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WO2025059461A1 - Composés cristallins, compositions pharmaceutiques et méthodes de traitement d'une maladie - Google Patents

Composés cristallins, compositions pharmaceutiques et méthodes de traitement d'une maladie Download PDF

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Publication number
WO2025059461A1
WO2025059461A1 PCT/US2024/046608 US2024046608W WO2025059461A1 WO 2025059461 A1 WO2025059461 A1 WO 2025059461A1 US 2024046608 W US2024046608 W US 2024046608W WO 2025059461 A1 WO2025059461 A1 WO 2025059461A1
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crystalline compound
cancer
peak
compound
ray powder
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Alexander HURD
Shon Pulley
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Rome Therapeutics Inc
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Rome Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • LINE-1 Long Interspersed Nuclear Element 1
  • LINE-1 are class I transposable elements in the DNA of some organisms and comprise about 17% of the human genome.
  • LINE-1 harbors two open reading frames, ORF1 and ORF2, which in turn respectively encode ORF1p, which has nucleic acid chaperone activity, and ORF2p, with reverse transcriptase (RT) and endonuclease activities.
  • RT reverse transcriptase
  • LINE-1 retrotransposition activity is mediated by ORF2p.
  • the majority of LINE-1 elements in the human genome contain inactivating mutations but a small percentage of LINE-1 elements are intact and have retained the ability to retrotranspose.
  • LINE-1 elements are thought to disrupt the genome through insertions, deletions, rearrangements and recombinations.
  • LINE-1 activity is normally tightly regulated in the germline by DNA methylation, histone modifications, and piRNA.
  • Retrotransposons are transposable elements which are associated with the pathogenesis of many diseases such as cancer, autoimmune disease, neurological disorders and aging, among others. (Zhang, et al, Frontiers in Cell and Dev.
  • LINE-1 RNA and protein overexpression can promote apoptosis, DNA damage and repair, and cellular plasticity, which can promote tumor progression. Furthermore, genomic hypomethylation can induce expression of repetitive sequences which can drive a pro-inflammatory response characterized by overproduction of type 1 interferon. (Zhang, 2020).
  • Pathogenic interferon production is a characteristic feature of type I interferonopathies. These include rare genetic diseases with occurrence rates from 1:10,000 to 1:1,000,000. Pathological induction of type I interferon causes immune system hyperactivation that leads to systemic inflammation which can affect the nervous system, lung and blood vessels, among other organ systems.
  • Aicardi-Gout Italian Syndrome is a monogenic inflammatory encephalomyopathy driven by mutations in genes that are critical in maintaining homeostatic cytosolic nucleic acid oligomers. As a result, increased level of cytoplasmic nucleic acid accumulation leads heightened interferon response.
  • LINE-1 reverse transcriptase products have been implicated as a primary source of pro-inflammatory nucleic acids in AGS patients. Administering a combination of three nucleoside reverse transcriptase inhibitors to AGS patients for 12 months effectively reduced their systemic interferon response.
  • the pathogenic interferon response responsible for AGS has also been implicated in the pathogenesis of SLE ,with several case studies identifying monogenic forms of SLE driven by hypomorphic alleles of nucleic acid metabolizing enzymes such as TREX1. 2 32017260 400807-030WO (212251) [0007] Hypomethylated and highly expressed LINE-1 has been found in many patients with autoimmune diseases such as systemic lupus erythematosus (SLE), cutaneous lupus, Sjögren’s syndrome (SS) and psoriasis. (Zhang et al).
  • SLE systemic lupus erythematosus
  • SS Sjögren’s syndrome
  • psoriasis psoriasis.
  • LINE-1 has also been found to be significantly upregulated in patients with dermatomyositis (DM), with significantly elevated levels of QUZMXNMXVU i IUL QUZMXNMXVU k) #@[XQ_ITI MZ IS' J. Am. Acad, Dermatol., 84(4):1103-1105 (2020)).
  • LINE-1 has also been implicated in neurological disorders such as ataxia telangiectasia (AT), Rett syndrome, Friederichs's ataxia, perisupranuclear palsy, amyotrophic lateral sclerosis, frontotemporal dementia and schizophrenia.
  • AT ataxia telangiectasia
  • Rett syndrome Friederichs's ataxia
  • perisupranuclear palsy amyotrophic lateral sclerosis
  • frontotemporal dementia schizophrenia.
  • LINE-1 is also implicated in the aging process and frontotemporal lobe degeneration. (Zhang, 2020).
  • Cancer continues to be a significant health problem despite the substantial research efforts and scientific advances reported in the literature for treating this disease. Solid tumors, including prostate cancer, breast cancer, and lung cancer remain highly prevalent among the world population. Leukemias and lymphomas also account for a significant proportion of new cancer diagnoses. Current treatment options for these cancers are not effective for all patients and/or can have substantial adverse side effects. New therapies are needed to address this unmet need in cancer therapy.
  • High LINE-1 activity has been found in many tumor tissues.
  • LINE-1 RT uses a procedure termed target-site-primed reverse transcription (TPRT) which involves nicking of the genomic DNA followed by reverse transcription and insertion of LINE-1 into the genome.
  • TPRT target-site-primed reverse transcription
  • LINE-1 mediated gene rearrangement can trigger oncogene amplification.
  • LINE-1 can mediate the deletion of tumor suppressor genes (Zhang, 2020).
  • Inhibition of LINE-1 RT in cancer cells either via RNA interference-dependent silencing of active LINE-1 elements or using RT inhibitory compounds can reduce cancer cell proliferation, promote cancer cell differentiation and can retard tumor progression in certain animal models. (Sciamann et al, Frontiers in Chemistry, 4:6 (Feb.2016)).
  • LINE1 has also been shown to promote tumor metastasis.
  • HERVs Human endogenous retroviruses
  • RTs reverse transcriptases
  • HERVs play a role in early development by rewiring the gene regulatory network of the preimplantation embryo (Fu et al, Biomolecules, 11(6):829 (2021)). HERV expression appears to be a hallmark of the undifferentiated state, the acquisition of phenotypic plasticity and stem cell character (Balestrieri et al, Frontiers in Microbiology, 9:1448 (2018)); traits associated with aggressive cancer and poor patient outcomes. HERV expression is normally tightly controlled in normal adult tissues but is reported to be aberrantly expressed in cancer (Downey et al, Int. J.
  • crystalline forms of a compound can have different physical and chemical (i.e., physicochemical) properties such as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspendability and dissolution rate, and biological availability.
  • 4 32017260 400807-030WO (212251) [0014] The present disclosure addresses the foregoing needs and provides other related advantages.
  • One aspect of the disclosure provides solid forms of Compound I: [0017] Another aspect of the form of Compound II: [0018] Further description of provided herein.
  • the compounds may be presented in a pharmaceutical composition containing a pharmaceutically acceptable carrier.
  • the disclosed compounds and compositions may be used for treating medical disorders, such as by inhibiting LINE1 reverse transcriptase and/or HERV-K reverse transcriptase.
  • one aspect of the disclosure provides a method of treating a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder, comprising 5 32017260 400807-030WO (212251) administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein to treat the disorder.
  • FIG.1 depicts an XRPD diffractogram of Compound II.
  • FIG.2 depicts an XRPD pattern overlay of crystalline forms A, B, C, and D of Compound I.
  • FIG.3 depicts an XRPD diffractogram of crystalline Form A of Compound I.
  • FIG.4 depicts TGA and DSC thermograms of crystalline Form A of Compound I.
  • FIG.5 depicts a DVS analysis of crystalline Form A of Compound I.
  • FIG.6 depicts an XRPD diffractogram used in indexing crystalline Form A of Compound I.
  • FIG.7 depicts an XRPD diffractogram of crystalline Form C of Compound I.
  • FIG.8 depicts TGA and DSC thermograms of crystalline Form C of Compound I.
  • FIG.9 depicts an XRPD diffractogram used in indexing of crystalline Form B of Compound I.
  • FIG.10 depicts TGA and DSC thermograms of crystalline Form B of Compound I.
  • FIG.11 depicts a DVS analysis of crystalline Form B of Compound I.
  • FIG.12 depicts an XRPD diffractogram of crystalline Form D of Compound I.
  • FIG.13 depicts TGA and DSC thermograms of crystalline Form D of Compound I.
  • FIG.14 is a graph depicting normalized interferon levels in THP1-Dual TM KO- TREX1 xenografts from mice treated once daily, for four days with decitabine (DAC) and varying doses of Compound A. The graph depicts data obtained on day 5, with tumor harvested 24 hours after the final decitabine dosing on day 4.
  • DAC decitabine
  • the present disclosure provides crystalline oxopyrimidinyl-((isobutyryloxy) methyl)tetrahydrofuranyl compounds, pharmaceutical compositions containing crystalline compounds, and methods of treatment using the crystalline compounds.
  • Differences between solid forms of an active pharmaceutical compound can have profound effects on the properties of the compound. For example, differences can arise in the crystallinity, solubility, intrinsic dissolution rate, bioavailability, stability to mechanical grinding, storage stability, and stability in aqueous and other media of a polymorphic form of a compound as compared to the amorphous and other polymorphic forms of the same compound.
  • Polymorphism refers to the ability of a solid substance to exist in one or more distinct crystal structures (i.e., with one or more distinct arrangements of molecules relative to each other in the crystal lattice).
  • Different polymorphs of a substance may have different physical properties such as bioavailability, solubility, intrinsic dissolution rate and calorimetric behavior (e.g., melting point).
  • Different polymorphs may also exhibit differences in stability (e.g., differences in stability with respect to conversion to other crystalline or amorphous forms or differences in stability to grinding).
  • the physical properties of an active pharmaceutical ingredient may affect the drug product safety performance and efficacy. It is therefore advantageous to identify polymorphic forms of a drug substance which have pharmaceutically acceptable properties.
  • Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.
  • mammals e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like
  • the term “inhibit”, “inhibition”, or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.
  • the term “effective amount” refers to the amount of a compound that will elicit a biological or medical response in a subject, for example, the reduction or inhibition of enzyme or protein activity relative to the baseline levels before treatment.
  • an “effective amount” of a compound is one which is sufficient to effect some beneficial change or desired results (e.g., a therapeutic, ameliorative, inhibitory, or preventative result).
  • An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
  • the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • treatment of cancer may mean prolonging the period of time where tumor burden does not increase (progression-free survival), reduction of the tumor burden, extension of the overall survival time of a patient, amelioration of symptoms associated with the cancer, prevention of metastasis, slowing of metastasis, and the like.
  • Treatment of an autoimmune disease includes reduction of the symptoms of the disease, extension of time between disease flare-ups, remission of disease, prevention of worsening of the disease, and the like.
  • Treatment of neurological disease may include improvement of cognitive function, reduction of the rate of cognitive loss, reduction of symptoms, and the like.
  • treatment is administered after one or more symptoms have developed. In some embodiments, treatment is administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility 8 32017260 400807-030WO (212251) factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • pharmaceutical composition refers to the combination of an active agent with a carrier, adjuvant, or vehicle, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • the term “pharmaceutically acceptable carrier, adjuvant, and/or vehicle” refers to any non-toxic carrier, adjuvant, and/or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as potassium sorbate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents.
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixture
  • compositions also can include stabilizers and/or preservatives.
  • carriers, vehicles and adjuvants see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975].
  • combination refers to simultaneous, separate, or sequential administration. In one aspect of the disclosure, “combination” refers to simultaneous administration. In another aspect of the disclosure, “combination” refers to separate administration. In another aspect of the disclosure, “combination” refers to sequential administration. Where the administration is separate or sequential, the delay in administering the one or more additional therapeutic agents is done at an interval designed such as not to lose the beneficial effect of the combination.
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited 9 32017260 400807-030WO (212251) components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • the term “comprising” or “comprises” is used in reference to compounds, uses, compositions, methods, and respective component(s) thereof that are essential to the method or composition, yet open to the inclusion of unspecified elements, whether essential or not.
  • compositions specifying a percentage are by weight unless otherwise specified.
  • “About,” as used herein, means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth.
  • crystals may contain trace amount of water or other solvents not bound in the crystal lattice.
  • “Amorphous” refers to a solid state wherein the molecules are present in a disordered arrangement and do not form a distinguishable crystal lattice or unit cell.
  • “Chemical purity” refers to the overall level of a desired product. If a compound is present in enantiomeric forms, “chemical purity” as used herein would include both enantiomeric forms in the calculation of the overall level of the desired product. If a compound is present in solvate forms, “chemical purity” as used herein would include the solvate in the calculation of 10 32017260 400807-030WO (212251) the overall level of the desired product.
  • Impurities may be in the form of, e.g., the presence of unwanted process reagents, process intermediates, degradation products or oxidation products.
  • the chemical purity is high, that is greater than 90% chemical purity, especially above 92.5%, 95%, 96%, 97%, 98%, 99%, 99.9, and includes 100%. Purity may be measured by a variety of techniques, including HPLC analysis.
  • “Enantiomer” and “enantiomeric” refers to a molecule that cannot be superimposed on its mirror image and hence is optically active, wherein the enantiomer rotates the plane of polarized light in one direction and its minor image compound rotates the plane of polarized light to the same degree, in the opposite direction.
  • Enantiomeric excess refers to a difference between the amount of one enantiomer and the amount of the other enantiomer that is present in the product mixture.
  • the enantiomeric excess value in each example given below gives an indication of the relative amount of each enantiomer. The value is defined as the difference between the relative percentages for the two enantiomers. Thus, for example, when the percentage of the (S)- enantiomer of the compound of the invention is 97.5% and the percentage for the (R)-enantiomer is 2.5%, the enantiomeric excess for the (S)-enantiomer is 95%.
  • Enantiomerically pure or “enantiomeric purity” is a measure of how much more of one enantiomer there is than the other enantiomer in a mixture of enantiomers. For example, a mixture of 99% (S)-enantiomer and 1% (R)-enantiomer has 99% enantiomeric purity of the (S)- enantiomer. Enantiomerically pure is preferably at least 95% or at least 98% enantiomeric purity, more preferably at least about 99%. In another embodiment enantiomerically is about 99.90% to about 100% enantiomeric purity.
  • “Volume of solvent” refers to the volume of solvent, expressed in liters at ambient temperature, used in a process to dissolve 1 kg of solid material. For example, 5 volumes of solvent used in a process starting with 1 kg of starting material would equal 5 liters of solvent. 11 32017260 400807-030WO (212251)
  • “Non-solvate polymorph” or “non-solvate crystalline form” refer to a crystalline form that does not have a solvent bound in the crystal lattice, for example an anhydrous polymorph.
  • Crystals may contain trace amount of solvent not bound in the crystal lattice.
  • “Polymorph” refers to the different crystal structures (of solvated or non-solvated forms) in which a compound can crystallize.
  • “Racemic” or “racemate”, and other like terms refer to generally equimolar proportions of a (S)-compound and a (R)- compound.
  • “Solvate”, “solvate polymorph” or “solvate crystalline form” refer to a crystalline form that has solvate bound in the crystal lattice.
  • substantially pure crystal form unless otherwise specified is to be understood as a substance free of other crystal forms, or amorphous form, at amounts detectable with typical analytical methods such as X-ray powder diffraction and/or solid state infrared absorption, i.e., containing less than 10% of other crystal forms. Preferably, there is less than 5%, more preferably less than 2%, and even more preferably less than l% of any other crystal form, or amorphous form, of the compound present.
  • crystalline Compounds [0066] One aspect of the disclosure provides crystalline compounds. The compounds may be used in the pharmaceutical compositions and therapeutic methods described herein. For example, one aspect of the disclosure provides a crystalline Compound I: 12 32017260 400807-030WO (212251)
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2u): 4.6 ⁇ 0.2, 7.6 ⁇ 0.2, 9.3 ⁇ 0.2, 14.0 ⁇ 0.2, 15.3 ⁇ 0.2, 19.2 ⁇ 0.2, and 23.1 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 5.1 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 6.7 ⁇ 0.2.
  • the X-ray powder diffraction 13 32017260 400807-030WO (212251) pattern further comprises a peak at the following diffraction angle (2u): 7.4 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 9.2 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 17.8 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 19.3 ⁇ 0.2.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2u): 4.61 ⁇ 0.20, 7.64 ⁇ 0.20, 9.26 ⁇ 0.20, 13.98 ⁇ 0.20, 15.33 ⁇ 0.20, 19.20 ⁇ 0.20, and 23.10 ⁇ 0.20.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 5.06 ⁇ 0.20.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 6.73 ⁇ 0.20.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 7.35 ⁇ 0.20. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 9.19 ⁇ 0.20. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 17.82 ⁇ 0.20. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 19.30 ⁇ 0.20.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2u): 7.64 ⁇ 0.20, 9.26 ⁇ 0.20, 13.98 ⁇ 0.20, 15.33 ⁇ 0.20, 19.20 ⁇ 0.20, and 23.10 ⁇ 0.20.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 4.61 ⁇ 0.20.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 5.06 ⁇ 0.20.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 6.73 ⁇ 0.20. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 7.35 ⁇ 0.20. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 9.19 ⁇ 0.20. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the 14 32017260 400807-030WO (212251) following diffraction angle (2u): 17.82 ⁇ 0.20.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 19.30 ⁇ 0.20.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2u): 7.6 ⁇ 0.2, 9.3 ⁇ 0.2, 14.0 ⁇ 0.2, 15.3 ⁇ 0.2, 19.2 ⁇ 0.2, and 23.1 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 4.6 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 5.1 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 6.7 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 7.4 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 9.2 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 17.8 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 19.3 ⁇ 0.2.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising at least six peaks selected from the following diffraction angles (2u): 4.6 ⁇ 0.2, 5.1 ⁇ 0.2, 6.7 ⁇ 0.2, 7.4 ⁇ 0.2, 7.6 ⁇ 0.2, 9.2 ⁇ 0.2, 9.3 ⁇ 0.2, 14.0 ⁇ 0.2, 15.3 ⁇ 0.2, 17.8 ⁇ 0.2, 19.2 ⁇ 0.2, 19.3 ⁇ 0.2, and 23.1 ⁇ 0.2.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising at least seven peaks selected from said diffraction angles (2u).
  • the relative intensity of the peak at said diffraction angles (2u) is at least 20%. In certain embodiments, the relative intensity of the peak at said diffraction angles (2u) is at least 15%. In certain embodiments, the relative intensity of the peak at said diffraction angles (2u) is at least 10%. In certain embodiments, the relative intensity of the peak at said diffraction angles (2u) is at least 5%.
  • the crystalline compound is characterized by the following X- ray powder diffraction pattern expressed in terms of diffraction angle 2u, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak): 15 32017260 400807-030WO (212251) Angle [ 2u ] d-spacing [ ⁇ ] Relative Intensity [%] 461 ⁇ 020 19153 ⁇ 0830 100 16 32017260 400807-030WO (212251) Angle [ 2u ] d-spacing [ ⁇ ] Relative Intensity [%] 1930 ⁇ 020 4595 ⁇ 0047 11 .
  • the compound is characterized by having an x-ray powder diffraction (XRPD) pattern comprising three, four, five, six or seven or more peaks having an 17 32017260 400807-030WO (212251) approximate 2u ⁇ 0.20 value selected from the group consisting of: 4.61, 5.06, 6.73, 7.35, 7.64, 9.19, 9.26, 13.98, 15.33, 17.82, 19.20, 19.30, and 23.10.
  • the X-ray powder diffraction pattern is substantially as shown in FIG.3.
  • the compound has a melting point onset as determined by differential scanning calorimetry in the range of from about 124 degrees Celsius to about 128 degrees Celsius.
  • the compound has a melting point onset as determined by differential scanning calorimetry at about 126 degrees Celsius.
  • the compound has a peak melting temperature of about 130 degrees Celsius measured by differential scanning calorimetry (DSC).
  • the compound is characterized as having a differential scanning calorimetry (DSC) thermogram having a peak at a temperature of about 130.2°C, and an onset at about 126.4°C, measured with a heating rate of 10°C /min.
  • the compound is characterized as having a differential scanning calorimetry (DSC) thermogram having a heat of fusion of about 49.2 J/g.
  • the compound has a differential scanning calorimetry curve substantially the same as shown in FIG.4.
  • Part B Crystalline Form B of Compound I
  • One aspect of the disclosure provides crystalline Form B of Compound I.
  • the crystalline form may be characterized according to, for example, XRPD, differential scanning calorimetry, and thermogravimetric analysis. Exemplary features are described in more detail below.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2u): 4.4 ⁇ 0.2, 5.8 ⁇ 0.2, 7.5 ⁇ 0.2, 9.7 ⁇ 0.2, 15.1 ⁇ 0.2, 18.1 ⁇ 0.2, and 22.7 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 7.3 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 8.7 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 8.8 ⁇ 0.2. In certain embodiments , the X-ray powder diffraction pattern further comprises a peak at the 18 32017260 400807-030WO (212251) following diffraction angle (2u): 8.9 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 9.6 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 12.43 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 13.9 ⁇ 0.2.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2u): 4.44 ⁇ 0.20, 5.78 ⁇ 0.20, 7.51 ⁇ 0.20, 9.65 ⁇ 0.20, 15.08 ⁇ 0.20, 18.05 ⁇ 0.20, and 22.71 ⁇ 0.20.
  • the X- ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 7.31 ⁇ 0.20.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 8.71 ⁇ 0.20. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 8.79 ⁇ 0.20. In certain embodiments , the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 8.89 ⁇ 0.20. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 9.57 ⁇ 0.20.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 12.43 ⁇ 0.20. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 13.89 ⁇ 0.20.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising at least six peaks selected from the following diffraction angles (2u): 4.4 ⁇ 0.2, 5.8 ⁇ 0.2, 7.3 ⁇ 0.2, 7.5 ⁇ 0.2, 8.7 ⁇ 0.2, 8.8 ⁇ 0.2, 8.9 ⁇ 0.2, 9.6 ⁇ 0.2, 9.7 ⁇ 0.2, 12.4 ⁇ 0.2, 13.9 ⁇ 0.2, 15.1 ⁇ 0.2, 18.1 ⁇ 0.2, and 22.7 ⁇ 0.2.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising at least seven peaks selected from said diffraction angles (2u).
  • the relative intensity of the peak at said diffraction angles (2u) is at least 20%. In certain embodiments, the relative intensity of the peak at said diffraction angles (2u) is at least 15%. In certain embodiments, the relative intensity of the peak at said diffraction angles (2u) is at least 10%.
  • the compound is characterized as having an x-ray powder diffraction (XRPD) pattern comprising three, four, five, six or seven or more peaks having an approximate 2u ⁇ 0.20 value selected from the group consisting of: 4.44, 5.78, 7.31, 7.51, 8.71, 8.79, 8.89, 9.57, 9.65, 12.43, 13.89, 15.08, 18.05, and 22.71.
  • XRPD x-ray powder diffraction
  • the X-ray powder diffraction pattern is substantially as shown in FIG.9.
  • the compound has a melting point onset as determined by differential scanning calorimetry in the range of from about 125 degrees Celsius to about 129 degrees Celsius.
  • the compound has a melting point onset as determined by differential scanning calorimetry at about 127 degrees Celsius. In certain embodiments, the compound has a peak melting temperature of about 132 degrees Celsius measured by differential scanning calorimetry (DSC). [0091] In certain embodiments, the compound is characterized as having a differential scanning calorimetry (DSC) thermogram having a peak at a temperature of about 132.0°C, and an onset at about 127.1°C, measured with a heating rate of 10°C /min. In certain embodiments, 21 32017260 400807-030WO (212251) the compound is characterized as having a differential scanning calorimetry (DSC) thermogram having a heat of fusion of about 50.1 J/g.
  • DSC differential scanning calorimetry
  • the compound has a differential scanning calorimetry curve substantially the same as shown in FIG.10.
  • Part C Crystalline Form C of Compound I
  • the crystalline form may be characterized according to, for example, XRPD, differential scanning calorimetry, and thermogravimetric analysis. Exemplary features are described in more detail below.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2u): 4.4 ⁇ 0.3, 5.0 ⁇ 0.3, 6.5 ⁇ 0.3, 7.2 ⁇ 0.3, 9.1 ⁇ 0.3, 13.9 ⁇ 0.3, and 17.8 ⁇ 0.3.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 18.2 ⁇ 0.3.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 19.2 ⁇ 0.3.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 22.1 ⁇ 0.3.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2u): 4.4 ⁇ 0.2, 5.0 ⁇ 0.2, 6.5 ⁇ 0.2, 7.2 ⁇ 0.2, 9.1 ⁇ 0.2, 13.9 ⁇ 0.2, and 17.8 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 18.2 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 19.2 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 22.1 ⁇ 0.2. [0096] In certain embodiments, the relative intensity of the peak at said diffraction angles (2u) is at least 20%. In certain embodiments, the relative intensity of the peak at said diffraction angles (2u) is at least 15%. In certain embodiments, the relative intensity of the peak at said diffraction angles (2u) is at least 10%.
  • the X-ray powder diffraction pattern is substantially as shown in FIG.7.
  • the compound has a melting point onset as determined by differential scanning calorimetry in the range of from about 127 degrees Celsius to about 131 degrees Celsius. In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry at about 129 degrees Celsius. [0099] In certain embodiments, the compound has a peak melting temperature of about 132 degrees Celsius measured by differential scanning calorimetry (DSC).
  • the compound is characterized as having a differential scanning calorimetry (DSC) thermogram having a peak at a temperature of about 131.9°C, and an onset at about 128.5°C, measured with a heating rate of 10°C /min.
  • the compound is characterized as having a differential scanning calorimetry (DSC) thermogram having a heat of fusion of about 49.9 J/g.
  • the compound has a differential scanning calorimetry curve substantially the same as shown in FIG.8. Part D: Crystalline Form D of Compound I [00101] One aspect of the disclosure provides crystalline Form D of Compound I.
  • the crystalline form may be characterized according to, for example, XRPD, differential scanning calorimetry, and thermogravimetric analysis. Exemplary features are described in more detail below.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2u): 4.2 ⁇ 0.3, 5.7 ⁇ 0.3, 7.3 ⁇ 0.3, 9.5 ⁇ 0.3, 10.4 ⁇ 0.3, 13.9 ⁇ 0.3, and 22.3 ⁇ 0.3.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 8.8 ⁇ 0.3.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 12.2 ⁇ 0.3. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 15.9 ⁇ 0.3. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 19.1 ⁇ 0.3. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 29.9 ⁇ 0.3.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2u): 4.2 ⁇ 0.2, 5.7 ⁇ 0.2, 7.3 ⁇ 0.2, 9.5 ⁇ 0.2, 10.4 ⁇ 0.2, 13.9 ⁇ 0.2, and 22.3 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 8.8 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 12.2 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 15.9 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 19.1 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 29.9 ⁇ 0.2. [00104] In certain embodiments, the relative intensity of the peak at said diffraction angles (2u) is at least 20%. In certain embodiments, the relative intensity of the peak at said diffraction angles (2u) is at least 15%.
  • the relative intensity of the peak at said diffraction angles (2u) is at least 10%.
  • the X-ray powder diffraction pattern is substantially as shown in FIG.12.
  • the compound has a melting point onset as determined by differential scanning calorimetry in the range of from about 126 degrees Celsius to about 130 degrees Celsius. In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry at about 128 degrees Celsius. In certain embodiments, the compound has a peak melting temperature of about 132 degrees Celsius measured by differential scanning calorimetry (DSC).
  • the compound is characterized as having a differential scanning calorimetry (DSC) thermogram having a peak at a temperature of about 132.2°C, and an onset at about 127.7°C, measured with a heating rate of 10°C /min.
  • the compound is characterized as having a differential scanning calorimetry (DSC) thermogram having a heat of fusion of about 49.9 J/g.
  • the compound has a differential scanning calorimetry curve substantially the same as shown in FIG.13. 24 32017260 400807-030WO (212251) Part E: Crystalline Compound II [00109]
  • One aspect of the disclosure provides a crystalline Compound II.
  • the crystalline form may be characterized according to, for example, XRPD, differential scanning calorimetry, and thermogravimetric analysis. Exemplary features are described in more detail below.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2u): 8.9 ⁇ 0.3, 13.3 ⁇ 0.2, 19.6 ⁇ 0.3, 20.7 ⁇ 0.3, 21.6 ⁇ 0.3, 26.8 ⁇ 0.3, and 35.7 ⁇ 0.3.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 16.7 ⁇ 0.3.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 18.1 ⁇ 0.3. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 27.7 ⁇ 0.3. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 29.1 ⁇ 0.3. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 33.9 ⁇ 0.3.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 35.0 ⁇ 0.3.
  • the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2u): 8.9 ⁇ 0.2, 13.3 ⁇ 0.2, 19.6 ⁇ 0.2, 20.7 ⁇ 0.2, 21.6 ⁇ 0.2, 26.8 ⁇ 0.2, and 35.7 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 16.7 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 18.1 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 27.7 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 29.1 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 33.9 ⁇ 0.2.
  • the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (2u): 35.0 ⁇ 0.2. 25 32017260 400807-030WO (212251) [00112]
  • the compound is characterized as having an x-ray powder diffraction (XRPD) pattern comprising three, four, five, six or seven or more peaks having an approximate 2u value selected from the group consisting of: 8.9, 13.3, 16.7, 18.1, 19.6, 20.7, 21.6, 26.8, 27.7, 29.1, 33.9, 35.0, and 35.7.
  • the compound is characterized as having an x-ray powder diffraction (XRPD) pattern comprising three, four, five, six or seven or more peaks having an 2u value selected from the group consisting of: 8.9 ⁇ 0.3, 13.3 ⁇ 0.2, 16.7 ⁇ 0.3, 18.1 ⁇ 0.3, 19.6 ⁇ 0.3, 20.7 ⁇ 0.3, 21.6 ⁇ 0.3, 26.8 ⁇ 0.3, 27.7 ⁇ 0.3, 29.1 ⁇ 0.3, 33.9 ⁇ 0.3, 35.0 ⁇ 0.3, and 35.7 ⁇ 0.3.
  • XRPD x-ray powder diffraction
  • the compound is characterized as having an x-ray powder diffraction (XRPD) pattern comprising three, four, five, six or seven or more peaks having an 2u value selected from the group consisting of: 8.9 ⁇ 0.2, 13.3 ⁇ 0.2, 16.7 ⁇ 0.2, 18.1 ⁇ 0.2, 19.6 ⁇ 0.2, 20.7 ⁇ 0.2, 21.6 ⁇ 0.2, 26.8 ⁇ 0.2, 27.7 ⁇ 0.2, 29.1 ⁇ 0.2, 33.9 ⁇ 0.2, 35.0 ⁇ 0.2, and 35.7 ⁇ 0.2.
  • the relative intensity of the peak at said diffraction angles (2u) is at least 20%.
  • the relative intensity of the peak at said diffraction angles (2u) is at least 15%. In certain embodiments, the relative intensity of the peak at said diffraction angles (2u) is at least 10%.
  • the X-ray powder diffraction pattern is substantially as shown in FIG.1.
  • Part F General Additional Features
  • Crystalline forms in Parts A through E above may be further characterized.
  • the crystalline form is characterized according to chemical purity.
  • the crystalline form has a chemical purity of at least about 95%.
  • the crystalline form has a chemical purity of at least about 98%.
  • the crystalline form has a chemical purity of at least about 99%.
  • the crystalline form has a chemical purity in the range of about 98.00% to about 99.00%. In certain embodiments, the crystalline form has a chemical purity in the range of about 99.00% to about 99.95%. In certain embodiments, the crystalline form is a substantially pure crystal form. 26 32017260 400807-030WO (212251) [00117] In certain embodiments, the crystalline form is isolated. II. Therapeutic Applications [00118] It is contemplated that crystalline forms in Section 1 above provide therapeutic benefits to subjects suffering from a medical disorder, such as cancer, autoimmune disorders, and/or neurological disorders.
  • One aspect of the disclosure provides a method of treating a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein to treat the disorder.
  • Another aspect of the disclosure provides a method of inhibiting LINE1 reverse transcriptase activity in a subject, comprising contacting a LINE1 reverse transcriptase with an effective amount of a compound disclosed herein to inhibit the activity of said LINE1 reverse transcriptase.
  • the method further comprises inhibiting HERV-K reverse transcriptase activity in the subject.
  • Another aspect of the disclosure provides a method of inhibiting HERV-K reverse transcriptase activity in a subject, comprising contacting a HERV-K reverse transcriptase with an effective amount of a compound disclosed herein to inhibit the activity of said HERV-K reverse transcriptase.
  • the subject has a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder.
  • the disorder is cancer.
  • Yet another aspect of the disclosure provides a method of treating a viral infection. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein (such as a crystalline Compound I) to treat the viral infection.
  • the compound is crystalline Compound I. Cancer 27 32017260 400807-030WO (212251) [00125]
  • the disorder is cancer.
  • the cancer is a solid tumor or leukemia.
  • the cancer is a solid tumor.
  • the cancer is a carcinoma or melanoma.
  • the cancer is a carcinoma.
  • the cancer is a sarcoma.
  • the cancer is a melanoma.
  • the cancer is a lymphoma.
  • the cancer is a leukemia.
  • the cancer is breast cancer, ovarian cancer, uterine cancer, cervical cancer, prostate cancer, testicular cancer, lung cancer, leukemia, head and neck cancer, oral cancer, esophageal cancer, stomach cancer, bile duct cancer, gallbladder cancer, bladder cancer, urinary tract cancer, colon cancer, rectal cancer, thyroid cancer, pancreatic cancer, kidney cancer, liver cancer, brain cancer, skin cancer, or eye cancer.
  • the cancer is breast cancer, ovarian cancer, uterine cancer, cervical cancer, prostate cancer, testicular cancer, lung cancer, leukemia, head and neck cancer, oral cancer, esophageal cancer, stomach cancer, bile duct cancer, gallbladder cancer, or bladder cancer.
  • the cancer has (i) expression of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; (ii) activity of LINE1 reverse transcriptase; (iii) expression of HERV-K RNA, and/or (iv) activity of HERV-K reverse transcriptase.
  • the cancer has (i) expression of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; and/or (ii) activity of LINE1 reverse transcriptase.
  • the cancer has expression of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide.
  • the cancer has expression of LINE1 RNA.
  • the cancer has expression of LINE1 ORF1 polypeptide.
  • the cancer has expression of LINE1 ORF2 polypeptide.
  • the cancer has activity of LINE1 reverse transcriptase.
  • the cancer has (i) expression of HERV-K RNA, and/or (ii) activity of HERV-K reverse transcriptase. In certain embodiments, the cancer has expression of HERV-K RNA. In certain embodiments, the cancer has activity of HERV-K reverse transcriptase.
  • the cancer has elevated (i) levels of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; (ii) activity of LINE1 reverse transcriptase; (iii) levels of HERV-K RNA, and/or (iv) activity of HERV-K reverse transcriptase.
  • the cancer has elevated (i) levels of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; and/or (ii) activity of LINE1 reverse transcriptase.
  • the cancer has elevated levels of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide. In certain embodiments, the cancer has elevated levels of LINE1 RNA. In certain embodiments, the cancer has elevated levels of LINE1 ORF1 polypeptide. In certain embodiments, the cancer has elevated levels of LINE1 ORF2 polypeptide. In certain embodiments, the cancer has elevated activity of LINE1 reverse transcriptase. [00133] In certain embodiments, the cancer has elevated (i) levels of HERV-K RNA, and/or (ii) activity of HERV-K reverse transcriptase. In certain embodiments, the cancer has elevated levels of HERV-K RNA.
  • the cancer has elevated activity of HERV-K reverse transcriptase.
  • the cancer is an epithelial cancer.
  • the epithelial cancer is pancreatic cancer, colorectal cancer, breast cancer, prostate cancer, esophageal cancer, head and neck cancer, renal cancer, ovarian cancer, or lung cancer.
  • the cancer is pancreatic cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, ovarian cancer, or lung cancer.
  • the cancer is pancreatic cancer.
  • the cancer is pancreatic adenocarcinoma.
  • the cancer is colorectal cancer.
  • the cancer comprises microsatellite instable (MSI) colorectal cancer or microsatellite stable (MSS) colorectal cancer.
  • the cancer is breast cancer.
  • the cancer is prostate cancer.
  • the cancer is esophageal cancer.
  • the cancer is head and neck cancer.
  • the cancer is renal cancer.
  • the cancer is ovarian cancer.
  • the cancer is lung cancer.
  • the lung cancer is non-small cell lung carcinoma or small cell lung carcinoma.
  • the cancer is non-small cell lung carcinoma.
  • the cancer is small cell lung carcinoma.
  • the cancer is a preneoplastic or early cancer lesion.
  • the cancer is intraductal papillary mucinous neoplasm (IPMN), pancreatic intraepithelial neoplasia (PanIN), ductal carcinoma in situ (DCIS), or Barrett’s Esophagus.
  • the cancer is pancreatic intraepithelial neoplasia (PanIN).
  • the cancer is ductal carcinoma in situ (DCIS).
  • the cancer is Barrett’s Esophagus.
  • the cancer has elevated levels of pericentrometric human satellite II (HSATII) RNA.
  • the cancer is a microsatellite instable (MSI) cancer.
  • the cancer is a microsatellite stable (MSS) cancer.
  • the cancer is associated with long interspersed nuclear element-1 (LINE-1) reverse transcriptase (RT). In further aspects of these embodiments, the cancer is associated with high levels of LINE-1 RT activity.
  • the cancer is selected from B cell lymphomas (e.g., B cell chronic lymphocytic leukemia, B cell non-Hodgkin lymphoma, cutaneous B cell lymphoma, diffuse large B cell lymphoma), basal cell carcinoma, bladder cancer, blastoma, brain metastasis, breast cancer, Burkitt lymphoma, carcinoma (e.g., adenocarcinoma (e.g., of the gastroesophageal junction)), cervical cancer, colon cancer, colorectal cancer (colon cancer and rectal cancer), endometrial carcinoma, esophageal cancer, Ewing sarcoma, follicular lymphoma, gastric cancer, gastroesophageal junction carcinoma, gastrointestinal cancer, glioblastoma (e.g., glioblastoma multiforme, e.g., newly diagnosed or recurrent), glioma, head and neck cancer (e.g., head and neck cancer (e.g., head and
  • the cancer is a virus-associated cancer.
  • virus-associated cancer means any cancer in which a virus is known to play a role.
  • Epstein-Barr virus (EBV) has been reported to be associated with the endemic variant of Burkitt lymphoma and certain other lymphomas. Infection by human papilloma virus (HPV) is believed to be responsible for certain types of cervical and/or genital cancer.
  • EBV Epstein-Barr virus
  • HPV human papilloma virus
  • HPV human papilloma virus
  • Human T-cell leukemia virus 1 has been reported to be linked adult T-cell leukemia/lymphoma (ATLL).
  • Human T-cell leukemia virus 2 (HTLV-2) has been reported to be linked to cutaneous T-cell lymphoma.
  • the cancer is a cancer associated with EBV, HPV, HTLV-1, HTLV-2, or HHV-8.
  • the cancer is Burkitt lymphoma, cervical cancer, genital cancer, adult T-cell leukemia/lymphoma, cutaneous T-cell lymphoma, or Kaposi’s sarcoma.
  • the cancer is a cancer other than a virus-associated cancer.
  • the cancer is a cancer other than a cancer associated with EBV, HPV, HTLV-1, HTLV-2, or HHV-8.
  • the cancer is a cancer other than Burkitt lymphoma, cervical cancer, genital cancer, adult T-cell leukemia/lymphoma, cutaneous T-cell lymphoma, or Kaposi’s sarcoma. In one embodiment, the cancer is a tumor associated with Li_Fraumeni syndrome.
  • the cancer is renal cell carcinoma, or kidney cancer, mesothelioma, hepatobiliary (hepatic and biliary duct), bone cancer, rhabdomyosarcoma, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small 31 32017260 400807-030WO (212251) intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, adrenocortical carcinoma, sarcoma
  • the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma.
  • HCC hepatocellular carcinoma
  • the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments,
  • the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST.
  • MPNST peripheral nerve sheath tumors
  • the cancer is Waldenstrom macroglobulinemia. In some embodiments, the cancer is medulloblastoma. [00143] In certain embodiments, the cancer is a leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic 32 32017260 400807-030WO (212251) leukemia), polycythemia vera, lymphoma (e.g., Hodgkin disease or non-Hodgkin disease), Waldenstrom macroglobulinemia, multiple myeloma, or heavy chain disease.
  • a leukemia e.g., acute leukemia, acute lymphocytic leukemia, acute mye
  • the cancer is a solid tumor such as a sarcoma or carcinoma (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma,
  • the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
  • the cancer is acoustic neuroma, astrocytoma (e.g.
  • GBM Glioblastoma
  • the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor.
  • JPA juvenile pilocytic astrocytoma
  • medulloblastoma optic nerve glioma
  • pineal tumor pineal tumor
  • PNET primitive neuroectodermal tumors
  • rhabdoid tumor rhabdoid tumor.
  • Autoimmune Diseases and Disorders 33 32017260 400807-030WO (212251) [00146]
  • the disorder is an autoimmune disorder.
  • autoimmune disorders and “autoimmune diseases” are used interchangeably, and include those diseases and disorders which are traditionally classified as autoimmune disorders, as well as inflammatory disorders and immune disorders (excluding viral infections).
  • the intention with the terms “autoimmune disease” and “autoimmune disorder” is to include all diseases and disorders which are driven by innate immune responses and adaptive immune responses which initiate some sort of innate immune inflammatory response. It is the applicant’s intent to have the terms “autoimmune disease” and “autoimmune disorder” include the full scope of diseases and disorders which are driven by innate inflammation, with the exception of viral infections.
  • the invention provides for treatment of an autoimmune disorder.
  • Traditional autoimmune disorders commonly occur when the immune system attacks normal cells and/or tissues in the body.
  • Inflammatory disorders often present with chronic inflammation (among other symptoms) in the absence of infection.
  • Autoimmune disorders also include symptoms which arise when the cellular immune system reacts against the body’s autoantigens.
  • the autoimmune disease or disorder is associated with high levels of LINE-1 and/or HERV-K RNA protein expression.
  • One embodiment of the invention is a method of treating type I interferonopathies.
  • the type I interferonopathy is a congenital disorder associated with type I interferon overexpression.
  • the congenital type I interferonopathy is selected from Aicardi-Goutines syndrome (AGS), Singleton-Merten syndrome, proteasome-associated autoinflammatory syndromes, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), STING-associated vasculopathy with onset in infancy (SAVI), Japanese autoinflammatory syndrome with lipodystrophy (JASL), spondyloenchondrodysplasia (SPENCD), ISG15 deficiency, Ubiquitin- Specific Peptidase 18 deficiency (pseudo-TORCH syndrome), chronic atypical neurophilic dermatitis with lipodystrophy, DNA II deficiency, trichoheptoenteric syndrome 2, retinal vasculopathy with cerebral leukodystrophy, familial chilblain lupus, and X-linked reticulate pigmentary disorder (XLPDR).
  • AGS Aicardi-Goutaires syndrome
  • the type I interferonopathy is an acquired disorder in the IFN system. 34 32017260 400807-030WO (212251) [00149]
  • the invention provides a method of treating an autoimmune disease which results in an overproduction of interferon.
  • the interferon expressed includes type I interferon.
  • the autoimmune disease is associated with elevated LINE-1 activity and/or expression.
  • the autoimmune disease is associated with elevated HERV-K RNA activity and/or expression.
  • the autoimmune disorder is selected from the group consisting of achalasia, Addison’s disease, adult Still’s disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), Balo disease, Behcet’s disease, benign mucosal pemphigoid, bullous pemphigoid, Castleman disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneur
  • the autoimmune disorder is selected from Aicardi-Goutines syndrome, rheumatoid arthritis, psoriasis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), graft versus host disease, scleroderma, type I diabetes, dermatomyositis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, vasculitis, and Sjögren’s syndrome.
  • the autoimmune disorder is Aicardi-Gout insects syndrome (AGS).
  • the autoimmune disorder is systemic lupus erythematosus (SLE).
  • the autoimmune disease is lupus nephritis. In a further embodiment, the autoimmune disease is cutaneous lupus erythematosus (CLE). In another embodiment, the autoimmune disease is dermatomyositis. 36 32017260 400807-030WO (212251) [00153] In certain embodiments, the autoimmune disorder is a type 1 interferonopathy.
  • the autoimmune disorder is type 1 diabetes, Aicardi-Goutines syndrome (AGS), systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), familial chilblain lupus, systemic sclerosis, STING-associated vasculopathy with onset in infancy (SAVI), Sjögren’s syndrome, or dermatomyositis.
  • AGS Aicardi-Goutines syndrome
  • SLE systemic lupus erythematosus
  • CLE lupus nephritis
  • CLE cutaneous lupus erythematosus
  • familial chilblain lupus familial chilblain lupus
  • systemic sclerosis STING-associated vasculopathy with onset in infancy (SAVI), Sjögren’s syndrome, or dermatomyositis.
  • the immune disorder is a type 1 interferonopathy, type 1 diabetes, Aicardi-Goutines syndrome (AGS), systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), dermatomyositis, or Sjogren’s syndrome.
  • the autoimmune disorder is systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), or familial chilblain lupus.
  • the immune disorder is systemic lupus erythematosus (SLE).
  • the autoimmune disorder is type 1 diabetes. In certain embodiments, the autoimmune disorder is familial chilblain lupus. In certain embodiments, the autoimmune disorder is systemic sclerosis. In certain embodiments, the autoimmune disorder is STING-associated vasculopathy with onset in infancy (SAVI). In certain embodiments, the autoimmune disorder is Sjögren’s syndrome. [00155] In certain embodiments, the autoimmune disorder is inflammatory bowel disease, Crohn’s disease, or ulcerative colitis. In certain embodiments, the autoimmune disorder is inflammatory bowel disease. In certain embodiments, the autoimmune disorder is Crohn’s disease. In certain embodiments, the autoimmune disorder is ulcerative colitis.
  • the autoimmune disorder is drug-induced colitis, such as colitis associated with the administration of checkpoint inhibitors to cancer patients.
  • the autoimmune disorder is osteoarthritis, nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, pericarditis, gout, or myositis.
  • NASH nonalcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • COPD chronic obstructive pulmonary disease
  • pulmonary fibrosis pulmonary hypertension
  • pericarditis gout
  • myositis myositis
  • the autoimmune disorder is Reiter's syndrome, exfoliative psoriatic dermatitis, pemphigus vulgaris, autoimmune uveitis, pulmonary hemosiderosis, amyloidosis, aphthous stomatitis, thyroiditis, gastritis, adrenalitis (Addison's disease), ovaritis, primary biliary cirrhosis, myasthenia gravis, gonadal failure, hypoparathyroidism, alopecia, 37 32017260 400807-030WO (212251) malabsorption syndrome, pernicious anemia, hepatitis, hypopituitarism, diabetes insipidus, or sicca syndrome.
  • Reiter's syndrome exfoliative psoriatic dermatitis, pemphigus vulgaris, autoimmune uveitis, pulmonary hemosiderosis, amyloidosis, aphthous stomatitis, thyroiditis, gastritis, adrenal
  • the disorder is a neurological disorder.
  • the neurological disorder is Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson’s disease, Huntington’s disease, peripheral neuropathy, age- related macular degeneration, Creutzfeldt-Jacob disease, stroke, prion disease, frontotemporal dementia, Pick’s disease, progressive supranuclear palsy, spinocerebellar ataxias, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, or major depression.
  • the neurological disorder is Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson’s disease, Huntington’s disease, or dementia. In another embodiment, the neurological disorder is ALS or progressive supranuclear palsy.
  • the neurological disorder is peripheral neuropathy, age-related macular degeneration, Creutzfeldt-Jacob disease, stroke, prion disease, frontotemporal dementia, Pick’s disease, progressive supranuclear palsy, spinocerebellar ataxias, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, or major depression.
  • the neurological disorder is Alzheimer’s disease.
  • the neurological disorder is amyotrophic lateral sclerosis (ALS). In another embodiment, the neurological disorder is multiple sclerosis. In a further embodiment, the neurological disorder is Parkinson’s disease. In another embodiment, the neurological disorder is Huntington’s disease. In another embodiment, the neurological disorder is dementia. In certain embodiments, the neurological disorder is age-related macular degeneration. In a further embodiment, the neurological disorder is progressive supranuclear palsy. In certain embodiments, the neurological disorder is stroke.
  • ALS amyotrophic lateral sclerosis
  • the neurological disorder is multiple sclerosis.
  • the neurological disorder is Parkinson’s disease.
  • the neurological disorder is Huntington’s disease.
  • the neurological disorder is dementia.
  • the neurological disorder is age-related macular degeneration.
  • the neurological disorder is progressive supranuclear palsy. In certain embodiments, the neurological disorder is stroke.
  • the viral infection is an infection by human immunodeficiency viruses 1 or 2 (HIV-1 or HIV-2), human T-cell leukemia viruses 1 or 2 (HTLV-1 or HTLV-2), 38 32017260 400807-030WO (212251) respiratory syncytial virus (RSV), human papilloma virus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex viruses 1 or 2 (HSV-1 or HSV-2), human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus), or a flavivirus selected from Yellow Fever virus, Dengue virus, Japanese Encephalitis, and West Nile virus.
  • RSV respiratory syncytial virus
  • HPV human papilloma virus
  • HPV human papilloma virus
  • the viral infection is an infection by hepatitis B virus (HBV). In certain embodiments, the viral infection is an infection by hepatitis C virus (HCV). In certain embodiments, the viral infection is an infection by Epstein-Barr virus (EBV). In certain embodiments, the viral infection is an infection by varicella zoster virus (VZV). In certain embodiments, the viral infection is an infection by cytomegalovirus (CMV). In certain embodiments, the viral infection is an infection by herpes simplex viruses 1 or 2 (HSV-1 or HSV-2). In certain embodiments, the viral infection is an infection by human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus).
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • EBV Epstein-Barr virus
  • VZV varicella zoster virus
  • CMV cytomegalovirus
  • the viral infection is an infection by herpes simplex viruses 1 or 2 (HS
  • the viral infection is an infection by a flavivirus selected from Yellow Fever virus, Dengue virus, Japanese Encephalitis, and West Nile virus. [00163] In certain embodiments, the viral infection is an infection by an adenovirus. In certain embodiments, the viral infection is an infection by a herpesvirus. In certain embodiments, the viral infection is an infection by a poxvirus. In certain embodiments, the viral infection is an infection by a parvovirus. In certain embodiments, the viral infection is an infection by a reovirus. In certain embodiments, the viral infection is an infection by a picornavirus. In certain embodiments, the viral infection is an infection by a rhinovirus or enterovirus.
  • the viral infection is an infection by a togavirus. In certain embodiments, the viral infection is an infection by an orthomyxovirus. In certain embodiments, the viral infection is an 39 32017260 400807-030WO (212251) infection by a rhabdovirus. In certain embodiments, the viral infection is an infection by a retrovirus. In certain embodiments, the viral infection is an infection by a hepadnavirus. [00164] In certain embodiments, the viral infection is an infection by a coronavirus. In some embodiments, the coronavirus is an alpha, beta, gamma, or delta coronavirus.
  • the viral infection is an infection by a coronavirus selected from 229E (alpha coronavirus), NL63 (alpha coronavirus), OC43 (beta coronavirus), HKU1 (beta coronavirus), MERS-CoV (beta coronavirus), SARS-CoV (beta coronavirus), and SARS-CoV-2 (coronavirus disease 2019, or COVID-19).
  • the viral infection is an infection by an influenza virus.
  • the viral infection is an infection by a type A or type B influenza virus.
  • the viral infection is an infection by an influenza virus selected from H5N1, H1N1, and H3N2.
  • the viral infection is an infection by a poliovirus. In certain embodiments, the viral infection is an infection by a type 1 poliovirus. In certain embodiments, the viral infection is an infection by a type 2 poliovirus. In certain embodiments, the viral infection is an infection by a type 3 poliovirus.
  • the subject has (i) expression of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; (ii) activity of LINE1 reverse transcriptase; (iii) expression of HERV-K RNA, and/or (iv) activity of HERV-K reverse transcriptase.
  • the subject has (i) expression of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; and/or (ii) activity of LINE1 reverse transcriptase.
  • the subject has (i) elevated expression of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; and/or (ii) elevated activity of LINE1 reverse transcriptase.
  • the subject has expression of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide.
  • the subject has expression of LINE1 RNA.
  • the subject has expression of LINE1 ORF1 polypeptide. In certain embodiments, the subject has expression of LINE1 ORF2 polypeptide. In certain embodiments, the subject has activity of LINE1 reverse transcriptase. 40 32017260 400807-030WO (212251) [00169] In certain embodiments, the subject has (i) expression of HERV-K RNA, and/or (ii) activity of HERV-K reverse transcriptase. In certain embodiments, the subject has expression of HERV-K RNA. In certain embodiments, the subject has activity of HERV-K reverse transcriptase.
  • the subject has elevated (i) levels of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; (ii) activity of LINE1 reverse transcriptase; (iii) levels of HERV-K RNA, and/or (iv) activity of HERV-K reverse transcriptase.
  • the subject has elevated (i) levels of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; and/or (ii) activity of LINE1 reverse transcriptase.
  • the subject has elevated levels of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide. In certain embodiments, the subject has elevated levels of LINE1 RNA. In certain embodiments, the subject has elevated levels of LINE1 ORF1 polypeptide. In certain embodiments, the subject has elevated levels of LINE1 ORF2 polypeptide. In certain embodiments, the subject has elevated activity of LINE1 reverse transcriptase. [00172] In certain embodiments, the subject has elevated (i) levels of HERV-K RNA, and/or (ii) activity of HERV-K reverse transcriptase. In certain embodiments, the subject has elevated levels of HERV-K RNA.
  • the subject has elevated activity of HERV-K reverse transcriptase.
  • the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human. In certain embodiments, the subject is a companion animal. In certain embodiments, the subject is a canine, feline, or equine.
  • a compound described herein such as a crystalline Compound I, or other compounds in Section I
  • a medical disorder such as a medical disorder described herein.
  • compositions which comprise a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers, adjuvant, and/or vehicle.
  • compositions 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), 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; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.
  • the invention provides a pharmaceutical composition comprising a compound described herein (e.g., a crystalline Compound I) and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound described herein (e.g., a crystalline Compound I) and a pharmaceutically acceptable carrier.
  • 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 in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
  • 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. 42 32017260 400807-030WO (212251) [00180] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (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 and/or the particular mode of administration.
  • the amount of active ingredient which 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.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles 43 32017260 400807-030WO (212251) (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;
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or 44 32017260 400807-030WO (212251) 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 formulated for rapid release, e.g., freeze-dried. 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 which 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 which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more 45 32017260 400807-030WO (212251) 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.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. [00197] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
  • 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 sugars, alcohols, 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.
  • 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 which delay absorption such as aluminum monostearate and gelatin.
  • 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% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • 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.
  • 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.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • 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 which 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 or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the 48 32017260 400807-030WO (212251) 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.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg.
  • the effective amount may be less than when the agent is used alone.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
  • the adjustment is then verified with octane, phenyl salicylate, indium, tin, and zinc.
  • the sample was placed into a hermetically sealed aluminum DSC pan, the weight was accurately recorded, the lid was pierced, and the sample was inserted into the DSC cell.
  • a weighed aluminum pan configured as the sample pan was placed on the reference side of the cell.
  • Dynamic Vapor Sorption (DVS): Automated vapor sorption (VS) data were collected on a Surface Measurement System DVS Intrinsic instrument. Samples were not dried prior to analysis. Sorption and desorption data were collected over a range from 5% to 95% RH at 10% RH increments under a nitrogen purge. The equilibrium criterion used for analysis was less than 0.0100% weight change in 5 minutes with a maximum equilibration time of 3 hours. Data were not corrected for the initial moisture content of the samples.
  • Thermogravimetric Analysis (TGA): TG analyses were performed using a Mettler- Toledo TGA/DSC3+ analyzer.
  • Temperature and enthalpy adjustments were performed using indium, phenyl salicylate, aluminum, gold, tin, and zinc, and then verified with indium. The balance was verified with a certified standard weight.
  • the samples were placed in an open aluminum pan. The pan was hermetically sealed, the lid pierced, then inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on the reference platform. The furnace was heated under nitrogen. The samples were analyzed from 25 °C to 350 °C at 10 °C/min.
  • An elliptically graded multilayer mirror was [YML ZV NVK[Y :[ @i H(XI_Y ZPXV[OP ZPM YWMKQTMU IUL VUZV ZPM LMZMKZVX) DXQVX ZV ZPM IUIS_YQY' I silicon specimen (NIST SRM 640f) was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position.
  • Step 1 To a stirred solution of (2R,3S,4R,5R)-5-((benzoyloxy)methyl)-3- fluorotetrahydrofuran-2,4-diyl dibenzoate (1700 g) in DCM (1700 mL, 1 V) was added HBr in AcOH (40%) (1700 mL, 1 V) at RT. (endothermic, clear solution) Stirred at RT for 3 h. HPLC showed all starting material was fully consumed. (SM ⁇ 1%) The reaction was quenched by water (1.7 L, 1 V). Organic phase was collected and the water phase was extracted by DCM (500 ml) twice.
  • Step 2 Into a stirred solution of fluorouracil (725.9 g, 2.0 eq) in Dioxane (9.44 L, 8 V) was added BSA (2270.6 g, 4.0 eq) in portions.
  • Step 3 To a stirred solution of Compound 2 (1157 g, 1.0 eq) in MeOH (11.6 L, 10 V) was added NaOH (97.96 g, 1.0 eq) in portions at 0 o C. The mixture was moved to room temperature and stirred for additional 3 h. HPLC showed the completion of the reaction. The reaction mixture was filtrated and the filtrate was collected. (Removal of the insoluble inorganic salt) The resulting solution was directly concentrated in vacuo to afford a viscous white solid.
  • Step 4 To a stirred solution of diol 3 (785 g, 1.0 eq) and imidazole (606.87 g, 3.0 eq) in DMF (7.9 L, 10 V) was added TBSCl (671.77 g, 1.5 eq) in portions at 0 o C under N 2 . The reaction mixture was then moved to room temperature and stirred for 16 h. HPLC showed the completion of the reaction. (Notably, 100 g and 785 g batch were worked up together) The reaction was quenched by H 2 O (15 L, 20 V) at 0 o C. (exothermic) The resulting solution was then extracted with EA (10 L) for 3 times.
  • Step 6 To a stirred solution of compound 5 (971 g, 1.0 eq) in MeOH (9.7 L, 10 V) was added NH4F (552.60 g, 10.0 eq) in one portion at room temperature. (Most of the NH4F dissolved) Then moved to 60 o C and stirred for 16 h. HPLC showed the completion of the reaction. (5 fully consumed) The reaction was cooled down to room temperature and concentrated directly. The residue was dissolved in EA (10 L, 10 V) and H2O (10 L, 10 V). Organic phase was collected and washed with H 2 O (10 L, 10 V) for additional four times.
  • Step 7 To a stirred solution of 6 (460 g, 1 equiv) in MeCN (9.20 L, 20 V) was added IBX (480.15 g, 2.00 equiv) in one portion at room temperature. (No obvious heat release) The reaction system was then move to 65 oC and stirred for 4h. HPLC showed completion of the reaction. (SM less than 3%) The reaction was cooled down to room temperature. The mixture was filtrated and the filtration cake was washed with MeCN (1 L).
  • Step 8 Into a stirred solution of 7 (463 g, 1 eq.) and HCHO (926 mL, 37%, 2 V) in dioxane (4.6 L, 10 V) was added NaOH (926 mL, 2 M in H2O, 2 V) at 0 o C within 10 min. (no obvious heat release) The reaction mixture was then moved to room temperature and stirred for 16 h. HPLC/LCMS showed the completion of reaction, stage I.
  • Step 9 Into a stirred solution of 8 (452 g, 1 eq.) in Pyridine (2260 mL, 5 V) and DCM (6.78 L, 15 V) was added Tf2O (562.71 g, 2.5 eq.) at -30 o C dropwise in 30 min. (Obvious heat release observed). The cold bath was then removed, making the reaction temperature return to room temperature naturally.
  • Step 10 Into a stirred solution of 9 (616 g, 1 equiv) in THF (6.2 L, 10 V) was added TEA (150.08 g, 2 equiv) in one portion at room temperature. (No heat release) The reaction was moved to 60 o C and stirred for 2 h. HPLC showed the completion of stage I. (SM ⁇ 1%) LiCl (314.35 g, 10 equiv) was added directly at 60 o C in one portion and reaction was further stirred at 60 o C for 12 h. HPLC then showed the completion of stage II. (10A ⁇ 1%) NaOH (1 M in H2O, 1.48 L, 2 equiv) was added directly at 60 o C.
  • Step 11 Into a stirred solution of Compound 10 (160 g, 1 eq.) and Imidazole (37.24 g, 2 eq.) in DCM (3.20 L, 20 V) was added TBSCl (49.47 g, 1.2 eq.) in one portion under 0 oC. (No obvious heat release) The reaction was moved to room temperature and stirred for additional 16 h. HPLC showed the completion of the reaction.
  • Step 12 Into a stirred solution of crude 11 (166 g, 1 eq.), DMAP (87.01 g, 3 eq.) and TEA (96.09 g, 4 eq.) in ACN (3.3 L, 20 V) was added TsCl (135.77 g, 3 eq.) in one portion at room temperature. (No obvious heat release) The reaction was stirred for 2 h. HPLC then indicated the completion of the reaction, stage I. The reaction was cooled down to 0 o C and NH4OH (498 mL, 3 V) was added dropwise within 10 min. (heat release observed) The reaction was moved to room temperature and stirred for additional 2 h.
  • Step 13 Into a stirred solution of crude 12 (80 g, 1 eq.) in MeOH (800 mL, 10 V) was added HCl (2.0 M in H2O, 229.13 mL, 4 eq.) in one portion under 0 o C. (No obvious heat release) The reaction was then moved to 60 o C and stirred for 3 h. HPLC then showed the completion of the reaction. The reaction was concentrated in vacuo directly, then H 2 O (160 ml, 56 32017260 400807-030WO (212251) 2 V) and EA (240 ml, 3 V) was added. EA phase was separated and the water phase was further extracted with EA (160 ml, 2 V).
  • the filtrate was added to reactor A and charged with lithium chloride (1.41 kg, 3.00 eq.). The reaction was warmed to 50 ⁇ 5°C and stirred at least 5 hours. The reaction was then cooled to 5 ⁇ 5°C and charged with sodium hydroxide solution (4% in H 2 O) (11.10 kg, 1.00 eq.) dropwise over 60 minutes. The reaction was then stirred at least 1 hour at 15 ⁇ 5°C. The reaction was then cooled to 0 ⁇ 5°C and quenched by dropwise addition of a citric acid solution (15% in H 2 O) (53.50 kg, 10V) over 60 minutes.
  • a citric acid solution (15% in H 2 O)
  • Step 3 The crude material from step 2 was added to a rotary evaporator at 40 ⁇ 5°C and concentrated until the volume was 2.5V. Methanol (23.09 kg, 7.0 vol.) was added to the rotary evaporator and the mixture was concentrated until the volume was 2.5V. Methanol (23.09 kg, 7.0 vol.) was added to the rotary evaporator again and allowed to cool to room temperature. Under nitrogen protection, the solution was transferred to reactor A.
  • Step 4 Methyl tert-butyl ether (38.52 kg, 13V) was added to reactor A and warmed to 25 ⁇ 5°C.5 (5.71kg, 1.00eq) was then added into reactor A followed by 4-dimethyl- aminopyridine (0.156 kg, 0.10eq). Triethylamine (3.87 kg, 3.00eq) was then added dropwise. The reaction was cooled to 10 ⁇ 5°C. Isobutyric anhydride (5.06 kg, 2.50eq) was then added dropwise over 30 minutes.
  • the reaction was then warmed to 25 ⁇ 5°C, stirred at least 0.5 hours and then cooled to 10 ⁇ 10°C.
  • the reaction was then quenched with citric acid solution (15% in H2O) (42.80 kg, 10V) and the organic phase was washed with a sodium bicarbonate solution (5% in H2O) (21.60 kg, 5V, Batch: N/A).
  • the organic phased was combined with silica gel (4.00 kg) stirred at least 2 hours, and filtered through diatomite (0.80 kg) wetted with methyl tert-butyl ether (2.96 kg, 1V).
  • Step 5 Acetonitrile (21.33 kg, 6V) was added to reactor A and warmed to 25 ⁇ 5°C. Triazole (4.46 kg, 6.50eq) and ethylbis(propan-2-yl)amine (11.57 kg, 9.00eq) were then added to reactor A and the mixture was cooled to 0 ⁇ 5 o C. POCl 3 (2.56 kg, 1.70eq.) was added slowly over 0.5 hours.
  • the reaction was then stirred at least 1 hour at 0 ⁇ 5°C.6 in acetonitrile was then added slowly over 0.5 hour. The reaction was then warmed to 25 ⁇ 5°C and stirred at least 1 hour. The reaction was then cooled to 5 ⁇ 5°C followed by addition of NH4OH (3.49 kg, 2.5eq) into reactor over 1h. the resulting mixture was stirred at least 3 hours at 10 ⁇ 5°C. The reaction was then quenched with a citric acid solution (15% in H2O) (72.23 kg, 15V) added dropwise followed by isopropyl acetate and separated. The organics were then co-distilled two times with isopropyl acetate (39.15 kg, 10V).
  • the XRPD spectrum is provided in FIG.3.
  • the TGA and DSC thermograms are provided in FIG.4.
  • DVS testing of this material provided a 0.6% weight gain from 5% to 95% RH, equivalent to 0.2 mol/mol water with a subsequent 0.6% weight loss from the 95% to 5% (FIG. 5.).
  • This material overall exhibited limited hygroscopicity.
  • Post-DVS XRPD of the material showed that it remained Form A + minor Form B when it was collected after DVS sorption/desorption cycle at 5% RH (FIG.5).
  • Peaks observed in the XRPD from Crystalline Form A of Compound I are listed in Table 1 below.
  • Exemplary prominent peaks for crystalline Form A of Compound I are provided in Table 2 below.
  • the white solids product was analyzed by XRPD, TGA, DSC and DVS as described herein.
  • the XRPD spectrum used in indexing is provided FIG.9.
  • TGA and DSC thermograms are provided in FIG.10.
  • a DVS isotherm plot is provided in FIG.11.
  • Peaks observed in the XRPD from Crystalline Form B of Compound I are listed in Table 3 below.
  • Exemplary prominent peaks for crystalline Form B of Compound I are provided in Table 4 below. Table 3.
  • Crystalline Form B of Compound I was also made according to the following procedure. [00251] To a solution of 1H-1,2,4-triazole(247 g, 3.59 mol, 6.50 eq) in ACN (1.50 L) was added DIEA (642 g, 4.97 mol, 9.00 eq) at 0 o C.
  • Compound A was determined to have an IC 50 ⁇ IS[M d *)*/* fA) :VTWV[UL 9 PIL IU IC50 ⁇ IS[M QU ZPM XIUOM VN NXVT 7 *),/* fA ZV d +fA) EXAMPLE 8 – THP1 TREX1 KO Inhibition Assay [00257] Compound A and Compound B were tested for their ability to alter the type 1 interferon XMYWVUYM QU G>D+ ;[IS GE ⁇ H+ @C KMSSY ZXMIZML ]QZP /(I ⁇ I(,n(LMV ⁇ _K_ZQLQUM) 8YYI_ WXVKML[XMY and results are described below.
  • THP1-DualTM KO-TREX1 cells were ZXMIZML ]QZP I LVYM ZQZXIZQVU VN I ZMYZ KVTWV[UL ISVUM VX QU ZPM WXMYMUKM VN +fA /(I ⁇ I(,n( deoxycytidine (Sigma-Aldrich, cat# 189825). Type 1 Interferon and cell viability were assessed after six days of treatment. [00259] Stock solution of the test compound was prepared in DMSO followed by a three-fold dilution in DMSO. Additional 50x dilution was prepared in cell culture media for each dilution. 10 ⁇ L of diluted test compound was then added to a 96-well plate.
  • the cell pellet was prepared for lysis. [00267] A RIPA lysis buffer (#BP-115, Boston BioProducts) was added to a Halt protease and phosphate inhibitor cocktail (#78440, ThermoFisher), and the mixture was cooled on ice. About 30 ⁇ L of the lysis buffer mix was added to the cells.
  • decitabine DAC
  • test Compound A at one of six doses (0.3mg/kg PO, 1mg/kg PO, 3mg/kg PO, 10mg/kg PO, 30mg/kg PO, 100mg/kg PO) once daily, for 5 days.
  • Two additional groups were administered (1) decitabine and test compound vehicle control SC+PO, once daily, for 5 days, and (2) decitabine at 5mg/kg SC, once daily, for 5 days.
  • Decitabine was formulated in sterile PBS, pH 7.4.
  • Test compound was formulated in 20% HPBCD in 50 mM citrate buffer (pH 4.5).
  • Tumors were harvested 4h post-last dose administered on day 5, grinded in PBS at 50 Hz for 5 min, kept on ice for 30 min while being vortexed every 5 min. Tumors were then centrifuged, and Pierce TM BCA Protein Assay Kit was used to measure protein concentration. Equal amounts of proteins were added to 96-well black plates, and luciferase signal was measured using the QUANTI-Luc TM detection medium according to manufacturer’s instructions. Luminescence was measured using the EnVision® 2105 Multimode Plate Reader. Part II – Results [00272] Experimental results are depicted in Fig.14. Data was normalized relative to interferon signal from vehicle group.

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Abstract

La présente divulgation concerne des composés d'oxopyrimidinyl-((isobutyryloxy)méthyl)tétrahydrofuranyle cristallins, des compositions pharmaceutiques contenant des composés cristallins, et des méthodes de traitement utilisant les composés cristallins.
PCT/US2024/046608 2023-09-14 2024-09-13 Composés cristallins, compositions pharmaceutiques et méthodes de traitement d'une maladie Pending WO2025059461A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010030858A1 (fr) * 2008-09-15 2010-03-18 Enanta Pharmaceuticals, Inc. Dérivés de nucléosides 4'-allène-substitués
WO2023178133A1 (fr) * 2022-03-15 2023-09-21 Rome Therapeutics, Inc. Composés et méthodes pour traiter une maladie

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010030858A1 (fr) * 2008-09-15 2010-03-18 Enanta Pharmaceuticals, Inc. Dérivés de nucléosides 4'-allène-substitués
WO2023178133A1 (fr) * 2022-03-15 2023-09-21 Rome Therapeutics, Inc. Composés et méthodes pour traiter une maladie

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