identification of the major pathological species accumulating in the spinal cord of ALS patients represents a seminal advance for ALS research. To date, TDP-43 is the only protein that has been both genetically and pathologically linked with sporadic ALS, which represents the predominant form of the disease. Multiple papers have identified mutations in TDP-43 associated with sporadic and familial ALS (Sreedharan, J., et al.
  • TDP-43 represents one of the most promising targets for pharmacotherapy of ALS.
  • TDP-43 is a nuclear RNA binding protein that translocates to the cytoplasm in times of cellular stress, where it forms cytoplasmic inclusions. These inclusions then colocalize with reversible protein-mRNA aggregates termed "stress granules" (SGs) (Anderson P. and Kedersha, N. (2008) Trends Biochem Sci 33: 141-150; Kedersha, N. and Anderson, P. (2002) Biochem Soc Trans 30:963-969; Lagier-Tourenne, C, et al. (2010) Hum Mol Genet 19:R46-R64). Under many stress-inducing conditions (e.g.
  • TDP-43 co- localization with SGs approaches 100%.
  • the reversible nature of SG-based aggregation offers a biological pathway that can be applied to reverse the pathology and toxicity associated with TDP-43 inclusion formation.
  • the relationship between TDP-43 and stress granules is important because it provides a novel approach for dispersing TDP-43 inclusions using physiological pathways that normally regulate this reversible process, rather than direct physical disruption of protein aggregation by a small molecule pharmaceutical.
  • the invention provides a compound of Formula (I):
  • Ring A is heterocyclyl, aryl, or heteroaryl
  • X is C(R ) or N
  • L 1 is a bond or Ci-C 6 alkylene
  • L 2 is Ci-C 6 alkylene optionally substituted with 1-5 R 5
  • R 1 is hydrogen, halo or -OR A
  • R 2 is Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 heteroalkyl, or Ci-C 6 haloalkyl
  • each R 3 is independently Ci-C 6 alkyl, halo, cyano, or oxo, wherein each alkyl is optionally substituted with 1-8 R 6
  • each R 4 is independently Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 heteroalkyl, Ci-C 6 haloalkyl, halo, or -OR A
  • Ring A is aryl (e.g., monocyclic aryl). In some embodiments,
  • Ring A is phenyl ). In some embodiments, Ring A is phenyl and q is 0 or 1. In some embodiments, R 4 is halo (e.g., fluoro) or -OR A (e.g., -OCH 3 ). In some embodiments, R 4 is halo (e.g., fluoro). In some embodiments, R 4 is -OR A , (e.g., -OCH 3 ).
  • Ring A is heteroaryl. In some embodiments, Ring A is a monocyclic heteroaryl. In some embodiments, Ring A is a nitrogen-containing heteroaryl. In some embodiments Ring A is a 6-membered heteroaryl. In some embodiments, Ring A is
  • Ring A is pyridyl and q is 0.
  • Ring A is heterocyclyl. In some embodiments, Ring A is a monocyclic heterocyclyl. In some embodiments, Ring A is an oxygen-containing heterocyclyl. In some embodiments Ring A is a 4-membered heterocyclyl. In some embodiments, Ring A is
  • oxetanyl e.g., .
  • Ring A is oxetanyl and q is 0.
  • X is CR 1 (e.g., CH). In some embodiments, X is N.
  • L 1 is a bond. In some embodiments, L 1 is Ci-C 6 alkylene (e.g., Q alkylene).
  • L 2 is Ci-C 2 alkylene (e.g., ethylene or methylene). In some embodiments, L 2 is C 2 alkylene (e.g., ethylene). In some embodiments, L 2 is Ci alkylene (methylene). In some embodiments, L 2 is substituted with 1-5 R 5 . In some embodiments, each R 5 is independently Ci-C 6 alkyl or halo. In some embodiments, R 5 is Ci-C 6 alkyl (e.g., methyl). In some embodiments, R 5 is halo (e.g., fluoro).
  • two R 5 are taken together with the atoms to which they are attached to form a ring (e.g., cycloalkyl or heterocyclyl). In some embodiments, two R 5 are taken together with the atoms to which they are attached to form a cycloalkyl ring (e.g., cyclopropyl). In some embodiments, two R 5 are taken together with the atoms to which they are attached to form a heterocyclyl ring (e.g., oxetanyl).
  • a ring e.g., cycloalkyl or heterocyclyl
  • a cycloalkyl ring e.g., cyclopropyl
  • two R 5 are taken together with the atoms to which they are attached to form a heterocyclyl ring (e.g., oxetanyl).
  • L 1 is a bond and L 2 is Ci-C 2 alkylene (e.g., ethylene or methylene). In some embodiments, L 1 is Ci alkylene and L 2 is Ci-C 2 alkylene (e.g., ethylene or methylene.
  • R 2 is Ci-C 6 alkyl or Ci-C 6 haloalkyl.
  • R 2 is Ci-C 6 alkyl (e.g., Ci-C 2 alkyl, e.g., ethyl).
  • R 2 is Ci-C 6 haloalkyl (e.g., C ⁇ - C 2 haloalkyl, e.g., -CH 2 CF 3 ).
  • n is 0. In some embodiments, n is 1.
  • o is 0. In some embodiments, o is 1.
  • n is 0 and o is 0. In some embodiments, n is 1 and o is 0. In some embodiments, n is 0 and o is 1.
  • p is 0. In some embodiments, p is 1. In some embodiments, p is 1, and R 3 is oxo.
  • Ring A is phenyl, pyridyl, or oxetanyl
  • X is CH or N
  • L 1 is a bond or methylene
  • L 2 is Ci-C 2 alkylene optionally substituted with 1-5 R 5
  • R 2 is ethyl or -CH 2 CF 3
  • R 3 is oxo
  • each R 4 is independently fluoro or -OCH 3
  • each R 5 is independently methyl or fluoro
  • two R 5 are taken together with the atoms to which they are attached to form cyclopropyl or oxetanyl
  • each of n and o is indepedendently 0 or 1, wherein the sum of n + o is not greater than 1
  • q is independently 0 or 1
  • p is 0 or 1.
  • the compound of Formula (I) or Formula (I-a) is selected from:
  • the compound of Formula (I) is a compound of Formula (I-b):
  • L 1 is Ci-C 6 alkylene
  • L 2 is Ci-C 6 alkylene substituted with 1-5 R 5
  • R 2 is Ci-C 6 alkyl or Ci-C 6 haloalkyl
  • each R 3 is independently Ci-C 6 alkyl, halo, cyano, or oxo, wherein each alkyl is optionally substituted with 1-8 R 6
  • each R 4 is independently Ci-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, Ci-C 6 heteroalkyl, Ci-C 6 haloalkyl, halo, or -OR A , wherein each alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with 1-5 R 7
  • each R 5 is independently Ci-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, Ci-C 6 heteroalkyl, Ci-C 6 haloalkyl
  • q is 0 or 1. In some embodiments, q is 1. In some embodiments, R 4 is halo (e.g., fluoro) or -OR A (e.g., -OCH). In some embodiments, R 4 is halo (e.g., fluoro). In some embodiments, R 4 is -OR A , (e.g., -OCH 3 ).
  • L 1 is Ci-C 6 alkylene (e.g., Ci alkylene).
  • L 2 is Ci-C 2 alkylene (e.g., ethylene or methylene). In some embodiments, L 2 is C2 alkylene (e.g., ethylene). In some embodiments, L 2 is Ci alkylene (methylene).
  • L 2 is substituted with 1-5 R 5 .
  • R 5 is Ci-C 6 alkyl (e.g., methyl).
  • two R 5 are taken together with the atoms to which they are attached to form a ring (e.g., cycloalkyl or heterocyclyl).
  • two R 5 are taken together with the atoms to which they are attached to form a cycloalkyl ring (e.g., cyclopropyl).
  • two R 5 are taken together with the atoms to which they are attached to form a heterocyclyl ring (e.g., oxetanyl).
  • L 1 is Ci alkylene and
  • L 2 is Ci-C 2 alkylene (e.g., ethylene or methylene.
  • R 2 is Ci-C 6 alkyl or Ci-C 6 haloalkyl.
  • R 2 is Ci-C 6 alkyl (e.g., Ci-C 2 alkyl, e.g., ethyl).
  • R 2 is Ci-C 6 haloalkyl (e.g., C ⁇ - C 2 haloalkyl, e.g., -CH 2 CF 3 ).
  • n is 0. In some embodiments, n is 1.
  • o is 0. In some embodiments, o is 1.
  • n is 1 and o is 0. In some embodiments, n is 0 and o is 1.
  • p is 0.
  • each R 6 , R 7 , and R 8 is independently Ci-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, Ci-C 6 heteroalkyl, Ci-C 6 haloalkyl, halo, cyano, oxo, cycloalkyl, or heterocyclyl; each of n and o is indepedendently 0 or 1, wherein the sum of n + o is not greater than 1; q is independently 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
  • q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, R 4 is halo (e.g., fluoro) or -OR A (e.g., -OCH). In some embodiments, R 4 is halo (e.g., fluoro). In some embodiments, R 4 is -OR A , (e.g., -OCH 3 ).
  • X is CR 1 (e.g., CH). In some embodiments, X is N.
  • L 1 is a bond. In some embodiments, L 1 is Ci-C 6 alkylene (e.g., Ci alkylene).
  • L 2 is Ci-C 2 alkylene (e.g., ethylene or methylene). In some embodiments, L 2 is C2 alkylene (e.g., ethylene). In some embodiments, L 2 is Ci alkylene (methylene).
  • L 2 is substituted with 1-5 R 5 .
  • each R 5 is independently Ci-C 6 alkyl or halo.
  • R 5 is Ci-C 6 alkyl (e.g., methyl).
  • R 5 is halo (e.g., fluoro).
  • two R 5 are taken together with the atoms to which they are attached to form a ring (e.g., cycloalkyl or heterocyclyl).
  • two R 5 are taken together with the atoms to which they are attached to form a cycloalkyl ring (e.g., cyclopropyl).
  • two R 5 are taken together with the atoms to which they are attached to form a heterocyclyl ring (e.g., oxetanyl).
  • L 1 is a bond and L 2 is Ci-C 2 alkylene (e.g., ethylene or methylene). In some embodiments, L 1 is Ci alkylene and L 2 is Ci-C 2 alkylene (e.g., ethylene or methylene.
  • n is 0. In some embodiments, n is 1.
  • o is 0. In some embodiments, o is 1. In some embodiments, n is 0 and o is 0. In some embodiments, n is 1 and o is 0. In some embodiments, n is 0 and o is 1.
  • p is 0. In some embodiments, p is 1. In some embodiments, p is 1, and R 3 is oxo.
  • the compound of Formula (I-c) is selected from:
  • the invention provides a pharmaceutical composition
  • a compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • a pharmaceutical composition comprising a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) or a
  • the invention provides a method of modulating stress granule formation, the method comprising contacting a cell with a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)).
  • a compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • stress granule formation is inhibited.
  • the stress granule is disaggregated.
  • stress granule formation is stimulated.
  • a compound of Formula (I) inhibits the formation of a stress granule.
  • the compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • a compound Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) disaggregates a stress granule.
  • the compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • the stress granule comprises tar DNA binding protein-43 (TDP- 43), T-cell intracellular antigen 1 (TIA- 1), TIA1 cytotoxic granule-associated RNA binding protein-like 1 (TIAR, TIAL1), GTPase activating protein binding protein 1 (G3BP-1), GTPase activating protein binding protein 2 (G3BP-2), tris tetraprolin (TTP, ZFP36), fused in sarcoma (FUS), or fragile X mental retardation protein (FMRP, FMR1).
  • TDP- 43 T-cell intracellular antigen 1
  • TIAR TIA1 cytotoxic granule-associated RNA binding protein-like 1
  • G3BP-1 GTPase activating protein binding protein 1
  • G3BP-2 GTPase activating protein binding protein 2
  • TTP tris tetraprolin
  • FUS fused in sarcoma
  • FMRP fragile X mental retardation protein
  • the stress granule comprises tar DNA binding protein-43 (TDP- 43), T-cell intracellular antigen 1 (TIA-1), TIA1 cytotoxic granule-associated RNA binding protein-like 1 (TIAR, TIAL1), GTPase activating protein binding protein 1 (G3BP-1), GTPase activating protein binding protein 2 (G3BP-2), fused in sarcoma (FUS), or fragile X mental retardation protein (FMRP, FMR1).
  • TDP- 43 T-cell intracellular antigen 1
  • TIAR TIAL1
  • GTPase activating protein binding protein 1 G3BP-1
  • GTPase activating protein binding protein 2 GTPase activating protein binding protein 2
  • FUS fragile X mental retardation protein
  • FMRP fragile X mental retardation protein
  • the stress granule comprises tar DNA binding protein-43 (TDP- 43), T-cell intracellular antigen 1 (TIA-1), TIA1 cytotoxic granule-associated RNA binding protein-like 1 (TIAR, TIAL1), GTPase activating protein binding protein 1 (G3BP-1), GTPase activating protein binding protein 2 (G3BP-2), or fused in sarcoma (FUS).
  • TDP- 43 T-cell intracellular antigen 1
  • G3BP-1 GTPase activating protein binding protein 1
  • G3BP-2 GTPase activating protein binding protein 2
  • FUS fused in sarcoma
  • the stress granule comprises tar DNA binding protein-43 (TDP- 43).
  • the stress granule comprises T-cell intracellular antigen 1 (TIA-1).
  • the stress granule comprises TIA-1 cytotoxic granule-associated RNA binding protein-like 1 (TIAR, TIAL1).
  • the stress granule comprises GTPase activating protein binding protein 1 (G3BP-1).
  • the stress granule comprises GTPase activating protein binding protein 2 (G3BP-2).
  • the stress granule comprises tris tetraprolin (TTP, ZFP36).
  • the stress granule comprises fused in sarcoma (FUS).
  • the stress granule comprises fragile X mental retardation protein (FMRP, FMR1).
  • FMRP fragile X mental retardation protein
  • the invention provides a method of modulating TDP-43 inclusion formation, the method comprising contacting a cell with a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)).
  • a compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • TDP-43 inclusion formation is inhibited.
  • the TDP-43 inclusion is disaggregated.
  • TDP-43 inclusion formation is stimulated.
  • a compound of Formula (I) inhibits the formation of a TDP-43 inclusion.
  • the compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • a compound of Formula (I) (e.g., a compound of Formula (I-a), (I- b), or (I-c)) disaggregates a TDP-43 inclusion.
  • the compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) can disperses or disaggregate a TDP-43 inclusion by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% (i.e., complete dispersal) relative to a control.
  • the invention provides a method for treatment of a neurodegenerative disease or disorder, a musculoskeletal disease or disorder, a cancer, an ophthalmological disease or disorder (e.g., a retinal disease or disorder), and/or a viral infection, the method comprising administering an effective amount of a compound of Formula (I) (e.g., a compound of Formula
  • the methods are performed in a subject suffering from a neurodegenerative disease or disorder, a musculoskeletal disease or disorder, a cancer, an ophthalmological disease or disorder (e.g., a retinal disease or disorder), and/or a viral infection.
  • a neurodegenerative disease or disorder e.g., a musculoskeletal disease or disorder, a cancer, an ophthalmological disease or disorder (e.g., a retinal disease or disorder), and/or a viral infection.
  • the methods are performed in a subject suffering from a neurodegenerative disease or disorder. In some embodiments, the methods are performed in a subject suffering from a musculoskeletal disease or disorder. In some embodiments, the methods are performed in a subject suffering from a cancer. In some embodiments, the methods are performed in a subject suffering from an ophthalmological disease or disorder (e.g., a retinal disease or disorder). In some embodiments, the methods are performed in a subject suffering from a viral infection or viral infections.
  • the methods comprise administering a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) to a subject in need thereof.
  • a compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • the subject is a mammal.
  • the subject is a nematode.
  • the subject is human.
  • the methods further comprise the step of diagnosing the subject with a neurodegenerative disease or disorder, a musculoskeletal disease or disorder, a cancer, an ophthalmological disease or disorder (e.g., a retinal disease or disorder), or a viral infection prior to administration of a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)).
  • the methods further comprise the step of diagnosing the subject with a neurodegenerative disease or disorder prior to administration of a compound of Formula (I-a), (I-b), or (I-c)).
  • the methods further comprise the step of diagnosing the subject with a neurodegenerative disease or disorder prior to administration of a compound of Formula
  • 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, and scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (poly Q) -repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia
  • encephalopathies hereditary spastic paraparesis, Leigh' s syndrome, demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury) autism, other diseases or disorders relating to the aberrant expression of TDP-43 and altered proteostasis, and any combination thereof.
  • sleep disorders e.g., narcolepsy, fatal familial insomnia
  • acute brain injuries e.g., stroke, head injury
  • autism other diseases or disorders relating to the aberrant expression of TDP-43 and altered proteostasis, and any combination thereof.
  • 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), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Huntington's chorea, Creutzfeld-Jacob disease, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), Pick's disease, primary progressive aphasia, corticobasal dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA), spinocerebellar ataxia, spinal degenerative disease/motor neuron degenerative diseases, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack
  • FTD
  • the neurodegenerative disease is frontotemporal dementia (FTD).
  • FTD frontotemporal dementia
  • the neurodegenerative disease is Alzheimer's disease or amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the musculoskeletal disease is selected from the group consisting of muscular dystrophy, facioscapulohumeral muscular dystrophy (e.g., FSHD1 or FSHD2), Freidrich's ataxia, progressive muscular atrophy (PMA), mitochondrial encephalomyopathy
  • MELAS multiple sclerosis, inclusion body myopathy, inclusion body myositis (e.g., sporadic inclusion body myositis), post-polio muscular atrophy (PPMA), motor neuron disease, myotonia, myotonic dystrophy, sacropenia, multifocal motor neuropathy, inflammatory myopathies, paralysis, and other diseases or disorders relating to the aberrant expression of TDP-43 and altered proteostasis.
  • inclusion body myopathy e.g., sporadic inclusion body myositis
  • PPMA post-polio muscular atrophy
  • motor neuron disease myotonia, myotonic dystrophy, sacropenia, multifocal motor neuropathy, inflammatory myopathies, paralysis, and other diseases or disorders relating to the aberrant expression of TDP-43 and altered proteostasis.
  • PPMA post-polio muscular atrophy
  • motor neuron disease myotonia
  • myotonic dystrophy e.g., myotonic dys
  • compounds of Formula (I) may be used to prevent or treat symptoms caused by or relating to said
  • musculoskeletal diseases e.g., kyphosis, hypotonia, foot drop, motor dysfunctions, muscle weakness, muscle atrophy, neuron loss, muscle cramps, altered or aberrant gait, dystonias, astrocytosis (e.g., astrocytosis in the spinal cords), liver disease, respiratory disease or respiratory failure, inflammation, headache, and pain (e.g., back pain, neck pain, leg pain, or inflammatory pain).
  • the cancer is selected from the group consisting of breast cancer, a melanoma, adrenal gland cancer, biliary tract cancer, bladder cancer, brain or central nervous system cancer, bronchus cancer, blastoma, carcinoma, a chondrosarcoma, cancer of the oral cavity or pharynx, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma, hepatic carcinoma, hepatoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, non-small cell lung cancer, ophthalmological cancer, osteosarcoma, ovarian cancer, pancreas cancer, peripheral nervous system cancer, prostate cancer, sarcoma, salivary gland cancer, small bowel or appendix cancer, small-cell lung cancer, squamous cell cancer, stomach cancer, testis cancer, thyroid cancer, urinary bladder cancer, uterine or endometrial cancer, vulval cancer, and any combination thereof.
  • the cancer is selected from the group consisting of blastoma, carcinoma, a glioblastoma, hepatic carcinoma, lymphoma, leukemia, and any combination thereof.
  • the cancer is selected from Hodgkin' s lymphoma or non- Hodgkin' s lymphoma. In some embodiments, the cancer is a non-Hodgkin' s lymphoma, selected from the group consisting of a B-cell lymphoma (e.g.
  • diffuse large B-cell lymphoma diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal B-cell lymphomas, mucosa-associated lymphoid tissue (MALT) lymphomas, modal marginal zone B-cell lymphoma, splenic marginal zone B- cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's
  • T-cell lymphoma e.g. , precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell lymphoma (e.g.
  • T-cell lymphoma chronic adult T-cell lymphoma, acute adult T-cell lymphoma, lymphomatous adult T-cell lymphoma), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma nasal type (ENKL), enteropathy-associated intestinal T-cell lymphoma (EATL) (e.g. , Type I EATL and Type II EATL), and anaplastic large cell lymphoma (ALCL)).
  • ENKL enteropathy-associated intestinal T-cell lymphoma
  • EATL enteropathy-associated intestinal T-cell lymphoma
  • ACL anaplastic large cell lymphoma
  • the ophthalmological disease or disorder is selected from macular degeneration (e.g. , age-related macular degeneration), diabetes retinopathy, histoplasmosis, macular hole, macular pucker, Bietti's crystalline dystrophy, retinal detachment, retinal thinning, retinoblastoma, retinopathy of prematurity,
  • macular degeneration e.g. , age-related macular degeneration
  • diabetes retinopathy e.g. , histoplasmosis, macular hole, macular pucker, Bietti's crystalline dystrophy, retinal detachment, retinal thinning, retinoblastoma, retinopathy of prematurity
  • Usher' s syndrome vitreous detachment, Refsum disease, retinitis pigmentosa, onchocerciasis, choroideremia, Leber congenital amaurosis, retinoschisis (e.g. , juvenile retinoschisis), Stargardt disease, ophthalmoplegia, and the like.
  • the ophthalmological disease or disorder is selected from macular degeneration (e.g. , age-related macular degeneration), diabetes retinopathy, histoplasmosis, macular hole, macular pucker, Bietti's crystalline dystrophy, retinoblastoma, retinopathy of prematurity, Usher' s syndrome, Refsum disease, retinitis pigmentosa, onchocerciasis, choroideremia, Leber congenital amaurosis, retinoschisis (e.g. , juvenile retinoschisis), Stargardt disease, and the like.
  • macular degeneration e.g. , age-related macular degeneration
  • diabetes retinopathy e.g., histoplasmosis, macular hole, macular pucker, Bietti's crystalline dystrophy, retinoblastoma, retinopathy of prematurity, Usher' s syndrome, Refsum disease, retinitis pigmento
  • the viral infection is caused by a virus selected from the group consisting of West Nile virus, respiratory syncytial virus (RSV), herpes simplex virus 1, herpes simplex virus 2, Epstein-Barr virus (EBV), hepatitis virus A, hepatitis virus B, hepatitis virus C, influenza viruses, chicken pox, avian flu viruses, smallpox, polio viruses, HIV- 1, HIV-2, Ebola virus, and any combination thereof.
  • RSV respiratory syncytial virus
  • EBV Epstein-Barr virus
  • hepatitis virus A hepatitis virus B
  • hepatitis virus C influenza viruses, chicken pox, avian flu viruses, smallpox, polio viruses, HIV- 1, HIV-2, Ebola virus, and any combination thereof.
  • the viral infection is caused by a virus selected from the group consisting of herpes simplex virus 1, herpes simplex virus 2, Epstein-Barr virus (EBV), hepatitis virus A, hepatitis virus B, hepatitis virus C, HIV- 1, HIV-2, Ebola virus, and any combination thereof.
  • a virus selected from the group consisting of herpes simplex virus 1, herpes simplex virus 2, Epstein-Barr virus (EBV), hepatitis virus A, hepatitis virus B, hepatitis virus C, HIV- 1, HIV-2, Ebola virus, and any combination thereof.
  • the viral infection is HIV- 1 or HIV-2.
  • the pathology of the neurodegenerative disease or disorder, musculoskeletal disease or disorder, cancer, ophthalmological disease or disorder (e.g., retinal disease or disorder), and/or viral infection comprises stress granules.
  • pathology of the disease or disorder comprises stress granules.
  • stress granules By comprising stress granules is meant that number of stress granules in a cell in the subject is changed relative to a control and/or healthy subject or relative to before onset of said disease or disorder.
  • Exemplary diseases and disorders pathology of which incorporate stress granules include, but are not limited to, neurodegenerative diseases, musculoskeletal diseases, cancers, ophthalmological diseases (e.g., retinal diseases), and viral infections.
  • the invention provides methods of diagnosing a neurodegenerative disease, a musculoskeletal disease, a cancer, an ophthalmological disease (e.g., a retinal disease), or a viral infection in a subject, the method comprising administering a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) to the subject.
  • a compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • a compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • the invention provides methods of modulating stress granules comprising contacting a cell with a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)).
  • a compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • the invention provides methods of modulating TDP-43 inclusion formation comprising contacting a cell with a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)).
  • a compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • TDP-43 is inducibly expressed.
  • the cell line is a neuronal cell line.
  • the cell is treated with a physiochemical stressor.
  • the physicochemical stressor is selected from arsenite, nutrient deprivation, heat shock, osmotic shock, a virus, genotoxic stress, radiation, oxidative stress, oxidative stress, a mitochondrial inhibitor, and an endoplasmic reticular stressor.
  • the physicochemical stressor is ultraviolet or x-ray radiation.
  • the physicochemical stressor is oxidative stress induced by FeCl 2 or CuCl 2 and a peroxide.
  • the invention provides a method of screening for modulators of TDP-43 aggregation comprising contacting a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) with a cell that expresses TDP-43 and develops spontaneous inclusions.
  • a compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c)
  • the stress granule comprises TDP-43, i.e., is a TDP-43 inclusion.
  • a compound of Formula (I) e.g., a compound of Formula (I-a), (I-b), or (I-c) is a modulator of TDP-43 inclusions.
  • the invention provides a method of treating a B-cell or T-cell lymphoma, the method comprising administering a compound of Formula (I) to a subject in need thereof:
  • the B-cell or T-cell lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal B-cell lymphomas, mucosa-associated lymphoid tissue (MALT) lymphomas, modal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, Waldenstrom' s macroglobulinemia, hairy cell leukemia, primary central nervous system (CNS) lymphoma, precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma, smoldering adult T-cell lymphoma,
  • CNS
  • the invention provides a method of treating a neurodegenerative disease selected from the group consisting of frontotemporal dementia 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 , bovine spongiform encephalopathy, Kuru, scrapie, Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, progressive bulbar palsy (PBP), psuedobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, HIV- associated dementia, progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post- polio syndrome (PPS), pantothenate kinase-associated neurodegeneration (PANK), Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism
  • the invention provides a method of treating a musculoskeletal disease by administering a compound of Formula (I) to a subject in need thereof:
  • the musculoskeletal disease is selected from the group consisting of muscular dystrophy, facioscapulohumeral muscular dystrophy (e.g., FSHD1 or FSHD2), Freidrich' s ataxia, progressive muscular atrophy (PMA), mitochondrial encephalomyopathy (MELAS), multiple sclerosis, inclusion body myopathy, inclusion body myositis (e.g., sporadic inclusion body myositis), post-polio muscular atrophy (PPMA), motor neuron disease, myotonia, myotonic dystrophy, sacropenia, multifocal motor neuropathy, inflammatory myopathies, and paralysis.
  • muscular dystrophy e.g., FSHD1 or FSHD2
  • PMA progressive muscular atrophy
  • MELAS mitochondrial encephalomyopathy
  • PPMA post-polio muscular atrophy
  • motor neuron disease myotonia
  • myotonic dystrophy sacropenia
  • sacropenia multifocal motor neuropathy
  • the invention provides a method of treating an ophthalmological disease or disorder, the method comprising administering a compound of Formula (I) to a subject in need thereof:
  • the ophthalmological disease e.g., retinal disease
  • the ophthalmological disease is selected from the group consisting of macular degeneration, age-related macular degeneration, diabetes retinopathy, histoplasmosis, macular hole, macular pucker, Bietti' s crystalline dystrophy, retinal detachment, retinal thinning, retinoblastoma, retinopathy of prematurity, Usher's syndrome, vitreous detachment, Refsum disease, retinitis pigmentosa, onchocerciasis, choroideremia, Leber congenital amaurosis, retinoschisis, juvenile retinoschisis, Stargardt disease, ophthalmoplegia, or any combination thereof.
  • the invention provides a method of treating a viral infection caused by the Ebola virus, the method comprising administering a compound of Formula (I) to a subject in need thereof:
  • the subject is a mammal. In some embodiments, the subject is human.
  • the method further comprises the step of diagnosing the subject with the neurodegenerative disease or disorder, musculoskeletal disease or disorder, cancer, ophthalmological disease or disorder, or viral infection prior to onset of said administration.
  • the pathology of said neurodegenerative disease or disorder, said musculoskeletal disease or disorder, said cancer, said ophthalmological disease or disorder, and said viral infection comprises stress granules.
  • the pathology of said neurodegenerative disease, said musculoskeletal disease or disorder, said cancer, said ophthalmological disease or disorder, and said viral infection comprises TDP-43 inclusions.
  • TDP-43 and other RNA-binding proteins function in both the nucleus and cytoplasm to process mRNA, e.g. , by splicing mRNA, cleaving mRNA introns, cleaving untranslated regions of mRNA or modifying protein translation at the synapse, axon, dendrite or soma. Therefore, targeting other proteins that function in an analogous manner to TDP-43 or by processing mRNA may also be beneficial to prevent and treat neurodegeneration resulting from disease.
  • the fragile X mental retardation 1 (FMRP) protein is essential for normal cognitive development (Nakamoto, M., et al. (2007) Proc Natl Acad Sci U.S.A. 104: 15537-15542).
  • the signaling systems that affect TDP-43 function might also affect this protein, thus improving cognitive function. This can be particularly important at the synapse where neurons
  • the cellular stress response follows a U-shaped curve. Overinduction of this pathway, such as observed in many neurodegenerative diseases, can be harmful for cells. However, a decreased stimulation of this pathway can also be harmful for cells, e.g. , in the case of an acute stress, such as a stroke. Thus, the appropriate action for some diseases is the inhibition of stress granule formation, while for other diseases, stimulation of stress granule formation is beneficial.
  • the TDP-43 protein in a stress granule may be wild-type or a mutant form of TDP-43.
  • the mutant form of TDP-43 comprises an amino acid addition, deletion, or substitution, e.g., relative to the wild type sequence of TDP-43.
  • the mutant form of TDP-43 comprises an amino acid substitution relative to the wild type sequence, e.g., a G294A, A135T, Q331K, or Q343R substitution.
  • the TDP-43 protein in a stress granule comprises a post-translational modification, e.g., phosphorylation of an amino acid side chain, e.g., T103, S104, S409, or S410.
  • post-translational modification of the TDP-43 protein in a stress granule may be modulated by treatment with a compound of the invention.
  • compounds of Formula (I) can be used to delay the progression of neurodegenerative illnesses where the pathology incorporates stress granules.
  • Such illnesses include ALS and frontotemporal dementia, in which TDP-43 is the predominant protein that accumulates to form the pathology.
  • This group also includes Alzheimer' s disease and FTLD-U, where TDP-43 and other stress granule proteins co-localize with tau pathology.
  • modulators of TDP-43 inclusions such as compounds of Formula (I) can act to block the enzymes that signal stress granule formation (e.g.
  • compounds of Formula (I) may also reverse stress granules that might not include TDP-43. Accordingly, compounds of Formula (I) can be used for treatment of neurodegenerative diseases and disorders in which the pathology incorporates stress granules, such as Huntington' s chorea and Creutzfeld- Jacob disease.
  • Compounds of Formula (I) may also be used for treatment of neurodegenerative diseases and disorders that involve TDP-43 multisystem proteinopathy.
  • 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 oc- 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),
  • FTD frontotemporal dementia
  • FTLD frontotemporal dementia
  • IBMPFD inclusion body myopathy
  • ALS amyotrophic lateral sclerosis with dementia
  • ALS amyotrophic lateral sclerosis with dementia
  • 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 supranuclear palsy (PSP), progressive bulbar palsy (PBP), psuedobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA Type I (e
  • a-synucleopathy refers to a neurodegenerative disorder or disease involving aggregation of oc-synuclein or abnormal oc-synuclein in nerve cells in the brain (Ostrerova, N., et al. (1999) J Neurosci
  • cc-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.
  • Musculoskeletal diseases and disorders as defined herein are conditions that affect the muscles, ligaments, tendons, and joints, as well as the skeletal structures that support them. Without wishing to be bound by a theory, aberrant expression of certain proteins, such as the full-length isoform of DUX4, has been shown to inhibit protein turnover and increase the expression and aggregation of cytotoxic proteins including insoluble TDP-43 in skeletal muscle cells (Homma, S. et al. Ann Clin Transl Neurol (2015) 2: 151-166).
  • compounds of Formula (I), Formula (II), and Formula (III) may be used to prevent or treat a musculoskeletal disease, e.g., a musculoskeletal disease that results in accumulation of TDP-43 and other stress granule proteins, e.g., in the nucleus, cytoplasm, or cell bodies of a muscle cell or motor neuron.
  • a musculoskeletal disease e.g., a musculoskeletal disease that results in accumulation of TDP-43 and other stress granule proteins, e.g., in the nucleus, cytoplasm, or cell bodies of a muscle cell or motor neuron.
  • Exemplary musculoskeletal diseases include muscular dystrophy, facioscapulohumeral muscular dystrophy (e.g., FSHD1 or FSHD2), Freidrich's ataxia, progressive muscular atrophy (PMA), mitochondrial encephalomyopathy (MELAS), multiple sclerosis, inclusion body myopathy, inclusion body myositis (e.g., sporadic inclusion body myositis), post-polio muscular atrophy (PPMA), motor neuron disease, myotonia, myotonic dystrophy, sacropenia, spasticity, multifocal motor neuropathy, inflammatory myopathies, paralysis, and other diseases or disorders relating to the aberrant expression of TDP-43 and altered proteostasis.
  • PMA progressive muscular atrophy
  • MELAS mitochondrial encephalomyopathy
  • multiple sclerosis inclusion body myopathy
  • inclusion body myositis e.g., sporadic inclusion body myositis
  • PPMA post-polio muscular atrophy
  • compounds of Formula (I) may be used to prevent or treat symptoms caused by or relating to said musculoskeletal diseases, e.g., kyphosis, hypotonia, foot drop, motor dysfunctions, muscle weakness, muscle atrophy, neuron loss, muscle cramps, altered or aberrant gait, dystonias, astrocytosis (e.g., astrocytosis in the spinal cords), liver disease, inflammation, headache, pain (e.g., back pain, neck pain, leg pain, inflammatory pain), and the like.
  • a musculoskeletal disease or a symptom of a musculoskeletal disease may overlap with a neurodegenerative disease or a symptom of a neurodegenerative disease.
  • drugs targeting different elements of the stress response can be anti-neoplastic.
  • rapamycin blocks mTOR, upregulates autophagy and inhibits some types of tumors.
  • Proteasomal inhibitors, such as velcade (Millenium Pharma) are used to treat some cancers.
  • HSP90 inhibitors, such as 17- allylaminogeldanamycin (17AAG) are currently in clinical trials for cancer.
  • compounds of Formula (I) may also be used for treatment of cancer, as a greater understanding of the role of TDP-43 in RNA processing and transcription factor signaling has recently begun to emerge (Lagier-Tourenne, C, et al. (2010) Hum Mol Genet 19:R46-R64; Ayala, Y. M., et al. (2008) Proc Natl Acad Sci U.S.A. 105(10):3785-3789).
  • TDP-43 modulators can be combined with one or more cancer therapies, such as chemotherapy and radiation therapy.
  • cancer in a subject refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features.
  • cancer cells will be in the form of a tumor, but such cells may exist alone within an animal, or may be a non-tumorigenic cancer cell, such as a leukemia cell.
  • cancer cells will be in the form of a tumor; such cells may exist locally within an animal, or circulate in the blood stream as independent cells, for example, leukemic cells.
  • Examples of cancer include but are not limited to breast cancer, a melanoma, adrenal gland cancer, biliary tract cancer, bladder cancer, brain or central nervous system cancer, bronchus cancer, blastoma, carcinoma, a
  • chondrosarcoma cancer of the oral cavity or pharynx, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma, hepatic carcinoma, hepatoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, non-small cell lung cancer, ophthalmological cancer, osteosarcoma, ovarian cancer, pancreas cancer, peripheral nervous system cancer, prostate cancer, sarcoma, salivary gland cancer, small bowel or appendix cancer, small-cell lung cancer, squamous cell cancer, stomach cancer, testis cancer, thyroid cancer, urinary bladder cancer, uterine or endometrial cancer, vulval cancer, and the like.
  • cancers include, but are not limited to, ACTH-producing tumors, acute lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head & neck cancer, ophthalmological cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and/or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer,
  • Exemplary lymphomas include Hodgkin's lymphoma and non-Hodgkin's lymphoma. Further exemplification of non-Hodgkin's lymphoma include, but are not limited to, B-cell lymphomas (e.g.
  • diffuse large B-cell lymphoma diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal B-cell lymphomas, mucosa-associated lymphoid tissue (MALT) lymphomas, modal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, Waldenstrom' s macroglobulinemia, hairy cell leukemia, and primary central nervous system (CNS) lymphoma) and T-cell lymphomas (e.g.
  • T- lymphoblastic lymphoma precursor T- lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell lymphoma (e.g. , smoldering adult T-cell lymphoma, chronic adult T-cell lymphoma, acute adult T-cell lymphoma, lymphomatous adult T-cell lymphoma), angioimmunoblastic T- cell lymphoma, extranodal natural killer T-cell lymphoma nasal type (ENKL), enteropathy- associated intestinal T-cell lymphoma (EATL) (e.g. , Type I EATL and Type II EATL), and anaplastic large cell lymphoma (ALCL)).
  • T-cell lymphoma e.g. , smoldering adult T-cell lymphoma, chronic adult T-cell lymphoma, acute adult T-cell lymphoma, lymphomatous adult T-cell lymphoma
  • Ophthalmological diseases and disorders affect the retina and other parts of the eye and may contribute to impaired vision and blindness.
  • ophthalmological diseases e.g., retinal diseases
  • ophthalmological diseases are characterized by the accumulation of protein inclusions and stress granules within or between cells of the eye, e.g., retinal cells and nearby tissues.
  • an ophthalmological disease e.g., retinal disease
  • Exemplary ophthalmological diseases include, but are not limited to, macular degeneration (e.g. , age-related macular degeneration), diabetes retinopathy, histoplasmosis, macular hole, macular pucker, Bietti's crystalline dystrophy, retinal detachment, retinal thinning, retinoblastoma, retinopathy of prematurity, Usher's syndrome, vitreous detachment, Refsum disease, retinitis pigmentosa, onchocerciasis, choroideremia, Leber congenital amaurosis, retinoschisis (e.g. , juvenile retinoschisis), Stargardt disease,
  • macular degeneration e.g. , age-related macular degeneration
  • diabetes retinopathy histoplasmosis
  • macular hole macular pucker
  • Bietti's crystalline dystrophy retinal detachment
  • retinal thinning retinoblastoma
  • Viral infections Stress granules often form during viral illnesses, as viral infections often involve hijacking the cellular reproductive machinery toward production of viral proteins. In this case, inhibitors of stress granules can be useful for interfering with viral function. Other viruses appear to inhibit SG formation to prevent the cell from mobilizing a stress response. In such a case, an inducer of stress granules can interfere with viral activity and help combat viral infections (e.g. , Salubrinal, an eIF2a phosphatase inhibitor and stress granule inducer). Two viruses for which SG biology has been investigated include West Nile virus and respiratory syncytial virus (RSV) (Emara, M.E. and Brinton, M. A. (2007) Proc. Natl.
  • RSV respiratory syncytial virus
  • viruses include, but are not limited to, West Nile virus, respiratory syncytial virus (RSV), Epstein-Barr virus (EBV), hepatitis A, B, C, and D viruses, herpes viruses, influenza viruses, chicken pox, avian flu viruses, smallpox, polio viruses, HIV, Ebola virus, and the like. Definitions
  • the terms “compounds” and “agent” are used interchangeably to refer to the inhibitors/antagonists/agonists of the invention.
  • 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.
  • “decrease”, “reduced”, “reduction” , “decrease” or “inhibit” are all used herein generally to mean a decrease by a statistically significant amount.
  • “reduced”, “reduction”, “decrease” or “inhibit” means a decrease by at least 1% as compared to a reference level, for example a decrease by 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. absent level as compared to a reference sample), or any decrease between 1-100%, e.g., 10-100% as compared to a reference level.
  • the terms “increased”,”increase”, “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase”, “enhance” or “activate” means an increase by at least 1% as compared to a reference level, for example a decrease by 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
  • 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.
  • 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 intrasternal injection and infusion.
  • the compositions are administered by intravenous infusion or injection.
  • 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 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 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. Generally, 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, cynomologous 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.
  • 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
  • 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.
  • modulator of stress granule and “stress granule modulator” refer to compounds and compositions of Formula (I) that modulate the formation and/or disaggregation of stress granules.
  • TDP-43 inclusion refers to protein-mRNA aggregates that comprise a TDP-43 protein.
  • the TDP-43 protein in a stress granule can be wild-type or a mutant form of TDP-43.
  • modulator of TDP-43 inclusion and “TDP-43 inclusion modulator” refer to compounds and compositions of Formula (I) and Formula (II) that modulate the formation and/or disaggregation of cytoplasmic TDP-43 inclusions.
  • substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • the term "Ci_ 6 alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, butyl, and pentyl.
  • 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.
  • the symbol - ⁇ > ⁇ indicates the point at which the displayed moiety is attached to the remainder of the molecule, solid support, etc.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 24 carbon atoms (“C1-C24 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-C12 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-C 8 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-C6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-C5 alkyl”).
  • an alkyl group has 1 to 4 carbon atoms ("Ci-C4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-C 3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("Ci-C 2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2 - Cealkyl”).
  • Ci-Cealkyl groups include methyl (Ci), 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 Ci_io alkyl (e.g., -CH 3 ).
  • the alkyl group is substituted Ci_6 alkyl.
  • 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 (“C2-C24 alkenyl”).
  • an alkenyl group has 2 to 10 carbon atoms ("C2-C1 0 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2 -C 6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms (“C 2 -C5 alkenyl”).
  • 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 -Cio alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms ("C 2 -C8 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 -C5 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 -C4 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.
  • the alkynyl group is substituted C 2 -6 alkynyl.
  • heteroalkyl refers to a non-cyclic stable straight or branched chain, 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 -0-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. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -CH 2 O, -NR C R D , or the like.
  • alkylene alkenylene
  • alkynylene alone or as part of another substituent, mean, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, or alkynyl, respectively.
  • alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • alkylene, alkenylene, or alkynylene group may be described as, e.g., a Ci-C 6 -membered alkylene, Ci-C 6 -membered alkenylene, or Ci-C 6 -membered alkynylene, wherein the term "membered” refers to the non- hydrogen atoms within the moiety. Still further, for alkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
  • 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 -C14 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 ("Ci 4 aryl”; e.g., anthracyl).
  • An aryl group may be described as, e.g., a C 6 -Cio-membered aryl, wherein the term "membered” refers to the non-hydrogen ring atoms within the moiety.
  • Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
  • Each instance of an aryl group may be independently optionally substituted, i.e. , unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents.
  • the aryl group is unsubstituted C 6 -Ci4 aryl.
  • the aryl group is substituted C 6 -Ci4 aryl.
  • heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic array) 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").
  • heteroaryl groups that contain one or more nitrogen atoms, 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 6-10-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.
  • the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6- membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl,
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Other exemplary heteroaryl groups include heme and heme derivatives.
  • cycloalkyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C3-C1 0 cycloalkyl”) and zero heteroatoms in the non-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").
  • a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C1 0 cycloalkyl").
  • a cycloalkyl group may be described as, e.g., a C4-C7-membered cycloalkyl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • Exemplary C 3 -C 6 cycloalkyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3 -C 8 cycloalkyl groups include, without limitation, the aforementioned C 3 -C 6 cycloalkyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), cubanyl (C 8 ), bicyclo[l.l.l]pentanyl (C 5 ),
  • C 3 -C1 0 cycloalkyl groups include, without limitation, the aforementioned C 3 -C8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C1 0 ), cyclodecenyl (Cio), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C1 0 ), spiro[4.5]decanyl (C1 0 ), and the like.
  • the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated.
  • Cycloalkyl also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system.
  • Each instance of a cycloalkyl group may be independently optionally substituted, i.e. , unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents.
  • the cycloalkyl group is unsubstituted C 3 -C1 0 cycloalkyl.
  • the cycloalkyl group is a substituted C 3 -C1 0 cycloalkyl.
  • Heterocyclyl refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclyl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • a heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, 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 heterocyclyl 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 3-10 membered heterocyclyl.
  • the heterocyclyl group is substituted 3- 10 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system 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 heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl").
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl").
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Cyano refers to the radical -CN.
  • halo or halogen, independently or as part of another substituent, mean, unless otherwise stated, a fluorine (F), chlorine (CI), 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., -Ci-C 6 alkyl-CFs , -Ci-C 6 alkyl-Cf ⁇ F).
  • Non- limiting examples of haloalkyl include trifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl, diflurormethyl, and fluroisopropyl.
  • nitro refers to -NO 2 .
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, 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 and/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) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al. ,
  • 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.
  • enantiomeric ally 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
  • 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 compositions provided herein can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound.
  • 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 described herein may also comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 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 0 and 18 0; and the like.
  • 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.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
  • 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 invention 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 invention.
  • the term "substituted” or “substituted with” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may itself be further substituted), as well as halogen, carbonyl (e.g., aldehyde, ketone, ester, carboxyl, or formyl), thiocarbonyl (e.g., thioester, thiocarboxylate, or thioformate), amino, -N(R b )(R c ), wherein each R b and R c is independently H or Ci-C 6 alkyl
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • 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 invention 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.
  • compositions containing compounds described herein such as a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) or pharmaceutically acceptable salt thereof can be used to treat or ameliorate a disorder described herein, for example, a neurodegenerative disease, a cancer, an ophthalmological disease (e.g., a retinal disease), or a viral infection.
  • a disorder described herein for example, a neurodegenerative disease, a cancer, an ophthalmological disease (e.g., a retinal disease), or a viral infection.
  • Formula (I-a), (I-b), or (I-c)) 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 compounds in the pharmaceutical compositions, 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 compounds in the pharmaceutical compositions e.g., the solubility of compounds in the pharmaceutical compositions
  • the potency and activity of the compounds e.g., the solubility of compounds in the pharmaceutical compositions
  • the potency and activity of the compounds e.g., the solubility of compounds in the pharmaceutical compositions
  • the manner of administration of the pharmaceutical compositions e.g., administration of the pharmaceutical compositions.
  • composition where the compound is combined with one or more pharmaceutically acceptable diluents, excipients or carriers.
  • the compounds according to the invention 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 invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms such as described below or by other conventional methods known to those of skill in the art.
  • compositions comprising a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • pharmaceutically acceptable carriers additives
  • the pharmaceutical compositions of the present invention 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.
  • parenteral administration for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation
  • parenteral application for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin
  • topical application for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin
  • intravaginally or intrarectally for example, as a pessary, cream or foam
  • sublingually (6) ocularly
  • transdermally (8) transmucosally; (9) nasally; or (10) intrathecally.
  • 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. 35 3,270,960.
  • terapéuticaally effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect, e.g., by inhibiting TDP-43 inclusions, 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.
  • phrases "pharmaceutically acceptable carrier” as used herein means a
  • composition or vehicle such as a liquid or solid filler, diluent, excipient, 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, excipient, 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 carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • “pharmaceutically acceptable salts” in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J Pharm Sci 66: 1-19).
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g. , from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge et al., supra).
  • 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 can also be present in the 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
  • Formulations of the present invention include those suitable for oral, nasal, topical
  • the formulations 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. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention 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 non-aqueous 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 invention as an active ingredient.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • a compound of the present invention 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
  • 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 invention 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, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions 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.
  • These 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.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention 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 and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • 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.
  • 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 invention for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention 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 invention.
  • 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 intrasternal injection and infusion.
  • Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more
  • 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.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the addition of the active compound of the invention 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 can be prepared and administered 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.
  • 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, a disease or disorder associated with cancer, a disease or disorder associated with viral infection, or one or more complications related to such diseases or disorders but need not have already undergone treatment.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • the compound and the pharmaceutically active agent can be administrated to the subject in the same pharmaceutical composition or in different pharmaceutical compositions (at the same time or at different times).
  • the compound and the pharmaceutically active agent can be administered within 5 minutes, 10 minutes, 20 minutes, 60 minutes, 2 hours, 3 hours, 4, hours, 8 hours, 12 hours, 24 hours of administration of the other agent.
  • routes of administration can be different.
  • the amount of compound that can be combined with a carrier material to produce a single dosage form will generally be that amount of the inhibitor that produces a therapeutic effect. Generally out of one hundred percent, this amount will range from about 0.1% to 99% of inhibitor, preferably from about 5% to about 70%, most preferably from 10% to about 30%.
  • Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g. , for determining the LD 50 (the dose lethal to 50% of the population) and the ED5 0 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD5 0 /ED5 0 .
  • Compositions that exhibit large therapeutic indices are preferred.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED5 0 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the therapeutic which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • Levels in plasma may be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay.
  • the dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
  • the compositions are administered so that the compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) is given at a dose from 1 ng/kg to 200 mg/kg, 10 ng/kg to 100 mg/kg, 10 ng/kg to 50 mg/kg, 100 ng/kg to 20 mg/kg, 100 ng/kg to 10 mg/kg, 100 ng/kg to 1 mg/kg, 1 ⁇ g/kg to 100 mg/kg, 1 ⁇ g/kg to 50 mg/kg, 1 ⁇ g/kg to 20 mg/kg, 1 ⁇ g/kg to 10 mg/kg, 1 ⁇ g/kg to 1 mg/kg, 10 ⁇ g/kg to 10 mg/kg, 10 ⁇ g/kg to 50 mg/kg, 10 ⁇ g/kg to 20 mg/kg, 10 ⁇ g/kg to 10 mg/kg, 10 ⁇ g/kg
  • ranges given here include all intermediate ranges, e.g. , the range 1 mg/kg to 10 mg/kg includes 1 mg/kg to 2 mg/kg, 1 mg/kg to 3 mg/kg, 1 mg/kg to 4 mg/kg, 1 mg/kg to 5 mg/kg, 1 mg/kg to 6 mg/kg, 1 mg/kg to 7 mg/kg, 1 mg/kg to 8 mg/kg, 1 mg/kg to 9 mg/kg, 2 mg/kg to 10 mg/kg, 3 mg/kg to 10 mg/kg, 4 mg/kg to 10 mg/kg, 5 mg/kg to 10 mg/kg, 6 mg/kg to 10 mg/kg, 7 mg/kg to 10 mg/kg, 8 mg/kg to 10 mg/kg, 9 mg/kg to 10 mg/kg, and the like.
  • ranges intermediate to the given above are also within the scope of this invention, for example, in the range 1 mg/kg to 10 mg/kg, dose ranges such as 2 mg/kg to 8 mg/kg, 3 mg/kg to 7 mg/kg, 4 mg/kg to 6 mg/kg, and the like.
  • the dosing schedule can vary from once a week to daily depending on a number of clinical factors, such as the subject's sensitivity to the drugs.
  • the desired dose can be administered at one time or divided into subdoses, e.g. , 2-4 subdoses and administered over a period of time, e.g. , at appropriate intervals through the day or other appropriate schedule.
  • sub-doses can be administered as unit dosage forms.
  • administration is chronic, e.g.
  • one or more doses daily over a period of weeks or months are administration daily, twice daily, three times daily or four or more times daily over a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more.
  • the present invention contemplates formulation of the subject compounds in any of the aforementioned pharmaceutical compositions and preparations. Furthermore, the present invention contemplates administration via any of the foregoing routes of administration. One of skill in the art can select the appropriate formulation and route of administration based on the condition being treated and the overall health, age, and size of the patient being treated.
  • LCMS Chromatography/Mas s Spectrometry
  • Example 1 Synthesis of Compound 100 Preparation of compound 2: To a mixture of phenethylamine 1 (15 g, 124 mmol, 1.0 eq) and 4- chlorobutanoyl chloride (19 g, 136 mmol, 1.1 eq) in 300 mL of DMF was added triethylamine (25 g, 248 mmol, 2.0 eq) in one portion at 20°C under N 2 . The mixture was stirred at 20°C for 2hrs, then NaH was added (15 g, 371 mmol, 60% purity, 3.0 eq) at 0°C and the reaction was stirred for 16 hours at 20°C. The reaction was monitored by TLC and allowed to run until complete.
  • reaction mixture was quenched by addition of 200 mL of aqueous NH 4 C1 at 0°C, and then and extracted with three 200 mL portions of ethyl acetate.
  • the combined organic layers were washed twice with 300 mL of brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by silica gel column
  • reaction mixture was quenched by addition 2 mL of water at 20°C, and then extracted with three 2 mL portions of ethyl acetate. The combined organic layers were washed with three 2 mL portions of brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition) to afford compound 102(26.1 mg, 52.0 ⁇ , 5.6% yield, 94.7% purity, TFA salt) as a yellow oil.
  • reaction mixture was quenched with 10 mL of iced saturated aqueous NH 4 C1 and extracted with three 10 mL portions of ethyl acetate.
  • the combined organic layers were washed with twice 20 mL of brine, dried over Na 2 S0 4 , filtered and the filtrate was concentrated to give the residue.
  • reaction mixture was quenched by 40 mL of icy saturated aqueous NH 4 CI, then 6 mL of IN HC1 was added until the reaction liquid became clear.
  • the mixture was diluted with 5 mL of saturated aqueous NaHCC ⁇ and extracted with two 20 mL portions of ethyl acetate. The combined organic layers were washed with 30 mL of brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give 0.4 g of compound 50 as a crude yellow oil.
  • indole-2-carboxylic acid chloride To a solution of indole-2-carboxylic acid (200 mg, 1.2 mmol, 1.0 eq) in 2 mL of DCM was added oxalyl chloride (236 mg, 1.9 mmol, 1.5 eq) and DMF (9.1 mg, 124.0 ⁇ , 0.1 eq) at 0°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent to afford 223 mg of crude indole-2-carboxylic acid chloride as a yellow solid, which was used into the next step without further purification.
  • reaction mixture was quenched by adding 5 mL of saturated aqueous NH 4 C1 at 0°C, and then diluted with 5 mL of ethyl acetate and extracted with another 5 mL portion of ethyl acetate.
  • the combined organic layers were washed with 5 mL of brine, dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give 130 mg of crude compound 63 as yellow oil, which was used into the next step without further purification.
  • reaction mixture was quenched with 300 ml of ice- water and extracted with three 150 ml portions of dichloromethane. The combined organic layers were washed twice with 200 ml of brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to afford 12 g of compound 72 as a colorless oil.
  • reaction mixture was added dropwise to 150 mL of icy saturated aqueous NH 4 CI to quench any remaining NaH, then the mixture was extracted twice with 100 mL of ethyl acetate. The combined organic layers were washed with 100 mL of brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give 12.9 g of compound 78as a brown oil.
  • reaction mixture was quenched by 40 mL of icy saturated aqueous NH 4 C1, then HC1 (1M, -lOmL) added until the reaction liquid turned clear.
  • the mixture was diluted with 40 mL of ethyl acetate and 5 mL aqueous NaHCC ⁇ was added.
  • the organic layer was washed with 30 mL of brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give an oil.
  • the residue was purified by prep-HPLC (neutral condition) to give 500 mg of compound 82 as a yellow gum.
  • the aqueous phase was separated, adjusted to pH >7 with NaOH, and extracted with 5 mL of ethyl acetate, then the organic phase was washed with 5 mL of brine, dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give 220 mg of crude compound 94 as a yellow oil, which was used into the next step without further purification.
  • Exemplary compounds of the invention were evaluated for efficacy in inhibiting TDP-43 inclusions using a concentration-response assay. Briefly, PC 12 cells stably expressing a GFP- tagged mutant form of TDP-43 (TDP-43 Q331K ::eGFP) were pre-treated for 1 hour with exemplary compounds and stressed with 15 ⁇ sodium arsenite for 23 hours to induce TDP-43
  • A represents an IC 50 value of ⁇ 250 nM
  • B represents an IC 50 value of 250 nm to 5 ⁇
  • C represents an IC 50 value of 5 ⁇ to 10 ⁇
  • D represents an IC 50 value of > 10 ⁇ .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés, des compositions et des procédés permettant de moduler la formation d'inclusions et de granules de stress dans des cellules associées à l'apparition de maladies neurodégénératives, de troubles musculo-squelettiques, de cancer, de maladies ophtalmologiques et d'infections virales.
PCT/US2018/027969 2017-04-19 2018-04-17 Composés, compositions et procédés d'utilisation associés WO2018195075A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762487180P 2017-04-19 2017-04-19
US62/487,180 2017-04-19

Publications (1)

Publication Number Publication Date
WO2018195075A1 true WO2018195075A1 (fr) 2018-10-25

Family

ID=63856471

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2018/027969 WO2018195075A1 (fr) 2017-04-19 2018-04-17 Composés, compositions et procédés d'utilisation associés

Country Status (1)

Country Link
WO (1) WO2018195075A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012162249A1 (fr) * 2011-05-20 2012-11-29 Benjamin Wolozin Identification de composés qui dispersent des inclusions de tdp-43
WO2017066705A1 (fr) * 2015-10-14 2017-04-20 Aquinnah Pharmaceuticals, Inc. Composés, compositions et méthodes d'utilisation contre des granules de stress

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012162249A1 (fr) * 2011-05-20 2012-11-29 Benjamin Wolozin Identification de composés qui dispersent des inclusions de tdp-43
WO2017066705A1 (fr) * 2015-10-14 2017-04-20 Aquinnah Pharmaceuticals, Inc. Composés, compositions et méthodes d'utilisation contre des granules de stress

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE Pubchem 25 November 2010 (2010-11-25), Database accession no. 47089913 *
DATABASE Pubchem 27 May 2009 (2009-05-27), Database accession no. 25288226 *

Similar Documents

Publication Publication Date Title
US20230303489A1 (en) Compounds, compositions and methods of use
WO2017066705A1 (fr) Composés, compositions et méthodes d'utilisation contre des granules de stress
DE60316542T2 (de) 7-azaindole als inhibitoren c-jun n-terminaler kinasen zur behandlung neurodegenerativer störungen
US9296703B2 (en) Substituted N-(3-(pyrimidin-4-yl)phenyl)acrylamide analogs as tyrosine receptor kinase BTK inhibitors
WO2020117877A1 (fr) Composés, compositions et procédés d'utilisation associés
TW200900395A (en) Heteroarylamide pyrimidone compounds
TW200904436A (en) Arylamide pyrimidone derivatives
JP6985271B2 (ja) アルキニルジヒドロキノリンスルホンアミド化合物
CA3102762A1 (fr) Activateurs de l'eaat2 et leurs methodes d'utilisation
JP2019504016A (ja) アルキルジヒドロキノリンスルホンアミド化合物
CA3180058A1 (fr) Derives de pyrazolo[1,5-a]pyrimidine ayant une activite multimodale contre la douleur
CN114929670A (zh) 治疗化合物和其使用方法
WO2013005798A1 (fr) Nouveau dérivé à noyau hétérocyclique azoté
WO2018195075A1 (fr) Composés, compositions et procédés d'utilisation associés
CN110709401B (zh) 杂环化合物
EP4053110A1 (fr) Modificateur de dérivé cyclique à quatre chaînons, procédé de préparation et application de celui-ci
WO2023060173A1 (fr) Composés, compositions et procédés d'utilisation associés
EP3356333A1 (fr) Formes cristallines d'un modulateur allostérique positif du récepteur m1
WO2024040266A2 (fr) Analogues de benzoimidazole et d'indole disubstitués en tant que modulateurs de pink1
CN115557949A (zh) 四环类衍生物、其制备方法及其在医药上的应用
CN115215883A (zh) Usp7抑制剂
KR20220162159A (ko) Sstr4 작용제로서의 n-헤테로아릴알킬-2-(헤테로사이클릴 및 헤테로사이클릴메틸)아세트아미드 유도체
LARSEN et al. Patent 3001857 Summary

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18787072

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18787072

Country of ref document: EP

Kind code of ref document: A1