WO2023060173A1 - Compounds, compositions and methods of use - Google Patents

Compounds, compositions and methods of use Download PDF

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Publication number
WO2023060173A1
WO2023060173A1 PCT/US2022/077670 US2022077670W WO2023060173A1 WO 2023060173 A1 WO2023060173 A1 WO 2023060173A1 US 2022077670 W US2022077670 W US 2022077670W WO 2023060173 A1 WO2023060173 A1 WO 2023060173A1
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disease
chloro
cancer
compound
mmol
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PCT/US2022/077670
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French (fr)
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Joseph P. Vacca
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Aquinnah Pharmaceuticals, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems

Definitions

  • TDP-43 protein was identified as one of the major components of protein inclusions that typify the neurogenerative diseases Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Dementia with ubiquitin inclusions (FTLD-U) (Ash, P.E., et al.
  • TDP-43 biology Abnormalities in 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 Neurosci 30:639-649; Gitcho, M.A., et al. (2008) Ann Neurol 63(4): 535-538; Johnson, B.S., et al. (2009) J Biol Chem 284:20329-20339; Ling, S.C., et al. (2010) Proc Natl Acad Sci U.S.A.107:13318-13323; Sreedharan, J., et al. (2008) Science 319:1668-1672).
  • 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):e13250).
  • 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.
  • aggregates that accumulate in neurodegenerative diseases like ALS, FTLD-U, Parkinson's disease and Huntington's disease accumulate slowly and are very difficult to disaggregate or perhaps can't be disaggregated.
  • the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I): Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of the variables and subvariables thereof are described herein, for example, in the Detailed Description below.
  • the compound of Formula (I) is of Formula (Ia) Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein each of the variables and subvariables thereof are described herein, for example, in the Detailed Description below.
  • the compound of Formula (I) is of Formula (Ib) Formula (Ib) or a pharmaceutically acceptable salt thereof, wherein each of the variables and subvariables thereof are described herein, for example, in the Detailed Description below.
  • a compound of Formula (I), (Ia), or (Ib) is formulated as a composition (e.g., a pharmaceutical composition).
  • 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), (Ia), or (Ib) to a subject in need thereof.
  • the invention provides methods of diagnosing 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), (Ia), or (Ib) to a subject.
  • the compound of Formula (I), (Ia), or (Ib) can be modified with a label.
  • the invention provides methods of modulating stress granules comprising administering a compound of Formula (I), (Ia), or (Ib) to a cell or a subject in need thereof.
  • the subject has 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 invention provides methods of modulating TDP-43 inclusion formation comprising administering a compound of Formula (I), (Ia), or (Ib) to a cell or a subject in need thereof.
  • the subject has 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 invention provides a method of screening for modulators of TDP- 43 aggregation comprising contacting a compound of Formula (I), (Ia), or (Ib) with the cell that expresses TDP-43 and develops spontaneous inclusions.
  • a compound of Formula (I), (Ia), or (Ib) with the cell that expresses TDP-43 and develops spontaneous inclusions.
  • 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. (2008) Science 319:1668-1672; Gitcho, M.A., et al. (2008) Ann Neurol 63(4):535-538; Neumann, M., et al. (2006) Science 314:130-133).
  • TDP-43 Inhibitors of cell death and inclusions linked to TDP-43 represent a novel therapeutic approach to ALS, and may also elucidate the biochemical pathway linked to the formation of TDP-43 inclusions (Boyd, J.B., et al. (2014) J Biomol Screen 19(1):44-56). As such, 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.
  • TDP-43 can co- localize with SGs.
  • the reversible nature of SG-based aggregation offers a biological pathway that might be applied to reverse the pathology and toxicity associated with TDP-43 inclusion formation.
  • agents that inhibit SG formation also inhibit formation of TDP-43 inclusions (Liu-Yesucevitz, L., et al.
  • TDP-43 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 SG process.. Investigating the particular elements of the SG pathway that regulate TDP-43 inclusion formation can identify selective approaches for therapeutic intervention to delay or halt the progression of disease. Stress granule biology also regulates autophagy and apoptosis, both of which are linked to neurodegeneration. Hence, compounds inhibiting TDP-43 aggregation may play a role in inhibiting neurodegeneration.
  • X is wherein m is 0, 1, 2, 3, or 4.
  • X is wherein m is 0 or 1. In some embodiments, X is . In some embodiments, m is 0.
  • R 2 is Me or Cl.
  • R 3 is H, Me, or Cl. In some embodiments, R 2 is H and R 3 is Me or Cl. In some embodiments, R 2 is Me or Cl, and R 3 is H or G is N.
  • the compound is of Formula (Ib): Formula (Ib) or a pharmaceutically acceptable salt thereof, wherein each R 8 is independently halo, C 1 -C 6 alkyl, -OR B , -C(O)OR B , or C 1 -C 6 haloalkyl; each R 9 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, halo, cyano, nitro, azido, C 3 -C 7 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, - OR B , -C(O)R D , -C(O)NR A R C , -C(O)OR B , -NR A R C , -NR A C(O)R D , –S(O)xR E ,
  • each R 9 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -O-C 1 -C 6 haloalkyl, C 1 -C 6 haloalkyl, halo, cyano, C 3 -C 7 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted by 1-5 R 11 .
  • At least one R 9 group is methyl or chloro.
  • one R 9 is chloro or methyl and the other R 9 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, halo, cyano, C 3 -C 7 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted by 1-5 R 11 .
  • one R 9 is chloro, methyl, methoxy, CF 3 , -OCF 3 , or CN
  • the other R 9 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 - C 6 alkoxy, C 1 -C 6 haloalkyl, halo, cyano, C 3 -C 7 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted by 1-5 R 11 .
  • one R 9 is chloro, methyl, methoxy, CF 3 , -OCF 3 , or CN
  • the other R 9 is phenyl, C 3 -C 7 cycloalkyl, monocyclic 4-7 membered heterocycloalkyl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S), or monocyclic 5-6 membered heteroaryl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S); wherein the phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 R 11 .
  • one R 9 is chloro and the other R 9 is phenyl, C 3 -C 7 cycloalkyl, monocyclic 4-7 membered heterocycloalkyl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S), or monocyclic 5-6 membered heteroaryl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S); wherein the phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 R 11 .
  • one R 9 is chloro and the other R 9 is C 3 -C 7 cycloalkyl or monocyclic 4-7 membered heterocycloalkyl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S), wherein the cycloalkyl or heterocycloalkyl, is optionally substituted with 1-3 R 11 .
  • one R 9 group is chloro and the other R 9 group is selected from the group consisting of wherein n is 0, 1, 2, 3, 4, or 5.
  • one R 9 group is chloro and the other R 9 group is selected from the group consisting of wherein n is 0, 1, 2, 3, 4, or 5.
  • n is 0.
  • the compound is In some embodiments, heterocycloalkyl is monocyclic 4-7 membered heterocycloalkyl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S). In some embodiments, heteroaryl is monocyclic 5-6 membered heteroaryl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S); wherein the heterocycloalkyl or heteroaryl is optionally substituted with 1-3 R 11 . In some embodiments, L is a bond. In some embodiments, the compound of Formula (I), (Ia), or (Ib) is selected from a compound described in the specification.
  • the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound disclosed herein.
  • Deuterated Compounds e.g., some compounds of Formula (I), (Ia), or (Ib)
  • compounds described herein are deuterium-enriched.
  • Deuterium (D or 2 H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes 1 H (hydrogen or protium), D ( 2 H or deuterium), and T ( 3 H or tritium). The natural abundance of deuterium is 0.015%.
  • isotopic enrichment factor means the ratio between the isotopic abundance of D at the specified position in a compound of this invention and the naturally occurring abundance of that isotope.
  • a compound e.g., a compound of Formula (I), (Ia), or (Ib)
  • deuterium-enrichment a compound of Formula (I), (Ia), or (Ib)
  • deuterium-enriched compounds are referred to as “deuterium-enriched” compounds. If not specifically noted, the percentage of enrichment refers to the percentage of deuterium present in the compound.
  • a compound of this invention has an isotopic enrichment factor for each deuterium present at a site designated at a potential site of deuteration on the compound of at least 3500 (52.5.% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent of other deuterated sites.
  • the compounds of Formula (I), (Ia), or (Ib) comprise an amount of deuterium-enrichment that is more than the amount of deuterium-enrichment present in naturally occurring compounds of Formula (I), (Ia), or (Ib).
  • deuterium-enriched can be achieved by either exchanging protons with deuterium or by synthesizing the molecule with enriched starting materials.
  • the compound is a compound from Table 1. Table 1: Exemplary Compounds
  • use of a compound of Formula (I), (Ia), or (Ib) can also refer to use of a pharmaceutical compistion including a compound of Formula (I), (Ia), or (Ib).
  • the invention provides a method of modulating stress granule formation, the method comprising contacting a cell with a compound of Formula (I), (Ia), or (Ib) .
  • stress granule formation is inhibited.
  • the stress granule is disaggregated.
  • stress granule formation is stimulated.
  • a compound of Formula (I), (Ia), or (Ib) inhibits the formation of a stress granule.
  • the compound of Formula (I), (Ia), or (Ib) can inhibit the formation of a stress granule by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at 32 least 70%, at least 80%, at least 90%, at least 95%, or 100% (i.e., complete inhibition) relative to a control.
  • a compound of Formula (I), (Ia), or (Ib) disaggregates a stress granule.
  • the compound of Formula (I), (Ia), or (Ib) can disperses or disaggregate a stress granule 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 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).
  • 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). In some embodiments, the stress granule comprises GTPase activating protein binding protein 1 (G3BP-1). In some embodiments, the stress granule comprises GTPase activating protein binding protein 2 (G3BP-2). In some embodiments, the stress granule comprises tris tetraprolin (TTP, ZFP36). In some embodiments, the stress granule comprises fused in sarcoma (FUS). In some embodiments, 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), (Ia), or (Ib).
  • TDP-43 inclusion formation is inhibited.
  • the TDP- 43 inclusion is disaggregated.
  • TDP-43 inclusion formation is stimulated.
  • a compound of Formula (I), (Ia), or (Ib) inhibits the formation of a TDP-43 inclusion.
  • the compound of Formula (I), (Ia), or (Ib) can inhibit the formation of 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 inhibition) relative to a control.
  • a compound of Formula (I), (Ia), or (Ib) disaggregates a TDP-43 inclusion.
  • the compound of Formula (I), (Ia), or (Ib) 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), (Ia), or (Ib) to a subject in need thereof.
  • 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.
  • 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. In some embodiments, the methods comprise administering a compound of Formula (I), (Ia), or (Ib) to a subject in need thereof. In some embodiments, the subject is a mammal.
  • the subject is a nematode. In some embodiments, the subject is human. In some embodiments, 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), (Ia), or (Ib). In some embodiments, 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), (Ia), or (Ib).
  • a neurodegenerative disease or disorder prior to administration of a compound of Formula (I), (Ia), or (Ib).
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Huntington’s chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, and 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
  • FTD
  • 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).
  • the neurodegenerative disease is Alzheimer's disease or amyotrophic lateral sclerosis (ALS).
  • 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.
  • compounds of Formula (I), (Ia), or (Ib) 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).
  • astrocytosis e.g., astrocytosis in the spinal cords
  • liver disease e.g., respiratory disease or respiratory failure
  • inflammation e.g., 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. In some embodiments, the cancer is selected from Hodgkin’s lymphoma or non- Hodgkin’s lymphoma.
  • 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, 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, Waldenström’s macroglobulinemia, hairy cell leukemia, and primary central nervous system (CNS) lymphoma) and a T-cell lymphoma (e.g., precursor T-ly
  • 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, 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.
  • macular degeneration e.g., age-related macular degeneration
  • diabetes retinopathy histoplasmosis
  • macular hole macular pucker
  • retinal detachment e.g., retinal thinning
  • 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 histoplasmosis
  • macular hole macular pucker
  • Bietti’s crystalline dystrophy retinoblastoma
  • retinopathy of prematurity retinopathy of prematurity
  • Usher’s syndrome Refsum disease
  • 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.
  • 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), (Ia), or (Ib) to the subject.
  • the invention provides methods of diagnosing a neurodegenerative disease in a subject, the method comprising administering a compound of Formula (I), (Ia), or (Ib) to the subject.
  • a compound of Formula (I), (Ia), or (Ib) can be modified with a label.
  • the invention provides methods of modulating stress granules comprising contacting a cell with a compound of Formula (I), (Ia), or (Ib).
  • the invention provides methods of modulating TDP-43 inclusion formation comprising contacting a cell with a compound of Formula (I), (Ia), or (Ib).
  • 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), (Ia), or (Ib) with a cell that expresses TDP-43 and develops spontaneous inclusions.
  • the stress granule comprises TDP-43, i.e., is a TDP-43 inclusion.
  • a compound of Formula (I), (Ia), or (Ib) is a modulator of TDP-43 inclusions.
  • 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 communicate.
  • the signaling systems that conpounds of Formula (I), (Ia), or (Ib) target may also modify these processes, which play a role in neurodegeneration or mental health illnesses (e.g., schizophrenia).
  • 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.
  • 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.
  • 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), (Ia), or (Ib) can act to block the enzymes that signal stress granule formation (e.g., the three enzymes that phosphorylate eIF2a: PERK, GCN2 and HRI), compounds of Formula (I), (Ia), or (Ib) may also reverse stress granules that might not include TDP-43.
  • compounds of Formula (I), (Ia), or (Ib) 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), (Ia), or (Ib) may also be used for treatment of neurodegenerative diseases and disorders that involve TDP-43 multisystem proteinopathy.
  • 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.
  • neurodegenerative diseases include neurodegenerative movement disorders and neurodegenerative conditions relating to memory loss and/or dementia.
  • Neurodegenerative diseases include tauopathies and ⁇ - synucleopathies.
  • Exemplary neurodegenerative diseases include, but are not limited to, Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with dementia (ALSD), Huntington's disease (HD), Huntington’s chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat
  • ⁇ -synucleopathy refers to a neurodegenerative disorder or disease involving aggregation of ⁇ -synuclein or abnormal ⁇ -synuclein in nerve cells in the brain (Ostrerova, N., et al. (1999) J Neurosci 19:5782:5791; Rideout, H.J., et al. (2004) J Biol Chem 279:46915-46920).
  • ⁇ -Synucleopathies include, but are not limited to, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Pick's disease, Down's syndrome, multiple system atrophy, amylotrophic lateral sclerosis (ALS), Hallervorden-Spatz syndrome, and the like.
  • tauopathy refers to a neurodegenerative disease associated with the pathological aggregation of tau protein in the brain. Tauopathies include, but are not limited to, Alzheimer’s disease, Pick's disease, corticobasal degeneration, Argyrophilic grain disease (AGD), progressive supranuclear palsy, Frontotemporal dementia, Frontotemporal lobar degeneration, or Pick's complex.
  • 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), (Ia), or (Ib) 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
  • PPMA post-polio muscular atrophy
  • motor neuron disease myotonia
  • myotonic dystrophy sacropenia
  • sacropenia spasticity
  • compounds of Formula (I), (Ia), or (Ib) 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.
  • astrocytosis e.g., astrocytosis in the spinal cords
  • liver disease inflammation
  • headache e.g., back pain, neck pain, leg pain, inflammatory pain
  • a musculoskeletal disease or a symptom of a musculoskeletal disease may overlap with a neurodegenerative disease or a symptom of a neurodegenerative disease.
  • Cancers Cancer cells grow quickly and in low oxygen environments by activating different elements of the cellular stress response.
  • 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), (Ia), or (Ib) 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.
  • cancer examples 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,
  • 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, 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, Waldenström’s macroglobulinemia, hairy cell leukemia, and primary central nervous system (CNS) lymphom
  • 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, ophthalmoplegia, and the like.
  • macular degeneration e.g., age-related macular degeneration
  • diabetes retinopathy histoplasmosis
  • macular hole macular pucker
  • Bietti’s crystalline dystrophy crystalline dystrophy
  • retinal detachment retina
  • 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. Acad.
  • 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 Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below.
  • the compounds are small organic or inorganic molecules, e.g., with molecular weights less than 7500 amu, preferably less than 5000 amu, and even more preferably less than 2000, 1500, 1000, 750, 600, or 500 amu.
  • one class of small organic or inorganic molecules are non- peptidyl, e.g., containing 2, 1, or no peptide and/or saccharide linkages.
  • administer refers to the placement of a composition into a subject by a method or route which results in at least partial localization of the composition at a desired site such that desired effect is produced.
  • a compound or composition described herein can be administered by any appropriate route known in the art including, but not limited to, oral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, nasal, rectal, intrathecal, and topical (including buccal and sublingual) administration.
  • oral or parenteral routes including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, nasal, rectal, intrathecal, and topical (including buccal and sublingual) administration.
  • the terms “decrease”, “reduced”, “reduction” , “decrease” or “inhibit” are all used herein generally to mean a decrease by a statistically significant amount.
  • the terms “reduced”, “reduction”, “decrease” or “inhibit” mean a decrease by at least 0.1% as compared to a reference level, for example a decrease by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g. absent level as compared to a reference sample), or any decrease between 1-100%, e.g., 10-100% as compared to a reference level.
  • a 100% decrease e.g. absent level as compared to a reference sample
  • the terms “increased”,”increase”, “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount.
  • the terms “increased”, “increase”, “enhance” or “activate” mean an increase by at least 0.1% as compared to a reference level, for example a decrease by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase (e.g.
  • treatment delaying or preventing the onset of such a disease or disorder, reversing, alleviating, ameliorating, inhibiting, slowing down or stopping the progression, aggravation or deterioration the progression or severity of a condition associated with such a disease or disorder.
  • At least one symptom of a disease or disorder is alleviated by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%.
  • an amount of a compound or combination effective to treat a disorder e.g., a disorder as described herein
  • “therapeutically effective amount” or “effective amount” 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.
  • 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., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon.
  • Patient or subject includes any subset of the foregoing, e.g., all of the above, but excluding one or more groups or species such as humans, primates or rodents.
  • the subject is a mammal, e.g., a primate, e.g., a human.
  • the terms, “patient” and “subject” are used interchangeably herein.
  • nucleic acid refers to a polymeric form of nucleotides, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide.
  • nucleotides either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide.
  • the terms should also be understood to include, as equivalents, analogs of either RNA or DNA made from nucleotide analogs, and, as applicable to the embodiment being described, single-stranded (such as sense or antisense) and double-stranded polynucleotides.
  • the terms “modulator of stress granule” and “stress granule modulator” refer to compounds and compositions of Formula (I), (Ia), or (Ib) that modulate the formation and/or disaggregation of stress granules.
  • TDP-43 inclusion refers to protein aggregates that comprise TDP-43 proteins. The TDP-43 protein in the inclusion 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), (Ia), or (Ib) 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.
  • C1-6 alkyl is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl and hexyl.
  • each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the Markush group defined for R.
  • alkyl refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 24 carbon atoms (“C1-C 2 4 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 (“C1-C 8 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1 -C 6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-C 5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-C 4 alkyl”).
  • an alkyl group has 1 to 3 carbon atoms (“C 1 -C 3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1 -C 2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2 - C 6 alkyl”).
  • C 1 -C 6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n–propyl (C 3 ), isopropyl (C 3 ), n–butyl (C 4 ), tert–butyl (C 4 ), sec–butyl (C 4 ), iso–butyl (C 4 ), n–pentyl (C 5 ), 3– pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3–methyl–2–butanyl (C 5 ), tertiary amyl (C 5 ), and n– hexyl (C 6 ).
  • alkyl groups include n–heptyl (C 7 ), n–octyl (C 8 ) and the like.
  • Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkyl group is unsubstituted C1–10 alkyl (e.g., –CH 3 ).
  • the alkyl group is substituted C1–6 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 (“C 2 -C 24 alkenyl”).
  • an alkenyl group has 2 to 10 carbon atoms (“C 2 -C 10 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C 2 -C 8 alkenyl”).
  • 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 -C 5 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 -C 10 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C 2 -C 8 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms (“C 2 -C 6 alkynyl”).
  • an alkynyl group has 2 to 5 carbon atoms (“C 2 -C 5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2 -C 4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2 -C 3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl).
  • C 2 -C 4 alkynyl groups include ethynyl (C 2 ), 1–propynyl (C 3 ), 2–propynyl (C 3 ), 1– butynyl (C 4 ), 2–butynyl (C 4 ), and the like.
  • Each instance of an alkynyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkynyl group is unsubstituted C 2 –10 alkynyl. In certain embodiments, the alkynyl group is substituted C 2–6 alkynyl.
  • the term "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 -O-Si(CH 3 ) 3 .
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as –CH 2 O-, –NR C R D , or the like, it will be understood that the terms heteroalkyl and –CH 2 O- or –NR C R D are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity.
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as –CH 2 O-, –NR C R D , or the like.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“ C 6 -C 14 aryl”).
  • an aryl group has six ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • An aryl group may be described as, e.g., a C 6 -C 10 -membered aryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • 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 -C 14 aryl.
  • the aryl group is substituted C 6 -C 14 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., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is unsubstituted 5–14 membered heteroaryl.
  • the heteroaryl group is substituted 5–14 membered heteroaryl.
  • Exemplary 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, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • 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.
  • heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more heterocycloalkyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of carbons continue to designate the number of carbons in the heteroaryl ring system.
  • ring systems of this type include 7,8-dihydro-5H-pyrano[4,3-b]pyridine and 1,4,6,7-tetahydropyrano[4,3-b]pyrrole.
  • cycloalkyl refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C 3 -C 10 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”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3 -C 6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5 -C 10 cycloalkyl”).
  • a cycloalkyl group may be described as, e.g., a C 4 -C 7 -membered cycloalkyl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • Exemplary C 3 -C 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[1.1.1]pentanyl (C 5 ), bicyclo[2.2.2]octanyl (C 8 ), bicyclo[2.1.1]hexanyl (C 6 ), bicyclo[3.1.1]heptanyl (C 7 ), and the like.
  • Exemplary C 3 -C 10 cycloalkyl groups include, without limitation, the aforementioned C 3 -C 8 cycloalkyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro–1H–indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • the cycloalkyl group is 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 -C 10 cycloalkyl.
  • the cycloalkyl group is a substituted C 3 -C 10 cycloalkyl.
  • Heterocycloalkyl 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 hetercycloalkyl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a hetercycloalkyl group can either be monocyclic (“monocyclic hetercycloalkyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic hetercycloalkyl), and can be saturated or can be partially unsaturated.
  • Heterocycloalkyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocycloalkyl also includes ring systems wherein the hetercycloalkyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or hetercycloalkyl ring, or ring systems wherein the hetercycloalkyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the hetercycloalkyl or aryl or heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the hetercycloalkyl ring system.
  • a hetercycloalkyl group may be described as, e.g., a 3-7-membered hetercycloalkyl, 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 hetercycloalkyl may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted hetercycloalkyl”) or substituted (a “substituted hetercycloalkyl”) with one or more substituents.
  • the hetercycloalkyl group is unsubstituted 3–10 membered hetercycloalkyl. In certain embodiments, the hetercycloalkyl group is substituted 3–10 membered hetercycloalkyl. In some embodiments, a hetercycloalkyl 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 hetercycloalkyl”).
  • a hetercycloalkyl 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 hetercycloalkyl”).
  • a hetercycloalkyl 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 hetercycloalkyl”).
  • the 5–6 membered hetercycloalkyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered hetercycloalkyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered hetercycloalkyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary 3–membered hetercycloalkyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4–membered hetercycloalkyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5–membered hetercycloalkyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5–dione.
  • Exemplary 5–membered hetercycloalkyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin–2–one.
  • Exemplary 5–membered hetercycloalkyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6–membered hetercycloalkyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6–membered hetercycloalkyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6–membered hetercycloalkyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered hetercycloalkyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered hetercycloalkyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5–membered hetercycloalkyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6– membered hetercycloalkyl 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 (Cl), bromine (Br), or iodine (I) atom.
  • haloalkyl can include alkyl structures that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl includes haloalkyl groups in which the halo is fluorine (e.g., -C 1 -C 6 alkyl-CF 3 , -C 1 -C 6 alkyl-C 2 F).
  • Non- limiting examples of haloalkyl include trifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl, diflurormethyl, and fluroisopropyl.
  • hydroxy refers to the radical –OH.
  • nitro refers to –NO 2 .
  • a carbon atom substituted with oxo froms a carbonyl group - C O.
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or hetercycloalkyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, 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.
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • an enantiomerically pure compound can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure R–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R–compound.
  • the enantiomerically pure R–compound in such compositions can, for example, comprise, at least about 95% by weight R–compound and at most about 5% by weight S–compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure S–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S–compound.
  • the enantiomerically pure S– compound in such compositions can, for example, comprise, at least about 95% by weight S– compound and at most about 5% by weight R–compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • Compound described herein may also comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium);
  • C may be in any isotopic form, including 12 C, 13 C, and 14 C;
  • O may be in any isotopic form, including 16 O and 18 O; and the like.
  • 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 and Routes of Administration Pharmaceutical compositions containing compounds described herein such as a compound of Formula (I), (Ia), or (Ib) 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.
  • the amount and concentration of compounds of Formula (I), (Ia), or (Ib) 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.
  • 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.
  • another aspect of the present invention provides pharmaceutically acceptable 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.
  • 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., those targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) transmucosally; (9) nasally
  • oral administration for example,
  • compounds can be implanted into a patient or injected using a drug delivery system. See, for example, Urquhart, et al., (1994) Ann Rev Pharmacol Toxicol 24:199-236; Lewis, ed. “Controlled Release of Pesticides and Pharmaceuticals” (Plenum Press, New York, 1981); U.S. Patent No.3,773,919; and U.S. Patent No.353,270,960.
  • therapeutically 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.
  • pharmaceutically acceptable carrier means 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 eth
  • pharmaceutically acceptable salt is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)).
  • Certain specific compounds of the present 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.
  • wetting agents 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 (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • 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.
  • 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
  • the pharmaceutical 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 such as dragees, capsules, pills and granules, 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.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the 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.
  • compositions can be formulated for delivery via a dialysis port. Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. 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.
  • 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.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • microorganisms 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.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • 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 rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form.
  • 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. Alternatively, 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. Freedman and CO., San Francisco, U.S.A., 1969 or “Livestock Feeds and Feeding” O and B books, Corvallis, Ore., U.S.A., 1977).
  • 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 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.
  • the methods described herein can be used to treat domesticated animals and/or pets.
  • a subject can be male or female.
  • a subject can be one who has been previously diagnosed with or identified as suffering from or having a neurodegenerative disease or disorder, 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. Dosages 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. For example, 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). When administrated 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. When the inhibitor and the pharmaceutically active agent are administered in different pharmaceutical compositions, 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.
  • 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 LD50 (the dose lethal to 50% of the population) and the ED 50 (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 LD 50 /ED 50 .
  • 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 ED 50 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.
  • compositions are administered so that the compound of Formula (I), (Ia), or (Ib) 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 to 1 mg/kg, 100 ⁇ g/kg to 50 mg/kg, 100 ⁇ g/kg to 20 mg/kg, 1 mg/kg to 100 mg/kg, 1 mg/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.
  • the 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.
  • duration and frequency of treatment it is typical for skilled clinicians to monitor subjects in order to determine when the treatment is providing therapeutic benefit, and to determine whether to increase or decrease dosage, increase or decrease administration frequency, discontinue treatment, resume treatment or make other alteration to treatment regimen.
  • 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.
  • Such 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.
  • dosing schedules 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.
  • 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.
  • EXAMPLES Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results.
  • General All oxygen and/or moisture sensitive reactions were carried out under N2 atmosphere in glassware that was flame-dried under vacuum (0.5 mmHg) and purged with N2 prior to use.
  • LCMS Liquid Chromatography/Mass Spectrometry
  • Step 3 Synthesis of tert-butyl(5-chloro-4-((3-chloro-5-cyclopropylphenyl)carbamoyl)pyridin-2- yl)carbamate
  • 2-((tert-butoxycarbonyl)amino)-5-chloroisonicotinic acid (220 mg, 0.8038 mmol) in DMF (3 mL) were added 3-chloro-5-cyclopropylaniline (134.8 mg, 0.8038 mmol), HATU (458.5 mg, 1.2057 mmol) and DIEA (519.4 mg, 4.019 mmol). The mixture was stirred at room temperature for 16 h.
  • Step 4 Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide (Compound 102)
  • 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (170 mg, 0.6144 mmol) in DMF (2 mL) were added 3-chloro-5-cyclopropylaniline (103 mg, 0.6144 mmol), HATU (350.4 mg, 0.9216 mmol) and DIEA (397.0 mg, 3.0719 mmol).
  • 3-chloro-5-cyclopropylaniline 103 mg, 0.6144 mmol
  • HATU 350.4 mg, 0.9216 mmol
  • DIEA 397.0 mg, 3.0719 mmol
  • Step 2 Synthesis of methyl 5-chloro-2-((3-chloropropyl)sulfonamido)isonicotinate
  • a solution of methyl 2-amino-5-chloropyridine-4-carboxylate (1.18 g, 6.32 mmol) in DCM (50 mL) were added TEA (3.84 g, 38 mmol) and 3-chloropropane-1-sulfonyl chloride (3.36 g, 18.9 mmol). The mixture was stirred at room temperature for 2 hrs.
  • Step 3 Synthesis of methyl 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinate A solution of methyl 5-chloro-2-((3-chloropropyl)sulfonamido)isonicotinate (4.0 g crude) and TEA (3.71 g, 36.6 mmol) in MeOH (50 mL) was stirred at 80 °C for 4 hrs.
  • Step 2 Synthesis of 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinic acid
  • Step 3 Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(1,1-dioxido-1,2-thiazinan-2-
  • 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinic acid 100 mg, 0.344 mmol
  • 3-chloro-5-cyclopropylaniline 69.2 mg, 0.4128 mmol
  • DIEA 133.4 mg, 1.032 mmol
  • Example 6 Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(2-oxopyrrolidin-1- yl)isonicotinamide (Compound 106)
  • Scheme 6 Synthesis of Compound 106 Step 1 Synthesis of methyl 5-chloro-2-(4-chlorobutanamido)isonicotinate To a solution of methyl 2-amino-5-chloroisonicotinate (1 g, 5.4 mmol) and TEA (1.09 g, 10.8 mmol) in 12 mL DCM was added 4-chlorobutanoyl chloride (1.52 g, 10.8 mol), the mixture was stirred at room temperature for 16 h.
  • Example 7 Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(2-oxopiperidin-1- yl)isonicotinamide (Compound 107)
  • Scheme 7 Synthesis of Compound 107 Step 1 Synthesis of methyl 5-chloro-2-(5-chloropentanamido)isonicotinate To a solution of methyl 2-amino-5-chloroisonicotinate (1 g, 0.0054 mol) and TEA (1.09 g, 0.0108 mol) in 10 mL DCM was added 5-chloropentanoyl chloride (1.67 g, 0.0108 mol), the mixture was stirred at room temperature for 16 h.
  • Step 3 Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(2-oxopiperidin-1- yl)isonicotinamide (Compound 107)
  • 3-chloro-5-cyclopropylaniline 327.5 mg, 1.9539 mmol
  • AlMe 3 187.8 mg, 2.6052 mmol
  • Example 8 Synthesis of Compound 218 Scheme 8 Synthesis of Compound 218 Step 1 Synthesis of methyl 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinate To a solution of methyl 2-amino-5-chloropyridine-4-carboxylate (1 g, 5.4 mmol) and 4- chlorobutane-1-sulfonyl chloride (1.24 g, 6.4 mmol) in DCM (15 mL) was slowly added TEA (1.64 g, 16.2 mmol), the mixture was stirred at 25 °C for 16 h.
  • Step 3 Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(1,1-dioxido-1,2-thiazinan-2- yl)isonicotinamide
  • 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinic acid 100 mg, 0.344 mmol
  • 3-chloro-5-cyclopropylaniline 69.2 mg, 0.4128 mmol
  • DIEA 133.4 mg, 1.032 mmol
  • Example 9 Synthesis of Compound 217 Scheme 9 Synthesis of Compound 217 Step 1 Synthesis of methyl 2-amino-5-methylisonicotinate To a solution of methyl 2-amino-5-bromopyridine-4-carboxylate (1.5 g, 6.5 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (3.05 g, 24.3 mmol), K3PO4 (2.76 g, 13 mmol) and SPhos (0.53 g, 1.3 mmol) in DMSO (20 mL) was added Pd(OAc)2 (145.9 mg, 0.65 mmol), the mixture was stirred at 80 °C under N2 for 16 h.
  • Pd(OAc)2 145.9 mg, 0.65 mmol
  • Step 4 Synthesis of N-(3-chloro-5-cyclopropylphenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)-5- methylisonicotinamide
  • 2-(1,1-dioxidoisothiazolidin-2-yl)-5-methylisonicotinic acid 100 mg, 0.39 mmol
  • 3-chloro-5-cyclopropylaniline 78.5 mg, 0.47 mmol
  • DIEA 100.9 mg, 0.78 mmol
  • HATU 222.55 mg, 0.59 mmol
  • Example 10 Synthesis of Compound 200 Scheme 10 Synthesis of Compound 200 Step 1 Synthesis of tert-butyl 3-(3-chloro-5-(2-(1,1-dioxidoisothiazolidin-2-yl)-5- methylisonicotinamido)phenyl)azetidine-1-carboxylate
  • a solution of methyl 2-amino-5-chloropyridine-4-carboxylate (1.0 g, 5.4 mmol) and TEA (1.64 g, 5.4 mmol) in DCM (5 mL) was added ethanesulfonyl chloride (0.69 g, 5.4 mmol), the mixture was stirred at 25 °C for 16 hours.
  • Step 2 Synthesis of methyl 5-chloro-2-(N-methylethylsulfonamido)isonicotinate
  • a solution of methyl 5-chloro-2-ethanesulfonamidopyridine-4-carboxylate (200 mg, 0.7176 mmol) in DMF (5 mL) was slowly added NaH (17.2 mg, 60% in oil, 0.7176 mmol), the mixture was stirred at 25 °C for 1 h.
  • MeI (152.8 mg, 1.0764 mmol) was added dropwise to the mixture and the solution was stirred at 25 °C for 1 h.
  • LC-MS was checked, and the reaction was completed.
  • Step 4 Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(N- methylethylsulfonamido)isonicotinamide
  • 5-chloro-2-(N-methylethanesulfonamido)pyridine-4-carboxylic acid 60 mg, 0.2153 mmol
  • 3-chloro-5-cyclopropylaniline 43.3 mg, 0.2583 mmol
  • DIEA 83.5 mg, 0.6459 mmol
  • HATU 98.2 mg, 0.2583 mmol
  • Example 13 Preparation of Compound 160 Scheme 13 Synthesis of Compound 160 Step 1 Synthesis of 4-bromo-2H-1,2,3-triazole To a solution of 4,5-dibromo-2H-1,2,3-triazole (2 g, 8.8 mmol) in 20 mL of water was added Na2SO3 (3.33 g, 26.4 mmol). The reaction mixture was stirred at 100 °C for 24 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was extracted with ethyl acetate (100 mL ⁇ 2).
  • Step 2 Synthesis of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole
  • NaH 40 mg, 60% in oil, 1.62 mmol
  • SEMCl 270 mg, 1.622 mmol
  • Example 14 Synthesis of Compound 212 Step 1 Synthesis of 4-(3-chloro-5-nitrophenyl)morpholine To a solution of 1-chloro-3-fluoro-5-nitrobenzene (500 mg, 2.85 mmol) and morpholine (297.8 mg, 3.4179 mmol) in DMSO (5 mL) was added K 2 CO 3 (787.3 mg, 5.70 mmol), the mixture was stirred at 80 °C for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, H 2 O was added and the mixture was extracted with ethyl acetate for 3 times. The combined organic phases were washed with brine, dried over Na 2 SO 4 and filtered.
  • K 2 CO 3 787.3 mg, 5.70 mmol
  • Example 15 Synthesis of Compound 190 To a solution of methyl 2-chloro-6-methylpyridine-4-carboxylate (4 g, 21.6 mmol), NH2Boc (3.83 g, 32.4 mmol) and Cs 2 CO 3 (21.11 g, 64.8 mmol) in dioxane (30 mL) were added XPhos (1.54 g, 3.2 mmol) and Pd(OAc)2 (0.48 g, 2.1 mmol), the mixture was stirred at 100 °C for 16 h. LC-MS was checked, and the reaction was completed.
  • Step 5 Synthesis of methyl 3-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)-2-methylisonicotinate
  • a solution of methyl 3-chloro-6-((3-chloro-N-((3- chloropropyl)sulfonyl)propyl)sulfonamido)-2-methylisonicotinate 1.5 g crude, 4.4 mmol
  • TEA 1.34 g, 13.2 mmol
  • Step 6 Synthesis of methyl 3-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)-2-methylisonicotinate
  • methyl 3-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)-2- methylisonicotinate 160 mg, 0.525 mmol
  • LiOH 44 mg, 1.8375 mmol
  • the mixture was stirred at 25 °C for 1 h.
  • Step 7 Synthesis of 3-chloro-N-(3-chloro-5-morpholinophenyl)-6-(1,1-dioxidoisothiazolidin-2- yl)-2-methylisonicotinamide
  • 3-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)-2-methylisonicotinic acid 150 mg, 0.5160 mmol
  • 3-chloro-5-(morpholin-4-yl)aniline 120.71 mg, 0.56760 mmol
  • DIEA 133.38 mg, 1.032 mmol
  • Step 2 Synthesis of methyl 6 amino 23 dimethylisonicotinate
  • DMSO DMSO
  • SPhos 628.2 mg, 1.53 mmol
  • Pd(OAc)2 229 mg, 1.02 mmol
  • K3PO4 6.50 g, 30.6 mmol
  • Step 3 Synthesis of methyl 6-(1,1-dioxidoisothiazolidin-2-yl)-2,3-dimethylisonicotinate
  • methyl 6-amino-2,3-dimethylpyridine-4-carboxylate 1.5 g, 8.3239 mmol
  • TEA 4.2 g, 41.62 mmol
  • 3-chloropropane-1-sulfonyl chloride 4.42 g, 24.97 mmol
  • Step 5 Synthesis of N-(3-chloro-5-cyclopropylphenyl)-6-(1,1-dioxidoisothiazolidin-2-yl)-2,3- dimethylisonicotinamide
  • 6-(1,1-dioxidoisothiazolidin-2-yl)-2,3-dimethylisonicotinic acid 100 mg, 0.37 mmol
  • 3-chloro-5-cyclopropylaniline 62.02 mg, 0.37 mmol
  • DIEA 143.5 mg, 1.11 mmol
  • HATU 168.82 mg, 0.44 mmol
  • Example 17 Preparation of Compound 211 Step 1 Synthesis of tert-butyl (3-chloro-5-iodophenyl)carbamate To a solution of 3-chloro-5-iodo-benzoic acid (6 g, 21.2 mmol) in toluene (35 mL) were added dropwise DPPA (5.83 g, 21.2 mmol) and TEA (2.14 g, 21.2 mmol) at 25 °C. After the addition, the mixture was stirred at this temperature for 1 hour and 80 °C for 1 hour. Then, tert- butanol (1.89 g, 25.4 mmol) was added dropwise. The resulting mixture was stirred at 110 °C for 12 hours.
  • DPPA 5.83 g, 21.2 mmol
  • TEA 2.14 g, 21.2 mmol
  • Step 3 Synthesis of tert-butyl (3-chloro-5-(tetrahydrofuran-3-yl)phenyl)carbamate
  • a solution of NiCl2.DME (0.12 g, 0.5 mmol) and dtbbpy (0.17 g, 0.6 mmol) in DMAc (20 mL) was stirred at room temperature for a while.
  • Step 5 Synthesis of 5-chloro-N-(3-chloro-5-(tetrahydrofuran-3-yl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide
  • 3-chloro-5-(oxolan-3-yl)aniline hydrochloride 100 mg, 0.43 mmol
  • 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid 141.8 mg, 0.36 mmol
  • TCFH 143.8 mg, 0.51 mmol
  • NMI (122.7 mg, 1.49 mmol
  • Example 19 Synthesis of Compound 195 Step 1 Synthesis of 5-chloro-N-(3-chloro-5-nitrophenyl)-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide
  • 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid 500 mg, 1.81 mmol
  • 3-chloro-5-nitroaniline 312 mg, 1.81 mmol
  • DIEA 701 mg, 5.42 mmol
  • HATU 825 mg, 2.17 mmol
  • Step 3 Synthesis of 5-chloro-N-(3-chloro-5-(4-chlorobutanamido)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide
  • N-(3-amino-5-chlorophenyl)-5-chloro-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide 200 mg, 0.5 mmol
  • TEA 151 mg, 1.5 mmol
  • 4-chlorobutanoyl chloride 84 mg, 0.6 mmol
  • Step 4 Synthesis of 5-chloro-N-(3-chloro-5-(2-oxopyrrolidin-1-yl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide
  • To a solution of 5-chloro-N-(3-chloro-5-(4-chlorobutanamido)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (100 mg, 0.2 mmol) in DMF (3 mL) was added NaH (9.5 mg, 60% in oil, 0.4 mmol).
  • Example 21 Synthesis of Compound 187 Step 1 Synthesis of 4-(3-chloro-5-nitrophenyl)-3-methylmorpholine To a solution of 1-bromo-3-chloro-5-nitrobenzene (1.0 g, 4.2 mmol), 3- methylmorpholine (0.42 g, 4.2 mmol), BINAP (0.52 g, 0.8 mmol) and Cs2CO3 (2.74 g, 8.4 mmol) in dioxane (10 mL) was added Pd(OAc)2 (0.09 g, 0.4 mmol), the mixture was stirred at 90 °C under N2 for 16 hours. LC-MS was checked, and the reaction was completed.
  • Example 22 Synthesis of Compound 172 To a mixture of 3-chloro-5-nitrobenzoic acid (1 g, 5.00 mmol) in DMF (10 mL) were added piperidine (0.47 g, 5.50 mmol), HATU (2.28 g, 6.00 mmol) and DIEA (1.29 g, 0.01 mol), then it was stirred at 25 °C for 2 hours under N2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL * 3), the organic layer was washed with brine (100 mL * 2), dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 23 Synthesis of Compound 148 To a solution of tert-butyl 4-formyl-1H-pyrazole-1-carboxylate (1.0 g, 5.1 mmol) in 20 mL MeOH was added TsNHNH 2 (0.95 g, 5.1 mol) portion wise and the mixture was stirred under nitrogen at 25 °C for 90 mins. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure to afford tert-butyl (E)-4-((2- tosylhydrazineylidene)methyl)-1H-pyrazole-1-carboxylate (1.8 g, 86% yield) as a white solid.
  • Step 2 Synthesis of 4-(3-bromo-5-chlorobenzyl)-1H-pyrazole To a solution of tert-butyl (E)-4-((2-tosylhydrazineylidene)methyl)-1H-pyrazole-1- carboxylate (1.64 g, 4.5 mmol) and (3-bromo-5-chlorophenyl)boronic acid (1.59 g, 6.8 mmol) in dioxane (40 mL) was added K2CO3 (0.93 g, 6.8 mmol). Then the temperature was raised to 110 °C and stirred at this temperature for 16 h. LC-MS was checked, and the reaction was completed.
  • Step 3 Synthesis of 4-(3-bromo-5-chlorobenzyl)-1H-pyrazole To a solution of 4-(3-bromo-5-chlorobenzyl)-1H-pyrazole (330 mg, 1.22 mmol) in THF (10 mL) was added sodium hydride (44 mg, 1.82 mmol, 60% in oil) at 0°C under nitrogen and the mixture was stirred at this temperature for 30 min. Then SEMCl (223mg, 1.34 mmol) was added to the mixture and the reaction mixture was stirred at 25 °C for 1 h. LC-MS was checked, and the reaction was completed.
  • sodium hydride 44 mg, 1.82 mmol, 60% in oil
  • Step 4 Synthesis of N-benzyl-3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)methyl)aniline
  • 4-(3-bromo-5-chlorobenzyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole 258 mg, 0.64 mmol
  • phenylmethanamine 103 mg, 0.96 mmol
  • t-BuOK 216 mg, 1.92 mmol
  • BINAP 80 mg, 0.13 mmol
  • Pd2(dba) 3 60 mg, 0.06 mmol
  • Step 5 Synthesis of 3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)methyl)aniline
  • N-benzyl-3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol- 4-yl)methyl)aniline 180 mg, 0.42 mmol
  • Pd/C 9 mg, 0.08 mmol
  • Step 6 Synthesis of 5-chloro-N-(3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)methyl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide
  • 3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)methyl)aniline 120 mg, 0.35 mmol
  • 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid 145 mg, 0.53 mmol
  • DIPEA 137 mg, 1.06 mmol
  • Example 24 Synthesis of Compound 157 Step 1 Synthesis of 4-(3-bromo-5-chlorobenzyl)-1-methyl-1H-pyrazole To a solution of 4-(3-bromo-5-chlorobenzyl)-1H-pyrazole (400 mg, 1.47 mmol) in DMF (10 mL) was added sodium hydride (53 mg, 2.21 mmol) portion wise at 0 °C under nitrogen and the mixture was stirred at this temperature for 30 min. Then MeI (251 mg, 1.77 mmol) was added dropwise and the mixture was stirred at 25 °C for 1 h. LC-MS was checked, and the reaction was completed.
  • Step 2 Synthesis of N-(3-chloro-5-((1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-1,1- diphenylmethanimine
  • 4-(3-bromo-5-chlorobenzyl)-1-methyl-1H-pyrazole 324 mg, 1.13 mmol
  • diphenylmethanimine 247 mg, 1.36 mmol
  • t-BuOK 382 mg, 3.40 mmol
  • BINAP 141 mg, 0.23 mmol
  • Pd2(dba) 3 104 mg, 0.11 mmol
  • Step 2 Synthesis of methyl 5-chloro-2-(5-methyl-1,1-dioxidoisothiazolidin-2-yl)isonicotinate
  • methyl 2-amino-5-chloroisonicotinate (0.68 g, 3.6 mmol) and triethylamine (1.11 g, 10.9 mmol) in DCM (10 mL)
  • 4-chlorobutane-2-sulfonyl chloride 1.2 g crude
  • Example 26 Synthesis of Compound 169 Step 1 Synthesis of (E/Z)-4-methyl-N'-(2-methyltetrahydro-4H-pyran-4- ylidene)benzenesulfonohydrazide To a solution of 2-methyloxan-4-one (1.00 g, 8.80 mmol) in MeOH (10 mL) was added 4-methylbenzenesulfonhydrazide (1.64 g, 8.80 mmol), then it was stirred at 25 °C for 0.5 h.
  • Step 2 Synthesis of 4-(3-chloro-5-nitrophenyl)-6-methyl-3,6-dihydro-2H-pyran/4-(3-chloro-5- nitrophenyl)-2-methyl-3,6-dihydro-2H-pyran
  • 1-bromo-3-chloro-5-nitrobenzene (1.23 g, 5.20 mmol)
  • (E/Z)-4- methyl-N'-(2-methyltetrahydro-4H-pyran-4-ylidene)benzenesulfonohydrazide (2.20 g, 7.80 mmol) in dioxane (12 mL) were added Pd(PPh3)2Cl2 (0.73 g, 1.00 mmol) and Cs2CO3 (3.39 g, 10.40 mmol), then it was stirred at 100 °C for 16 hours under N2 atmosphere.
  • Step 5 Synthesis of 5-chloro-N-(3-chloro-5-(2-methyltetrahydro-2H-pyran-4-yl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 169)
  • 3-chloro-5-(2-methyltetrahydro-2H-pyran-4-yl)aniline 60 mg, 0.27 mmol
  • 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid 88 mg, 0.32 mmol
  • DIEA 69 mg, 0.53 mmol
  • HATU 121 mg, 0.32 mmol
  • Example 27 Synthesis of Compound 161 Step 1 Synthesis of (E)-4-methyl-N'-((tetrahydro-2H-pyran-4- yl)methylene)benzenesulfonohydrazide To a solution of tetrahydro-2H-pyran-4-carbaldehyde (1 g, 8.8 mmol) in 8 mL MeOH was added TsNHNH 2 (1.64 g, 0.0088 mol) portion wise under nitrogen and the mixture was stirred at 25 °C for 90 mins. LC-MS was checked, and the reaction was completed.
  • Step 3 Synthesis of N-(3-chloro-5-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-1,1- diphenylmethanimine
  • 4-(3-bromo-5-chlorobenzyl)tetrahydro-2H-pyran 470 mg, 1.6 mmol
  • diphenylmethanimine 441 mg, 2.4 mmol
  • t-BuOK 546 mg, 4.87 mmol
  • BINAP 404 mg, 0.65 mmol
  • Pd 2 (dba) 3 297 mg, 0.32 mmol
  • Step 4 Synthesis of N-(3-chloro-5-(pyridin-2-ylmethyl)phenyl)-1,1-diphenylmethanimine
  • 2-(3-bromo-5-chlorobenzyl)pyridine 370 mg, 1.31 mmol
  • diphenylmethanimine 356 mg, 1.96 mmol
  • BINAP 163 mg, 0.26 mmol
  • t BuOK 220 mg, 1.96 mmol
  • Pd2(dba) 3 240 mg, 0.26 mmol
  • Step 6 Synthesis of 5-chloro-N-(3-chloro-5-(pyridin-2-ylmethyl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 156)
  • 3-chloro-5-(pyridin-2-ylmethyl)aniline 120 mg, 0.55 mmol
  • 5-chloro-2- (1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid 152 mg, 0.55 mmol
  • DIEA 142 mg, 1.10 mmol
  • HATU 250 mg, 0.66 mmol
  • Step 3 Synthesis of 4-(3-chloro-5-nitrophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole
  • NaH 32 mg, 60% in oil, 1.3 mmol
  • SEMCl 161 mg, 0.96 mmol
  • Step 4 Synthesis of 3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)oxy)aniline
  • 4-(3-chloro-5-nitrophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole 270 mg, 0.73 mmol
  • NH 4 Cl 195 mg, 3.64 mmol
  • Fe powder 203 mg, 3.64 mmol
  • Step 5 Synthesis of 5-chloro-N-(3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)oxy)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide
  • 3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)oxy)aniline 120 mg, 0.35 mmol
  • 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid 117 mg, 0.42 mmol
  • DIEA 136 mg, 1.06 mmol
  • Example 31 Synthesis of Compound 110 To a solution of 3-amino-5-bromobenzoic acid (5 g, 23.1 mmol) in 60 mL EtOH was added 4 mL con.H 2 SO 4 dropwise, the mixture was stirred at 80 °C for 1 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was quenched with sat. Na 2 CO 3 aq., the mixture was extracted with ethyl acetate (100 mL*3).
  • Step 2 Synthesis of ethyl 3-amino-5-(3,6-dihydro-2H-pyran-4-yl)benzoate
  • ethyl 3-amino-5-bromobenzoate 1.5 g, 6.1 mmol
  • 2-(3,6-dihydro-2H- pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.54 g, 7.32 mmol)
  • Step 4 Synthesis of ethyl 3-(5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamido)-5- (tetrahydro-2H-pyran-4-yl)benzoate (Compound 110)
  • 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid 300 mg, 1.08 mmol
  • 3-amino-5-(tetrahydro-2H-pyran-4-yl)benzoate 324 mg, 1.30 mmol
  • DIEA 420 mg, 3.25 mmol
  • HATU 824 mg, 2.17 mmol
  • Step 1 Synthesis of 3-(5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamido)-5-(tetrahydro- 2H-pyran-4-yl)benzoic acid
  • Example 33 In vitro efficacy assay of exemplary compounds
  • Exemplary compounds of the invention were evaluated for efficacy in inhibiting TDP-43 inclusions cellular imaging based assays.
  • the cellular model is in human neuroblastoma SH SY5Y cells (ATCC, cat#: CRL-2266).
  • the parent cell line was first engineered to stably express a tetracycline repressor protein (designated as TREx-SY5Y cells, customer cell line development by ThermoFisher). Wild-type human TDP-43 with a C-terminus eGFP tag was synthesized and cloned into pcDNA5/TO expression vector (ThermoFisher).
  • TDP- 43WT::eGFP The plasmid was transfected into TREx-SY5Y cells using Lipofectamine 2000 and hygromycin resistant colonies were selected. Expression of TDP- 43WT::eGFP was examined under fluorescent microscopy and Western blot upon tetracycline induction. The clone that is used for TDP-43 aggregation assay is referred to as SY5Y TDP- 43WT cells hereafter. Compound inhibition of TDP-43 aggregation was tested in an 8-point dose curve in 96- well format. Briefly, TDP-43WT::eGFP expression was induced with 1 uM tetracycline for 24 hrs (SY5Y TDP-43WT cells).
  • the cells were then pre-treated for 1 hour with exemplary compounds before adding sodium arsenite to a final concentration of 15 ⁇ M and incubated for another 23 hrs.
  • the cell monolayers were washed in PBS and fixed in 4% paraformaldehyde (PFA), diluted from 16% stock (Electron Microscopy Sciences cat: #15710-S).
  • PFA paraformaldehyde
  • the inhibitory effect on TDP-43 aggregation was measured using CellInsight CX7 high content imager (ThermoFisher).
  • the percentage of cells with TDP-43 aggregates was calculated based on the total number of cells identified by DAPI staining.
  • An 8-point dose response curve was generated, and the IC 50 for each compound tested was determined and is summarized in Table 3 below.
  • “A” indicates an IC 50 of less than 100 nM
  • “B” indicates an IC 50 range from 100 nM to 500 nM
  • “C” indicates an IC 50 range from 500 nM to 2 ⁇ M
  • “D” indicates an IC 50 greater than 2 ⁇ M.

Abstract

Herein, compounds, compositions and methods for modulating inclusion formation and stress granules in cells related to the onset of neurodegenerative diseases, musculoskeletal diseases, cancer, ophthalmological diseases, and viral infections are described.

Description

COMPOUNDS, COMPOSITIONS AND METHODS OF USE CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to United States Provisional Patent Application No.63/252,844, filed October 6, 2021. The contents of the foregoing application are hereby incorparted by reference in their entirety. FIELD OF THE INVENTION 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. BACKGROUND OF THE INVENTION One of the hallmarks of many neurodegenerative diseases is the accumulation of protein inclusions in the brain and central nervous system. These inclusions are insoluble aggregates of proteins and other cellular components that cause damage to cells and result in impaired function. Proteins such as tau, Į-synuclein, huntingtin and β-amyloid have all been found to form inclusions in the brain and are linked to the development of a number of neurodegenerative diseases, including Alzheimer’s disease and Huntington’s disease. Recently, the TDP-43 protein was identified as one of the major components of protein inclusions that typify the neurogenerative diseases Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Dementia with ubiquitin inclusions (FTLD-U) (Ash, P.E., et al. (2010) Hum Mol Genet 19(16):3206-3218; Hanson, K.A., et al. (2010) J Biol Chem 285:11068-11072; Li, Y., et al. (2010) Proc Natl Acad Sci U.S.A.107(7):3169-3174; Neumann, M., et al. (2006) Science 314:130-133; Tsai, K.J., et al. (2010) J Exp Med 207:1661-1673; Wils, H., et al. (2010) Proc Natl Acad Sci U.S.A.170:3858-3863). Abnormalities in 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 Neurosci 30:639-649; Gitcho, M.A., et al. (2008) Ann Neurol 63(4): 535-538; Johnson, B.S., et al. (2009) J Biol Chem 284:20329-20339; Ling, S.C., et al. (2010) Proc Natl Acad Sci U.S.A.107:13318-13323; Sreedharan, J., et al. (2008) Science 319:1668-1672). In addition, 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):e13250). 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. Currently, it is believed that aggregates that accumulate in neurodegenerative diseases like ALS, FTLD-U, Parkinson's disease and Huntington's disease accumulate slowly and are very difficult to disaggregate or perhaps can't be disaggregated. Thus, there is a need in the art for compostions and methods that can rapidly disaggregate these accumulating proteins, more specifically, TDP-43 and/or inhibit the formation of aggregates altogether. SUMMARY OF THE INVENTION In one aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I):
Figure imgf000003_0002
Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of the variables and subvariables thereof are described herein, for example, in the Detailed Description below. In some embodiments, the compound of Formula (I) is of Formula (Ia)
Figure imgf000003_0001
Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein each of the variables and subvariables thereof are described herein, for example, in the Detailed Description below. In some embodiments, the compound of Formula (I) is of Formula (Ib)
Figure imgf000004_0001
Formula (Ib) or a pharmaceutically acceptable salt thereof, wherein each of the variables and subvariables thereof are described herein, for example, in the Detailed Description below. In embodiments, a compound of Formula (I), (Ia), or (Ib) is formulated as a composition (e.g., a pharmaceutical composition). In another aspect, 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), (Ia), or (Ib) to a subject in need thereof. In another aspect, the invention provides methods of diagnosing 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), (Ia), or (Ib) to a subject. For use in diagnosis, the compound of Formula (I), (Ia), or (Ib) can be modified with a label. In another aspect, the invention provides methods of modulating stress granules comprising administering a compound of Formula (I), (Ia), or (Ib) to a cell or a subject in need thereof. In embodiments, the subject has 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 another aspect, the invention provides methods of modulating TDP-43 inclusion formation comprising administering a compound of Formula (I), (Ia), or (Ib) to a cell or a subject in need thereof. In embodiments, the subject has 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 another aspect, the invention provides a method of screening for modulators of TDP- 43 aggregation comprising contacting a compound of Formula (I), (Ia), or (Ib) with the cell that expresses TDP-43 and develops spontaneous inclusions. Still other objects and advantages of the invention will become apparent to those of skill in the art from the disclosure herein, which is simply illustrative and not restrictive. Thus, other embodiments will be recognized by the skilled artisan without departing from the spirit and scope of the invention. DETAILED DESCRIPTION OF THE INVENTION Amyotrophic lateral sclerosis (ALS), also known as 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). There is currently no therapy for ALS, and the average survival time of patients from the onset of the disease is roughly four years. 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). Studies over the past decade have indicated that 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. (2008) Science 319:1668-1672; Gitcho, M.A., et al. (2008) Ann Neurol 63(4):535-538; Neumann, M., et al. (2006) Science 314:130-133). Inhibitors of cell death and inclusions linked to TDP-43 represent a novel therapeutic approach to ALS, and may also elucidate the biochemical pathway linked to the formation of TDP-43 inclusions (Boyd, J.B., et al. (2014) J Biomol Screen 19(1):44-56). As such, 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., arsenite treatment, nutrient deprivation), TDP-43 can co- localize with SGs. The reversible nature of SG-based aggregation offers a biological pathway that might be applied to reverse the pathology and toxicity associated with TDP-43 inclusion formation. Studies show that agents that inhibit SG formation also inhibit formation of TDP-43 inclusions (Liu-Yesucevitz, L., et al. (2010) PLoS One 5(10):e13250). 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 SG process.. Investigating the particular elements of the SG pathway that regulate TDP-43 inclusion formation can identify selective approaches for therapeutic intervention to delay or halt the progression of disease. Stress granule biology also regulates autophagy and apoptosis, both of which are linked to neurodegeneration. Hence, compounds inhibiting TDP-43 aggregation may play a role in inhibiting neurodegeneration. Compounds Accordingly, in one aspect, the invention provides a compound of Formula (I):
Figure imgf000006_0001
Formula (I) or a pharmaceutically acceptable salt thereof, wherein: X is
Figure imgf000006_0002
Y is C=O or S(O)2; G is N or CR3; R2 is H, C1-C6 alkyl, C1-C6 haloalkyl, or halo; R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, or halo; wherein at least one of R2 and R3 is a substituent which is not H; R6 is H or C1-C6 alkyl optionally substituted with 1-4 R8; R7 is C1-C6 alkyl or -N(R10)-C1-C6 alkyl, each of which is optionally substituted with 1-4 R8; or R6 and R7, taken together with the atoms to which they are attached, form a 4-7 membered heterocycloalkyl ring, optionally substituted with 1-5 R8, wherein said heterocycloalkyl ring either includes no ring heteroatoms other than the N to which R6 is attached and in the Y group to which R7 is attached, or includes one additional N ring atom substituted with R10; each R8 is independently halo, C1-C6 alkyl, -ORB, -C(O)ORB, or C1-C6 haloalkyl; each R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, nitro, azido, C3-C7 cycloalkyl, hetercycloalkyl, aryl, heteroaryl, - ORB C(O)RD C(O)ORB NRARC NRAC(O)RD S(O) RE OS(O) RE C(O)NRAS(O) RE NRAS(O)xRE, or –S(O)xNRA; wherein each cycloalkyl, hetercycloalkyl, aryl, or heteroaryl is optionally substituted by 1-5 R11; each R10 is independently H, C1-C6 alkyl or C1-C6 haloalkyl; each R11 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, nitro, azido, oxo, cycloalkyl, -ORB, -C(O)RD, -C(O)ORB, -NRARC, -NRAC(O)RD, –S(O)xRE, –OS(O)xRE, –C(O)NRAS(O)xRE, –NRAS(O)xRE, or –S(O)xNRA each RA, RB, RC, RD, or RE is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, hetercycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with 1-4 R8; or RA and RC, together with the atoms to which each is attached, form a hetercycloalkyl ring optionally substituted with 1-4 R8; and x is 0, 1, or 2. In another aspect, the compound is of Formula (I):
Figure imgf000007_0001
Formula (I) or a pharmaceutically acceptable salt thereof, wherein: X is Y is C=O or S(O)2; G is N or CR3; R2 is H, C1-C6 alkyl, C1-C6 haloalkyl, or halo; R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, or halo; wherein at least one of R2 and R3 is a substituent which is not H; R6 is H or C1-C6 alkyl optionally substituted with 1-4 R8; R7 is C1-C6 alkyl, C3-C7 cycloalkyl, -N(R10)-C1-C6 alkyl, or -N(R10)-C3-C7 cycloalkyl, each of which is optionally substituted with 1-4 R8; or R6 and R7, taken together with the atoms to which they are attached, form a 4-7 membered heterocycloalkyl ring, optionally substituted with 1-5 R8, wherein said heterocycloalkyl ring either includes no ring heteroatoms other than the N to which R6 is attached and in the Y group to which R7 is attached, or includes one additional N ring atom substituted with R10 each R8 is independently halo, C1-C6 alkyl, -ORB, -C(O)ORB, or C1-C6 haloalkyl; each R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, nitro, azido, -ORB, -C(O)RD, -C(O)NRARC, -C(O)ORB, -NRARC, - NRAC(O)RD, –S(O)xRE, –OS(O)xRE, –C(O)NRAS(O)xRE, –NRAS(O)xRE, –S(O)xNRA, or -L-Z; L is a bond, -O-, -NRA-, or -(CH2)1-3-; Z is C3-C7 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each Z is optionally substituted by 1-5 R11; each R10 is independently H, C1-C6 alkyl or C1-C6 haloalkyl; each R11 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, nitro, azido, oxo, cycloalkyl, -ORB, -C(O)RD, -C(O)NRARC, - C(O)ORB, -NRARC , -NRAC(O)RD, –S(O)xRE, –OS(O)xRE, –C(O)NRAS(O)xRE, –NRAS(O)xRE, or –S(O)xNRA; or two R11, together with the atom to which they are attached, form C(O); each RA, RB, RC, RD, or RE is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, hetercycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with 1-4 R8; or RA and RC, together with the atoms to which each is attached, form a heterocycloalkyl ring optionally substituted with 1-4 R8; and x is 0, 1, or 2. In some embodiments, the compound is of Formula (Ia):
Figure imgf000008_0001
Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000008_0002
Y is C=O or S(O)2; R2 is H, C1-C6 alkyl, C1-C6 haloalkyl, or halo; R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, or halo; wherein at least one of R2 and R3 is not H; R6 is H or C1-C6 alkyl optionally substituted with 1-4 R8; R7 is C1-C6 alkyl, C3-C7 cycloalkyl, -N(R10)-C1-C6 alkyl, or -N(R10)- C3-C7 cycloalkyl, each of which is optionally substituted with 1-4 R8; or R6 and R7, taken together with the atoms to which they are attached, form a 4-7 membered heterocycloalkyl ring, optionally substituted with 1-5 R8, wherein said heterocycloalkyl ring either includes no heteroatoms other than the N to which R6 is attached and in the Y group to which R7 is attached, or includes one additional N ring atom substituted with R10; each R8 is independently halo, C1-C6 alkyl, -ORB, -C(O)ORB, or C1-C6 haloalkyl; each R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, nitro, azido, C3-C7 cycloalkyl, hetercycloalkyl, aryl, heteroaryl, - ORB, -C(O)RD, -C(O)NRARC, -C(O)ORB, -NRARC, -NRAC(O)RD, –S(O)xRE, –OS(O)xRE, – C(O)NRAS(O)xRE, –NRAS(O)xRE, –S(O)xNRA, or -L-Z; L is a bond, -O-, -NRA-, or -(CH2)1-3-; Z is C3-C7 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each Z is optionally substituted by 1-5 R11; each R10 is independently H, C1-C6 alkyl or C1-C6 haloalkyl; each R11 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, nitro, azido, oxo, cycloalkyl, -ORB, -C(O)RD, -C(O)NRARC, - C(O)ORB, -NRARC, -NRAC(O)RD, –S(O)xRE, –OS(O)xRE, –C(O)NRAS(O)xRE, –NRAS(O)xRE, or –S(O)xNRA; or two R11, together with the atom to which they are attached, form C(O); each RA, RB, RC, RD, or RE is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with 1-4 R8; or RA and RC, together with the atoms to which each is attached, form a hetercycloalkyl ring optionally substituted with 1-4 R8; and x is 0, 1, or 2. In some embodiments, X is
Figure imgf000010_0001
wherein m is 0, 1, 2, 3, or 4. In some embodiments, X is
Figure imgf000010_0002
wherein m is 0 or 1. In some embodiments, X is
Figure imgf000010_0003
. In some embodiments, m is 0. In some embodiments, R2 is Me or Cl. In some embodiments, R3 is H, Me, or Cl. In some embodiments, R2 is H and R3 is Me or Cl. In some embodiments, R2 is Me or Cl, and R3 is H or G is N. In some embodiments, the compound is of Formula (Ib):
Figure imgf000010_0004
Formula (Ib) or a pharmaceutically acceptable salt thereof, wherein each R8 is independently halo, C1-C6 alkyl, -ORB, -C(O)ORB, or C1-C6 haloalkyl; each R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, nitro, azido, C3-C7 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, - ORB, -C(O)RD, -C(O)NRARC, -C(O)ORB, -NRARC, -NRAC(O)RD, –S(O)xRE, –OS(O)xRE, – C(O)NRAS(O)xRE, –NRAS(O)xRE, –S(O)xNRA, or -L-Z; L is a bond, -O-, -NRA-, or -(CH2)1-3-; Z is C3-C7 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each Z is optionally substituted by 1-5 R11; each R11 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, nitro, azido, oxo, cycloalkyl, -ORB, -C(O)RD, -C(O)ORB, -NRARC, -NRAC(O)RD, –S(O)xRE, –OS(O)xRE, –C(O)NRAS(O)xRE, –NRAS(O)xRE, or –S(O)xNRA; or two R11, together with the atom to which they are attached, form C(O); each RA, RB, RC, RD, or RE is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with 1-4 R8. or RA and RC, together with the atoms to which each is attached, form a hetercycloalkyl ring optionally substituted with 1-4 R8; and x is 0, 1, or 2. In some embodiments, each R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -O-C1-C6 haloalkyl, C1-C6 haloalkyl, halo, cyano, C3-C7 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted by 1-5 R11. In some embodiments, at least one R9 group is methyl or chloro. In some embodiments, one R9 is chloro or methyl and the other R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, halo, cyano, C3-C7 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted by 1-5 R11. In some embodiments, one R9 is chloro, methyl, methoxy, CF3, -OCF3, or CN, and the other R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 alkoxy, C1-C6 haloalkyl, halo, cyano, C3-C7 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted by 1-5 R11.. In some embodiments, one R9 is chloro, methyl, methoxy, CF3, -OCF3, or CN, and the other R9 is phenyl, C3-C7 cycloalkyl, monocyclic 4-7 membered heterocycloalkyl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S), or monocyclic 5-6 membered heteroaryl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S); wherein the phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 R11. In some embodiments, one R9 is chloro and the other R9 is phenyl, C3-C7 cycloalkyl, monocyclic 4-7 membered heterocycloalkyl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S), or monocyclic 5-6 membered heteroaryl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S); wherein the phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 R11. In some embodiments, one R9 is chloro and the other R9 is C3-C7 cycloalkyl or monocyclic 4-7 membered heterocycloalkyl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S), wherein the cycloalkyl or heterocycloalkyl, is optionally substituted with 1-3 R11. In some embodiments, one R9 group is chloro and the other R9 group is selected from the group consisting of
Figure imgf000012_0001
wherein n is 0, 1, 2, 3, 4, or 5. In some embodiments, one R9 group is chloro and the other R9 group is selected from the group consisting of
Figure imgf000012_0002
wherein n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, the compound is
Figure imgf000012_0003
In some embodiments, heterocycloalkyl is monocyclic 4-7 membered heterocycloalkyl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S). In some embodiments, heteroaryl is monocyclic 5-6 membered heteroaryl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S); wherein the heterocycloalkyl or heteroaryl is optionally substituted with 1-3 R11. In some embodiments, L is a bond. In some embodiments, the compound of Formula (I), (Ia), or (Ib) is selected from a compound described in the specification. In another aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound disclosed herein. Deuterated Compounds In some embodiments, compounds described herein (e.g., some compounds of Formula (I), (Ia), or (Ib)) are deuterium-enriched. Deuterium (D or 2H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes 1H (hydrogen or protium), D (2H or deuterium), and T (3H or tritium). The natural abundance of deuterium is 0.015%. One of ordinary skill in the art recognizes that in all chemical compounds with a H atom, the H atom actually represents a mixture of H and D, with about 0.015% being D. Thus, compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015% should be considered unnatural and, as a result, novel over their non- enriched counterparts. The effects of deuterium modification on a compound’s metabolic properties are not predictable, even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated compound can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem.1991, 34, 2871-76). Many compounds have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each compound. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated specifically as “D” or “deuterium,” the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term”D” or “deuterium” indicates at least 45% incorporation of deuterium). The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance of D at the specified position in a compound of this invention and the naturally occurring abundance of that isotope. Increasing the amount of deuterium present in a compound (e.g., a compound of Formula (I), (Ia), or (Ib)) is called “deuterium-enrichment,” and such compounds are referred to as “deuterium-enriched” compounds. If not specifically noted, the percentage of enrichment refers to the percentage of deuterium present in the compound. In other embodiments, a compound of this invention has an isotopic enrichment factor for each deuterium present at a site designated at a potential site of deuteration on the compound of at least 3500 (52.5.% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent of other deuterated sites. For example, if there are two sites of deuteration on a compound one site could be deuterated at 52.5% while the other could be deuterated at 75%. The resulting compound would be considered to be a compound wherein the isotopic enrichment factor is at least 3500 (52.5%). Because the natural abundance of deuterium is about 0.015%, a small percentage of naturally occurring compounds of Formula (I), (Ia), or (Ib) would be expected to have one naturally occurring compound with one deuterium present. In some embodiments, the compounds of Formula (I), (Ia), or (Ib) comprise an amount of deuterium-enrichment that is more than the amount of deuterium-enrichment present in naturally occurring compounds of Formula (I), (Ia), or (Ib). All percentages given for the amount of deuterium present are mole percentages. It can be difficult in the laboratory to achieve 100% deuteration at any one site of a lab scale amount of compound (e.g., milligram or greater). When 100% deuteration is recited or a deuterium atom is specifically shown in a structure, it is assumed that a small percentage of hydrogen may still be present. Deuterium-enriched can be achieved by either exchanging protons with deuterium or by synthesizing the molecule with enriched starting materials. In some embodiments, the compound is a compound from Table 1. Table 1: Exemplary Compounds
Figure imgf000015_0001
Figure imgf000016_0001
15
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Methods of Use In the following methods, use of a compound of Formula (I), (Ia), or (Ib) can also refer to use of a pharmaceutical compistion including a compound of Formula (I), (Ia), or (Ib). In another aspect, the invention provides a method of modulating stress granule formation, the method comprising contacting a cell with a compound of Formula (I), (Ia), or (Ib) . In some embodiments, stress granule formation is inhibited. In some embodiments, the stress granule is disaggregated. In some embodiments, stress granule formation is stimulated. In some embodiments, a compound of Formula (I), (Ia), or (Ib) inhibits the formation of a stress granule. The compound of Formula (I), (Ia), or (Ib) can inhibit the formation of a stress granule by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at 32 least 70%, at least 80%, at least 90%, at least 95%, or 100% (i.e., complete inhibition) relative to a control. In some embodiments, a compound of Formula (I), (Ia), or (Ib) disaggregates a stress granule. The compound of Formula (I), (Ia), or (Ib) can disperses or disaggregate a stress granule 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. In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, the stress granule comprises tar DNA binding protein-43 (TDP- 43). In some embodiments, the stress granule comprises T-cell intracellular antigen 1 (TIA-1). In some embodiments, the stress granule comprises TIA-1 cytotoxic granule-associated RNA binding protein-like 1 (TIAR, TIAL1). In some embodiments, the stress granule comprises GTPase activating protein binding protein 1 (G3BP-1). In some embodiments, the stress granule comprises GTPase activating protein binding protein 2 (G3BP-2). In some embodiments, the stress granule comprises tris tetraprolin (TTP, ZFP36). In some embodiments, the stress granule comprises fused in sarcoma (FUS). In some embodiments, the stress granule comprises fragile X mental retardation protein (FMRP, FMR1). In another aspect, the invention provides a method of modulating TDP-43 inclusion formation, the method comprising contacting a cell with a compound of Formula (I), (Ia), or (Ib). In some embodiments, TDP-43 inclusion formation is inhibited. In some embodiments, the TDP- 43 inclusion is disaggregated. In some embodiments, TDP-43 inclusion formation is stimulated. In some embodiments, a compound of Formula (I), (Ia), or (Ib) inhibits the formation of a TDP-43 inclusion. The compound of Formula (I), (Ia), or (Ib) can inhibit the formation of 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 inhibition) relative to a control. In some embodiments, a compound of Formula (I), (Ia), or (Ib) disaggregates a TDP-43 inclusion. The compound of Formula (I), (Ia), or (Ib) 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. In another aspect, 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), (Ia), or (Ib) to a subject in need thereof. In some embodiments, 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. In some embodiments, 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. In some embodiments, the methods comprise administering a compound of Formula (I), (Ia), or (Ib) to a subject in need thereof. In some embodiments, the subject is a mammal. In some embodiments, the subject is a nematode. In some embodiments, the subject is human. In some embodiments, 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), (Ia), or (Ib). In some embodiments, 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), (Ia), or (Ib). In some embodiments, 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 (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.g., Werdnig-Hoffmann disease), SMA Type II, SMA Type III (e.g., Kugelberg-Welander disease), and congenital SMA with arthrogryposis), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post- polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease/motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam- Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler’s disease, Krabbe’s disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder’s disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform 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. In some embodiments, 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, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), hippocampal sclerosis, corticobasal degeneration, Alexander disease, Cockayne syndrome, and any combination thereof. In some embodiments, the neurodegenerative disease is frontotemporal dementia (FTD). In some embodiments, the neurodegenerative disease is Alzheimer's disease or amyotrophic lateral sclerosis (ALS). In some embodiments, 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. In some embodiments, compounds of Formula (I), (Ia), or (Ib) 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). In some embodiments, 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. In some embodiments, the cancer is selected from the group consisting of blastoma, carcinoma, a glioblastoma, hepatic carcinoma, lymphoma, leukemia, and any combination thereof. In some embodiments, 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, 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, Waldenström’s macroglobulinemia, hairy cell leukemia, and primary central nervous system (CNS) lymphoma) and a T-cell lymphoma (e.g., 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)). In some embodiments, the ophthalmological disease or disorder (e.g., retinal 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, 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. In some embodiments, the ophthalmological disease or disorder (e.g., retinal 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the viral infection is HIV-1 or HIV-2. In some embodiments, 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. In some embodiments, pathology of the disease or disorder comprises 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. In another aspect, 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), (Ia), or (Ib) to the subject. In some embodiments, the invention provides methods of diagnosing a neurodegenerative disease in a subject, the method comprising administering a compound of Formula (I), (Ia), or (Ib) to the subject. For use in diagnosis, a compound of Formula (I), (Ia), or (Ib) can be modified with a label. In another aspect, the invention provides methods of modulating stress granules comprising contacting a cell with a compound of Formula (I), (Ia), or (Ib). In another aspect, the invention provides methods of modulating TDP-43 inclusion formation comprising contacting a cell with a compound of Formula (I), (Ia), or (Ib). In some embodiments, TDP-43 is inducibly expressed. In some embodiments, the cell line is a neuronal cell line. In some embodiments, the cell is treated with a physiochemical stressor. In some embodiments, 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. In some embodiments, the physicochemical stressor is ultraviolet or x-ray radiation. In some embodiments, the physicochemical stressor is oxidative stress induced by FeCl2 or CuCl2 and a peroxide. In yet another aspect, the invention provides a method of screening for modulators of TDP-43 aggregation comprising contacting a compound of Formula (I), (Ia), or (Ib) with a cell that expresses TDP-43 and develops spontaneous inclusions. In some embodiments, the stress granule comprises TDP-43, i.e., is a TDP-43 inclusion. Accordingly, in some embodiments, a compound of Formula (I), (Ia), or (Ib) is a modulator of TDP-43 inclusions. In some embodiments, the subject is a mammal. In some embodiments, the subject is human. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. For instance, 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 communicate. Without wishing to be bound by a theory, the signaling systems that conpounds of Formula (I), (Ia), or (Ib) target may also modify these processes, which play a role in neurodegeneration or mental health illnesses (e.g., schizophrenia). 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. In some embodiments, the TDP-43 protein in a stress granule may be wild-type or a mutant form of TDP-43. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, post-translational modification of the TDP-43 protein in a stress granule may be modulated by treatment with a compound of the invention. Methods of Treatment Neurodegenerative diseases: Without wishing to be bound by a theory, compounds of Formula (I), (Ia), or (Ib) 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. Because modulators of TDP-43 inclusions, such as compounds of Formula (I), (Ia), or (Ib), can act to block the enzymes that signal stress granule formation (e.g., the three enzymes that phosphorylate eIF2a: PERK, GCN2 and HRI), compounds of Formula (I), (Ia), or (Ib) may also reverse stress granules that might not include TDP-43. Accordingly, compounds of Formula (I), (Ia), or (Ib) 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), (Ia), or (Ib) may also be used for treatment of neurodegenerative diseases and disorders that involve TDP-43 multisystem proteinopathy. The term “neurodegenerative disease” as used herein, 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 α- synucleopathies. Exemplary neurodegenerative diseases include, but are not limited to, Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with dementia (ALSD), Huntington's disease (HD), Huntington’s chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive 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.g., Werdnig-Hoffmann disease) SMA Type II, SMA Type III (e.g., Kugelberg-Welander disease), and congenital SMA with arthrogryposis), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase- associated neurodegeneration (PANK), spinal degenerative disease/motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, Lytigo-bodig (amyotrophic lateral sclerosis- parkinsonism dementia), Guam-Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler’s disease, Krabbe’s disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Schilder’s disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome, hereditary spastic paraparesis, Leigh’s syndrome, demyelinating diseases, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury) and autism. As used herein, the term "α-synucleopathy" refers to a neurodegenerative disorder or disease involving aggregation of α-synuclein or abnormal α-synuclein in nerve cells in the brain (Ostrerova, N., et al. (1999) J Neurosci 19:5782:5791; Rideout, H.J., et al. (2004) J Biol Chem 279:46915-46920). α-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. As used herein, the term “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: 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). As such, compounds of Formula (I), (Ia), or (Ib) 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. 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. In addition, compounds of Formula (I), (Ia), or (Ib) 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. In some embodiments, a musculoskeletal disease or a symptom of a musculoskeletal disease may overlap with a neurodegenerative disease or a symptom of a neurodegenerative disease. Cancers: Cancer cells grow quickly and in low oxygen environments by activating different elements of the cellular stress response. Researchers have shown that drugs targeting different elements of the stress response can be anti-neoplastic. For example, 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. Without wishing to be bound by a theory, compounds of Formula (I), (Ia), or (Ib) 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). Additionally, TDP-43 modulators can be combined with one or more cancer therapies, such as chemotherapy and radiation therapy. A "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. Often, 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. In some circumstances, 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. Other exemplary 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, ovary (germ cell) cancer, prostate cancer, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, soft-tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer of the vulva, Wilm's tumor, and the like. 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, 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, Waldenström’s macroglobulinemia, hairy cell leukemia, and primary central nervous system (CNS) lymphoma) and T-cell lymphomas (e.g., 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)). Ophthalmological diseases: Ophthalmological diseases and disorders (e.g., retinal diseases and disorders) as defined herein affect the retina and other parts of the eye and may contribute to impaired vision and blindness. Several ophthalmological diseases (e.g., retinal 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. In addition, an ophthalmological disease (e.g., retinal disease) may also be a symptom of or precursor to neurogenerative diseases, such as ALS and FTD (Ward, M.E., et al. (2014) J Exp Med 211(10):1937). Therefore, use of compounds that may inhibit formation of protein inclusions and stress granules, including compounds of Formula (I), (Ia), or (Ib), may play an important role in the prevention or treatment of ophthalmological diseases (e.g., retinal diseases). Exemplary ophthalmological diseases (e.g., retinal 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, ophthalmoplegia, and the like. 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. Acad. Sci. USA 104(21): 9041-9046). Therefore, use of compounds that may inhibit formation of protein inclusions and stress granules, including compounds of Formula (I), (Ia), or (Ib), may be useful for the prevention and/or treatment of a viral infection. Exemplary 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 Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. Unless explicitly stated otherwise, or apparent from context, the terms and phrases below do not exclude the meaning that the term or phrase has acquired in the art to which it pertains. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. As used herein, the terms “compounds” and “agent” are used interchangeably to refer to the inhibitors/antagonists/agonists of the invention. In certain embodiments, 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. In certain embodiments, one class of small organic or inorganic molecules are non- peptidyl, e.g., containing 2, 1, or no peptide and/or saccharide linkages. Unless otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” The term “about” when used in connection with percentages may mean ±1%. The singular terms “a,” “an,” and “the” refer to one or to more than one, unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. As used herein, the term “administer” refers to the placement of a composition into a subject by a method or route which results in at least partial localization of the composition at a desired site such that desired effect is produced. A compound or composition described herein can be administered by any appropriate route known in the art including, but not limited to, oral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, nasal, rectal, intrathecal, and topical (including buccal and sublingual) administration. The terms “decrease”, “reduced”, “reduction” , “decrease” or “inhibit” are all used herein generally to mean a decrease by a statistically significant amount. In some embodiments, the terms “reduced”, “reduction”, “decrease” or “inhibit” mean a decrease by at least 0.1% as compared to a reference level, for example a decrease by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g. 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. In some embodiments, the terms “increased”, “increase”, “enhance” or “activate” mean an increase by at least 0.1% as compared to a reference level, for example a decrease by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase (e.g. absent level as compared to a reference sample), or any increase between 1-100%, e.g., 10-100% as compared to a reference level. By “treatment”, “prevention” or “amelioration” of a disease or disorder is meant 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. In one embodiment, at least one symptom of a disease or disorder is alleviated by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%. As used herein, an amount of a compound or combination effective to treat a disorder (e.g., a disorder as described herein), “therapeutically effective amount” or “effective amount” 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. As used herein, 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., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon. Patient or subject includes any subset of the foregoing, e.g., all of the above, but excluding one or more groups or species such as humans, primates or rodents. In certain embodiments, the subject is a mammal, e.g., a primate, e.g., a human. The terms, “patient” and “subject” are used interchangeably herein. The terms, “patient” and “subject” are used interchangeably herein. The term "nucleic acid" as used herein refers to a polymeric form of 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. As used herein, the terms “modulator of stress granule” and “stress granule modulator” refer to compounds and compositions of Formula (I), (Ia), or (Ib) that modulate the formation and/or disaggregation of stress granules. The term “TDP-43 inclusion” as used herein refers to protein aggregates that comprise TDP-43 proteins. The TDP-43 protein in the inclusion can be wild-type or a mutant form of TDP-43. As used herein, the terms “modulator of TDP-43 inclusion” and “TDP-43 inclusion modulator” refer to compounds and compositions of Formula (I), (Ia), or (Ib) that modulate the formation and/or disaggregation of cytoplasmic TDP-43 inclusions. Selected Chemical Definitions At various places in the present specification, 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. For example, the term “C1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl and hexyl. For compounds of the invention in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the Markush group defined for R. It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. If a compound of the present invention is depicted in the form of a chemical name and as a formula, in case of any discrepancy, the formula shall prevail. The symbol , whether utilized as a bond or displayed perpendicular to a bond indicates the point at which the displayed moiety is attached to the remainder of the molecule, solid support, etc. The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. As used herein, “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 (“C1-C8 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”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-C4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-C3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-C2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2- C6alkyl”). Examples of C1-C6alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert–butyl (C4), sec–butyl (C4), iso–butyl (C4), n–pentyl (C5), 3– pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2–butanyl (C5), tertiary amyl (C5), and n– hexyl (C6). Additional examples of alkyl groups include n–heptyl (C7), n–octyl (C8) 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. In certain embodiments, the alkyl group is unsubstituted C1–10 alkyl (e.g., –CH3). In certain embodiments, the alkyl group is substituted C1–6 alkyl. As used herein, “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”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-C10 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-C8 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-C6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-C5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-C4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-C3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 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 C2-C4 alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1– butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), 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. In certain embodiments, the alkenyl group is unsubstituted C2–10 alkenyl. In certain embodiments, the alkenyl group is substituted C2–6 alkenyl. As used herein, the term “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 (“C2-C24 alkenyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-C10 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-C8 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-C6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-C5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-C4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-C3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1– butynyl (C4), 2–butynyl (C4), 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. In certain embodiments, the alkynyl group is unsubstituted C2–10 alkynyl. In certain embodiments, the alkynyl group is substituted C2–6 alkynyl. As used herein, the term "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. Exemplary heteroalkyl groups include, but are not limited to: -CH2-CH2-O-CH3, -CH2-OH, - CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -NHCH2-, -C(O)NH- , -C(O)N(CH3), -C(O)N(CH2CH3)-, -C(O)N(CH2CF3)-, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, - CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2- CH3. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH- OCH3 and -CH2-O-Si(CH3)3. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as –CH2O-, –NRCRD, or the like, it will be understood that the terms heteroalkyl and –CH2O- or –NRCRD 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 –CH2O-, –NRCRD, or the like. As used herein, “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 ʌ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“ C6-C14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). An aryl group may be described as, e.g., a C6-C10-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. In certain embodiments, the aryl group is unsubstituted C6-C14 aryl. In certain embodiments, the aryl group is substituted C6-C14 aryl. As used herein, “heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π 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”). In 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. In some embodiments, 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”). In some embodiments, 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”). In some embodiments, 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”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, 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, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. 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. “heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more heterocycloalkyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of carbons continue to designate the number of carbons in the heteroaryl ring system. Exemplary ring systems of this type include 7,8-dihydro-5H-pyrano[4,3-b]pyridine and 1,4,6,7-tetahydropyrano[4,3-b]pyrrole. As used herein, “cycloalkyl” refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-C10 cycloalkyl”) and zero heteroatoms in the non–aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-C8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-C10 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 C3-C6 cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, without limitation, the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C10 cycloalkyl groups include, without limitation, the aforementioned C3-C8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, 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. In certain embodiments, the cycloalkyl group is unsubstituted C3-C10 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-C10 cycloalkyl. “Heterocycloalkyl” as used herein 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 hetercycloalkyl”). In heterocycloalkyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A hetercycloalkyl group can either be monocyclic (“monocyclic hetercycloalkyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic hetercycloalkyl), and can be saturated or can be partially unsaturated. Heterocycloalkyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocycloalkyl” also includes ring systems wherein the hetercycloalkyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or hetercycloalkyl ring, or ring systems wherein the hetercycloalkyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the hetercycloalkyl or aryl or heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the hetercycloalkyl ring system. A hetercycloalkyl group may be described as, e.g., a 3-7-membered hetercycloalkyl, 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 hetercycloalkyl may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted hetercycloalkyl”) or substituted (a “substituted hetercycloalkyl”) with one or more substituents. In certain embodiments, the hetercycloalkyl group is unsubstituted 3–10 membered hetercycloalkyl. In certain embodiments, the hetercycloalkyl group is substituted 3–10 membered hetercycloalkyl. In some embodiments, a hetercycloalkyl 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 hetercycloalkyl”). In some embodiments, a hetercycloalkyl 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 hetercycloalkyl”). In some embodiments, a hetercycloalkyl 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 hetercycloalkyl”). In some embodiments, the 5–6 membered hetercycloalkyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered hetercycloalkyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered hetercycloalkyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary 3–membered hetercycloalkyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4–membered hetercycloalkyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered hetercycloalkyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5–dione. Exemplary 5–membered hetercycloalkyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin–2–one. Exemplary 5–membered hetercycloalkyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered hetercycloalkyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered hetercycloalkyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6–membered hetercycloalkyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered hetercycloalkyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered hetercycloalkyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5–membered hetercycloalkyl groups fused to a C6 aryl ring (also referred to herein as a 5,6–bicyclic hetercycloalkyl ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6– membered hetercycloalkyl groups fused to an aryl ring (also referred to herein as a 6,6–bicyclic hetercycloalkyl ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. As used herein, “cyano” refers to the radical –CN. As used herein, “halo” or “halogen,” independently or as part of another substituent, mean, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. As used herein, “haloalkyl” can include alkyl structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” includes haloalkyl groups in which the halo is fluorine (e.g., -C1-C6 alkyl-CF3, -C1-C6 alkyl-C2F). Non- limiting examples of haloalkyl include trifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl, diflurormethyl, and fluroisopropyl. As used herein, “hydroxy” refers to the radical –OH. As used herein, “nitro” refers to –NO2. As used herein, “oxo” refers to =O, in which both bonds from the oxygen are connected to the same atom. For example, a carbon atom substituted with oxo froms a carbonyl group - C=O. Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or hetercycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring- forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, 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. For example, 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., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. As used herein, a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, 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. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R–compound. In certain embodiments, the enantiomerically pure R–compound in such compositions can, for example, comprise, at least about 95% by weight R–compound and at most about 5% by weight S–compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S–compound. In certain embodiments, 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. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier. Compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D or deuterium), and 3H (T or tritium); C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 16O and 18O; and the like. Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., the ability to inhibit the formation of TDP-43 inclusions), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound. In general, 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. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Also for purposes of this invention, the term "hydrocarbon" is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted. Pharmaceutical Compositions and Routes of Administration Pharmaceutical compositions containing compounds described herein such as a compound of Formula (I), (Ia), or (Ib) 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. The amount and concentration of compounds of Formula (I), (Ia), or (Ib) 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. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition), where the compound is combined with one or more pharmaceutically acceptable diluents, excipients or carriers. The compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine. In certain embodiments, 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. Regardless of the route of administration selected, 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. Thus, another aspect of the present invention provides pharmaceutically acceptable 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. As described in detail below, 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., those targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) transmucosally; (9) nasally; or (10) intrathecally. Additionally, compounds can be implanted into a patient or injected using a drug delivery system. See, for example, Urquhart, et al., (1994) Ann Rev Pharmacol Toxicol 24:199-236; Lewis, ed. “Controlled Release of Pesticides and Pharmaceuticals” (Plenum Press, New York, 1981); U.S. Patent No.3,773,919; and U.S. Patent No.353,270,960. The phrase "therapeutically effective amount" as used herein 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. The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" as used herein mean 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. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, 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. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins such as Captisol®; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. The term "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. When compounds of the present invention contain relatively acidic functionalities, 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. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are 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. 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. Examples of pharmaceutically acceptable antioxidants 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. Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. 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. In general, 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. A compound of the present invention may also be administered as a bolus, electuary or paste. In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical 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, such as dragees, capsules, pills and granules, 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. They may be sterilized by, for example, filtration through a bacteria- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. 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. Examples of 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. In addition to the active ingredient, 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. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations of the pharmaceutical compositions of the 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. Alternatively or additionally, 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, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. 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. In some embodiments, the compositions are administered by intravenous infusion or injection. The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and 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 pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention 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. 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. These 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. In some cases, 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. When 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. Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed. The way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as "Applied Animal Nutrition", W.H. Freedman and CO., San Francisco, U.S.A., 1969 or "Livestock Feeds and Feeding" O and B books, Corvallis, Ore., U.S.A., 1977). 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. Preferably, the subject is a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but are not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of disorders associated with neurodegenerative disease or disorder, cancer, or viral infections. In addition, the methods described herein can be used to treat domesticated animals and/or pets. A subject can be male or female. A subject can be one who has been previously diagnosed with or identified as suffering from or having a neurodegenerative disease or disorder, 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. Dosages 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. For example, 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). When administrated 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. When the inhibitor and the pharmaceutically active agent are administered in different pharmaceutical compositions, 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 LD50 (the dose lethal to 50% of the population) and the ED50 (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 LD50/ED50. 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 ED50 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 IC50 (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. Generally, the compositions are administered so that the compound of Formula (I), (Ia), or (Ib) 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 μg/kg to 100 mg/kg, 1 μg/kg to 50 mg/kg, 1 μg/kg to 20 mg/kg, 1 μg/kg to 10 mg/kg, 1 μg/kg to 1 mg/kg, 10 μg/kg to 10 mg/kg, 10 μg/kg to 50 mg/kg, 10 μg/kg to 20 mg/kg, 10 μg/kg to 10 mg/kg, 10 μg/kg to 1 mg/kg, 100 μg/kg to 50 mg/kg, 100 μg/kg to 20 mg/kg, 1 mg/kg to 100 mg/kg, 1 mg/kg to 50 mg/kg, 1 mg/kg to 20 mg/kg, 1 mg/kg to 10 mg/kg, 1 μg/kg to 10 mg/kg, 10 mg/kg to 100 mg/kg, 10 mg/kg to 50 mg/kg, 10 mg/kg to 20 mg/kg, or 50 mg/kg to 100 mg/kg. It is to be understood that 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. It is to be further undertood that the 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. With respect to duration and frequency of treatment, it is typical for skilled clinicians to monitor subjects in order to determine when the treatment is providing therapeutic benefit, and to determine whether to increase or decrease dosage, increase or decrease administration frequency, discontinue treatment, resume treatment or make other alteration to treatment regimen. 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. Such sub-doses can be administered as unit dosage forms. In some embodiments, administration is chronic, e.g., one or more doses daily over a period of weeks or months. Examples of dosing schedules 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. EXAMPLES Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results. General. All oxygen and/or moisture sensitive reactions were carried out under N2 atmosphere in glassware that was flame-dried under vacuum (0.5 mmHg) and purged with N2 prior to use. All reagents and solvents were purchased from commercial vendors and used as received, or synthesized according to the footnoted references. NMR spectra were recorded on a Bruker 400 (400 MHz 1H, 75 MHz 13C) or Varian (400 MHz 1H, 75 MHz 13C) spectrometer. Proton and carbon chemical shifts are reported in ppm (į) referenced to the NMR solvent. Data are reported as follows: chemical shifts, multiplicity (br = broad, s = singlet, t = triplet, q = quartet, m = multiplet; coupling constant (s) in Hz). Unless otherwise indicated NMR data were collected at 25 °C. Flash chromatography was performed using 100-200 mesh Silica Gel. Liquid Chromatography/Mass Spectrometry (LCMS) was performed on Agilent 1200HPLC and 6110MS. Analytical thin layer chromatography (TLC) was performed on 0.2 mm silica gel plates. Visualization was accomplished with UV light and aqueous potassium permanganate (KMnO4) stain followed by heating. Table 2: Abbreviations
Figure imgf000070_0001
Figure imgf000070_0002
EXAMPLE 1. Synthesis of 2-amino-5-chloro-N-(3-chloro-5- cyclopropylphenyl)isonicotinamide (Compound 101)
Figure imgf000071_0001
Scheme 1 Synthesis of Compound 101 Step 1 Synthesis of methyl 2-((tert-butoxycarbonyl)amino)-5-chloroisonicotinate
Figure imgf000071_0002
To the solution of methyl 2-amino-5-chloropyridine-4-carboxylate (300 mg, 1.6078 mmol) in DCM (12 mL) were added Boc2O (526.4 mg, 2.4116 mmol) and TEA (488.1 mg, 4.8233 mmol). The mixture was stirred at 45 °C for 16 h. After the reaction, the mixture was cooled to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography to give the desired product (310 mg, 63.66% yield) as a yellow solid. LCMS (ESI) calcd for C12H16ClN2O4+ [M + H]+ m/z 287, found 287. Step 2 Synthesis of 2-((tert-butoxycarbonyl)amino)-5-chloroisonicotinic acid
Figure imgf000071_0003
To the solution of methyl 2-((tert-butoxycarbonyl)amino)-5-chloroisonicotinate (260 mg, 0.9037 mmol) in MeOH (16 mL) was added LiOH (216.89 mg, 9.0369 mmol). The mixture was stirred at room temperature for 16 h. After the reaction, the mixture was concentrated under reduced pressure and diluted with H2O (10 ml). To this residue was added aqueous 1N HCl aq. to adjust pH = 3 ~ 4 at 0 °C and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product (235 mg, 85.52% yield) as a yellow solid. LCMS (ESI) calcd for C11H14ClN2O4+ [M + H]+ m/z 273, found 273. Step 3 Synthesis of tert-butyl(5-chloro-4-((3-chloro-5-cyclopropylphenyl)carbamoyl)pyridin-2- yl)carbamate
Figure imgf000072_0001
To the solution of 2-((tert-butoxycarbonyl)amino)-5-chloroisonicotinic acid (220 mg, 0.8038 mmol) in DMF (3 mL) were added 3-chloro-5-cyclopropylaniline (134.8 mg, 0.8038 mmol), HATU (458.5 mg, 1.2057 mmol) and DIEA (519.4 mg, 4.019 mmol). The mixture was stirred at room temperature for 16 h. After the reaction, the resulting mixture was diluted with H2O (16 mL) and extracted with ethyl acetate (3*20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/ethyl acetate =1/1) to give the desired product (210 mg, 55.55% yield) as a yellow solid. LCMS (ESI) calcd for C16H14Cl2N3O3 + [M – tBu + H]+ m/z 366.0, found 366.0. Step 4 Synthesis of 2-amino-5-chloro-N-(3-chloro-5-cyclopropylphenyl)isonicotinamide (Compound 101)
Figure imgf000072_0002
To the solution of tert-butyl(5-chloro-4-((3-chloro-5- cyclopropylphenyl)carbamoyl)pyridin-2-yl)carbamate (210 mg, 0.4961 mmol) in DCM (5 mL) was added TFA (848.48 mg, 7.4415 mmol). The mixture was stirred at room temperature for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure to give the desired product (150 mg, 89.15% yield) as a yellow solid. LCMS (ESI) calcd for C15H14Cl2N3O + [M + H]+ m/z 322.1, found 322.0. 1H NMR (400 MHz, DMSO δ) 10.70 (s, 1H), 8.06 (s, 1H), 7.62 (s, 1H), 7.29 (s, 1H), 6.92 (s, 1H), 6.63 (s, 1H), 2.00 – 1.88 (m, 1H), 1.03 – 0.92 (m, 2H), 0.72 – 0.63 (m, 2H). Example 2: Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 102)
Figure imgf000073_0001
Scheme 2 Synthesis of Compound 102 Step 1 Synthesis of methyl 5-chloro-2-((3-chloropropyl)sulfonamido)isonicotinate
Figure imgf000073_0002
To the solution of methyl 2-amino-5-chloropyridine-4-carboxylate (300 mg, 1.6078 mmol) in DCM (8 mL) were added triethylamine (244.04 mg, 2.4117 mmol) and 3- chloropropane-1-sulfonyl chloride (853.98mg, 4.8234 mmol) at 0 °C. The mixture was stirred at rt for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure to afford the desired product (420 mg, 75.84% yield) as a yellow oil. LCMS (ESI) calcd for C10H13Cl2N2O4S + [M + H]+ m/z 327, found 327. Step 2 Synthesis of methyl 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinate
Figure imgf000074_0001
To the solution of methyl 5-chloro-2-((3-chloropropyl)sulfonamido)isonicotinate (400 mg, 1.2226 mmol) in MeOH (6 mL) was added TEA (185.6 mg, 1.8338 mmol).The mixture was stirred at 80 °C for 16 h. After the reaction, the mixture was cooled to room temperature, the resulting mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography to give the desired product (320 mg, 81.02% yield) as a yellow solid. LCMS (ESI) calcd for C10H12ClN2O4S + [M + H]+ m/z 291, found 291. Step 3 Synthesis of 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid
Figure imgf000074_0002
To the solution of methyl 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinate (270 mg, 0.9287 mmol) in MeOH (16 mL) was added LiOH (111.2 mg, 4.6435 mmol).The mixture was stirred at room temperature for 16 h. After the reaction, the mixture was concentrated under reduced pressure and diluted with H2O (10 ml). To this residue was added aqueous 1N HCl aq. to adjust pH= 3 ~ 4 at 0 °C and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product (190 mg, 66.54% yield) as a yellow solid. LCMS (ESI) calcd for C9H10ClN2O4S + [M + H]+ m/z 277, found 277. Step 4 Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide (Compound 102)
Figure imgf000075_0002
Figure imgf000075_0001
To the solution of 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (170 mg, 0.6144 mmol) in DMF (2 mL) were added 3-chloro-5-cyclopropylaniline (103 mg, 0.6144 mmol), HATU (350.4 mg, 0.9216 mmol) and DIEA (397.0 mg, 3.0719 mmol). The mixture was stirred at room temperature for 16 h. After the reaction, the resulted mixture was diluted with H2O (16 mL) and extracted with ethyl acetate (3*20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/ethyl acetate = 1:1) to give the desired product (120 mg, 43.52% yield) as a yellow solid. LCMS (ESI) calcd for C18H18Cl2N3O3S + [M + H]+ m/z 426, found 426. 1H NMR (400 MHz, DMSO) į 10.83 (s, 1H), 8.54 (s, 1H), 7.62 (s, 1H), 7.26 (d, J = 13.2 Hz, 2H), 6.95 (s, 1H), 3.90 (t, J = 6.4 Hz, 2H), 3.62 (t, J = 7.2 Hz, 2H), 2.41 (m, 2H), 2.03 – 1.89 (m, 1H), 1.06 – 0.94 (m, 2H), 0.74 – 0.63 (m, 2H). Example 3: Synthesis of 5-chloro-N-(3-chloro-5-(tetrahydro-2H-pyran-4-yl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 103)
Figure imgf000076_0001
Scheme 3 Synthesis of Compound 103 Step 1 Synthesis of 3-chloropropane-1-sulfonyl chloride (2)
Figure imgf000076_0002
To a solution of 1,2-oxathiolane 2,2-dioxide (5.0 g, 41 mmol) in SOCl2 (15 mL) was added DMF (300 mg, 4.1 mmol). The mixture was stirred at 80°C for 16 hrs. After the reaction, the mixture was cooled to room temperature, the resulting mixture was concentrated under reduced pressure to give 3-chloropropane-1-sulfonyl chloride (7.0 g, 91.75% yield) as a yellow oil. Step 2 Synthesis of methyl 5-chloro-2-((3-chloropropyl)sulfonamido)isonicotinate
Figure imgf000076_0003
To a solution of methyl 2-amino-5-chloropyridine-4-carboxylate (1.18 g, 6.32 mmol) in DCM (50 mL) were added TEA (3.84 g, 38 mmol) and 3-chloropropane-1-sulfonyl chloride (3.36 g, 18.9 mmol). The mixture was stirred at room temperature for 2 hrs. The resulting mixture was concentrated under reduced pressure to afford methyl 5-chloro-2-((3- chloropropyl)sulfonamido)isonicotinate (4.0 g, crude) as a yellow solid. Step 3 Synthesis of methyl 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinate
Figure imgf000077_0001
A solution of methyl 5-chloro-2-((3-chloropropyl)sulfonamido)isonicotinate (4.0 g crude) and TEA (3.71 g, 36.6 mmol) in MeOH (50 mL) was stirred at 80 °C for 4 hrs. After the reaction, the mixture was cooled to room temperature, the resulting mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography using petroleum ether / ethyl acetate = 1/1 as eluent to afford methyl 5-chloro-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinate (1.6 g, 42.8% yield) as a yellow solid. LCMS (ESI) calcd for C11H13ClNO4S+ [M + H]+ m/z 291.02, found 291.0. Step 4 Synthesis of 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid
Figure imgf000077_0002
To a solution of methyl 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinate (1.6 g, 5.5 mol) in MeOH (30 mL) was added LiOH (1.32 g, 55 mmol), the mixture was stirred at room temperature for 16 hrs. After the reaction, the mixture was concentrated under reduced pressure and diluted with H2O (100 mL), which was acidified with 1N HCl aq. to adjust pH = 3 - 4, the mixture was extracted with EtOAc 3 times. Combined with EtOAc phases, washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure to afford the desired product, which was dried under reduced pressure to give 5-chloro-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinic acid (1.056 g, 65.9% yield) as a yellow solid. LCMS (ESI) calcd for C9H10ClN2O4S+ [M + H]+ m/z 277.00, found 277.1. Step 5 Synthesis of 5-chloro-N-(3-chloro-5-(tetrahydro-2H-pyran-4-yl)phenyl)-2-(1,1-
Figure imgf000078_0001
To a solution of 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (300 mg, 1.08 mmol) in DMF (20 mL) were added 3-chloro-5-(oxan-4-yl)aniline (229.5 mg, 1.08 mmol), DIEA(420.4 mg, 3.25 mmol) and HATU (494.7 mg, 1.3 mmol). The mixture was stirred at room temperature for 2 hrs. After the reaction, the resulting mixture was diluted with H2O (100 ml) and extracted with EtOAc 3 times. Combined with organic layers, washed with brine (50 mL), dried over Na2SO4 and filtered, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography using petroleum ether / ethyl acetate = 1/1 as eluent to afford 5-chloro-N-(3-chloro-5-(tetrahydro-2H-pyran-4-yl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (40 mg, 7.84% yield) as a white solid. LCMS (ESI) calcd for C20H22Cl2N3O4S+ [M + H]+ m/z 470.06, found 470.2. 1H NMR (400 MHz, DMSO δ) 10.90 (s, 1H), 8.54 (s, 1H), 7.70 (s, 1H), 7.48 (s, 1H), 7.26 (s, 1H), 7.14 (s, 1H), 3.98 – 3.92 (m, 2H), 3.90 (d, J = 6.5 Hz, 2H), 3.62 (t, J = 7.2 Hz, 2H), 3.42 (t, J = 11.4 Hz, 2H), 2.79 (dd, J = 15.8, 7.6 Hz, 1H), 2.42 (p, J = 6.8 Hz, 2H), 1.71 (d, J = 11.7 Hz, 2H), 1.67 – 1.57 (m, 2H). Example 4: Synthesis of 2-acetamido-5-chloro-N-(3-chloro-5- cyclopropylphenyl)isonicotinamide (Compound 104)
Figure imgf000079_0002
Scheme 4 Synthesis of Compound 104 Step 1 Synthesis of tert-butyl(5-chloro-4-((3-chloro-5-cyclopropylphenyl)carbamoyl)pyridin-2- yl)carbamate
Figure imgf000079_0001
To a solution of 2-((tert-butoxycarbonyl)amino)-5-chloroisonicotinic acid (2 g, 7.3 mmol) in DMF (30 mL) were added 3-chloro-5-cyclopropylaniline (1.23 g, 7.3 mmol), HATU (4.18 g, 11 mmol) and DIEA (4.74 g, 36.6 mmol). The mixture was stirred at room temperature for 16 h. After the reaction, the resulting mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3*60 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/ethyl acetate = 1:1) to give the desired product (1.9 g, 55.27% yield) as a yellow solid. LCMS (ESI) calcd for C20H22Cl2N3O3+ [M + H]+ m/z 422, found 422. Step 2 Synthesis of 2-amino-5-chloro-N-(3-chloro-5-cyclopropylphenyl)isonicotinamide
Figure imgf000080_0001
To a solution of tert-butyl(5-chloro-4-((3-chloro-5- cyclopropylphenyl)carbamoyl)pyridin-2-yl)carbamate (1.9 g, 4.5 mmol) in DCM (30 mL) was added TFA (7.69 g, 67.5 mmol). The mixture was stirred at room temperature for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure to give the desired product (2 g, 98.59% yield) as a white solid. LCMS (ESI) calcd for C15H14Cl2N3O + [M + H]+ m/z 322, found 322. Step 3 Synthesis of 2-acetamido-5-chloro-N-(3-chloro-5-cyclopropylphenyl)isonicotinamide (Compound 104)
Figure imgf000080_0002
To the solution of 2-amino-5-chloro-N-(3-chloro-5-cyclopropylphenyl)isonicotinamide (1.8 g, 5.6 mmol) in HOAc (30 mL) was added Acetic anhydride (1.73 g, 16.9 mmol). The mixture was stirred at 100 °C for 16 h. After the reaction, the mixture was cooled to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1/1) to give the desired product (1.05 g, 46.54 % yield) as a white solid. LCMS (ESI) calcd for C17H16Cl2N3O2+ [M + H]+ m/z 364, found 364. 1H NMR (400 MHz, DMS δO) 10.88 (s, 1H), 10.80 (s, 1H), 8.56 – 8.48 (m, 1H), 8.23 (s, 1H), 7.63 (t, J = 2.0 Hz, 1H), 7.29 (t, J = 1.6 Hz, 1H), 6.94 (t, J = 1.6 Hz, 1H), 2.13 (s, 3H), 2.00 – 1.90 (m, 1H), 1.02 – 0.95 (m, 2H), 0.73 – 0.66 (m, 2H). Example 5: Step 3 Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(1,1-dioxido-1,2- thiazinan-2-yl)isonicotinamide (Compound 105)
Figure imgf000081_0001
Scheme 5 Synthesis of Compound 105 Step 1 Synthesis of methyl 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinate
Figure imgf000081_0002
To a solution of methyl 2-amino-5-chloropyridine-4-carboxylate (1 g, 5.4 mmol) and 4- chlorobutane-1-sulfonyl chloride (1.24 g, 6.4 mmol) in 15 mL DCM was slowly added TEA (1.64 g, 16.2 mmol), the mixture was stirred at 25 °C for 16 hrs. Then DCM was removed and MeOH (15 mL) was added, followed by TEA (1.64 g, 16.2 mmol), the mixture was stirred at 80 °C for 4 hrs. After the reaction, the solvent was removed under reduced pressure, the residue was purified by column chromatography using petroleum ether/ethyl acetate = 7:3 as eluent to afford methyl 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinate (422 mg, 25.93% yield) as a yellow oil. LCMS (ESI) calcd for C11H14ClN2O4S+ [M + H]+ m/z 305.04, found 305.0. Step 2 Synthesis of 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinic acid
Figure imgf000082_0001
To a solution of methyl 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinate (422 mg, 1.3847 mmol) in 10 mL THF/MeOH/H2O (v:v:v = 2:2:1) was added LiOH (119.4 mg, 4.9849 mmol), the mixture was stirred at 25 °C for 16 hrs. After the reaction, the mixture was diluted with H2O and acidified with 1N HCl to pH = 4, which was extracted with EtOAc for 3 times. Combined with EtOAc phases, washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure to afford 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2- yl)isonicotinic acid (315 mg, 74.33% yield) as a yellow solid. LCMS (ESI) calcd for C10H12ClN2O4S+ [M + H]+ m/z 291.02, found 291.1. Step 3 Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(1,1-dioxido-1,2-thiazinan-2-
Figure imgf000082_0002
To a solution of 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinic acid (100 mg, 0.344 mmol), 3-chloro-5-cyclopropylaniline (69.2 mg, 0.4128 mmol) and DIEA (133.4 mg, 1.032 mmol) in 2 mL DMF was added HATU (156.9 mg, 0.4128 mmol), the mixture was stirred at 25°C for 16 hrs. After the reaction, the H2O was added and the mixture was extracted with EtOAc for 3 times. Combined with EtOAc phases, washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduce pressure, the residue was purified by column chromatography using petroleum ether / ethyl acetate = 1/1 as eluent to afford 5-chloro-N-(3- chloro-5-cyclopropylphenyl)-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinamide (45 mg, 29.56% yield) as a white solid. LCMS (ESI) calcd for C19H19Cl2N3O3S+ [M + H]+ m/z 440.06, found 440.1. 1H NMR (400 MHz, DMSO) į 10.82 (s, 1H), 8.63 (s, 1H), 7.62 - 7.61 (m, 1H), 7.55 (s, 1H), 7.28 – 7.27 (m, 1H), 6.95 - 6.94 (m, 1H), 4.00 – 3.98 (m, 2H), 3.35 – 3.32 (m, 2H), 2.21 – 2.15 (m, 2H), 1.99 - 1.91 (m, 1H), 1.86 – 1.81 (m, 2H), 1.01 – 0.96 (m, 2H), 0.71 – 0.67 (m, 2H). Example 6: Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(2-oxopyrrolidin-1- yl)isonicotinamide (Compound 106)
Figure imgf000083_0001
Scheme 6 Synthesis of Compound 106 Step 1 Synthesis of methyl 5-chloro-2-(4-chlorobutanamido)isonicotinate
Figure imgf000083_0002
To a solution of methyl 2-amino-5-chloroisonicotinate (1 g, 5.4 mmol) and TEA (1.09 g, 10.8 mmol) in 12 mL DCM was added 4-chlorobutanoyl chloride (1.52 g, 10.8 mol), the mixture was stirred at room temperature for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure to afford the desired product (1.9 g, crude) as a yellow solid. LCMS (ESI) calcd for C11H13Cl2N2O3+ [M + H]+ m/z 291, found 291. Step 2 Synthesis of methyl 5-chloro-2-(2-oxopyrrolidin-1-yl)isonicotinate
Figure imgf000084_0001
NaH (0.29 g, 0.0071 mol) was added in portions to the solution of methyl 5-chloro-2-(4- chlorobutanamido)isonicotinate (1.9 g, crude) in dry DMF (20 mL) at 0 °C. The mixture was stirred at room tempera for 16 h. After the reaction, the mixture was quenched by addition of water (80 ml) and extracted with ethyl acetate (3 x 60 mL). The combined organic layer was washed with brine (50 ml), dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by flash chromatography to give the desired product (0.64 g, 35.38% yield) as a white solid. LCMS (ESI) calcd for C11H12ClN2O3+ [M + H]+ m/z 255, found 255. Step 3 Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(2-oxopyrrolidin-1- yl)isonicotinamide (Compound 106)
Figure imgf000084_0002
To a solution of methyl 5-chloro-2-(2-oxopyrrolidin-1-yl)isonicotinate (250 mg, 0.9817 mmol) in toluene (10 mL) were added 3-chloro-5-cyclopropylaniline (246.85 mg, 1.4725 mmol) and AlMe3 (141.54 mg, 1.9634 mmol) at 0°C, the resulting mixture was stirred at 100 °C for 16 h. After the reaction, the reaction mixture was partitioned between 30 mL of 1 M HCl and 60 mL of EtOAc. The organic phase was separated, washed with 15 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/ethyl acetate = 7:3) to give the desired product (130 mg, 32.58% yield) as a white solid. LCMS (ESI) calcd for C19H18Cl2N3O2+ [M + H]+ m/z 390, found 390. 1H NMR (400 MHz, DMSO δ) 10.82 (s, 1H), 8.59 (s, 1H), 8.45 (s, 1H), 7.63 (s, 1H), 7.29 (s, 1H), 6.94 (s, 1H), 4.01 (t, J = 7.2 Hz, 2H), 2.62 (t, J = 8.0 Hz, 2H), 2.09 (m, 2H), 1.98 – 1.91 (m, 1H), 1.02 – 0.95 (m, 2H), 0.72 – 0.66 (m, 2H). Example 7: Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(2-oxopiperidin-1- yl)isonicotinamide (Compound 107)
Figure imgf000085_0003
Scheme 7 Synthesis of Compound 107 Step 1 Synthesis of methyl 5-chloro-2-(5-chloropentanamido)isonicotinate
Figure imgf000085_0001
To a solution of methyl 2-amino-5-chloroisonicotinate (1 g, 0.0054 mol) and TEA (1.09 g, 0.0108 mol) in 10 mL DCM was added 5-chloropentanoyl chloride (1.67 g, 0.0108 mol), the mixture was stirred at room temperature for 16 h. After the reaction, the mixture was filtered and concentrated under reduced pressure to afford the desired product (2.3 g, crude) as a yellow oil. LCMS (ESI) calcd for C12H15Cl2N2O3+ [M + H]+ m/z 305, found 305. Step 2 Synthesis of methyl 5-chloro-2-(2-oxopiperidin-1-yl)isonicotinate
Figure imgf000085_0002
NaH (0.33 g, 0.0082 mol) was added in portions to the solution of methyl 5-chloro-2-(5- chloropentanamido)isonicotinate (2.3 g, crude) in dry DMF (20 mL) at 0 °C. The mixture was stirred at room temperature for 16 h. After the reaction, the mixture was quenched by addition of water (80 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by flash chromatography to give the desired product (0.55 g, 23.83% yield) as a yellow solid. LCMS (ESI) calcd for C12H14ClN2O3+ [M + H]+ m/z 269, found 269. Step 3 Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(2-oxopiperidin-1- yl)isonicotinamide (Compound 107)
Figure imgf000086_0001
To a solution of methyl 5-chloro-2-(2-oxopiperidin-1-yl)isonicotinate (350 mg, 1.3026 mmol) in toluene (10 mL) were added 3-chloro-5-cyclopropylaniline (327.5 mg, 1.9539 mmol) and AlMe3 (187.8 mg, 2.6052 mmol) at 0 °C, the resulting mixture was stirred at 100 °C for 16 h. After the reaction, the reaction mixture was partitioned between 40 mL of 1 M HCl and 80 mL of ethyl acetate. The organic phase was separated, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the desired product (30 mg, 5.47% yield) as a white solid. LCMS (ESI) calcd for C20H20Cl2N3O2+ [M + H]+ m/z 404, found 404. 1H NMR (400 MHz, DMSO δ) 10.81 (s, 1H), 8.62 (s, 1H), 7.96 (s, 1H), 7.62 (t, J = 1.6 Hz, 1H), 7.28 (d, J = 1.6 Hz, 1H), 6.93 (t, J = 1.6 Hz, 1H), 3.87 (t, J = 5.6 Hz, 2H), 3.73 (s, 2H), 1.96 – 1.81 (m, 5H), 1.01 – 0.96 (m, 2H), 0.69 (m, 2H). Example 8: Synthesis of Compound 218
Figure imgf000087_0002
Scheme 8 Synthesis of Compound 218 Step 1 Synthesis of methyl 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinate
Figure imgf000087_0001
To a solution of methyl 2-amino-5-chloropyridine-4-carboxylate (1 g, 5.4 mmol) and 4- chlorobutane-1-sulfonyl chloride (1.24 g, 6.4 mmol) in DCM (15 mL) was slowly added TEA (1.64 g, 16.2 mmol), the mixture was stirred at 25 °C for 16 h. Then DCM was removed under reduced pressure and MeOH (15 mL) was added, followed by the addition of TEA (1.64 g, 16.2 mmol). After the reaction, the mixture was stirred at 80 °C for 4 h. LC-MS was checked, and the reaction was completed. Then the solvent was removed under reduced pressure and the residue was purified by column chromatography (using petroleum ether/ethyl acetate = 7:3 as eluent) to afford methyl 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinate (422 mg, 25.93% yield) as a yellow oil. LCMS (ESI) calcd for C11H14ClN2O4S+ [M + H]+ m/z 305.04, found 305.0. Step 2 Synthesis of 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinic acid
Figure imgf000088_0001
To a solution of methyl 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinate (422 mg, 1.3847 mmol) in THF/MeOH/H2O (10 mL, v:v:v = 2:2:1) was added LiOH (119.4 mg, 4.9849 mmol), the mixture was stirred at 25 °C for 16 h. LC-MS was checked, and the reaction was completed. Then the mixture was diluted with H2O and acidified with 1N HCl to pH = 4. The resulting mixture was extracted with Ethyl acetate for 3 times. The organic phases were combined, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinic acid (315 mg, 74.33% yield) as a yellow solid. LCMS (ESI) calcd for C10H12ClN2O4S+ [M + H]+ m/z 291.02, found 291.1. Step 3 Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(1,1-dioxido-1,2-thiazinan-2- yl)isonicotinamide
Figure imgf000088_0002
To a solution of 5-chloro-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinic acid (100 mg, 0.344 mmol), 3-chloro-5-cyclopropylaniline (69.2 mg, 0.4128 mmol) and DIEA (133.4 mg, 1.032 mmol) in DMF (2 mL) was added HATU (156.9 mg, 0.4128 mmol), and the mixture was stirred at 25 °C for 16 hours. LC-MS was checked, and the reaction was completed. The reaction was quenched by addition of H2O and the mixture was extracted with ethyl acetate for 3 times. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (using petroleum ether / ethyl acetate = 1/1) to afford 5-chloro-N-(3- chloro-5-cyclopropylphenyl)-2-(1,1-dioxido-1,2-thiazinan-2-yl)isonicotinamide (Compound 218; 45 mg, 29.56% yield) as a white solid. LCMS (ESI) calcd for C19H19Cl2N3O3S+ [M + H]+ m/z 440.06, found 440.1. 1H NMR (400 MHz, DMSO δ) 10.82 (s, 1H), 8.63 (s, 1H), 7.62 - 7.61 (m, 1H), 7.55 (s, 1H), 7.28 - 7.27 (m, 1H), 6.95 - 6.94 (m, 1H), 4.00 - 3.98 (m, 2H), 3.35 - 3.32 (m, 2H), 2.21 - 2.15 (m, 2H), 1.99 - 1.91 (m, 1H), 1.86 - 1.81 (m, 2H), 1.01 - 0.96 (m, 2H), 0.71 - 0.67 (m, 2H). Example 9: Synthesis of Compound 217
Figure imgf000089_0001
Scheme 9 Synthesis of Compound 217 Step 1 Synthesis of methyl 2-amino-5-methylisonicotinate
Figure imgf000089_0002
To a solution of methyl 2-amino-5-bromopyridine-4-carboxylate (1.5 g, 6.5 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (3.05 g, 24.3 mmol), K3PO4 (2.76 g, 13 mmol) and SPhos (0.53 g, 1.3 mmol) in DMSO (20 mL) was added Pd(OAc)2 (145.9 mg, 0.65 mmol), the mixture was stirred at 80 °C under N2 for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was diluted with H2O and extracted with ethyl acetate for 3 times. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography using petroleum ether/ethyl acetate = 3:2 as eluent to afford methyl 2-amino-5- methylisonicotinate (0.96 g 87.69% yield) as a yellow solid. LCMS (ESI) calcd for C8H11N2O2 + [M + H]+ m/z 167.08, found 167.0. Step 2 Synthesis of methyl 2-(1,1-dioxidoisothiazolidin-2-yl)-5-methylisonicotinate
Figure imgf000090_0001
To a solution of methyl 2-amino-5-methylisonicotinate (960 mg, 5.78 mmol) and TEA (1.17 g, 11.55 mmol) in DCM (20 mL) was added 3-chloropropane-1-sulfonyl chloride (2.05 g, 11.55 mmol) dropwise at 0°C and the mixture was stirred at rt for 16 h. Then DCM was removed and MeOH (15 mL) was added, followed by addition of TEA (1.98 g, 19.56 mmol). The mixture was stirred at 80°C for 4 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 1:1 as eluent to afford methyl 2- (1,1-dioxidoisothiazolidin-2-yl)-5-methylisonicotinate (734 mg, 65.95% yield) as a yellow solid. LCMS (ESI) calcd for C11H14N2O4S+ [M + H]+ m/z 271.07, found 271.0. Step 3 Synthesis of 2-(1,1-dioxidoisothiazolidin-2-yl)-5-methylisonicotinic acid
Figure imgf000090_0002
To a solution of methyl 2-(1,1-dioxidoisothiazolidin-2-yl)-5-methylisonicotinate (700 mg, 2.59 mmol) in THF/MeOH/H2O (10 mL, v:v:v = 2:2:1) was added LiOH (217.6 mg, 9.065 mmol), the mixture was stirred at 25 °C for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was diluted with H2O and acidified with 1N HCl to pH = 4. The resulting mixture was extracted with ethyl acetate for 3 times. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-(1,1-dioxidoisothiazolidin-2-yl)-5-methylisonicotinic acid (730 mg, 98.99% yield) as a yellow solid. LCMS (ESI) calcd for C10H13N2O4S+ [M + H]+ m/z 257.05, found 257.0. Step 4 Synthesis of N-(3-chloro-5-cyclopropylphenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)-5- methylisonicotinamide
Figure imgf000091_0002
To a solution of 2-(1,1-dioxidoisothiazolidin-2-yl)-5-methylisonicotinic acid (100 mg, 0.39 mmol), 3-chloro-5-cyclopropylaniline (78.5 mg, 0.47 mmol) and DIEA (100.9 mg, 0.78 mmol) in DMF (5 mL) was added HATU (222.55 mg, 0.59 mmol), the mixture was stirred at 25 °C for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, H2O was added and the mixture was extracted with ethyl acetate for 3 times. Combined with organic phases, washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduce pressure and the residue was purified by column chromatography using petroleum ether / ethyl acetate = 1/1 as eluent to afford N-(3-chloro-5-cyclopropylphenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)-5-methylisonicotinamide (Compound 217; 86.9 mg, 52.13% yield) as a white solid. LCMS (ESI) calcd for C19H21ClN3O3S+ [M + H]+ m/z 406.09, found 406.1. 1H NMR (400 MHz, DMSO) į 10.62 (s, 1H), 8.30 (s, 1H), 7.65 (t, J = 1.8 Hz, 1H), 7.32 (d, J = 1.5 Hz, 1H), 7.14 (d, J = 6.9 Hz, 1H), 6.93 (dd, J = 8.2, 6.5 Hz, 1H), 3.90 (t, J = 6.5 Hz, 2H), 3.62 - 3.52 (m, 2H), 2.40 (p, J = 6.8 Hz, 2H), 2.27 (s, 3H), 2.00 - 1.89 (m, 1H), 1.02 - 0.94 (m, 2H), 0.74 - 0.62 (m, 2H). The following compound was prepared analogously:
Figure imgf000091_0001
Example 10: Synthesis of Compound 200
Figure imgf000092_0001
Scheme 10 Synthesis of Compound 200 Step 1 Synthesis of tert-butyl 3-(3-chloro-5-(2-(1,1-dioxidoisothiazolidin-2-yl)-5- methylisonicotinamido)phenyl)azetidine-1-carboxylate
Figure imgf000092_0002
To a solution of methyl 2-amino-5-chloropyridine-4-carboxylate (1.0 g, 5.4 mmol) and TEA (1.64 g, 5.4 mmol) in DCM (5 mL) was added ethanesulfonyl chloride (0.69 g, 5.4 mmol), the mixture was stirred at 25 °C for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether / ethyl acetate = 3/2 as eluent to afford methyl 5-chloro-2-ethanesulfonamidopyridine-4-carboxylate (0.22 g, 12.96% yield) as a white solid. LCMS (ESI) calcd for C9H12ClN2O4S+ [M + H]+ m/z 279.01, found 279.00. Step 2 Synthesis of methyl 5-chloro-2-(N-methylethylsulfonamido)isonicotinate
Figure imgf000092_0003
To a solution of methyl 5-chloro-2-ethanesulfonamidopyridine-4-carboxylate (200 mg, 0.7176 mmol) in DMF (5 mL) was slowly added NaH (17.2 mg, 60% in oil, 0.7176 mmol), the mixture was stirred at 25 °C for 1 h. Then, MeI (152.8 mg, 1.0764 mmol) was added dropwise to the mixture and the solution was stirred at 25 °C for 1 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed and diluted with H2O, the mixture was extracted with ethyl acetate for 3 times. The organic phases were combined, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl 5- chloro-2-(N-methylethanesulfonamido)pyridine-4-carboxylate (150 mg, 64.27% yield) as a white solid, which was used without further purification. LCMS (ESI) calcd for C10H14ClN2O4S+ [M + H]+ m/z 293.04, found 292.95. Step 3 Synthesis of 5-chloro-2-(N-methylethylsulfonamido)isonicotinic acid
Figure imgf000093_0001
To a solution of methyl 5-chloro-2-(N-methylethanesulfonamido)pyridine-4-carboxylate (150 mg, 0.5124 mmol) in THF/MeOH/H2O (5 mL, v:v:v = 2:2:1) was added LiOH (43 mg, 1.7933 mmol), the mixture was stirred at room temperature for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, adjusted pH = 3 - 4 by using 1N HCl aq. The mixture was extracted with ethyl acetate for 3 times, combined with organic phases, washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure to afford 5-chloro-2-(N-methylethanesulfonamido)pyridine-4-carboxylic acid (100 mg, 66.53% yield) as a white solid. LCMS (ESI) calcd for C9H12ClN2O4S+ [M + H]+ m/z 279.00, found 279.00. Step 4 Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(N- methylethylsulfonamido)isonicotinamide
Figure imgf000093_0002
To a solution of 5-chloro-2-(N-methylethanesulfonamido)pyridine-4-carboxylic acid (60 mg, 0.2153 mmol), 3-chloro-5-cyclopropylaniline (43.3 mg, 0.2583 mmol) and DIEA (83.5 mg, 0.6459 mmol) in DMF (5 mL) was added HATU (98.2 mg, 0.2583 mmol), the mixture was stirred at 25 °C for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by prep- HPLC to afford 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-(N- methylethanesulfonamido)pyridine-4-carboxamide (Compound 200; 20 mg, 21.46% yield) as a white solid. LCMS (ESI) calcd for C18H20Cl2N3O3S+ [M + H]+ m/z 428.06, found 428.05. 1H NMR (400 MHz, DMSO) į 10.81 (s, 1H), 8.60 (s, 1H), 7.63 (t, J = 1.8 Hz, 1H), 7.60 (s, 1H), 7.28 (s, 1H), 6.94 (t, J = 1.5 Hz, 1H), 3.55 (q, J = 7.4 Hz, 2H), 3.37 (s, 3H), 1.98 - 1.92 (m, 1H), 1.23 (t, J = 7.4 Hz, 3H), 1.01 - 0.96 (m, 2H), 0.71 - 0.67 (m, 2H). The following compounds were prepared analogously:
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0003
Example 11: Synthesis of Compound 194
Figure imgf000096_0001
Scheme 11 Synthesis of Compound 194 Step 1 Synthesis of N-(3-bromo-5-chlorophenyl)-5-chloro-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide
Figure imgf000096_0002
To a solution of 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (2 g, 7.2 mmol), 3-bromo-5-chloroaniline (1.78 g, 8.6 mmol) and DIEA (2.79 g, 21.6 mmol) in DMF (20 mL) was added HATU (3.29 g, 8.6 mmol), then the mixture was stirred at 25 °C for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, water was added and the mixture was extracted with ethyl acetate (25 mL * 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether / ethyl acetate = 1 / 1 as eluent to afford the N-(3-bromo-5-chlorophenyl)-5-chloro-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide (2.5 g, 70.83% yield) as a yellowish solid. LCMS (ESI) calcd for C15H13BrCl2N3O3S+ [M + H]+ m/z 465.92, found 465.85. Step 2 Synthesis of 5-chloro-N-(3-chloro-5-(1H-pyrazol-5-yl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide
Figure imgf000097_0001
To a solution of N-(3-bromo-5-chlorophenyl)-5-chloro-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide (150 mg, 0.3225 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (75 mg, 0.387 mmol) and K3PO4 (205 mg, 0.9675 mmol) in dioxane / H2O (4.5 mL, v:v = 8:1) was added Pd(dppf)Cl2DCM (26 mg, 0.0322 mmol), the mixture was stirred at 95 °C under N2 for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether / ethyl acetate = 1 : 3 as eluent to afford 5-chloro-N-(3- chloro-5-(1H-pyrazol-5-yl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 194; 70 mg, 46.23% yield) as a white solid. LCMS (ESI) calcd for C18H16Cl2N5O3S+ [M + H]+ m/z 452.03, found 452.00. 1H NMR (400 MHz, DMSO) į 13.05 (s, 1H), 10.97 (s, 1H), 8.55 (s, 1H), 8.07 (s, 1H), 7.83 (s, 2H), 7.64 (s, 1H), 7.29 (s, 1H), 6.76 (s, 1H), 3.92 (t, J = 6.5 Hz, 2H), 3.62 (t, J = 7.2 Hz, 2H), 2.69 (s, 1H), 2.45 - 2.38 (m, 2H). The following compounds were prepared analogously:
Figure imgf000098_0001
Figure imgf000099_0003
Example 12: Synthesis of Compound 192
Figure imgf000099_0001
Scheme 12 Synthesis of Compound 192 Step 1 Synthesis of 5-chloro-N-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide
Figure imgf000099_0002
To a solution of N-(3-bromo-5-chlorophenyl)-5-chloro-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide (200 mg, 0.43 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (131 mg, 0.516 mmol) and K3PO4 (127 mg, 1.29 mmol) in dioxane / H2O (9 mL, v:v = 8:1) was added Pd(dppf)Cl2DCM (35 mg, 0.043 mmol), the mixture was stirred at 95 °C under N2 for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 1:1 as eluent to afford 5-chloro-N-(3- chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide (150 mg, 54.49% yield) as a colorless oil. LCMS (ESI) calcd for C21H25BCl2N3O5S+ [M + H]+ m/z 512.10, found 512.00. Step 2 Synthesis of 5-chloro-N-(3-chloro-5-(thiazol-2-yl)phenyl)-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide
Figure imgf000100_0001
To a solution of 5-chloro-N-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (65 mg, 0.1269 mmol), 2- bromothiazole (31 mg, 0.1903 mmol), SPhos (10 mg, 0.0253 mmol) and K2CO3 (53 mg, 0.3807 mmol) in toluene / EtOH / H2O (2 mL, v:v:v = 7:2:1) was added Pd2(dba)3 (12 mg, 0.0126 mmol), the mixture was stirred at 100 °C under N2 for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 1:2 as eluent to afford 5-chloro-N-(3-chloro-5-(thiazol-2-yl)phenyl)-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide (Compound 192; 50 mg, 83.29% yield) as a white solid. LCMS (ESI) calcd for C18H15Cl2N4O3S2 + [M + H]+ m/z 469.00, found 469.00. 1H NMR (400 MHz, DMSO) į 11.12 (s, 1H), 8.56 (s, 1H), 8.27 (s, 1H), 7.99 (d, J = 3.2 Hz, 1H), 7.92 (s, 1H), 7.89 (d, J = 3.2 Hz, 1H), 7.77 (s, 1H), 7.32 (s,1H), 3.92 (t, J = 6.5 Hz, 2H), 3.62 (t, J = 7.2 Hz, 2H), 2.46 - 2.39 (m, 2H). The following compounds were prepared analogously:
Figure imgf000101_0001
Figure imgf000102_0003
Example 13: Preparation of Compound 160
Figure imgf000102_0001
Scheme 13 Synthesis of Compound 160 Step 1 Synthesis of 4-bromo-2H-1,2,3-triazole
Figure imgf000102_0002
To a solution of 4,5-dibromo-2H-1,2,3-triazole (2 g, 8.8 mmol) in 20 mL of water was added Na2SO3 (3.33 g, 26.4 mmol). The reaction mixture was stirred at 100 °C for 24 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1.09 g of 4-bromo-2H- 1,2,3-triazole (1.09 g, 79.55 % yield) as a yellow solid. LCMS (ESI) calcd for C2H2BrN3+ [M + H]+ m/z 147.94, found 147.9. Step 2 Synthesis of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole
Figure imgf000103_0001
To a solution of 4-bromo-2H-1,2,3-triazole (200 mg, 1.352 mmol) in 2 mL of THF were added NaH (40 mg, 60% in oil, 1.62 mmol) and a solution of SEMCl (270 mg, 1.622 mmol) in 1 mL of THF. The reaction mixture was stirred at rt for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to afford 4-bromo-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (200 mg, 50.34 % yield) as a colorless oil. LCMS (ESI) calcd for C8H16BrN3OSi+ [M + H]+ m/z 278.02, found 277.90. Step 3 Synthesis of 5-chloro-N-(3-chloro-5-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3- triazol-4-yl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide
Figure imgf000103_0002
To a solution of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (35 mg, 0.125 mmol), 5-chloro-N-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2- (1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (64 mg, 0.125 mmol) and Cs2CO3 (140 mg, 0.376 mmol) in dioxane/H2O (2 mL, v:v =4:1) was added Pd(dppf)Cl2DCM (9 mg, 0.0125 mmol), the reaction mixture was stirred at 90 °C overnight. The reaction mixture was poured into water and extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to afford 5- chloro-N-(3-chloro-5-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (30 mg, 38.95 % yield) as a colorless wax. LCMS (ESI) calcd for C23H28Cl2N6O4SSi+ [M + Na]+ m/z 605.21, found 605.0. Step 4 Synthesis of 5-chloro-N-(3-chloro-5-(1H-1,2,3-triazol-5-yl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide
Figure imgf000104_0001
160 A solution of 5-chloro-N-(3-chloro-5-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3- triazol-4-yl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (30 mg, 0.0513 mmol) in HCl (2 mL, 4M in dioxane) was stirred at rt for 1 h. The reaction mixture was concentrated, the residue was added drops of ammonia to adjusted pH = 9. The reaction mixture was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 5-chloro-N-(3-chloro-5-(2H-1,2,3-triazol-4- yl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 160; 20 mg, 85.19 % yield) as a white solid. LCMS (ESI) calcd for C17H14Cl2N6O3S+ [M + H]+ m/z 453.02, found 453.0. 1H NMR (400 MHz, DMSO δ) 15.46 (s, 0.2H), 15.14 (s, 0.44H), 11.04 (s, 0.8H), 10.77 (s, 0.17H), 10.06 (s, 0.17H), 8.68 (s, 0.17H), 8.56 (s, 0.76H), 8.53 (s, 0.18H), 8.33 (s, 0.34H), 8.14 (s, 0.81H), 7.82 (s, 0.81H), 7.73 (s, 0.82H), 7.30 (s, 0.83H), 7.23 (s, 0.38H), 7.14 (s, 0.17H), 6.59 (s, 0.17H), 3.93 - 3.90 (m, 2H), 3.64 - 3.60 (m, 2H), 2.42 - 2.38 (m, 2H). Example 14: Synthesis of Compound 212
Figure imgf000105_0001
Step 1 Synthesis of 4-(3-chloro-5-nitrophenyl)morpholine
Figure imgf000105_0002
To a solution of 1-chloro-3-fluoro-5-nitrobenzene (500 mg, 2.85 mmol) and morpholine (297.8 mg, 3.4179 mmol) in DMSO (5 mL) was added K2CO3 (787.3 mg, 5.70 mmol), the mixture was stirred at 80 °C for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, H2O was added and the mixture was extracted with ethyl acetate for 3 times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 3:2 as eluent to afford 4-(3-chloro-5- nitrophenyl)morpholine (513 mg, 73.48% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) į 7.68 - 7.67 (m, 1H), 7.63 (t, J = 2.1 Hz, 1H), 7.16 (t, J = 1.8 Hz, 1H), 3.90 - 3.88 (m, 4H), 3.28 - 3.26 (m, 4H). Step 2 Synthesis of 3-chloro-5-morpholinoaniline
Figure imgf000106_0001
To a solution of 4-(3-chloro-5-nitrophenyl)morpholine (500 mg, 2.06 mmol) and NH4Cl (551.1 mg, 10.30 mmol) in 11 mL EtOH/ H2O (v:v = 10:1) was added Fe powder (575.4 mg, 10.30 mmol) ^the reaction mixture was stirred at 80 °C for 2 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was filtered and the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 3:2 as eluent to afford 3-chloro-5-(morpholin-4-yl)aniline (387 mg, 87.43% yield) as a yellow solid. LCMS (ESI) calcd for C10H14ClN2O+ [M + H]+ m/z 213.08, found 213.15. Step 3 Synthesis of 5-chloro-N-(3-chloro-5-morpholinophenyl)-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide
Figure imgf000106_0003
Figure imgf000106_0002
To a solution of 3-chloro-5-(morpholin-4-yl)aniline (76.9 mg, 0.36 mmol) and 5-chloro- 2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (100 mg, 0.3614 mmol) in MeCN (5 mL) was added TCFH (121.7 mg, 0.43 mmol) and NMI (103.9 mg, 1.26 mmol), and the mixture was stirred at 25 °C for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether / ethyl acetate = 1:1 as eluent to afford 5-chloro- N-(3-chloro-5-morpholinophenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 212; 65 mg, 38.23% yield) as a white solid. LCMS (ESI) calcd for C19H21Cl2N4O4S+ [M + H]+ m/z 471.06, found 471.05. 1H NMR (400 MHz, DMSO) δ 10.75 (s, 1H), 8.53 (s, 1H), 7.25 - 7.17 (m, 2H), 7.17 (s, 1H), 6.80 (s, 1H), 3.92 - 3.89 (m, 2H), 3.74 - 3.71 (m, 4H), 3.63-3.60 (m,2H), 3.13 - 3.11 (m, 4H), 2.45 - 2.40 (m, 2H). The following compounds were prepared analogously: δ δ δ δ
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0002
Example 15: Synthesis of Compound 190
Figure imgf000111_0001
To a solution of methyl 2-chloro-6-methylpyridine-4-carboxylate (4 g, 21.6 mmol), NH2Boc (3.83 g, 32.4 mmol) and Cs2CO3 (21.11 g, 64.8 mmol) in dioxane (30 mL) were added XPhos (1.54 g, 3.2 mmol) and Pd(OAc)2 (0.48 g, 2.1 mmol), the mixture was stirred at 100 °C for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/Ethyl acetate = 5:1 as eluent to afford methyl 2-((tert- butoxycarbonyl)amino)-6-methylisonicotinate (2.5 g, 42.59% yield) as a yellow solid. LCMS (ESI) calcd for C13H19N2O4+ [M + H]+ m/z 267.13, found 267.10.
Figure imgf000112_0001
3 To a solution of methyl 2-((tert-butoxycarbonyl)amino)-6-methylisonicotinate (2.5 g, 9.4 mmol) in DCM (30 mL) was slowly added TFA (17.68 g, 155.1 mmol), and the mixture was stirred at 25 °C for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the DCM and excess of TFA were removed under reduced pressure and the residue was diluted with 200 mL 1N aq. Na2CO3 and extracted with ethyl acetate for 3 times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure to afford methyl 2-amino-6-methylisonicotinate (1.33 g, 82.98% yield) as a yellow solid. LCMS (ESI) calcd for C8H11N2O2+ [M + H]+ m/z 167.08, found 167.10.
Figure imgf000112_0002
4 To a solution of methyl 2-amino-6-methylpyridine-4-carboxylate (1.33 g, 8.0 mmol) and NCS (1.07 g, 8.0 mmol) in DMF (5 mL) was stirred at 50 °C for 1 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was filtered and the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 3:2 as eluent to afford methyl 6-amino-3-chloro-2- methylpyridine-4-carboxylate (1.2 g, 63.75% yield) as a yellow solid. LCMS (ESI) calcd for C8H10ClN2O2+ [M + H]+ m/z 201.12, found 201.10. Step 4 Synthesis of methyl 3-chloro-6-((3-chloro-N-((3- chloropropyl)sulfonyl)propyl)sulfonamido)-2-methylisonicotinate
Figure imgf000113_0001
To a solution of methyl 6-amino-3-chloro-2-methylpyridine-4-carboxylate (1.0 g, 5.0 mmol) and TEA (2.53 g, 25 mmol) in DCM (10 mL) was added 3-chloropropane-1-sulfonyl chloride (2.66 g, 15.0 mmol). The reaction mixture was stirred at 25 °C for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure, the residue was diluted with H2O (50 mL), which was extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure to afford methyl 3-chloro-6-((3- chloro-N-((3-chloropropyl)sulfonyl)propyl)sulfonamido)-2-methylisonicotinate (1.5 g, 57.00% yield) as a brown solid. LCMS (ESI) calcd for C14H20Cl3N2O6S2 + [M + H]+ m/z 483.01, found 483.00. Step 5 Synthesis of methyl 3-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)-2-methylisonicotinate
Figure imgf000113_0002
To a solution of methyl 3-chloro-6-((3-chloro-N-((3- chloropropyl)sulfonyl)propyl)sulfonamido)-2-methylisonicotinate (1.5 g crude, 4.4 mmol) in 10 mL MeOH was added TEA (1.34 g, 13.2 mmol), the mixture was stirred at 80 °C for 16 h. LC- MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by petroleum ether/ethyl acetate = 1:1 as eluent to afford methyl 3-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)-2-methylisonicotinate (1.16 g, 84.09% yield) as a yellow solid. LCMS (ESI) calcd for C11H14ClN2O4S+ [M + H]+ m/z 305.04, found 305.00. Step 6 Synthesis of methyl 3-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)-2-methylisonicotinate
Figure imgf000114_0002
To a solution of methyl 3-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)-2- methylisonicotinate (160 mg, 0.525 mmol) in 10 mL THF/MeOH/H2O = 2:2:1 was added LiOH (44 mg, 1.8375 mmol), the mixture was stirred at 25 °C for 1 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was adjusted pH = 2~3 using 1N HCl aq. and the mixture was extracted with ethyl acetate for 3 times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to afford 3-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)-2-methylisonicotinic acid (150 mg, 96.30% yield) as a yellow solid. LCMS (ESI) calcd for C10H12ClN2O4S+ [M + H]+ m/z 291.02, found 290.90. Step 7 Synthesis of 3-chloro-N-(3-chloro-5-morpholinophenyl)-6-(1,1-dioxidoisothiazolidin-2- yl)-2-methylisonicotinamide
Figure imgf000114_0001
To a solution of 3-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)-2-methylisonicotinic acid (150 mg, 0.5160 mmol), 3-chloro-5-(morpholin-4-yl)aniline (120.71 mg, 0.56760 mmol) and DIEA (133.38 mg, 1.032 mmol) in DMF (6 mL) was added HATU (294.30 mg, 0.7740 mmol), the mixture was stirred at 25 °C for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, H2O was added and the mixture was extracted with ethyl acetate for 3 times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduce pressure and the residue was purified by column chromatography to afford 3-chloro-N-(3-chloro-5-morpholinophenyl)-6-(1,1- dioxidoisothiazolidin-2-yl)-2-methylisonicotinamide (Compound 190; 50 mg, 19.57% yield) as a white solid. LCMS (ESI) calcd for C20H23Cl2N4O4S+ [M + H]+ m/z 485.04, found 485.1. 1H NMR (400 MHz, DMSO) δ 10.71 (s, 1H), 7.23 (s, 1H), 7.17 (s, 1H), 7.07 (s, 1H), 6.79 (s, 1H), 3.90 (t, J = 6.5 Hz, 2H), 3.81 - 3.66 (m, 4H), 3.60 (t, J = 7.2 Hz, 2H), 3.13 - 3.10 (m, 4H), 2.54 (s, 3H), 2.43 - 2.36 (m, 2H). The following compound was prepared analogously: δ
Figure imgf000115_0001
Example 16: Preparation of Compound 214
Figure imgf000116_0001
To a solution of methyl 2-amino-6-methylpyridine-4-carboxylate (2.23 g, 13.4 mmol) in DMF (50 mL) was added NBS (2.38 g, 13.4 mmol). The mixture was stirred at 50 °C for 1 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was diluted with H2O (150 ml) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2:1) to give methyl 6-amino-3-bromo-2-methylpyridine-4-carboxylate (2.5 g, 72.4% yield) as a yellow solid. LCMS (ESI) calcd for C8H9BrN2O2+ [M + H]+ m/z 244.98, found 244.95. Step 2 Synthesis of methyl 6 amino 23 dimethylisonicotinate
Figure imgf000117_0001
To a solution of methyl 6-amino-3-bromo-2-methylpyridine-4-carboxylate (2.5 g, 10.2 mmol) in DMSO (50 mL) were added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.28 g, 10.2 mmol), SPhos (628.2 mg, 1.53 mmol), Pd(OAc)2 (229 mg, 1.02 mmol) and K3PO4 (6.50 g, 30.6 mmol). The mixture was stirred at 80 °C for 16 h under N2. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was diluted with H2O (300 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1/1) to give methyl 6-amino- 2,3-dimethylpyridine-4-carboxylate (1.5 g, 81.6% yield) as a yellow solid. LCMS (ESI) calcd for C9H12N2O2 + [M + H]+ m/z 181.09, found 181.15. Step 3 Synthesis of methyl 6-(1,1-dioxidoisothiazolidin-2-yl)-2,3-dimethylisonicotinate
Figure imgf000117_0002
To a solution of methyl 6-amino-2,3-dimethylpyridine-4-carboxylate (1.5 g, 8.3239 mmol) and TEA (4.2 g, 41.62 mmol) in DCM (30 mL) was added 3-chloropropane-1-sulfonyl chloride (4.42 g, 24.97 mmol) at 0 °C, the mixture was stirred at rt for 16 h. Then DCM was removed and MeOH (50 mL) was added, followed by addition of TEA (5.06 g, 50 mmol), the mixture was stirred at 80 °C for 4 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 1:1 as eluent to afford methyl 6- (1,1-dioxidoisothiazolidin-2-yl)-2,3-dimethylisonicotinate (2.0 g, 67% yield) as a yellow solid. LCMS (ESI) calcd for C12H16N2O4S+ [M + H]+ m/z 285.08, found 285.05. Step 4 Synthesis of 6-(1,1-dioxidoisothiazolidin-2-yl)-2,3-dimethylisonicotinic acid
Figure imgf000117_0003
To a solution of methyl 6-(1,1-dioxidoisothiazolidin-2-yl)-2,3-dimethylisonicotinate (2.0 g, 7.03 mmol) in THF/MeOH/H2O (20 mL, v:v:v = 2:2:1) was added LiOH (0.59 g, 24.62 mmol). The mixture was stirred at rt for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was diluted with H2O and acidified with 1N HCl to pH = 4, the resulting mixture was extracted with ethyl acetate for 3 times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure to afford 6-(1,1-dioxidoisothiazolidin-2-yl)-2,3-dimethylisonicotinic acid (1.8 g, 94.7% yield) as a yellow solid. LCMS (ESI calcd for C11H15N2O4S+ [M + H]+ m/z 271.08, found 271.05. Step 5 Synthesis of N-(3-chloro-5-cyclopropylphenyl)-6-(1,1-dioxidoisothiazolidin-2-yl)-2,3- dimethylisonicotinamide
Figure imgf000118_0001
To a solution of 6-(1,1-dioxidoisothiazolidin-2-yl)-2,3-dimethylisonicotinic acid (100 mg, 0.37 mmol), 3-chloro-5-cyclopropylaniline (62.02 mg, 0.37 mmol), DIEA (143.5 mg, 1.11 mmol) in DMF (5 mL) was added HATU (168.82 mg, 0.44 mmol), the mixture was stirred at rt for 2 h. After the reaction. the mixture was diluted with H2O (50 ml) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep- HPLC to afford N-(3-chloro-5-cyclopropylphenyl)-6-(1,1-dioxidoisothiazolidin-2-yl)-2,3- dimethylisonicotinamide (Compound 214; 8.4 mg, 5.14% yield) as a white solid. LCMS (ESI) calcd for C20H22ClN3O3S+ [M + H]+ m/z 420.11, found 420.05. 1H NMR (400 MHz, DMSO) į 10.61 (s, 1H), 7.66 (dd, J = 15.6, 13.7 Hz, 1H), 7.32 (s, 1H), 6.96 (s, 1H), 6.91 (t, J = 1.6 Hz, 1H), 3.89 (t, J = 6.6 Hz, 2H), 3.56 (t, J = 7.3 Hz, 2H), 2.44 (s, 3H), 2.37 (dd, J = 14.0, 6.9 Hz, 2H), 2.19 (s, 3H), 1.98 - 1.89 (m, 1H), 1.01 - 0.94 (m, 2H), 0.72 - 0.65 (m, 2H). Example 17: Preparation of Compound 211
Figure imgf000119_0003
Figure imgf000119_0001
Step 1 Synthesis of tert-butyl (3-chloro-5-iodophenyl)carbamate
Figure imgf000119_0002
To a solution of 3-chloro-5-iodo-benzoic acid (6 g, 21.2 mmol) in toluene (35 mL) were added dropwise DPPA (5.83 g, 21.2 mmol) and TEA (2.14 g, 21.2 mmol) at 25 °C. After the addition, the mixture was stirred at this temperature for 1 hour and 80 °C for 1 hour. Then, tert- butanol (1.89 g, 25.4 mmol) was added dropwise. The resulting mixture was stirred at 110 °C for 12 hours. Then it was partitioned with sat. NaHCO3 and ethyl acetate. The organic phase was separated, which was washed with sat. NaHCO3, brine, dried with Na2SO4 and filtered. The mixture was concentrated under reduced pressure to give the crude tert-butyl N-(3-chloro-5- iodophenyl)carbamate, which was purified by column chromatography using petroleum ether/ethyl acetate = 5:1 as eluent to give pure tert-butyl (3-chloro-5-iodophenyl)carbamate (5.3 g, 69.81% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.42 (s, 1H), 7.35 (t, J = 1.4 Hz, 1H), 6.49 (s, 1H), 1.51 (s, 9H). Step 2 Synthesis of 1,3-dioxoisoindolin-2-yl tetrahydrofuran-3-carboxylate
Figure imgf000120_0001
To a solution of 2-hydroxyisoindole-1,3-dione (2 g, 12.3 mmol), oxolane-3-carboxylic acid (1.43 g, 12.3 mmol) and DMAP (0.08 g, 0.6 mmol) in DCM (30 mL) was added DCC (2.79 g, 13.5 mmol), the mixture was stirred at 25 °C for 16 h. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 5:1 as eluent to afford 1,3-dioxoisoindolin-2-yl tetrahydrofuran- 3-carboxylate (2.87 g, 84.55% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.92 - 7.87 (m, 2H), 7.82 - 7.78 (m, 2H), 4.15 - 4.12 (m, 2H), 3.99 - 3.87 (m, 2H), 3.50 - 3.43 (m, 1H), 2.44 - 2.29 (m, 2H). Step 3 Synthesis of tert-butyl (3-chloro-5-(tetrahydrofuran-3-yl)phenyl)carbamate
Figure imgf000120_0002
A solution of NiCl2.DME (0.12 g, 0.5 mmol) and dtbbpy (0.17 g, 0.6 mmol) in DMAc (20 mL) was stirred at room temperature for a while. Then, tert-butyl N-(3-chloro-5- iodophenyl)carbamate (1 g, 2.8 mmol), 1,3-dioxoisoindolin-2-yl tetrahydrofuran-3-carboxylate (1.1 g, 4.2 mmol) and Zn (0.37 g, 5.6 mmol) were added to the solution and the resulting mixture was stirred at 45 °C under N2 for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was quenched with 1N AcOH solution and extracted with ethyl acetate for 3 times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography using petroleum ether/ethyl acetate = 6:1 as eluent to afford tert- butyl (3-chloro-5-(tetrahydrofuran-3-yl)phenyl)carbamate (0.376 g, 46.43% yield) as a yellowish oil. LCMS (ESI) calcd for C14H18ClNO3+ [M - Me + H]+ m/z 283.10, found 283.05. Step 4 Synthesis of 3-chloro-5-(tetrahydrofuran-3-yl)aniline
Figure imgf000121_0001
To a solution of tert-butyl (3-chloro-5-(tetrahydrofuran-3-yl)phenyl)carbamate (370 mg, 1.2425 mmol) in ethyl acetate (5 mL) was added HCl (2M in ethyl acetate, 4 mL), the mixture was stirred at 25 °C for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was filtered and the filter cake was washed with ethyl acetate for several times to afford 3-chloro-5-(oxolan-3-yl)aniline (178 mg, 71.75% yield) as a white solid. LCMS (ESI) calcd for C10H13ClNO+ [M + H]+ m/z 198.07, found 198.1. Step 5 Synthesis of 5-chloro-N-(3-chloro-5-(tetrahydrofuran-3-yl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide
Figure imgf000121_0002
To a solution of 3-chloro-5-(oxolan-3-yl)aniline hydrochloride (100 mg, 0.43 mmol) and 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (141.8 mg, 0.36 mmol) in MeCN (5 mL) were added TCFH (143.8 mg, 0.51 mmol) and NMI (122.7 mg, 1.49 mmol) , the mixture was stirred at 25 °C for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether / ethyl acetate = 1:1 as eluent to afford 5-chloro- N-(3-chloro-5-(tetrahydrofuran-3-yl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 211; 60 mg, 29.85% yield) as a white solid. LCMS (ESI) calcd for C19H20Cl2N3O4S+ [M + H]+ m/z 456.05, found 456.05. 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 8.54 (s, 1H), 7.74 (s, 1H), 7.47 (s, 1H), 7.25 (s, 1H), 7.15 (s, 1H), 4.01 (t, J = 7.8 Hz, 1H), 3.96 - 3.90 (m, 3H), 3.80 - 3.75 (m, 1H), 3.63 - 3.55 (m, 3H), 3.40 - 3.36 (m, 1H), 2.69 (s, 1H), 2.43 - 2.35(m, 2H), 2.32 - 2.30 (m, 1H), 1.93 - 1.84 (m, 1H). The following compounds were prepared analogously:
Figure imgf000122_0001
Example 18: Synthesis of Compound 144
Figure imgf000123_0001
Step 1 Synthesis of 3-allyl-5-methoxyaniline
Figure imgf000123_0002
A mixture of 3-bromo-5-methoxyaniline (3 g, 14.8 mmol), allylboronic acid pinacol ester (2.98 g, 17.7 mmol), Pd(dppf)Cl2DCM (1.21 g, 1.4 mmol), K3PO4 (6.28 g, 29.6 mmol) in dioxane/H2O (20 mL, v:v = 9:1) was stirred at 95 °C for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was diluted with H2O and the resulted mixture was extracted with ethyl acetate for 3 times. Combined with organic phases, washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography using petroleum ether/ethyl acetate = 3:1 as eluent to afford 3-allyl-5-methoxyaniline (1.7 g, 41.89% yield) as a yellow oil. LCMS (ESI) calcd for C10H13NO+ [M + H]+ m/z 164.10, found 164.10. Step 2 Synthesis of 3-methoxy-5-propylaniline
Figure imgf000123_0003
To a solution of 3-allyl-5-methoxyaniline (1.7 g, 10.42 mmol) in MeOH (20 mL) was added Pd/C (203.2 mg, 10.42 mmol). The mixture was stirred at 25 °C for 16 h under H2. LC- MS was checked, and the reaction was completed. After the reaction, the mixture was filtered and the solvent was removed under reduced pressure and the residue was purified by flash column chromatography using petroleum ether/ethyl acetate = 5:1 as eluent to afford 3-methoxy- 5-propylaniline (812 mg, 47.18% yield) as a red oil. LCMS (ESI) calcd for C10H15NO+ [M + H]+ m/z 165.12, found 165.15. Step 3 Synthesis of 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)-N-(3-methoxy-5- propylphenyl)isonicotinamide
Figure imgf000124_0001
To a solution of 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (100 mg, 0.36 mmol), 3-methoxy-5-propylaniline (72 mg, 0.43 mmol) and DIEA (94 mg, 0.72 mmol) in DMF (5 mL) was added HATU (164.9 mg, 0.43 mmol), the mixture was stirred at 25 °C for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was diluted with H2O and the mixture was extracted with ethyl acetate for 3 times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography using petroleum ether/ethyl acetate = 1:1 as eluent to afford 5-chloro-2-(1,1-dioxidoisothiazolidin-2- yl)-N-(3-methoxy-5-propylphenyl)isonicotinamide (Compound 144; 100 mg, 65.27% yield) as a yellow solid. LCMS (ESI) calcd for C19H22ClN3O4S+ [M + H]+ m/z 424.10, found 424.10. 1H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 8.52 (s, 1H), 7.22 (s, 1H), 7.17 (t, J = 2.0 Hz, 1H), 7.10 (s, 1H), 6.57 (s, 1H), 3.91 (t, J = 6.5 Hz, 2H), 3.74 (s, 3H),3.62 (t, J = 7.2 Hz, 2H), 3.34 (s, 2H), 2.41 (m, 2H), 1.59 (dd, J = 15.0, 7.4 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H). The following compounds were prepared analogously:
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0003
Figure imgf000130_0002
Example 19: Synthesis of Compound 195
Figure imgf000130_0001
Step 1 Synthesis of 5-chloro-N-(3-chloro-5-nitrophenyl)-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide
Figure imgf000131_0001
To a solution of 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (500 mg, 1.81 mmol), 3-chloro-5-nitroaniline (312 mg, 1.81 mmol) and DIEA (701 mg, 5.42 mmol) in DMF (10 mL) was added HATU (825 mg, 2.17 mmol), the mixture was stirred at rt for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1:2) to afford 5-chloro-N-(3-chloro-5-nitrophenyl)-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide (360 mg, 43.9% yield) as a yellow oil. LCMS (ESI) calcd for C15H12Cl2N4O5S+ [M + H]+ m/z 430.99, found 430.95. Step 2 Synthesis of N-(3-amino-5-chlorophenyl)-5-chloro-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide
Figure imgf000131_0002
To a solution of 5-chloro-N-(3-chloro-5-nitrophenyl)-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide (360 mg, 0.83 mmol) in EtOH/H2O (11 mL, v:v = 10:1) were added Fe powder (233.1 mg, 4.2 mmol) and NH4Cl (223 mg, 4.2 mmol). The mixture was stirred at 80 °C for 2 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1:2) to afford N-(3-amino-5-chlorophenyl)-5- chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (270 mg, 76.6% yield) as a yellow oil. LCMS (ESI) calcd for C15H14Cl2N4O3S+ [M + H]+ m/z 401.02, found 400.8. Step 3 Synthesis of 5-chloro-N-(3-chloro-5-(4-chlorobutanamido)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide
Figure imgf000132_0001
To a solution of N-(3-amino-5-chlorophenyl)-5-chloro-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide (200 mg, 0.5 mmol) and TEA (151 mg, 1.5 mmol) in DCM (8 mL) was added 4-chlorobutanoyl chloride (84 mg, 0.6 mmol), the mixture was stirred at rt for 16 h. LC- MS was checked, and the reaction was completed. After the reaction, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (petroleum ether / ethyl acetate = 1:5) to afford 5-chloro-N-(3-chloro-5-(4- chlorobutanamido)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (160 mg, 60.3% yield) as a yellow solid. LCMS (ESI) calcd for C19H19Cl3N4O4S+ [M + H]+ m/z 505.02, found 505.2. Step 4 Synthesis of 5-chloro-N-(3-chloro-5-(2-oxopyrrolidin-1-yl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide
Figure imgf000132_0002
To a solution of 5-chloro-N-(3-chloro-5-(4-chlorobutanamido)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (100 mg, 0.2 mmol) in DMF (3 mL) was added NaH (9.5 mg, 60% in oil, 0.4 mmol). The mixture was stirred at rt for 1 h, which was purified by prep-HPLC to give 5-chloro-N-(3-chloro-5-(2-oxopyrrolidin-1-yl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 195; 11.6 mg, 12.4% yield) as a white solid. LCMS (ESI) calcd for C19H18Cl2N4O4S+ [M + H]+ m/z 469.04, found 468.9. 1H NMR (400 MHz, DMSO) 5 11.00 (s, 1H), 8.54 (s, 1H), 7.92 (d, J= 1.7 Hz, 1H), 7.69 (t, J = 1.7 Hz, lH), 7.56 (t, J= 1.8 Hz, 1H), 7.25 (s, 1H), 3.91 (t, J= 6.5 Hz, 2H), 3.82 (t, J= 7.0 Hz, 2H), 3.62 (t, J= 7.2 Hz, 2H), 2.53 (t, J= 6.1 Hz, 2H), 2.41 (p, J= 6.8 Hz, 2H), 2.06 (t, J= 15.2, 7.5 Hz, 2H).
Example 20: Synthesis of Compound 188
Figure imgf000133_0001
To a solution of (3-bromo-5-chlorophenyl)boronic acid (500 mg, 2. 1252 mmol) in z- PrOH (10 mL) were added Nih (133 mg, 0.4250 mmol), NaHMDS (1169 mg, 6.3756 mmol; 2 M in THF) and trans-2-aminocyclohcxanol hydrochloride (97 mg, 0.6375 mol). The mixture was stirred at 25 °C under N2 atmosphere for a while. Then 3-iodooxetane (782 mg, 4.2504 mmol) was added and the mixture was stirred at 85 °C under N2 atmosphere for 16 hours. LC- MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure. The residue was purified by column chromatography using petroleum ether / ethyl acetate = 10 : 1 as eluent to afford 3-(3-bromo-5-chlorophenyl)oxetane (350 mg, 63.21% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.43 (dd, J = 3.7, 1.7 Hz, 2H), 7.33 (d, J = 1.5 Hz, 1H), 5.07 (dd, J = 8.2, 6.2 Hz, 2H), 4.70 (t, J = 6.3 Hz, 2H), 4.18 - 4.11 (m, 1H). Step 2 Synthesis of 3-chloro-N-(4-methoxybenzyl)-5-(oxetan-3-yl)aniline
Figure imgf000134_0001
To a solution of 3-(3-bromo-5-chlorophenyl)oxetane (500 mg, 2.0201 mmol) in dioxane (10 mL) were added PMBNH2 (416 mg, 3.0301 mmol), palladium diacetate (91 mg, 0.4040 mmol), Cs2CO3 (1975 mg, 6.0603 mmol) and BINAP (252 mg, 0.4040 mol), the mixture was stirred at 90 °C under N2 atmosphere for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure. The residue was purified by column chromatography using petroleum ether / ethyl acetate = 4 :1 as eluent to afford 3-chloro-N-(4-methoxybenzyl)-5-(oxetan-3-yl)aniline (300 mg, 46.44% yield) as a yellow oil. LCMS (ESI) calcd for C17H19ClNO2+ [M + H]+ m/z 304.11, found 304.05. Step 3 Synthesis of 3-chloro-5-(oxetan-3-yl)aniline
Figure imgf000134_0002
To a solution of 3-chloro-N-(4-methoxybenzyl)-5-(oxetan-3-yl)aniline (350 mg, 1.1521 mmol) in ethyl acetate (10 mL) was added Pd / C (70 mg). The mixture was stirred at 40 °C for 16 hours under H2 atmosphere. LC-MS was checked, and the reaction was completed. After the reaction, the Pd / C was filtered out. Then the solvent was removed under reduced pressure. The residue was purified by column chromatography using petroleum ether / ethyl acetate = 5 : 1 as eluent to afford 3-chloro-5-(oxetan-3-yl)aniline (65 mg, 29.19% yield) as a yellow oil. LCMS (ESI) calcd for C11H14ClN2O+ [M + H]+ m/z 225.08, found 225.10. 1H NMR (400 MHz, CDCl3) δ 6.75 (t, J = 1.5 Hz, 1H), 6.60 (t, J = 1.7 Hz, 1H), 6.58 (t, J = 2.0 Hz, 1H), 5.02 (dd, J = 8.3, 6.1 Hz, 2H), 4.71 (t, J = 6.3 Hz, 2H), 4.11 - 4.05 (m, 1H). Step 4 Synthesis of 5-chloro-N-(3-chloro-5-(oxetan-3-yl)phenyl)-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide (Compound 188)
Figure imgf000135_0001
To a solution of 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (145 mg, 0.52 mmol) 3-chloro-5-(oxetan-3-yl)aniline (80 mg, 0.44 mmol) and DIEA (169 mg, 1.31 mmol) in DMF (4 mL) was added HATU (199 mg, 0.52 mmol), the mixture was stirred at 25 °C for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, water was added and the mixture was extracted with Ethyl acetate (15 mL) for 3 times. The combined organic layers were washed with brine, dried over Na2SO4 and filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography using petroleum ether / ethyl acetate = 1:1 as eluent to afford 5-chloro-N-(3-chloro-5-(oxetan-3- yl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 188; 80 mg, 39.23% yield) as a yellowish solid. LCMS (ESI) calcd for C18H18Cl2N3O4S+ [M + H]+ m/z 442.04, found 441.95. 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 8.55 (s, 1H), 7.76 (t, J = 1.9 Hz, 1H), 7.65 (s, 1H), 7.27 - 7.26 (m, 2H), 4.95 (dd, J = 8.3, 6.0 Hz, 2H), 4.58 (t, J = 6.3 Hz, 2H), 4.29 - 4.22 (m, 1H), 3.90 (dd, J = 12.1, 5.6 Hz, 2H), 3.64 - 3.59 (m, 2H), 2.45 - 2.38 (m, 2H). The following compound was prepared analogously:
Figure imgf000135_0002
Example 21: Synthesis of Compound 187
Figure imgf000136_0001
Step 1 Synthesis of 4-(3-chloro-5-nitrophenyl)-3-methylmorpholine
Figure imgf000136_0002
To a solution of 1-bromo-3-chloro-5-nitrobenzene (1.0 g, 4.2 mmol), 3- methylmorpholine (0.42 g, 4.2 mmol), BINAP (0.52 g, 0.8 mmol) and Cs2CO3 (2.74 g, 8.4 mmol) in dioxane (10 mL) was added Pd(OAc)2 (0.09 g, 0.4 mmol), the mixture was stirred at 90 °C under N2 for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether /ethyl acetate = 5:1 as eluent to afford 4-(3- chloro-5-nitrophenyl)-3-methylmorpholine (0.5 g, 40.48% yield) as a yellow solid. LCMS (ESI) calcd for C11H14ClN2O3+ [M + H]+ m/z 257.09, found 257.1. Step 2 Synthesis of 3-chloro-5-(3-methylmorpholin-4-yl)aniline
Figure imgf000137_0001
To a solution of 4-(3-chloro-5-nitrophenyl)-3-methylmorpholine (500 mg, 1.9486 mmol) and NH4Cl (625.2 mg, 11.6875 mmol) in 22 mL EtOH/H2O=10:1(v:v = 10:1) was added Fe powder (652.8 mg, 11.6875 mmol) at 50 °C. Then the temperature was raised to 80 °C and stirred at this temperature for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was filtered and the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 3:2 as eluent to afford 3-chloro-5-(3-methylmorpholin-4-yl)aniline (400 mg, 90.5% yield) as a yellow oil. LCMS (ESI) calcd for C11H15ClN2O+ [M + H]+ m/z 227.13, found 227.10. Step 3 Synthesis of 5-chloro-N-(3-chloro-5-(3-methylmorpholino)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 187)
Figure imgf000137_0002
To a solution of 3-chloro-5-(3-methylmorpholin-4-yl)aniline (150 mg, 0.66 mmol), 5- chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (220 mg, 0.79 mmol) and DIEA (257 mg, 1.99mmol) in DMF (5 mL) was added HATU (302 mg, 0.79 mmol), the mixture was stirred at 25 °C for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, H2O was added and the mixture was extracted with ethyl acetate for 3 times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduce pressure and the residue was purified by column chromatography to afford 5- chloro-N-(3-chloro-5-(3-methylmorpholino)phenyl)-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide (Compound 187; 60 mg, 18.7 yield%) as a yellow solid. LCMS (ESI) calcd for C20H23Cl2N4O4S+ [M + H]+ m/z 485.07, found 485.1. 1H NMR (400 MHz, DMSO) δ 10.73 (s, 1H), 8.53 (s, 1H), 7.23 - 7.20 (m, 2H), 7.12 (s, 1H), 6.74 (s, 1H), 3.92 - 3.83 (m, 4H), 3.70 (d, J = 11.5 Hz, 2H), 3.62 (t, J =7.2 Hz, 2H), 3.52 - 3.48(m, 1H), 3.18 (d, J = 11.7 Hz, 1H), 3.01 - 2.97 (m, 1H), 2.41 (t, J = 7.0 Hz, 2H), 1.04 (d, J = 6.6 Hz, 3H). The following compounds were prepared analogously:
Figure imgf000138_0001
Figure imgf000139_0001
Example 22: Synthesis of Compound 172
Figure imgf000140_0001
To a mixture of 3-chloro-5-nitrobenzoic acid (1 g, 5.00 mmol) in DMF (10 mL) were added piperidine (0.47 g, 5.50 mmol), HATU (2.28 g, 6.00 mmol) and DIEA (1.29 g, 0.01 mol), then it was stirred at 25 °C for 2 hours under N2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL * 3), the organic layer was washed with brine (100 mL * 2), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography using petroleum ether/ ethyl acetate = 5:1 as eluent to afford (3-chloro-5-nitrophenyl)(piperidin-1-yl)methanone (1.3 g, 94% yield) as a brown solid. 1H NMR (400 MHz, DMSO) δ 8.34 (t, J = 2.0 Hz, 1H), 8.15 - 8.12 (m, 1H), 7.98 - 7.95 (m, 1H), 3.60 (s, 2H), 3.25 (s, 2H), 1.60 (s, 4H), 1.47 (s, 2H). Step 2 Synthesis of (3-amino-5-chlorophenyl)(piperidin-1-yl)methanone
Figure imgf000141_0001
To a mixture of (3-chloro-5-nitrophenyl)(piperidin-1-yl)methanone (1.3 g, 4.80 mmol) in EtOH (16 mL) and H2O (2 mL) were added Fe powder (1.07 g, 19.2 mmol) and NH4Cl (1.28 g, 2.40 mmol), then it was stirred at 80 °C for 16 hours under N2 atmosphere. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 1/1) to afford (3-amino-5-chlorophenyl)(piperidin-1-yl)methanone (900 mg, 75% yield) as a yellow solid. LCMS (ESI): calcd. for C12H16ClN2O+ [M+H]+ m/z 239.10, found 239.1. Step 3 Synthesis of 3-chloro-5-(piperidin-1-ylmethyl)aniline
Figure imgf000141_0002
To a mixture of (3-amino-5-chlorophenyl)(piperidin-1-yl)methanone (350 mg, 1.47 mmol) in THF (5 mL) was added borane-tetrahydrofuran complex (486 mg, 5.86 mmol), then it was stirred at 75 °C for 5 hours. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was cooled in an ice bath and methanol (3.5 mL) was added. Then 6 M HCl (5 mL) was added dropwise to the mixture, which was heated to reflux for 30 minutes. The volatiles were then concentrated in vacuo, and the resulting mixture was cooled in an ice bath and 50% aqueous NaOH (5 mL) was added to adjust pH > 10. The mixture was then diluted with water and extracted with diethyl ether (50 mL * 3). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (MeOH/DCM = 3%) to afford 3-chloro-5-(piperidin-1- ylmethyl)aniline (200 mg, 48.5% yield) as yellow oil. LCMS (ESI): calcd. for C12H18ClN2+ [M+H]+ m/z 225.12, found 225.1. Step 4 Synthesis of 5-chloro-N-(3-chloro-5-(piperidin-1-ylmethyl)phenyl)-2-(1,1-
Figure imgf000142_0001
To a mixture of 3-chloro-5-(piperidin-1-ylmethyl)aniline (100 mg, 0.45 mmol) in DMF (2.5 mL) was added 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (148 mg, 0.53 mmol), HATU (203 mg, 0.53 mmol) and DIEA (115 mg, 0.89 mmol), then it was stirred at 25 °C for 0.5 hour. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL * 3). Combined with organic phases, washed with brine (150 mL * 2), dried over Na2SO4, filtered and concentrated to dryness. The crude product was purified by prep-HPLC to afford 5-chloro-N-(3- chloro-5-(piperidin-1-ylmethyl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 172; 94.4 mg, 43.0% yield) a white solid. LCMS (ESI): calcd. for C21H25Cl2N4O3S+ [M+H]+ m/z 483.10, found 483.0. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.39 (s, 1H), 7.96 (s, 1H), 7.53 (d, J = 4.4 Hz, 2H), 7.15 (s, 1H), 4.02 (t, J = 6.8 Hz, 2H), 3.69 (s, 2H), 3.45 (t, J = 7.2 Hz, 2H), 3.05 (s, 2H), 2.65 (s, 4H), 2.56 (t, J = 7.2 Hz, 2H), 1.77 - 1.71 (m, 4H). The following compounds were prepared analogously:
Figure imgf000142_0002
Figure imgf000143_0002
Example 23: Synthesis of Compound 148
Figure imgf000143_0001
To a solution of tert-butyl 4-formyl-1H-pyrazole-1-carboxylate (1.0 g, 5.1 mmol) in 20 mL MeOH was added TsNHNH2 (0.95 g, 5.1 mol) portion wise and the mixture was stirred under nitrogen at 25 °C for 90 mins. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure to afford tert-butyl (E)-4-((2- tosylhydrazineylidene)methyl)-1H-pyrazole-1-carboxylate (1.8 g, 86% yield) as a white solid. LCMS (ESI) calcd for C16H20N4O4S+ [M + H]+ m/z 365.12, found 365.0. 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.31 (d, J = 8.4 Hz, 2H), 2.42 (s, 3H), 1.64 (s, 9H). Step 2 Synthesis of 4-(3-bromo-5-chlorobenzyl)-1H-pyrazole
Figure imgf000144_0001
To a solution of tert-butyl (E)-4-((2-tosylhydrazineylidene)methyl)-1H-pyrazole-1- carboxylate (1.64 g, 4.5 mmol) and (3-bromo-5-chlorophenyl)boronic acid (1.59 g, 6.8 mmol) in dioxane (40 mL) was added K2CO3 (0.93 g, 6.8 mmol). Then the temperature was raised to 110 °C and stirred at this temperature for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using dichloromethane as eluent to afford 4-(3-bromo-5- chlorobenzyl)-1H-pyrazole (730 mg, 58% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.23 (brs, 1H), 8.14 (s, 1H), 7.43 (s, 2H), 7.36 (t, J = 1.6 Hz, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 3.82 (s, 2H). Step 3 Synthesis of 4-(3-bromo-5-chlorobenzyl)-1H-pyrazole
Figure imgf000144_0002
To a solution of 4-(3-bromo-5-chlorobenzyl)-1H-pyrazole (330 mg, 1.22 mmol) in THF (10 mL) was added sodium hydride (44 mg, 1.82 mmol, 60% in oil) at 0°C under nitrogen and the mixture was stirred at this temperature for 30 min. Then SEMCl (223mg, 1.34 mmol) was added to the mixture and the reaction mixture was stirred at 25 °C for 1 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was quenched with MeOH and the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether /dichloromethane=4:1 as eluent to afford 4-(3-bromo-5- chlorobenzyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (288 mg, 56% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.36 (t, J = 1.6 Hz, 1H), 7.34 (d, J = 0.8 Hz, 1H), 7.22 (t, J = 1.6 Hz, 1H), 7.11 (t, J = 1.6 Hz, 1H), 5.38 (s, 2H), 3.79 (s, 2H), 3.55 - 3.53 (m, 2H), 0.92 - 0.87 (m, 2H), -0.03 (s, 9H). Step 4 Synthesis of N-benzyl-3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)methyl)aniline
Figure imgf000145_0001
To the solution of 4-(3-bromo-5-chlorobenzyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole (258 mg, 0.64 mmol), phenylmethanamine (103 mg, 0.96 mmol), t-BuOK (216 mg, 1.92 mmol) and BINAP (80 mg, 0.13 mmol) in 7 mL toluene was added Pd2(dba)3 (59 mg, 0.06 mmol), the mixture was stirred at 100 °C for 2 h under N2. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 9:1 as eluent to afford N-benzyl-3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)methyl)aniline (200 mg, 69% yield) as a yellow oil. LCMS (ESI) calcd for C23H30ClN3OSi+ [M + H]+ m/z 428.18, found 428.1. Step 5 Synthesis of 3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)methyl)aniline
Figure imgf000145_0002
To a solution of N-benzyl-3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol- 4-yl)methyl)aniline (180 mg, 0.42 mmol) in 5 mL Ethyl acetate was added Pd/C (9 mg, 0.08 mmol) and the mixture was stirred under H2 at 35 °C for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was filtered and the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 9:1 as eluent to afford 3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-4-yl)methyl)aniline (120 mg, 76% yield) as a yellow oil. LCMS (ESI) calcd for C16H24ClN3OSi+ [M + H]+ m/z 338.14, found 338.1. Step 6 Synthesis of 5-chloro-N-(3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)methyl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide
Figure imgf000146_0001
To the solution of 3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)methyl)aniline (120 mg, 0.35 mmol), 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (145 mg, 0.53 mmol) and DIPEA (137 mg, 1.06 mmol) in DMF (4 mL) was added HATU (269 mg, 0.71 mmol), the mixture was stirred at 25 °C for 2 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 1:1 as eluent to afford 5-chloro-N-(3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)methyl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (210 mg, 84% yield) as a yellow solid. LCMS (ESI) calcd for C25H31Cl2N5O4SSi+ [M + H]+ m/z 596.13, found 596.1. Step 7 Synthesis of N-(3-((1H-pyrazol-4-yl)methyl)-5-chlorophenyl)-5-chloro-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 148)
Figure imgf000146_0002
148 A solution of 5-chloro-N-(3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol- 4-yl)methyl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (100 mg, 0.17 mmol) in dioxane (3 mL) and 4M-HCl-dioxane (3 mL) was stirred at 25 °C under nitrogen for 24 h. LC- MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by prep-HPLC to afford N-(3-((1H-pyrazol- 4-yl)methyl)-5-chlorophenyl)-5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 148; 8 mg, 10% yield) as a yellow solid. LCMS (ESI) calcd C19H17Cl2N5O3S+ [M + H]+ m/z 466.04, found 466.0. 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.86 (s, 1H), 8.52 (s, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.58 (s, 1H), 7.36 (s, 1H), 7.23 (s, 1H), 7.07 (s, 1H), 3.89 (t, J = 6.4 Hz, 2H), 3.80 (s, 2H), 3.61 (t, J = 7.2 Hz, 2H), 2.41 (t, J = 6.8 Hz, 2H). Example 24: Synthesis of Compound 157
Figure imgf000147_0002
Step 1 Synthesis of 4-(3-bromo-5-chlorobenzyl)-1-methyl-1H-pyrazole
Figure imgf000147_0001
To a solution of 4-(3-bromo-5-chlorobenzyl)-1H-pyrazole (400 mg, 1.47 mmol) in DMF (10 mL) was added sodium hydride (53 mg, 2.21 mmol) portion wise at 0 °C under nitrogen and the mixture was stirred at this temperature for 30 min. Then MeI (251 mg, 1.77 mmol) was added dropwise and the mixture was stirred at 25 °C for 1 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was quenched with MeOH and the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/dichloromethane = 3:1 as eluent to afford 4-(3-bromo-5- chlorobenzyl)-1-methyl-1H-pyrazole (354 mg, 80% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (t, J = 1.6 Hz, 1H), 7.32 (s, 1H), 7.22 (s, 1H), 7.15 (s, 1H), 7.11 (s, 1H), 3.88 (s, 3H), 3.76 (s, 2H). Step 2 Synthesis of N-(3-chloro-5-((1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-1,1- diphenylmethanimine
Figure imgf000148_0001
To the solution of 4-(3-bromo-5-chlorobenzyl)-1-methyl-1H-pyrazole (324 mg, 1.13 mmol), diphenylmethanimine(247 mg, 1.36 mmol), t-BuOK(382 mg, 3.40 mmol) and BINAP (141 mg, 0.23 mmol) in 10 mL toluene was added Pd2(dba)3 (104 mg, 0.11 mmol) and the mixture was stirred at 100 °C for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 4:1 as eluent to afford N-(3- chloro-5-((1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-1,1-diphenylmethanimine (183 mg, 40% yield) as a yellow oil. LCMS (ESI) calcd for C24H20ClN3 + [M + H]+ m/z 386.13, found 386.1. Step 3 Synthesis of 3-chloro-5-((1-methyl-1H-pyrazol-4-yl)methyl)aniline
Figure imgf000148_0002
A solution of N-(3-chloro-5-((1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-1,1- diphenylmethanimine (183 mg, 0.69 mmol) in 4M HCl-dioxane (5 mL) was stirred at 25 °C for 30 min. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure to afford crude product 3-chloro-5-((1-methyl-1H-pyrazol- 4-yl)methyl)aniline (200 mg, 95% yield, 50% purity) as a yellow solid, which was used for the next step directly. LCMS (ESI) calcd for C11H12ClN3+ [M + H]+ m/z 222.07, found 222.1. Step 4 Synthesis of 5-chloro-N-(3-chloro-5-((1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 157)
Figure imgf000149_0001
To the solution of 3-chloro-5-((1-methyl-1H-pyrazol-4-yl)methyl)aniline (100 mg, 0.45 mmol), 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (87 mg, 0.32 mmol) and DIEA (175 mg, 1.35 mmol) in DMF (5 mL) was added HATU (206 mg, 0.54 mmol), the mixture was stirred at 25 °C for 2 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by prep-HPLC to afford 5-chloro-N-(3-chloro-5-((1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-2- (1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 157; 36 mg, 16% yield) as a white solid. LCMS (ESI) calcd for C20H19Cl2N5O3S+ [M + H]+ m/z 480.06, found 480.0. 1H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 8.53 (s, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.50 (s, 1H), 7.36 (s, 1H), 7.27 (s, 1H), 7.23 (s, 1H), 7.07 (t, J = 1.6 Hz, 1H), 3.90 (t, J = 6.4 Hz, 2H), 3.77 (s, 3H), 3.76 (s, 2H), 3.61 (t, J = 7.2 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H). Example 25: Synthesis of Compound 153
Figure imgf000150_0001
A solution of 1,2-oxathiolane 2,2-dioxide (1 g, 0.0073 mol) in 10 mL SOCl2 was stirred at 80 °C for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure to afford the 1.2 g crude 4-chlorobutane-2- sulfonyl chloride as a yellow oil, which was used for next step directly. Step 2 Synthesis of methyl 5-chloro-2-(5-methyl-1,1-dioxidoisothiazolidin-2-yl)isonicotinate
Figure imgf000150_0002
To a solution of methyl 2-amino-5-chloroisonicotinate (0.68 g, 3.6 mmol) and triethylamine (1.11 g, 10.9 mmol) in DCM (10 mL) was added 4-chlorobutane-2-sulfonyl chloride (1.2 g crude) at 0 °C. Then the mixture was stirred at 25 °C for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, the DCM was removed and the residue was dissolved in 20 mL MeOH, then TEA (0.56 g, 5.45 mmol) was added and the mixture was stirred at 80 °C for 4 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether / ethyl acetate = 2 / 1 as eluent to afford methyl 5 -chloro-2-(5 -methyl- 1,1 -dioxidoisothiazolidin-2-yl)isonicotinate (1.1 g, 46.58% yield) as a yellow solid.
LCMS (ESI) calcd for C11H14C1N2O4S+ [M + H]+ m/z 305.04, found 304.95.
Step 3 Synthesis of 5-chloro-2-(5-methyl-l,l-dioxidoisothiazolidin-2-yl)isonicotinic acid
Figure imgf000151_0001
To a solution of methyl 5 -chloro-2-(5 -methyl- 1,1 -dioxidoisothiazolidin-2- yl)isonicotinate (1.1 g, 3.6 mmol) in 24 mL MeOH / H2O (v:v = 2: 1) was added LiOH (0.31 g, 12.9 mmol). The mixture was stirred at 25 °C for 2 hours. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure. Then IN HC1 in water was added to adjust pH = 2 ~ 3. The mixture was extracted with Ethyl acetate (20 mL) for 4 times. Combined with organic layers, washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure to afford 5 -chloro-2-(5 -methyl- 1,1- dioxidoisothiazolidin-2-yl)isonicotinic acid (0.9 g, 80.56% yield) as a yellow solid. LCMS (ESI) calcd for C10H11C1N204S+ [M + H]+ m/z 291.02, found 291.00.
Step 4 Synthesis of 5-chloro-N-(3-chloro-5-morpholinophenyl)-2-(5-methyl-l,l- dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 153)
Figure imgf000151_0002
To a solution of 3-chloro-5-morpholinoaniline (73 mg, 0.344 mmol), 5-chloro-2-(5- methyl-l,l-dioxidoisothiazolidin-2-yl)isonicotinic acid (100 mg, 0.344 mmol) and DIEA (133 mg, 1.032 mmol) in DMF (4 mL) was added HATU (157 mg, 0.4128 mmol), the mixture was stirred at 25 °C for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, water was added and the mixture was extracted with ethyl acetate (15 mL) for 3 times. The combined organic layers were washed with brine, dried over Na2SO4 and filtered, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether / ethyl acetate = 1 / 1 as eluent to afford 5-chloro-N-(3- chloro-5-morpholinophenyl)-2-(5-methyl-1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 153; 80 mg, 47.47% yield) as a white solid. LCMS (ESI) calcd for C20H23Cl2N4O4S+ [M + H]+ m/z 485.08, found 485.00. 1H NMR (400 MHz, DMSO) δ 10.75 (s, 1H), 8.54 (s, 1H), 7.25 (s, 2H), 7.17 (s, 1H), 6.80 (t, J = 1.8 Hz, 1H), 3.92 - 3.79 (m, 2H), 3.74 - 3.66 (m, 5H), 3.13 - 3.11 (m, 4H), 2.59 - 2.53 (m, 1H), 2.11 - 2.01 (m, 1H), 1.36 (d, J = 6.7 Hz, 3H). The following compounds were prepared analogously:
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Example 26: Synthesis of Compound 169
Figure imgf000156_0001
Step 1 Synthesis of (E/Z)-4-methyl-N'-(2-methyltetrahydro-4H-pyran-4- ylidene)benzenesulfonohydrazide
Figure imgf000156_0002
To a solution of 2-methyloxan-4-one (1.00 g, 8.80 mmol) in MeOH (10 mL) was added 4-methylbenzenesulfonhydrazide (1.64 g, 8.80 mmol), then it was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated to dryness to afford (E/Z)-4-methyl-N'-(2-methyltetrahydro- 4H-pyran-4-ylidene)benzenesulfonohydrazide (2.40 g, 92.0% yield) as a colorless oil. 1H NMR (400 MHz, DMSO) δ 10.26 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.00 - 3.92 (m, 1H), 3.34 - 3.23 (m, 2H), 2.84 - 2.65 (m, 1H), 2.38 (s, 3H), 2.26 - 2.14 (m, 1H), 2.08 - 1.90 (m, 1.5H), 1.76 - 1.65 (m, 0.5H), 1.13 (dd, J = 19.2, 6.0 Hz, 3H). Step 2 Synthesis of 4-(3-chloro-5-nitrophenyl)-6-methyl-3,6-dihydro-2H-pyran/4-(3-chloro-5- nitrophenyl)-2-methyl-3,6-dihydro-2H-pyran
Figure imgf000156_0003
To a mixture of 1-bromo-3-chloro-5-nitrobenzene (1.23 g, 5.20 mmol) and (E/Z)-4- methyl-N'-(2-methyltetrahydro-4H-pyran-4-ylidene)benzenesulfonohydrazide (2.20 g, 7.80 mmol) in dioxane (12 mL) were added Pd(PPh3)2Cl2 (0.73 g, 1.00 mmol) and Cs2CO3 (3.39 g, 10.40 mmol), then it was stirred at 100 °C for 16 hours under N2 atmosphere. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with brine (150 mL * 2), dried over Na2SO4, filtered and concentrated to dryness. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=3/1) to afford a mixture of 4-(3-chloro-5-nitrophenyl)-6-methyl-3,6-dihydro-2H-pyran and 4-(3-chloro-5-nitrophenyl)-2-methyl-3,6-dihydro-2H-pyran (180 mg, 13.4% yield) as a yellow solid. Step 3 Synthesis of 3-chloro-5-(6-methyl-3,6-dihydro-2H-pyran-4-yl)aniline/ 3-chloro-5-(2- methyl-3,6-dihydro-2H-pyran-4-yl)aniline
Figure imgf000157_0001
To a mixture of 4-(3-chloro-5-nitrophenyl)-6-methyl-3,6-dihydro-2H-pyran and 4-(3- chloro-5-nitrophenyl)-2-methyl-3,6-dihydro-2H-pyran (180 mg, 0.71 mmol) in EtOH (5 mL) and H2O (0.5 mL) were added Fe powder (198 mg, 3.55 mmol) and NH4Cl (190 mg, 3.55 mmol), then it was stirred at 80 °C for 16 hours under N2 atmosphere. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=3/1) to afford a mixture of 3-chloro-5-(6-methyl-3,6-dihydro-2H-pyran-4-yl)aniline and 3-chloro-5-(2-methyl-3,6-dihydro-2H-pyran-4-yl)aniline (160 mg, 95.7% yield) as a yellow oil. Step 4 Synthesis of 3-chloro-5-(2-methyltetrahydro-2H-pyran-4-yl)aniline
Figure imgf000157_0002
To a mixture of 3-chloro-5-(6-methyl-3,6-dihydro-2H-pyran-4-yl)aniline and 3-chloro-5- (2-methyl-3,6-dihydro-2H-pyran-4-yl)aniline (160 mg, 0.7152 mmol) in ethyl acetate (5 mL) was added PtO2 (32 mg, 0.14 mmol), then it was purged with H2 for 3 times and stirred at 25 °C for 16 hours under H2 atmosphere. LC-MS was checked, and the reaction was completed. After the reaction, the reaction mixture was filtered and the filter cake was washed with ethyl acetate (30 mL) for 3 times. The filtrate was concentrated to dryness to afford 3-chloro-5-(2- methyltetrahydro-2H-pyran-4-yl)aniline (60 mg, 33.4% yield) as a yellow oil. Step 5 Synthesis of 5-chloro-N-(3-chloro-5-(2-methyltetrahydro-2H-pyran-4-yl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 169)
Figure imgf000158_0001
To a mixture of 3-chloro-5-(2-methyltetrahydro-2H-pyran-4-yl)aniline (60 mg, 0.27 mmol), 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (88 mg, 0.32 mmol) and DIEA (69 mg, 0.53 mmol) in DMF (2.5 mL) was added HATU (121 mg, 0.32 mmol), then the mixture was stirred at 25 °C for 2 hours. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was diluted with water (15 mL) and extracted with ethyl acetate (30 mL * 3). Combined with organic phases, washed with brine (50 mL * 2), dried over Na2SO4, filtered and concentrated to dryness. The crude product was purified by flash chromatography to afford 5-chloro-N-(3-chloro-5-(2-methyltetrahydro-2H-pyran-4-yl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 169; 16.6 mg, 12.2% yield) as a white solid. LCMS (ESI) calcd for C21H24Cl2N3O4S+ [M + H]+ m/z 484.09, found 484.1. 1H NMR (400 MHz, MeOD) δ 10.88 (s, 1H), 8.54 (s, 1H), 7.68 (s, 1H), 7.48 (s, 1H), 7.26 (s, 1H), 7.12 (s, 1H), 3.91 (t, J = 6.4 Hz, 2H), 3.62 (t, J = 7.2 Hz, 2H), 3.52 - 3.43 (m, 2H), 2.87 - 2.77 (m, 1H), 2.44 - 2.38 (m, 2H), 1.82 - 1.66 (m, 2H), 1.59 - 1.49 (m, 1H), 1.33 - 1.22 (m, 2H), 1.13 (d, J = 6.0 Hz, 3H). The following compounds were prepared analogously:
Figure imgf000159_0001
Figure imgf000160_0003
Example 27: Synthesis of Compound 161
Figure imgf000160_0001
Step 1 Synthesis of (E)-4-methyl-N'-((tetrahydro-2H-pyran-4- yl)methylene)benzenesulfonohydrazide
Figure imgf000160_0002
To a solution of tetrahydro-2H-pyran-4-carbaldehyde (1 g, 8.8 mmol) in 8 mL MeOH was added TsNHNH2 (1.64 g, 0.0088 mol) portion wise under nitrogen and the mixture was stirred at 25 °C for 90 mins. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure to afford (2.4 g, 86% yield) (E)-4- methyl-N'-((tetrahydro-2H-pyran-4 yl)methylene)benzenesulfonohydrazide as a white solid. 1H NMR (400 MHz, MeOD) δ 7.75 (s, 2H), 7.73 (s, 1H), 7.38 (s, 2H), 7.36 (s, 1H), 7.11 (d, J = 4.4 Hz, 1H), 3.88 - 3.79 (m, 2H), 3.43 - 3.37 (m, 2H), 3.30 (p, J = 1.6 Hz, 1H), 2.42 (s, 3H), 1.61 (dd, J = 12.8, 2.4 Hz, 2H), 1.50 - 1.37 (m, 2H). Step 2 Synthesis of 4-(3-bromo-5-chlorobenzyl)tetrahydro-2H-pyran
Figure imgf000161_0001
To a solution of (E)-4-methyl-N'-((tetrahydro-2H-pyran-4- yl)methylene)benzenesulfonohydrazide (2 g, 7.08 mmol) and (3-bromo-5-chlorophenyl)boronic acid (2.5 g, 10.62 mmol) in dioxane (70 mL) was added K2CO3 (1.47 g, 10.62 mmol). Then the temperature was raised to 110 °C and stirred at this temperature for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/dichloromethane = 2:1 as eluent to afford 4-(3-bromo-5-chlorobenzyl)tetrahydro-2H-pyran (550 mg, 27% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (t, J = 1.6 Hz, 1H), 7.19 (s, 1H), 7.08 (s, 1H), 3.95 (dd, J = 11.2, 4.0 Hz, 2H), 3.37 - 3.30 (m, 2H), 2.49 (d, J = 7.2 Hz, 2H), 1.77 - 1.70 (m, 1H), 1.53 (dd, J = 13.2, 1.6 Hz, 2H), 1.39 - 1.23 (m, 2H). Step 3 Synthesis of N-(3-chloro-5-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-1,1- diphenylmethanimine
Figure imgf000161_0002
To the solution of 4-(3-bromo-5-chlorobenzyl)tetrahydro-2H-pyran (470 mg, 1.6 mmol), diphenylmethanimine (441 mg, 2.4 mmol), t-BuOK (546 mg, 4.87 mmol) and BINAP (404 mg, 0.65 mmol) in 15 mL toluene was added Pd2(dba)3 (297 mg, 0.32 mmol), and the mixture was stirred at 100 °C for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 9:1 as eluent to afford N-(3- chloro-5-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-1,1-diphenylmethanimine (270 mg, 40% yield) as a yellow solid. LCMS (ESI) calcd for C25H24ClNO+ [M + H]+ m/z 390.15, found 390.1. Step 4 Synthesis of 3-chloro-5-((tetrahydro-2H-pyran-4-yl)methyl)aniline
Figure imgf000162_0001
A solution of 3-chloro-N-(diphenylmethylidene)-5-(oxan-4-ylmethyl)aniline (270 mg, 0.69 mmol) in dioxane (3 mL) and 4M HCl-dioxane (3 mL) was stirred at 25 °C for 30 min. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure to afford crude 3-chloro-5-((tetrahydro-2H-pyran-4- yl)methyl)aniline (300 mg, 96% yield, 50% purity) as a yellow solid, which was used for the next step directly. LCMS (ESI) calcd for C12H16ClNO+ [M + H]+ m/z 226.09, found 226.0. Step 5 Synthesis of 5-chloro-N-(3-chloro-5-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-2-(1,1-
Figure imgf000162_0002
To the solution of 3-chloro-5-((tetrahydro-2H-pyran-4-yl)methyl)aniline (100 mg, 0.44 mmol), 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (110 mg, 0.40 mmol) and DIEA (215 mg, 1.66 mmol) in DMF (5 mL) was added HATU (253 mg, 0.66 mmol), the mixture was stirred at 25 °C for 2 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by prep-HPLC to afford 5-chloro-N-(3-chloro-5-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 161; 35 mg, 16% yield) as a white solid. LCMS (ESI) calcd for C21H23Cl2N3O4S+ [M + H]+ m/z 484.08, found 484.1. 1H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 8.54 (s, 1H), 7.66 (t, J = 2.0 Hz, 1H), 7.41 (s, 1H), 7.26 (s, 1H), 7.07 (s, 1H), 3.90 (t, J = 6.4 Hz, 2H), 3.81 (dd, J = 11.6, 2.8 Hz, 2H), 3.62 (t, J = 7.2 Hz, 2H), 3.23 (t, J = 10.4 Hz, 2H), 2.53 (s, 2H), 2.41 (t, J = 7.2 Hz, 2H), 1.76 -1.69 (m, 1H), 1.48 (d, J = 11.6 Hz, 2H), 1.26 - 1.15 (m, 2H). The following compounds were prepared analogously:
Figure imgf000163_0001
Example 28:Synthesis of Compound 156
Figure imgf000164_0001
Step 1 Step 2 1 2 3
Figure imgf000164_0002
Step 1 Synthesis of (E)-4-methyl-N'-(pyridin-2-ylmethylene)benzenesulfonohydrazide
Figure imgf000164_0003
To a solution of pyridine-2-carbaldehyde (1.00 g, 9.30 mol) in MeOH (10 mL) was added 4-methylbenzenesulfonhydrazide (1.73 g, 9.30 mol), the mixture was stirred at 25 °C for 1 hour. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure to afford (E)-4-methyl-N'-(pyridin-2- ylmethylene)benzenesulfonohydrazide (2.2 g, 81.7% yield) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 8.58 - 8.52 (m, 1H), 7.91 (s, 1H), 7.85 - 7.80 (m, 1H), 7.79 - 7.72 (m, 3H), 7.42 (d, J = 8.4 Hz, 2H), 7.40 - 7.36 (m, 1H), 2.36 (s, 3H). Step 2 Synthesis of [1,2,3]triazolo[1,5-a]pyridine
Figure imgf000164_0004
A mixture of (E)-4-methyl-N'-(pyridin-2-ylmethylene)benzenesulfonohydrazide (1.00 g, 3.60 mmol) in morpholine (0.63 g, 10 mmol) was stirred at 95 °C for 2 hours. LC-MS was checked, and the reaction was completed. After the reaction, the reaction mixture was concentrated to dryness. The crude product was purified by column chromatography on silica gel (petroleum ether /ethyl acetate = 3/1) to afford [1,2,3]triazolo[1,5-a]pyridine (400 mg, 83.3% yield) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 9.13 - 9.06 (m, 1H), 8.23 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.21 - 7.16 (m, 1H). Step 3 Synthesis of 2-(3-bromo-5-chlorobenzyl)pyridine
Figure imgf000165_0001
To a solution of [1,2,3]triazolo[1,5-a]pyridine (0.40 g, 3.40 mmol) in dioxane (10 mL) was added (3-bromo-5-chlorophenyl)boronic acid (1.20 g, 5.00 mmol), the mixture was stirred at 110 °C under N2 atmosphere for 1 hour. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 10%) to afford 2-(3-bromo-5- chlorobenzyl)pyridine (0.74 g, 64.7% yield) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 8.53 - 8.50 (m, 1H), 7.79 - 7.74 (m, 2H), 7.58 - 7.54 (m, 1H), 7.50 (s, 1H), 7.40 (s, 1H), 7.29 - 7.24 (m, 1H), 4.11 (s, 2H). Step 4 Synthesis of N-(3-chloro-5-(pyridin-2-ylmethyl)phenyl)-1,1-diphenylmethanimine
Figure imgf000165_0002
To a solution of 2-(3-bromo-5-chlorobenzyl)pyridine (370 mg, 1.31 mmol), diphenylmethanimine (356 mg, 1.96 mmol), BINAP (163 mg, 0.26 mmol) and tBuOK (220 mg, 1.96 mmol) in toluene (10 mL) was added Pd2(dba)3 (240 mg, 0.26 mmol), the mixture was stirred at 100 °C under N2 atmosphere for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ ethyl acetate = 3/1) to afford N-(3-chloro-5-(pyridin-2-ylmethyl)phenyl)-1,1-diphenylmethanimine (230 mg, 41.2% yield) as a yellow solid. LCMS (ESI) calcd for C25H20ClN2+ [M + H]+ m/z 383.13, found 383.1. Step 5 Synthesis of 3-chloro-5-(pyridin-2-ylmethyl)aniline
Figure imgf000166_0001
A solution of N-(3-chloro-5-(pyridin-2-ylmethyl)phenyl)-1,1-diphenylmethanimine (230 mg, 0.60 mmol) in THF (3 mL) was added HCl (0.5 mL), then it was stirred at 25 °C for 1 hour. LC-MS was checked, and the reaction was completed. After the reaction, the reaction mixture was concentrated to dryness to afford 3-chloro-5-(pyridin-2-ylmethyl)aniline (120 mg, 82.2% yield) as a yellow solid, which was used to next step without any purification LCMS (ESI) calcd for C12H12ClN2 + [M + H]+ m/z 219.07, found 218.7. Step 6 Synthesis of 5-chloro-N-(3-chloro-5-(pyridin-2-ylmethyl)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 156)
Figure imgf000166_0002
To a mixture of 3-chloro-5-(pyridin-2-ylmethyl)aniline (120 mg, 0.55 mmol), 5-chloro-2- (1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (152 mg, 0.55 mmol), and DIEA (142 mg, 1.10 mmol) in DMF (2.5 mL) was added HATU (250 mg, 0.66 mmol), then it was stirred at 25 °C for 2 hours. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was diluted with water (15 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with brine (50 mL * 2), dried over Na2SO4, filtered and concentrated to dryness. The crude product was purified by prep-HPLC to afford 5-chloro-N-(3- chloro-5-(pyridin-2-ylmethyl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 156; 101.1 mg, 36.7% yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 8.56 - 8.46 (m, 2H), 7.77 - 7.71 (m, 2H), 7.44 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.17 (s, 1H), 4.09 (s, 2H), 3.89 (t, J = 6.4 Hz, 2H), 3.61 (t, J = 7.2 Hz, 2H), 2.44 - 2.37 (m, 2H).
Figure imgf000167_0001
Figure imgf000167_0002
To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole- 1-carboxylate (1.5 g, 5.1 mmol) in 10 mL THF was added sodium hydroxide (5.1 mL of 2M, 10.2 mmol) followed by hydrogen peroxide (1.16 mL of 30% w/v, 10.2 mmol) and the reaction mixture was stirred at 0°C for 10 min firstly and then stirred at 25 °C for 1 hour. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was cooled to 0°C and diluted with DCM and 2 M HCl was added to adjust pH = 2 was reached. The organics were separated, dried and concentrated under reduced pressure to give tert-butyl 4-hydroxy-1H- pyrazole-1-carboxylate (0.9 g, 90% yield) as a white solid. LCMS (ESI) calcd for C16H24N4NaO6+ [2M + Na]+ m/z 391.16, found 390.9. Step 2 Synthesis of 4-(3-chloro-5-nitrophenoxy)-1H-pyrazole
Figure imgf000168_0001
To a solution of tert-butyl 4-hydroxy-1H-pyrazole-1-carboxylate (500 mg, 2.7 mmol) and 1-chloro-3-fluoro-5-nitrobenzene (332 mg, 1.9 mmol) in DMF (5 mL) was added K2CO3 (746 mg, 5.4 mmol). Then the temperature was raised to 90 °C and stirred at this temperature for 1 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether /dichloromethane = 9:1 as eluent to afford 4-(3-chloro-5-nitrophenoxy)-1H- pyrazole (210 mg, 31% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.42 (t, J = 2.0 Hz, 1H), 8.16 (t, J = 1.9 Hz, 1H), 8.12 (t, J = 1.9 Hz, 1H), 7.99 (s, 1H), 7.97 (t, J = 2.0 Hz, 1H), 7.79 (t, J = 2.0 Hz, 1H), 7.71 (s, 1H), 7.40 (t, J = 2.4 Hz, 1H). Step 3 Synthesis of 4-(3-chloro-5-nitrophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole
Figure imgf000168_0002
To a solution of 4-(3-chloro-5-nitrophenoxy)-1H-pyrazole (210 mg, 0.88 mmol) in THF (5 mL) was added NaH (32 mg, 60% in oil, 1.3 mmol) at 0 °C, the mixture was stirred at 0 °C under nitrogen for 30 min. Then SEMCl (161 mg, 0.96 mmol) was added to the mixture and the reaction mixture was stirred at 25 °C for 1 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was quenched with MeOH and the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether /dichloromethane = 95:5 as eluent to afford 4-(3-chloro-5-nitrophenoxy)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole (270 mg, 75% yield) as a yellow oil. LCMS (ESI) calcd for C15H20ClN3O4Si+ [M + H]+ m/z 370.09, found 370.1. Step 4 Synthesis of 3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)oxy)aniline
Figure imgf000169_0001
To the solution of 4-(3-chloro-5-nitrophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole (270 mg, 0.73 mmol) and NH4Cl (195 mg, 3.64 mmol) in 10 mL EtOH and 1mL H2O was added Fe powder (203 mg, 3.64 mmol) portionwise, and the mixture was stirred at 80 °C for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 94 : 6 as eluent to afford 3-chloro-5-((1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)oxy)aniline (240 mg, 87% yield) as a yellow oil. LCMS (ESI) calcd for C15H22ClN3O2Si+ [M + H]+ m/z 340.12, found 340.1. Step 5 Synthesis of 5-chloro-N-(3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)oxy)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide
Figure imgf000169_0002
To the solution of 3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)oxy)aniline (120 mg, 0.35 mmol), 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (117 mg, 0.42 mmol) and DIEA (136 mg, 1.06 mmol) in DMF (4 mL) was added HATU (268 mg, 0.70 mmol), the mixture was stirred at 25 °C for 2 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 65:35 as eluent to afford 5-chloro-N-(3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)oxy)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (85 mg, 36% yield) as a yellow solid. LCMS (ESI) calcd for C24H29Cl2N5O5SSi+ [M + H]+ m/z 598.10, found 598.1. Step 6 Synthesis of N-(3-((1H-pyrazol-4-yl)oxy)-5-chlorophenyl)-5-chloro-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide
Figure imgf000170_0001
The solution of 5-chloro-N-(3-chloro-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-4-yl)oxy)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (85 mg, 0.14 mmol) in dioxane (3 mL) and 4M HCl-dioxane (3 mL) was stirred at 25 °C under nitrogen for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by prep-HPLC to afford N-(3- ((1H-pyrazol-4-yl)oxy)-5-chlorophenyl)-5-chloro-2-(1,1-dioxidoisothiazolidin-2- yl)isonicotinamide (20 mg, 30% yield) as a white solid. LCMS (ESI) calcd C18H15Cl2N5O4S+ [M + H]+ m/z 468.02, found 467.9. 1H NMR (400 MHz, DMSO) δ 12.89 (s, 1H), 10.92 (s, 1H), 8.53 (s, 1H), 7.85 (s, 1H), 7.57 (t, J = 1.6 Hz, 1H), 7.49 (s, 1H), 7.23 (s, 1H), 7.21 (t, J = 2.4 Hz, 1H), 6.85 (t, J = 2.0 Hz, 1H), 3.89 (t, J = 6.4 Hz, 2H), 3.61 (t, J = 7.2 Hz, 2H), 2.40 (t, J = 7.2 Hz, 2H).
Figure imgf000170_0002
Step 1 Synthesis of (S)-4-(3-chloro-5-nitrophenyl)-3-(methoxymethyl)morpholine
Figure imgf000171_0002
To a mixture of (3S)-3-(methoxymethyl)morpholine (1 g, 7.60 mmol), 1-bromo-3-chloro- 5-nitrobenzene (2.16 g, 9.10 mmol), BINAP (0.95 g, 1.50 mmol) and Cs2CO3 (4.95 g, 15.20 mmol) in dioxane (10 mL) was added Pd(OAc)2 (0.34 g, 1.50 mmol), the mixture was stirred at 100 °C under N2 atmosphere for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether = 4% ~ 5%) to afford (S)-4-(3-chloro-5-nitrophenyl)-3-(methoxymethyl)morpholine (0.83 g, 36.8% yield) as a yellow solid. LCMS (ESI) calcd C12H16ClN2O4+ [M + H]+ m/z 287.08, found 286.9. Step 2 Synthesis of (S)-3-chloro-5-(3-(methoxymethyl)morpholino)aniline
Figure imgf000171_0001
To a mixture of (S)-4-(3-chloro-5-nitrophenyl)-3-(methoxymethyl)morpholine (800 mg, 2.79 mmol) and NH4Cl (746 mg, 13.95 mmol) in EtOH (12 ml) and H2O (2 mL) was added Fe powder (779 mg, 13.95 mmol) portionwise, then it was stirred at 80 °C under N2 atmosphere for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was filtered and the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether = 30%) to afford (S)-3- chloro-5-(3-(methoxymethyl)morpholino)aniline (690 mg, 86.6% yield) as yellow oil. LCMS (ESI) calcd C12H18ClN2O2 + [M + H]+ m/z 257.11, found 257.0. Step 3 Synthesis of (S)-5-chloro-N-(3-chloro-5-(3-(methoxymethyl)morpholino)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide
Figure imgf000172_0001
To a mixture of (S)-3-chloro-5-(3-(methoxymethyl)morpholino)aniline (400 mg, 1.56 mmol), 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (517 mg, 1.87 mmol) and DIEA (403 mg, 3.12 mmol) in DMF (3 mL) was added HATU (711 mg, 1.87 mmol), the mixture was stirred at 25 °C for 0.5 hour. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (80 mL * 3). The combined organic phases were washed with brine (100 mL * 2), dried over Na2SO4, filtered and concentrated to dryness. The crude product was purified by column chromatography on silica gel (MeOH/DCM=1%) to afford (S)-5-chloro-N-(3-chloro-5-(3- (methoxymethyl)morpholino)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (630 mg, 70.6% yield) as a light yellow solid. LCMS (ESI) calcd C21H25Cl2N4O5S+ [M + H]+ m/z 515.09, found 515.0. Step 4 Synthesis of (S)-5-chloro-N-(3-chloro-5-(3-(hydroxymethyl)morpholino)phenyl)-2-(1,1- dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 149)
Figure imgf000172_0003
Figure imgf000172_0002
To a mixture of (S)-5-chloro-N-(3-chloro-5-(3-(methoxymethyl)morpholino)phenyl)-2- (1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (630 mg, 1.22 mmol) in DCM (10 mL) was added BBr3 (1225 mg, 4.89 mmol) at 0 °C, then it was allowed to warm to 25 °C and stirred for 3 hours. LC-MS was checked, and the reaction was completed. After the reaction, the reaction mixture was quenched with MeOH (10 mL) and then concentrated to dryness. Then it was diluted with sat. NaHCO3 aq. (100 mL) and extracted with ethyl acetate (80 mL * 3). The combined organic phases were washed with brine (100 mL * 2), dried over Na2SO4, filtered and concentrated to dryness. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate =3/1) to afford (S)-5-chloro-N-(3-chloro-5-(3- (hydroxymethyl)morpholino)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide ( Compound 149; 266.6 mg, 43.0% yield) as a white solid. LCMS (ESI) calcd C20H23Cl2N4O5S+ [M + H]+ m/z 501.08, found 501.0. 1H NMR (400 MHz, DMSO) δ 10.73 (s, 1H), 8.53 (s, 1H), 7.23 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.73 (s, 1H), 4.83 (t, J = 5.2 Hz, 1H), 4.05 (d, J = 10.8 Hz, 1H), 3.94 - 3.88 (m, 3H), 3.68 - 3.50 (m, 6H), 3.29 - 3.19 (m, 2H), 3.04 - 2.96 (m, 1H), 2.44 - 2.38 (m, 2H). Example 31: Synthesis of Compound 110
Figure imgf000173_0001
To a solution of 3-amino-5-bromobenzoic acid (5 g, 23.1 mmol) in 60 mL EtOH was added 4 mL con.H2SO4 dropwise, the mixture was stirred at 80 °C for 1 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was quenched with sat. Na2CO3 aq., the mixture was extracted with ethyl acetate (100 mL*3). The combined organic phases were washed with brine dried over Na2SO4 and filtered the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 9:1 as eluent to afford ethyl 3-amino-5-bromobenzoate (4.7 g, 79% yield) as a yellow solid. LCMS (ESI) calcd for C9H10BrNO2+ [M + H]+ m/z 243.99, found 243.9. Step 2 Synthesis of ethyl 3-amino-5-(3,6-dihydro-2H-pyran-4-yl)benzoate
Figure imgf000174_0001
To a solution of ethyl 3-amino-5-bromobenzoate (1.5 g, 6.1 mmol), 2-(3,6-dihydro-2H- pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.54 g, 7.32 mmol) and K3PO4 (3.88 g, 18.3 mmol) in dioxane/H2O (60 mL, v:v = 10:1) was added Pd(dppf)Cl2DCM (0.5 g, 0.61 mmol), the mixture was stirred at 95 °C under N2 for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 3:1 as eluent to afford ethyl 3-amino-5-(3,6-dihydro-2H-pyran-4-yl)benzoate (1.3 g, 77% yield) as a yellow solid. LCMS (ESI) calcd for C14H17NO3+ [M + H]+ m/z 248.12, found 248.0. Step 3 Synthesis of ethyl 3-amino-5-(tetrahydro-2H-pyran-4-yl)benzoate
Figure imgf000174_0002
To a solution of ethyl 3-amino-5-(3,6-dihydro-2H-pyran-4-yl)benzoate (1.3 g, 5.3 mmol) in EtOH (70 mL) was added Pd/C (0.11 g, 1.06 mmol), the reaction mixture was stirred at 25°C under H2 for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was filtered and the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 1:1 as eluent to afford 3-amino-5-(tetrahydro-2H-pyran-4-yl)benzoate (1.1 g, 79% yield) as a white solid. LCMS (ESI) calcd for C14H19NO3+ [M + H]+ m/z 250.14, found 250.1. Step 4 Synthesis of ethyl 3-(5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamido)-5- (tetrahydro-2H-pyran-4-yl)benzoate (Compound 110)
Figure imgf000175_0001
To the solution of 5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinic acid (300 mg, 1.08 mmol), 3-amino-5-(tetrahydro-2H-pyran-4-yl)benzoate (324 mg, 1.30 mmol) and DIEA (420 mg, 3.25 mmol) in DMF (10 mL) was added HATU (824 mg, 2.17 mmol), the mixture was stirred at 25 °C for 2 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography using petroleum ether/ethyl acetate = 3:2 as eluent to afford ethyl 3-(5-chloro-2- (1,1-dioxidoisothiazolidin-2-yl)isonicotinamido)-5-(tetrahydro-2H-pyran-4-yl)benzoate (Compound 110; 430 mg, 70% yield) as a white solid. LCMS (ESI) calcd for C23H26ClN3O6S+ [M + H]+ m/z 508.12, found 508.0. 1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.54 (s, 1H), 8.19 (s, 1H), 7.87 (s, 1H), 7.63 (s, 1H), 7.27 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 3.98 - 3.94 (m, 2H), 3.91 (t, J = 6.4 Hz, 2H), 3.62 (t, J = 7.2 Hz, 2H), 3.45 (t, J = 11.6 Hz, 2H), 2.92 - 2.86 (m, 1H), 2.42 (p, J = 6.8 Hz, 2H), 1.75 (d, J = 12.4 Hz, 2H), 1.69 - 1.59 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H). Example 32: Synthesis of Compound 109
Figure imgf000176_0001
Step 1 Synthesis of 3-(5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamido)-5-(tetrahydro- 2H-pyran-4-yl)benzoic acid
Figure imgf000176_0002
To a solution of ethyl 3-(5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamido)-5- (tetrahydro-2H-pyran-4-yl)benzoate (314 mg, 0.62 mmol) in THF /MeOH/ H2O (7.5 mL, v:v:v =2:2:1) was added LiOH (37 mg, 1.55 mmol), the mixture was stirred at rt for 16 h. LC-MS was checked, and the reaction was completed. After the reaction, the mixture was concentrated under reduced pressure and diluted with H2O (7 mL). To this residue was added aqueous 1N HCl aq. at 0°C to adjust pH = 3 ~ 4. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-(5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamido)-5- (tetrahydro-2H-pyran-4-yl)benzoic acid (110 mg, 37% yield) as a yellow solid. LCMS (ESI) calcd for C21H22ClN3O6S+ [M + H]+ m/z 480.09, found 480.1. Step 2 Synthesis of 5-chloro-N-(3-(dimethylcarbamoyl)-5-(tetrahydro-2H-pyran-4-yl)phenyl)-2- (1,1-dioxidoisothiazolidin-2-yl)isonicotinamide (Compound 109)
Figure imgf000177_0001
To the solution of 3-(5-chloro-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamido)-5- (tetrahydro-2H-pyran-4-yl)benzoic acid (60 mg, 0.13 mmol), dimethylamine hydrochloride (12 mg, 0.15 mmol) and DIEA (81 mg, 0.63 mmol) in DMF (5 mL) was added HATU (95 mg, 0.25 mmol), the mixture was stirred at 25 °C for 2 h. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by prep-HPLC to afford 5-chloro-N-(3-(dimethylcarbamoyl)-5-(tetrahydro-2H- pyran-4-yl)phenyl)-2-(1,1-dioxidoisothiazolidin-2-yl)isonicotinamide ( Compound 109; 25 mg, 39% yield) as a white solid. LCMS (ESI) calcd for C23H27ClN4O5S+ [M + H]+ m/z 507.14, found 507.0. 1H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.53 (d, J = 2.8 Hz, 1H), 7.60 (dd, J = 4.4, 1.6 Hz, 2H), 7.25 (d, J = 2.4 Hz, 1H), 7.06 (s, 1H), 3.96 - 3.90 (m, 2H), 3.63 - 3.60 (m, 2H), 3.46 - 3.41 (m, 7.0 Hz, 2H), 2.98 (s, 3H), 2.92 (s, 3H), 2.84 - 2.79 (m, 1H), 2.41 (p, J = 6.8 Hz, 2H), 1.76 - 1.58 (m, 4H). Example 33: In vitro efficacy assay of exemplary compounds Exemplary compounds of the invention were evaluated for efficacy in inhibiting TDP-43 inclusions cellular imaging based assays. The cellular model is in human neuroblastoma SH SY5Y cells (ATCC, cat#: CRL-2266). The parent cell line was first engineered to stably express a tetracycline repressor protein (designated as TREx-SY5Y cells, customer cell line development by ThermoFisher). Wild-type human TDP-43 with a C-terminus eGFP tag was synthesized and cloned into pcDNA5/TO expression vector (ThermoFisher). The plasmid was transfected into TREx-SY5Y cells using Lipofectamine 2000 and hygromycin resistant colonies were selected. Expression of TDP- 43WT::eGFP was examined under fluorescent microscopy and Western blot upon tetracycline induction. The clone that is used for TDP-43 aggregation assay is referred to as SY5Y TDP- 43WT cells hereafter. Compound inhibition of TDP-43 aggregation was tested in an 8-point dose curve in 96- well format. Briefly, TDP-43WT::eGFP expression was induced with 1 uM tetracycline for 24 hrs (SY5Y TDP-43WT cells). The cells were then pre-treated for 1 hour with exemplary compounds before adding sodium arsenite to a final concentration of 15 ^M and incubated for another 23 hrs. At the end of the treatment the cell monolayers were washed in PBS and fixed in 4% paraformaldehyde (PFA), diluted from 16% stock (Electron Microscopy Sciences cat: #15710-S). The inhibitory effect on TDP-43 aggregation was measured using CellInsight CX7 high content imager (ThermoFisher). The percentage of cells with TDP-43 aggregates was calculated based on the total number of cells identified by DAPI staining. An 8-point dose response curve was generated, and the IC50 for each compound tested was determined and is summarized in Table 3 below. In the table, “A” indicates an IC50 of less than 100 nM, “B” indicates an IC50 range from 100 nM to 500 nM; “C” indicates an IC50 range from 500 nM to 2 μM; and “D” indicates an IC50 greater than 2 μM. Table 3: Efficacy of exemplary compounds of the invention
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0002
“-“ indicates no result available Compounds 102 and 103 both had IC50 values in SY5Y TDP-43WT cells of less than 100 nM, and in each case had significantly lower IC50 than Reference Compound A (lacking the pyridine nitrogen) run in the same assay as a control.
Figure imgf000182_0001
Reference Compound A EQUIVALENTS It will be recognized that one or more features of any embodiments disclosed herein may be combined and/or rearranged within the scope of the invention to produce further embodiments that are also within the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be within the scope of the present invention. Although the invention has been described and illustrated in the foregoing illustrative embodiments, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the details of implementation of the invention can be made without departing from the spirit and scope of the invention, which is limited only by the claims that follow. Features of the disclosed embodiments can be combined and/or rearranged in various ways within the scope and spirit of the invention to produce further embodiments that are also within the scope of the invention. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically in this disclosure. Such equivalents are intended to be encompassed in the scope of the following claims. All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. * * * * *

Claims

We claim: 1. A compound of Formula (I):
Figure imgf000184_0001
Formula (I) or a pharmaceutically acceptable salt thereof, wherein: X is Y is C=O or S(O)2; G is N or CR3; R2 is H, C1-C6 alkyl, C1-C6 haloalkyl, or halo; R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, or halo; wherein at least one of R2 and R3 is a substituent which is not H; R6 is H or C1-C6 alkyl optionally substituted with 1-4 R8; R7 is C1-C6 alkyl, C3-C7 cycloalkyl, -N(R10)-C1-C6 alkyl, or -N(R10)-C3-C7 cycloalkyl, each of which is optionally substituted with 1-4 R8; or R6 and R7, taken together with the atoms to which they are attached, form a 4-7 membered heterocycloalkyl ring, optionally substituted with 1-5 R8, wherein said heterocycloalkyl ring either includes no ring heteroatoms other than the N to which R6 is attached and in the Y group to which R7 is attached, or includes one additional N ring atom substituted with R10; each R8 is independently halo, C1-C6 alkyl, -ORB, -C(O)ORB, or C1-C6 haloalkyl; each R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, nitro, azido, -ORB, -C(O)RD, -C(O)NRARC, -C(O)ORB, -NRARC , - NRAC(O)RD, –S(O)xRE, –OS(O)xRE, –C(O)NRAS(O)xRE, –NRAS(O)xRE, –S(O)xNRA, or -L-Z; L is a bond, -O-, -NRA-, or -(CH2)1-3-; Z is C3-C7 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each Z is optionally substituted by 1-5 R11; each R10 is independently H, C1-C6 alkyl or C1-C6 haloalkyl; each R11 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, nitro, azido, oxo, cycloalkyl, -ORB, -C(O)RD, -C(O)NRARC, - C(O)ORB, -NRARC, -NRAC(O)RD, –S(O)xRE, –OS(O)xRE, –C(O)NRAS(O)xRE, –NRAS(O)xRE, or –S(O)xNRA; each RA, RB, RC, RD, or RE is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, hetercycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with 1-4 R8; or RA and RC, together with the atoms to which each is attached, form a heterocycloalkyl ring optionally substituted with 1-4 R8; and x is 0, 1, or 2. 2. The compound of claim 1 of Formula (Ia):
Figure imgf000185_0001
Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein: X is Y is C=O or S(O)2; R2 is H, C1-C6 alkyl, C1-C6 haloalkyl, or halo; R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, or halo; wherein at least one of R2 and R3 is not H; R6 is H or C1-C6 alkyl optionally substituted with 1-4 R8; R7 is C1-C6 alkyl, C3-C7 cycloalkyl, -N(R10)-C1-C6 alkyl, or -N(R10)-C3-C7 cycloalkyl, each of which is optionally substituted with 1-4 R8; or R6 and R7, taken together with the atoms to which they are attached, form a 4-7 membered heterocycloalkyl ring, optionally substituted with 1-5 R8, wherein said heterocycloalkyl ring either includes no ring heteroatoms other than the N to which R6 is attached and in the Y group to which R7 is attached, or includes one additional N ring atom substituted with R10; each R8 is independently halo, C1-C6 alkyl, -ORB, -C(O)ORB, or C1-C6 haloalkyl; each R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, nitro, azido, -ORB, -C(O)RD, -C(O)NRARC, -C(O)ORB, -NRARC, - NRAC(O)RD, –S(O)xRE, –OS(O)xRE, –C(O)NRAS(O)xRE, –NRAS(O)xRE, –S(O)xNRA, or -L-Z; L is a bond, -O-, -NRA-, or -(CH2)1-3-; Z is C3-C7 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each Z is optionally substituted by 1-5 R11; each R10 is independently H, C1-C6 alkyl or C1-C6 haloalkyl; each R11 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, nitro, azido, oxo, cycloalkyl, -ORB, -C(O)RD, -C(O)NRARC, - C(O)ORB, -NRARC , -NRAC(O)RD, –S(O)xRE, –OS(O)xRE, –C(O)NRAS(O)xRE, –NRAS(O)xRE, or –S(O)xNRA; or two R11, together with the atom to which they are attached, form C(O); each RA, RB, RC, RD, or RE is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, hetercycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with 1-4 R8; or RA and RC, together with the atoms to which each is attached, form a heterocycloalkyl ring optionally substituted with 1-4 R8; and x is 0, 1, or 2. 3. The compound of claim 1 or 2, wherein X is
Figure imgf000186_0001
wherein m is 0, 1,
2,
3, or 4.
4. The compound of claim 3, wherein X is
Figure imgf000186_0002
wherein m is 0 or 1.
5. The compound of claim 3, wherein X is
Figure imgf000187_0001
.
6. The compound of claim 3 or 4, wherein m is 0.
7. The compound of any one of claims 1-6, wherein R2 is Me or Cl.
8. The compound of any one of claims 1-7, wherein R3 is H, Me, or Cl.
9. The compound of any one of claims 1-6, wherein R2 is H and R3 is Me or Cl.
10. The compound of any one of claims 1-6, wherein R2 is Me or Cl, and R3 is H or G is N.
11. A compound of claim 2 of Formula (Ib):
Figure imgf000187_0002
Formula (Ib) or a pharmaceutically acceptable salt thereof, wherein each R8 is independently halo, C1-C6 alkyl, -ORB, -C(O)ORB, or C1-C6 haloalkyl; each R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, nitro, azido, C3-C7 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, - ORB, -C(O)RD, -C(O)NRARC, -C(O)ORB, -NRARC , -NRAC(O)RD, –S(O)xRE, –OS(O)xRE, – C(O)NRAS(O)xRE, –NRAS(O)xRE, –S(O)xNRA, or -L-Z; L is a bond, -O-, -NRA-, or -(CH2)1-3-; Z is C3-C7 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each Z is optionally substituted by 1-5 R11; each R11 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, nitro, azido, oxo, cycloalkyl, -ORB, -C(O)RD, -C(O)ORB, -NRARC, -NRAC(O)RD, –S(O)xRE, –OS(O)xRE, –C(O)NRAS(O)xRE, –NRAS(O)xRE, or –S(O)xNRA; or two R11, together with the atom to which they are attached, form C(O); each RA, RB, RC, RD, or RE is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with 1-4 R8. or RA and RC, together with the atoms to which each is attached, form a hetercycloalkyl ring optionally substituted with 1-4 R8; and x is 0, 1, or 2.
12. The compound of claim 11, wherein each R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, halo, cyano, C3-C7 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted by 1-5 R11.
13. The compound of claim 11 or 12, wherein at least one R9 group is methyl or chloro.
14. The compound of claim 13, wherein one R9 is chloro or methyl and the other R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, halo, cyano, C3-C7 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is optionally substituted by 1-5 R11.
15. The compound of claim 13, wherein one R9 is chloro and the other R9 is phenyl, C3-C7 cycloalkyl, monocyclic 4-7 membered heterocycloalkyl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S), or monocyclic 5-6 membered heteroaryl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S); wherein the phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 R11.
16. The compound of claim 13, wherein one R9 is chloro and the other R9 is C3-C7 cycloalkyl or monocyclic 4-7 membered heterocycloalkyl (wherein 1-2 of the ring atoms are heteroatoms selected from the group consisting of N, O, and S), wherein the cycloalkyl or heterocycloalkyl, is optionally substituted with 1-3 R11.
17. The compound of claim 13, wherein one R9 group is chloro and the other R9 group is selected from the group consisting of
Figure imgf000189_0001
wherein n is 0, 1, 2, 3, 4, or 5.
18. The compound of claim 16, wherein one R9 group is chloro and the other R9 group is selected from the group consisting of
Figure imgf000189_0002
wherein n is 0, 1, 2, 3, 4, or 5.
19. The compound of claim 17 or 18, wherein n is 0.
20. The compound of claim 19, wherein the compound is
Figure imgf000189_0003
21. The compound of any one of claims 1-19 wherein L is a bond.
22. The compound of any one of the preceding claims, wherein the compound of Formula (I), (Ia), or (Ib) is selected from a compound described in the specification.
23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1-22.
24. A method for modulating stress granules, wherein the method comprises administering to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition of claim 23 or a compound of any one of claims 1-22.
25. The method of claim 24, wherein 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), GTPase activating protein binding protein 1 (G3BP-1), GTPase activating protein binding protein 2 (G3BP-2), tris tetraprolin (TTP), fused in sarcoma (FUS), or fragile X mental retardation protein (FMRP).
26. A method for modulating TDP-43 inclusion formation, wherein the method comprises administering to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition of claim 23 or a compound of any one of claims 1-22.
27. The method of any one of claims 24-26, wherein the subject has a neurodegenerative disease or disorder, a musculoskeletal disease or disorder, a cancer, an ophthalmological disease or disorder, and/or a viral infection.
28. A method of treating a subject with a neurodegenerative disease or disorder, a musculoskeletal disease or disorder, a cancer, an ophthalmological disease or disorder, and/or a viral infection, wherein the method comprises administering to a subject in need thereof a pharmaceutically effective amount of a pharmaceutical composition of claim 23 or a compound of any one of claims 1-22.
29. The method of claim 28, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Huntington’s chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, 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.g., Werdnig-Hoffmann disease) SMA Type II, SMA Type III (e.g., Kugelberg-Welander disease), or congenital SMA with arthrogryposis), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post- polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease/motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam- Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler’s disease, Krabbe’s disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder’s disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform 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, or any combination thereof.
30. The method of claim 28, wherein 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.
31. The method of claim 28, wherein 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, or any combination thereof.
32. The method of claim 31, wherein the cancer is a lymphoma selected from a B-cell lymphoma or a T-cell lymphoma.
33. The method of claim 32, wherein 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, Waldenström’s macroglobulinemia, hairy cell leukemia, primary central nervous system (CNS) lymphoma, precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, 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), and anaplastic large cell lymphoma (ALCL).
34. The method of claim 27, wherein 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.
35. The method of claim 27, wherein 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.
36. The method of any one of claims 27-35, further comprising 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.
37. The method of any one of claims 27-36, wherein pathology of said neurodegenerative disease or disorder, said musculoskeletal disease or disorder, said cancer, said ophthalmological disease or disorder, or said viral infection comprises stress granules.
38. The method of any one of claims 27-37, wherein pathology of said neurodegenerative disease, said musculoskeletal disease or disorder, said cancer, said ophthalmological disease or disorder, or said viral infection comprises TDP-43 inclusions.
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