Compounds and methods for treating diseases

Abstract

The present invention provides compounds, compositions, and methods for treating medical disorders, such as cancer, autoimmune disorders, and / or neurological disorders, and inhibiting LINE1 reverse transcriptase and / or HERV-K reverse transcriptase using a compound of Formula I, or a pharma- ceutically acceptable salt thereof, or related compounds provided herein.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 424,723, filed November 11, 2022, U.S. Provisional Patent Application No. 63 / 354,620, filed June 22, 2022, and U.S. Provisional Patent Application No. 63 / 269,375, filed March 15, 2022, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Electronic Sequence Listing Reference This application has been submitted electronically via the Patent Center in XML format and contains a Sequence Listing, which is incorporated herein by reference in its entirety. The XML copy, created on March 9, 2023, is named 198109_seqlist.xml and is 11,441 bytes in size.

[0003] FIELD OF THE INVENTION The present invention provides compounds, compositions, and methods for treating medical disorders such as cancer, autoimmune disorders, and / or neurological disorders, and modulating LINE1 reverse transcriptase and / or HERV-K reverse transcriptase using a compound according to Formula I, or a pharmaceutically acceptable salt thereof, or related compounds provided herein. [Background technology]

[0004] Transposable elements (or transposons) are genomic DNA sequences that have the ability to move within the genome, leading to changes in their organization, increasing their size, and creating duplications and redundancies (Ukadike and Mustelin, J. Clin. Med., 10:856 (2021)). These genomic sequences are thought to have been introduced into the human genome either by infection with exogenous retroviruses that infected human ancestors millions of years ago, or by ancient descendants of retroviruses that retained the ability to embed and replicate in the human germline genome (Ukadike and Mustelin, 2021).

[0005] Long interspersed nuclear element 1 (LINE-1) is a class I transposable element in the DNA of several organisms, constituting approximately 17% of the human genome. LINE-1 has two open reading frames, ORF1 and ORF2, which encode ORF1p, which has nucleic acid chaperone activity, and ORF2p, which has reverse transcriptase (RT) and endonuclease activity, respectively (Reviewed in Babushok and Kazazian, Hum. Mut. 28:527-539, (2007)). LINE-1 retrotransposition activity is mediated by ORF2p. While the majority of LINE-1 elements in the human genome contain inactivating mutations, a small proportion of LINE-1 elements remain intact and retain the ability to retrotranspose. This ability varies both between individuals and between cell types within individuals. Active LINE-1 elements are thought to disrupt the genome through insertions, deletions, rearrangements, and recombinations. (Garcia-Perez et al., Development, 143:4101-4114 (2016)). LINE-1 activity is normally tightly regulated in the germline by DNA methylation, histone modifications, and piRNAs.

[0006] Retrotransposons are transposable elements associated with the pathogenesis of many diseases, including cancer, autoimmune diseases, neurological disorders, and aging (Zhang, et al., Frontiers in Cell and Dev. Bio., 8:657 (Aug. 2020); Kuriyama et al., Nature: Scientific Reports, 11:23146 (2021)). Overexpression of LINE-1 RNA and protein can promote apoptosis, DNA damage and repair, and cellular plasticity, which can promote tumor progression. Furthermore, genomic hypomethylation can induce the expression of repetitive sequences that can drive a pro-inflammatory response characterized by the overproduction of type 1 interferons (Zhang, 2020).

[0007] Pathogenic interferon production is a hallmark of type I interferonopathies, which include rare genetic disorders with an incidence of 1:10,000 to 1:1,000,000. Pathological induction of type I interferon causes immune system hyperactivation, leading to systemic inflammation that can affect the nervous system, lungs, and blood vessels, among other organ systems. (Nesterova et al., “Congenital and Acquired Interferonopathies: Differentiated Approaches to Interferon Therapy,” Innate Immunity in Health and Disease, Ed. Saxena and Prakash, IntechOpen, 2020). Aicardi-Goutières syndrome (AGS) is a monogenic inflammatory encephalomyopathic disorder caused by mutations in genes critical for maintaining homeostatic cytoplasmic nucleic acid oligomerization. As a result, increased levels of cytoplasmic nucleic acid accumulation lead to an increased interferon response. The double-stranded DNA products of LINE-1 reverse transcription are potential triggers for DNA-sensing receptors, such as cGAS, which activate the STING pathway, leading to type I interferon production (Zhao, J. Autoimmunity, 90:105-115 (2018)). LINE-1 reverse transcriptase products have been implicated as a major source of pro-inflammatory nucleic acids in patients with AGS. Administering a combination of three nucleoside reverse transcriptase inhibitors to patients with AGS for 12 months effectively reduced their systemic interferon response. The pathogenic interferon response involved in AGS is also implicated in the pathogenesis of SLE, and several case studies have identified monogenic forms of SLE driven by hypomorphic alleles of nucleic acid-metabolizing enzymes such as TREX1.

[0008] 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.). LINE-1 has also been found to be significantly upregulated in patients with dermatomyositis (DM), accompanied by significantly elevated levels of interferon-α and interferon-β (Kuriyama et al., J. Am. Acad. Dermatol., 84(4):1103-1105(2020)).

[0009] LINE-1 has also been implicated in neurological disorders such as ataxia-telangiectasia (AT), Rett syndrome, Friedreich's ataxia, paranuclear palsy, amyotrophic lateral sclerosis, frontotemporal dementia, and schizophrenia. Increased retrotransposition and elevated levels of type 1 interferon have been identified in each of these diseases. LINE-1 is also involved in the aging process and frontotemporal lobar degeneration. (Zhang, 2020)

[0010] Cancer remains a significant health problem despite significant research efforts and scientific advances reported in the literature to treat this disease. Solid tumors, including prostate, breast, and lung cancer, remain widely prevalent among the world's population. Leukemia and lymphoma also account for a significant proportion of new cancer diagnoses. Current treatment options for these cancers are not effective for all patients and / or may have significant adverse side effects. New therapies are needed to address this unmet need in cancer therapy.

[0011] High LINE-1 activity has been found in many tumor tissues. LINE-1 RT uses a procedure called target-site-primed reverse transcription (TPRT), which involves nicking genomic DNA, followed by reverse transcription and insertion of LINE-1 into the genome. LINE-1-mediated gene rearrangements can induce oncogene amplification. Additionally, LINE-1 can mediate the deletion of tumor suppressor genes (Zhang, 2020). Inhibition of LINE-1 RT in cancer cells, either through RNA interference-dependent silencing of active LINE-1 elements or using RT-inhibiting compounds, can reduce cancer cell proliferation, promote cancer cell differentiation, and delay tumor progression in certain animal models (Sciamann et al., Frontiers in Chemistry, 4:6 (Feb. 2016)). LINE-1 has also been shown to promote tumor metastasis. Furthermore, chronic production of type 1 interferons in the tumor microenvironment is associated with resistance to immune surveillance, which involves therapeutic blockade of interferons, which signal an increased anticancer immune response.

[0012] Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome and are thought to originate from ancient retroviral integration into the germline. Although the biology of HERVs remains poorly defined, accumulating evidence supports their pathological role in diverse diseases, including cancer, autoimmunity, neurodegenerative disorders, and aging. Functional proteins are produced by HERV-encoded genes, including reverse transcriptase (RT), which may contribute to pathologies resulting from aberrant HERV-K expression.

[0013] HERVs play a role in early development by rewiring gene regulatory networks in the preimplantation embryo (Fu et al., Biomolecules, 11(6):829 (2021)). HERV expression appears to be a hallmark of the undifferentiated state, phenotypic plasticity, and acquisition of stem cell properties (Balestrieri et al., Frontiers in Microbiology, 9:1448 (2018)), traits associated with aggressive cancers and poor patient outcomes. HERV expression is usually tightly regulated in normal adult tissues, but it has been reported to be aberrantly expressed in cancer (Downey et al., Int. J. Cancer, 137(6):1249-1257 (2015)), inflammatory diseases (Greenig, Peer J 7:e6711 (2019)), neurological diseases (Kury et al., Trends Mol. Med., 24(4):379-394 (2018)), aging (Gorbunova et al., Nature, 596(7870):43-53 (2021)), and viral diseases (Romer, Frontiers in Neuroscience, 15:648629-648629 (2021)). There have been numerous reports of upregulation of HERV-K [HML-2 (human endogenous MMTV-like) subtype-derived mRNA and protein in various solid and liquid tumor types (Dervan et al., 2019). et al., Front. Onc., 11:658489 (2021), Hohn et al., Front. Onc., 3:246 (2013). The association of disease with the expression of endogenous retrovirus- and HERV-encoded proteins during disease states suggests that antiretroviral therapy may be considered in the management of these conditions.

[0014] Thus, there exists a need for new therapeutic methods that provide improved efficacy and / or reduced side effects for treating medical disorders such as cancer, autoimmune diseases, neurological disorders, aging, and age-related diseases. The present invention addresses the aforementioned need and provides other related advantages. Summary of the Invention

[0015] Provided herein are compounds and compositions that are useful for the treatment of cancer, autoimmune disorders, and / or neurological disorders, among other uses. The compounds inhibit LINE1 reverse transcriptase activity and / or HERV-K reverse transcriptase activity. The compounds can be formulated in pharmaceutical compositions. Methods of treatment and methods of inhibiting LINE1 reverse transcriptase activity are provided.

[0016] One aspect of the present disclosure provides compounds that possess a combination of excellent properties, including potent inhibitory activity toward LINE1 reverse transcriptase, selectivity for inhibiting LINE1 reverse transcriptase, and excellent physical properties that make the compounds suitable for use as orally administered drugs. Selectivity for inhibiting LINE1 reverse transcriptase can be characterized according to the compound's ability to inhibit LINE1 reverse transcriptase while having substantially less inhibitory activity toward DNA polymerases (e.g., α, β, and γ). In part, because inhibition of DNA polymerases, such as DNA polymerase gamma, can result in toxicity in the form of mitochondrial toxicity, compounds that exhibit potent inhibitory activity toward LINE1 reverse transcriptase while having substantially less inhibitory activity toward DNA polymerases represent an important discovery and a significant scientific advance. Potent inhibitory activity toward LINE1 reverse transcriptase combined with low inhibitory activity toward DNA polymerases contributes to the subject compound's high therapeutic index, thereby providing a superior performance profile for the compound in medical therapy. Experimental results herein demonstrate these advantages.

[0017] Another aspect of the present disclosure provides compounds that have a combination of excellent properties, including potent inhibitory activity toward LINE1 reverse transcriptase, selectivity for inhibiting LINE1 reverse transcriptase, potent inhibition of pathogenic interferon responses in inflamed tissues, and excellent physical properties that make the compounds suitable for use as orally administered drugs. As described above, selectivity for inhibiting LINE1 reverse transcriptase can be characterized according to the compound's ability to inhibit LINE1 reverse transcriptase while having substantially less inhibitory activity toward DNA polymerases (e.g., α, β, and γ). In part, because inhibition of DNA polymerases such as DNA polymerase gamma can result in toxicity in the form of mitochondrial toxicity, compounds that exhibit potent inhibitory activity toward LINE1 reverse transcriptase while having substantially less inhibitory activity toward DNA polymerases would be an important discovery and a significant scientific advance. Compounds with potent inhibition of pathogenic interferon responses in inflamed tissues are useful for treating cancer, autoimmune diseases (e.g., SLE and CLE), neurological disorders, aging, and age-related diseases. The potent inhibitory activity towards LINE1 reverse transcriptase combined with low inhibitory activity towards DNA polymerases (e.g., α, β, and γ) contributes to the high therapeutic index of the subject compounds, thereby providing them with an excellent performance profile in medical therapy.

[0018] Another aspect of the present disclosure provides compounds that have a combination of excellent properties, including potent inhibitory activity toward HERV-K reverse transcriptase, selectivity for inhibiting HERV-K reverse transcriptase, and excellent physical properties that make the compounds suitable for use as orally administered drugs. Selectivity for inhibiting HERV-K reverse transcriptase can be characterized according to the compound's ability to inhibit HERV-K reverse transcriptase while having substantially less inhibitory activity toward DNA polymerases (e.g., α, β, and γ). In part, because inhibition of DNA polymerases, such as DNA polymerase gamma, can result in toxicity in the form of mitochondrial toxicity, compounds that exhibit potent inhibitory activity toward HERV-K reverse transcriptase while having substantially less inhibitory activity toward DNA polymerases represent an important scientific advance. Compounds that are potent inhibitors of HERV-K reverse transcriptase are useful for treating HERV-K reverse transcriptase-associated disorders. Potent inhibitory activity toward HERV-K reverse transcriptase combined with low inhibitory activity toward DNA polymerases contributes to the subject compound's high therapeutic index, thereby providing a superior performance profile for the compound in medical therapy.

[0019] Thus, one aspect of the present disclosure is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein B, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 Also provided herein are pharmaceutical compositions comprising compounds of Formula I.

[0020] Another aspect of the present disclosure is a compound represented by formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein. Also provided herein are pharmaceutical compositions comprising compounds of Formula II.

[0021] Another aspect of the present disclosure is a compound represented by formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein. Also provided herein are pharmaceutical compositions comprising compounds of Formula III.

[0022] Another aspect of the present disclosure is a compound represented by formula IV: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein. Also provided herein are pharmaceutical compositions comprising compounds of Formula IV.

[0023] Another aspect of the present disclosure is a compound represented by formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein. Also provided herein are pharmaceutical compositions comprising compounds of Formula V.

[0024] Another aspect of the present disclosure is a compound represented by formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein. Also provided herein are pharmaceutical compositions comprising the compound of Formula VI.

[0025] The disclosed compounds and compositions are designed to treat medical disorders by inhibiting LINE1 reverse transcriptase and / or HERV-K reverse transcriptase using the disclosed compounds. In particular, one aspect of the disclosure provides a compound according to Formula I, or a pharmaceutically acceptable salt thereof, in a method of treating a disorder selected from the group consisting of cancer, autoimmune disorders, and neurological disorders. Further description of additional sets of compounds useful in the method, including compounds of Formulas II, III, IV, V, and VI, is provided in the detailed description. Additional features of the method are described in the detailed description.

[0026] Another aspect of the present disclosure provides a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for a method of inhibiting LINE1 reverse transcriptase activity in a subject suffering from a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder. The method comprises contacting LINE1 reverse transcriptase with an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to inhibit the activity of the LINE1 reverse transcriptase. Additional further description of compounds useful in the method, including compounds of Formulas II, III, IV, V, and VI, is described in the detailed description. Additional features of the method are described in the detailed description.

[0027] Another aspect of the present disclosure provides a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for a method of inhibiting HERV-K reverse transcriptase activity in a subject suffering from a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder. The method comprises contacting HERV-K reverse transcriptase with an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to inhibit the activity of the HERV-K reverse transcriptase. Further description of additional sets of compounds useful in the method, including compounds of Formulas II, III, IV, V, and VI, is provided in the detailed description. Additional features of the method are provided in the detailed description. [Brief explanation of the drawings]

[0028] [Figure 1]In an in vivo decitabine challenge model, as described in Example 108, we show that repeated administration of decitabine induces interferon-stimulated gene (ISG) responses in the spleens of vehicle control animals.

[0029] [Figure 2A] 1 depicts the effect of repeated administration of Compound 23 in an in vivo decitabine challenge model, as described in Example 108. [Figure 2B] 1 depicts the effect of repeated administration of Compound 2 in an in vivo decitabine challenge model, as described in Example 108. [Figure 2C] 1 depicts the effect of repeated administration of Compound 2 in an in vivo decitabine challenge model, as described in Example 108.

[0030] [Figure 2D] 1 is a graph depicting the effect of repeated administration of Compound 2 on ISG scores in the spleen and kidney in an in vivo decitabine challenge model in BALB / c mice, as described in Example 108. [Figure 2E] 1 is a graph depicting the effect of repeated administration of Compound 40 on ISG scores in the spleen and kidney in an in vivo decitabine challenge model in BALB / c mice, as described in Example 108. [Figure 2F] FIG. 10 is a graph depicting the effect of repeated administration of Compound 67 at 30 mg / kg on ISG scores in the spleen and kidney in an in vivo decitabine challenge model in BALB / c mice, as described in Example 108. [Figure 2G] FIG. 10 is a graph depicting the effect of repeated administration of Compound 67 at 100 mg / kg on ISG scores in the spleen and kidney in an in vivo decitabine challenge model in BALB / c mice, as described in Example 108.

[0031] [Figure 3]1 shows the response of two exemplary PBMC donors to decitabine-induced interferon levels upon administration of various compounds of the present disclosure, as described in Example 110. A depicts a representative high responder, and B depicts a representative intermediate responder.

[0032] [Figure 4A] 1 shows baseline levels of pTBK1 with or without UVB exposure and with or without administration of the cGAS inhibitor G140 (InvivoGen), as described in Example 111.

[0033] [Figure 4B] 1 shows that the level of pTBK1 changes in a dose-dependent manner upon administration of various concentrations of compounds 2, 14, 40, and 44 alone or after UVB exposure, as described in Example 111. [Figure 4C] 1 shows that the level of pTBK1 changes in a dose-dependent manner upon administration of various concentrations of compounds 2, 14, 40, and 44 alone or after UVB exposure, as described in Example 111.

[0034] [Figure 5] FIG. 11 is a graph depicting interferon levels over time in THP1-Dual™ KO-TREX1 xenografts from mice treated with vehicle or decitabine (DAC) at 5 mg / kg IP once daily for 4 days, as described in Example 112.

[0035] [Figure 6] 1 is a graph depicting normalized interferon levels in THP1-Dual™ KO-TREX1 xenografts from mice treated once daily for 4 days with decitabine (DAC) and various doses of Compound 2, as described in Example 113. The graph depicts data obtained on day 5, when tumors were harvested 24 hours after the final decitabine dose on day 4.

[0036] [Figure 7]1 is a graph depicting the potentiation modeling curves of Compound 2 potentiation at four concentrations of stampidine (A) and Compound 2 potentiation at four concentrations of stampidine (B), as described in Example 114.

[0037] [Figure 8A] Graph depicting the effect of repeated administration of Compound 2 (A) and Compound 67 (B) on ISG scores in the heart and kidney of B6 / JGpt-Trex1<em>1Cd1194 / Gpt mice compared to control (B) in the in vivo B6 / JGpt-Trex1<em>1Cd1194 / Gpt mouse model, as described in Example 109. [Figure 8B] Graph depicting the effect of repeated administration of Compound 2 (A) and Compound 67 (B) on ISG scores in the heart and kidney of B6 / JGpt-Trex1<em>1Cd1194 / Gpt mice compared to control (B) in the in vivo B6 / JGpt-Trex1<em>1Cd1194 / Gpt mouse model, as described in Example 109. [Figure 8C] Graph depicting the effect of repeated administration of Compound 2 (A) and Compound 67 (B) on ISG scores in the heart and kidney of B6 / JGpt-Trex1<em>1Cd1194 / Gpt mice compared to control (B) in the in vivo B6 / JGpt-Trex1<em>1Cd1194 / Gpt mouse model, as described in Example 109.

[0038] [Figure 9] 1 is a graph depicting normalized interferon levels in THP1-Dual™ KO-TREX1 xenografts from mice treated with decitabine (DAC) and various doses of Compound 67 once daily for 4 days, as described in Example 115. The graph depicts data obtained on day 5, when tumors were harvested 24 hours after the final decitabine dose on day 4. DETAILED DESCRIPTION OF THE INVENTION

[0039] In certain embodiments, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: B is [ka] and R 1 is -H or [ka] Alk is, independently for each occurrence, a C2-C6 aliphatic group; R 2 is —H, C1-C6 aliphatic, C1-C3 haloaliphatic, C1-C3 hydroxyaliphatic, cyclopropyl, —CN, —N3, —O—(C1-C3 aliphatic), —F, or —Cl; R 3 is -H, R 4 is -OH, -Cl, -OCH3, -F, -N3, or [ka] and R 5 is -H or -F, R 6 is -H, -F, -Cl, C1-C6 aliphatic, C1-C4 haloaliphatic, -O-(C1-C4 aliphatic), cyclopropyl, or -OH.

[0040] The present invention further provides compounds of Formula II, III, IV, V, or VI as described herein. The present invention further provides compounds of Formula I and methods for treating medical disorders, such as cancer, autoimmune disorders, and / or neurological disorders, and inhibiting LINE1 reverse transcriptase and / or HERV-K reverse transcriptase using a compound according to Formula I, or a pharmaceutically acceptable salt thereof, or related compounds provided herein (such as a compound of Formula II, III, IV, V, or VI).

[0041] The present invention further provides compounds of Formulas IA, II-A, III-A, III-B, IV-A, and IV-B described herein. The present invention further provides compounds of Formula I and methods for treating medical disorders, such as cancer, autoimmune disorders, and / or neurological disorders, and inhibiting LINE1 reverse transcriptase and / or HERV-K reverse transcriptase using a compound according to Formula I, or a pharmaceutically acceptable salt thereof, or related compounds provided herein (such as compounds of Formulas IA, II-A, III-A, III-B, IV-A, and IV-B).

[0042] Various aspects of the present invention are described in the following sections, but an aspect of the present invention described in a particular section is not limited to any particular section. Further, if a variable is not accompanied by a definition, the previous definition of the variable takes precedence.

[0043] definition The compounds of the present invention include those described generally herein and are further illustrated by the classes, subclasses, and genera disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. These definitions apply whether a term is used alone or in combination with other terms, unless otherwise specified. Thus, the definition of "aliphatic" applies to "aliphatic" as well as "aliphatic" moieties such as "-O-aliphatic." For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001.

[0044] When used in describing a chemical group that can have multiple points of attachment, a hyphen (-) indicates the point of attachment of the group to the variable to which it is attached. [ka] The use of indicates the point of attachment of the group to the structure.

[0045] The term "aliphatic," whether used alone or as part of a larger moiety such as "haloaliphatic," refers to a saturated or unsaturated, straight-chain or branched, monovalent hydrocarbon radical. Unless otherwise specified, an aliphatic group typically has 1 to 6 carbon atoms. Examples of aliphatic groups include methyl, ethyl, ethynyl, ethenyl, propyl, propenyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

[0046] The term "haloaliphatic" includes mono-, poly-, and perhaloaliphatic groups where the halogens are independently selected from F, Cl, Br, and I, and the aliphatic groups are as described above. Examples of "haloaliphatic" groups include -CF, -CHF, -CFClH, -CHCHF, -CHCHCl, -CH=CHF, -CFCF, -CHCl, and the like.

[0047] The term "alkyl," whether used alone or as part of a larger moiety, such as "haloalkyl," means a saturated, straight-chain or branched, monovalent hydrocarbon radical. Unless otherwise specified, alkyl groups typically have 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

[0048] The term "haloalkyl" includes mono-, poly-, and perhaloalkyl groups where the halogens are independently selected from F, Cl, Br, and I, and the alkyl group is as described above. Examples of "haloalkyl" groups include -CF, -CHF, -CFClH, -CHCHF, -CHCHCl, -CFCF, -CHCl, and the like. The term "halomethyl" refers to a haloalkyl group containing a single carbon atom. The term "deuterohalomethyl" refers to a halomethyl group containing one or two deuterium atoms.

[0049] The term "alkoxy" refers to an aliphatic radical attached through an oxygen linking atom, also represented by -O-aliphatic, wherein the aliphatic group is as described above. Examples of "alkoxy" groups include -OCH, -OCHCH, -OCH=CH, and the like.

[0050] The term "hydroxyaliphatic" refers to an aliphatic group described above that is substituted with one or more -OH, as defined above. Examples of "hydroxyaliphatic" groups include -CHOH, -C(H)(OH)CH, -CHC(H)(OH)CHOH, and the like.

[0051] The term "halogen" means F, Cl, Br, or I.

[0052] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation. For example, an "unsaturated" aliphatic group includes both alkenyl and alkynyl moieties, such as ethynyl, ethenyl, 2-propenyl, 3-propenyl, 2-propynyl, etc.

[0053] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Acid salts include, for example, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0054] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower aliphatic sulfonates, and aryl sulfonates.

[0055] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, e.g., the R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having the present structures including the replacement of a carbon with a C-enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present invention.

[0056] Unless otherwise specified, when D is specifically listed at a position or shown in a chemical formula, the D represents a mixture of hydrogen and deuterium, with the amount of deuterium being about 100% (i.e., the abundance of deuterium ranges from at least 90% to up to 100%). In certain embodiments, the abundance of deuterium in D is 95% to 100%, or 97% to 100%. Deuterium ( 2 H) is 1H is a stable, non-radioactive isotope of hydrogen and has an atomic mass of 2.014. 1 H Hydrogen (i.e., protium), deuterium ( 2 H), and tritium ( 3 H). The natural abundance of deuterium is 0.015%. Those skilled in the art will understand that in all compounds containing H atoms, the H atoms are in fact 1 H Hydrogen, Deuterium ( 2 H), and tritium ( 3 H), recognizing that approximately 0.015% is deuterium.

[0057] When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, or 99.9% pure by weight relative to all other stereoisomers. Percent weight pure relative to other stereoisomers is the ratio of the weight of one stereoisomer to the weight of all stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, or 99.9% optically pure. Percent optical purity is determined by chiral liquid chromatography using area percent.

[0058] As used herein, the terms "a" and "an" mean "one or more" and include pluralities unless the context is inappropriate.

[0059] One or more compounds of the present invention may exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention is intended to encompass both solvated and unsolvated forms. "Solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, a solvate may be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" refers to a solvate in which the solvent molecule is HO.

[0060] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), and most preferably, humans.

[0061] The terms "inhibit," "inhibition," or "inhibiting" include a decrease in the baseline activity of a biological activity or process.

[0062] As used herein, the term "effective amount" refers to the amount of a compound that elicits a biological or medical response in a subject, e.g., a reduction or inhibition of enzyme or protein activity relative to pre-treatment baseline levels. Typically, an "effective amount" of a compound is an amount sufficient to produce some beneficial change or desired result (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 route of administration. As used herein, the term "treating" includes any effect that results in the improvement of a condition, disease, disorder, or the like, e.g., alleviating, reducing, modulating, ameliorating, or eliminating the symptoms thereof. For example, treating cancer can mean extending the time without tumor burden growth (progression-free survival), reducing tumor burden, extending the overall patient survival, improving symptoms associated with cancer, preventing metastasis, slowing metastasis, etc. Treating autoimmune diseases includes reducing disease symptoms, extending the time between disease flares, causing disease remission, preventing disease progression, etc. Treatment of neurological disorders can include improving cognitive function, reducing the rate of cognitive loss, reducing symptoms, and the like.

[0063] In some embodiments, treatment is administered after one or more symptoms have developed. In some embodiments, treatment is administered in the absence of symptoms. For example, 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 factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0064] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier, adjuvant, or vehicle that makes the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0065] As used herein, 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. Pharmaceutically acceptable carriers, adjuvants, and / or vehicles used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, phosphates, buffer substances such as glycine, sorbic acid, and 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, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The compositions may also include stabilizers and / or preservatives. For examples of carriers, vehicles, and adjuvants, see, e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0066] The term "combination" refers to simultaneous, separate, or sequential administration. In one aspect of the present disclosure, "combination" refers to simultaneous administration. In another aspect of the present disclosure, "combination" refers to separate administration. In another aspect of the present disclosure, "combination" refers to sequential administration. When administration is separate or sequential, the delay in administration of one or more additional therapeutic agents is at an interval designed not to eliminate the beneficial effect of the combination.

[0067] Throughout this specification, when compositions are described as having, including, or comprising specific components, or processes and methods are described as having, including, or comprising specific steps, it is additionally contemplated that there are compositions of the invention that consist essentially of, or consist of, the recited components, and that there are processes and methods of the invention that consist essentially of, or consist of, the recited processing steps.

[0068] As used herein, the terms "comprising" or "comprises" are used in reference to compounds, uses, compositions, methods, and their respective component(s) that are essential to the method or composition, but embrace the inclusion of unspecified elements, whether essential or not. The term "consisting of" refers to compounds, uses, compositions, methods, and their respective component(s) described herein, excluding any elements not recited in that description of the embodiment. The term "consisting essentially of" refers to elements required for a given embodiment. The term allows for the presence of elements that do not materially affect the basic and novel functional property(ies) of the embodiment.

[0069] Generally, compositions specifying percentages are by weight unless otherwise specified.

[0070] I. Description of Exemplary Compounds In a first embodiment, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: B is [ka] and R 1 is -H or [ka] Alk is, independently for each occurrence, a C2-C6 aliphatic group; R 2 is —H, C1-C6 aliphatic, C1-C3 haloaliphatic, C1-C3 hydroxyalkyl, cyclopropyl, —CN, —N3, —O—(C1-C3 aliphatic), —F, or —Cl; R 3 is -H, R 4 is -OH, -Cl, -OCH3, -F, -N3, or [ka] and R 5 is -H or -F, R 6 is -H, -F, -Cl, C1-C6 aliphatic, C1-C4 haloaliphatic, -O-(C1-C4 aliphatic), cyclopropyl, or -OH.

[0071] In a second embodiment, R of Formula I 1 and R 4 is independently for each occurrence ethyl, propyl, isopropyl, sec-butyl, tert-butyl, or iso-butyl, and the remainder of the variables are as described above for Formula I.

[0072] In a third embodiment, R in Formula I 1 -H or [ka] and the remainder of the variables are as described above for Formula I.

[0073] In a fourth embodiment, R in Formula I 1 is —H, and the remainder of the variables are as described above for Formula I or for any of the preceding embodiments.

[0074] In a fifth embodiment, R in Formula I 5 is —H, and the remainder of the variables are as described above for Formula I or for any of the preceding embodiments.

[0075] In a sixth embodiment, R in formula I 2 is not —H, and the remaining variables are as described above for Formula I or for any of the preceding embodiments.

[0076] In a seventh embodiment, R in Formula I 4 is -OH or [ka] and the remainder of the variables are as described above for Formula I or for any of the preceding embodiments.

[0077] In an eighth embodiment, R in Formula I 6 is -H, -F, -CH, -CHCH, -OCH, -OCHCH, -CH=CH, -CHF, or -CHCl, and the remainder of the variables are as described above for Formula I or for any of the preceding embodiments.

[0078] In a ninth embodiment, R in Formula I 6 is -H or -F, and the remainder of the variables are as described for Formula I or for any of Embodiments 1-7 above.

[0079] In a tenth embodiment, R in formula I 6 is —H, and the remainder of the variables are as described for Formula I or for any of Embodiments 1-7 above.

[0080] In a tenth embodiment, R in formula I 6 is -F, and the remainder of the variables are as described for Formula I or for any of Embodiments 1-7 above.

[0081] In a twelfth embodiment, B in formula I is [ka] and the remainder of the variables are as described above for Formula I or for any of the preceding embodiments.

[0082] In a further embodiment, B is [ka] In one aspect of this embodiment, B is [ka] In another aspect of this embodiment, B is [ka] In another aspect of this embodiment, B is [ka] In a further aspect of this embodiment, B is [ka] In another aspect of this embodiment, B is [ka] In one aspect of this embodiment, B is [ka] In any of these aspects of the twelfth embodiment, the remainder of the variables in formula I are as described above for any of the disclosed embodiments.

[0083] In a thirteenth embodiment, B in formula I is [ka] and the remainder of the variables are as described above for Formula I or for any of the preceding embodiments. In one aspect of this embodiment, B is [ka] In another aspect of this embodiment, B is [ka] In a further aspect of this embodiment, B is [ka] In any of these aspects of the thirteenth embodiment, the remainder of the variables in formula I are as described above for any of the disclosed embodiments.

[0084] In a fourteenth embodiment, R in formula I 2 is —CH, —CF, —N, —OCH, —CHCl, —CHF, —CHF, —CHCl, —CHClF, —CHCH, —CH═CH, cyclopropyl, or —C≡CH, and the remainder of the variables are as described above for Formula I or for any of the preceding embodiments.

[0085] In a fifteenth embodiment, R in formula I 2 is -N3, -CH3, -CH2Cl, -CH2F, -CH=CH2, or -C≡CH, and the remainder of the variables are as described above for Formula I or for any of embodiments 1-13. In one aspect of this embodiment, R 2 is -N3. In another aspect of this embodiment, R 2 is -CH=CH2. In a further embodiment, R 2 is —CH 2 F. In any aspect of this embodiment, the remaining variables are as described above for Formula I or for any of Embodiments 1-13.

[0086] In a sixteenth embodiment, R in formula I 2 is —CH 2 Cl, —CH 2 F, or —C≡CH, and the remainder of the variables are as described above for Formula I or for any of Embodiments 1-13.

[0087] In a seventeenth embodiment, R in formula I 2 is —CH≡CH, and the remaining variables are as described above for Formula I or for any of embodiments 1-13. In one aspect of this embodiment, R 2 is —CH2Cl. In another aspect of this embodiment, R 2 is —C≡CH. In any aspect of this embodiment, the remaining variables are as described above for Formula I or for any of Embodiments 1-13.

[0088] In an eighteenth embodiment, in compounds of formula I, R 4 is -OH and R 5 is -H, and R 6 is -H, and the remaining variables are as described above in any of embodiments 1, 2, 3, 4, 12, 13, 14, 15, 16, and 17 above. In one aspect of this embodiment, R of formula I 2 is —CH 2 Cl, and the remainder of the variables are as described in the first through fourth embodiments above.

[0089] In a nineteenth embodiment, the compound of formula I is selected from the group consisting of: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] or a pharmaceutically acceptable salt thereof. In one aspect, the compound of Formula I is selected from the compounds in Table 1.

[0090] In a twentieth embodiment, the present disclosure provides a compound of Table 1, 1-A, or 1-B herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, or 1-B herein. In certain embodiments, the compound is a compound of Table 1 or 1-A herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1 or 1-A herein. In certain embodiments, the compound is a compound of Table 1-A below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1-A below. In certain embodiments, the compound is a compound of Table 1-B below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1-B below.

[0091] In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, or 1-C herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, or 1-C herein. In certain embodiments, the compound is a compound of Table 1-C below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1-C below.

[0092] In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, or 1-C herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, or 1-C herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula II, Formula III, or Formula IV. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, or 1-C herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula II, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, or 1-C herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula II. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, or 1-C herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula III, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, or 1-C herein, wherein the compound is a compound of Formula III. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, or 1-C herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula IV, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, or 1-C herein, wherein the compound is a compound of Formula IV.

[0093] In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, or 1-C herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, or 1-C herein. In certain embodiments, the compound is a compound of Table 1-C below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1-C below.

[0094] In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, 1-C, or 1-D herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, 1-C, or 1-D herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula II, Formula III, or Formula IV. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, 1-C, or 1-D herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula II, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, 1-C, or 1-D herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula II. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, 1-C, or 1-D herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula III, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, 1-C, or 1-D herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula III. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, 1-C, or 1-D herein, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula IV, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Table 1, 1-A, 1-B, 1-C, or 1-D herein, wherein the compound is a compound of Formula IV. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 3 Table 4-1 Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 5-1 Table 5-2

[0095] A twenty-second embodiment is a pharmaceutical composition comprising a compound according to Formula I as described in any of the above embodiments, or a pharmaceutically acceptable salt thereof, and a carrier, excipient, and / or vehicle. Another embodiment is a pharmaceutical composition comprising a compound as described in any of the above embodiments, or a pharmaceutically acceptable salt thereof, and a carrier, excipient, and / or vehicle. Another embodiment is a pharmaceutical composition comprising a compound as described in any of the embodiments herein, or a pharmaceutically acceptable salt thereof, and a carrier, excipient, and / or vehicle.

[0096] In one aspect of any of the above embodiments, the compounds of Formula I exclude the compounds of Table 2. In another aspect of any of the above embodiments, the compounds of Formula I exclude the compounds of Tables 2, 2-A, and 2-B.

[0097] The present invention provides herein compounds according to formula IA: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1A is -C(O)R 5A , hydrogen, or -P(O)(OH)-OP(O)(OH)-OP(O)(OH)2; R 2A are (i) halomethyl, C 1-3 aliphatic, or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium, or (ii) -N; R 3A is -C(O)R 5A or hydrogen, R 4A is halo, hydrogen, or -OH; R 5A independently for each occurrence, C 1-20 aliphatic, C 1-20 Haloaliphatic, -C(H)(R 6A )-N(R7A )2, phenyl, -CH2-phenyl, or hydrogen, each phenyl being R 10A is replaced by m occurrences of R 6A is C 1-6 alkyl or hydrogen, 1-6 alkyl is optionally substituted with phenyl; R 7A independently for each occurrence: hydrogen, C 1-6 alkyl, -C(O)CH3, -C(O)OC(CH3)3, -C(O)O(CH2)phenyl, or -C(O)O(CH2)fluorenyl; R 8A is hydrogen, halo, -CH3, or -CF3, R 9A is halo, -CH3, or -CF3, R 10A independently for each occurrence, C 1-6 Alkyl, C 1-6 Alkoxyl, C 1-6 represents haloalkyl or halo, B A teeth, [ka] and m is 0, 1, or 2; R 4A is hydrogen, R 1A and R 3A At least one of the groups is -C(O)R 5A provided that: R 3A is hydrogen and R 4A is halo or -OH, and R 1A is hydrogen or -P(O)(OH)-OP(O)(OH)-OP(O)(OH), R 8A is halo, -CH3, or -CF3.

[0098] As generally described above, R 1A is -C(O)R 5A, hydrogen, or —P(O)(OH)—OP(O)(OH)—OP(O)(OH). In certain embodiments, R 1A is hydrogen or -P(O)(OH)-OP(O)(OH)-OP(O)(OH). In certain embodiments, R 1A is -C(O)R 5A or -P(O)(OH)-OP(O)(OH)-OP(O)(OH). In certain embodiments, R 1A is -C(O)R 5A or hydrogen 。 In certain embodiments, R 1A is -C(O)R 5A In certain embodiments, R 1A is hydrogen. In certain embodiments, R 1A is P(O)(OH)-OP(O)(OH)-OP(O)(OH). In certain embodiments, R 1A is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0099] As generally described above, R 2A are (i) halomethyl, C 1-3 aliphatic, or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium, or (ii) -N. In certain embodiments, R 2A is halomethyl. In certain embodiments, R 2A is C 1-3 In certain embodiments, R 2A is cyclopropyl. In certain embodiments, R 2A is optionally halomethyl having one or more hydrogens replaced with deuterium. In certain embodiments, R 2A is optionally C with one or more hydrogens replaced with deuterium 1-3 In certain embodiments, R 2A is cyclopropyl, optionally with one or more hydrogens replaced with deuterium. In certain embodiments, R 2Ais -N3. In certain embodiments, R 2A is halomethyl, C 1-3 aliphatic, or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium.

[0100] In certain embodiments, R 2A is —CHF, —CHBr, or —CHCl. ​​In certain embodiments, R 2A is —CHF. In certain embodiments, R 2A is -CD2F, -CD2Br, or -CD2Cl. In certain embodiments, R 2A is -CD2F. In certain embodiments, R 2A is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0101] As generally described above, R 3A is -C(O)R 5A or hydrogen. In certain embodiments, R 3A is -C(O)R 5A In certain embodiments, R 3A is hydrogen. In certain embodiments, R 3A is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0102] As generally described above, R 4A is halo, hydrogen, or —OH. In certain embodiments, R 4A is halo. In certain embodiments, R 4A is fluoro. In certain embodiments, R 4A is hydrogen. In certain embodiments, R 4A is —OH. In certain embodiments, R 1A is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0103] As generally described above, R 5Aindependently for each occurrence, C 1-20 aliphatic, C 1-20 Haloaliphatic, -C(H)(R 6A )-N(R 7A )2, phenyl, -CH2-phenyl, or hydrogen, each phenyl being R 10A In certain embodiments, R 5A independently for each occurrence, C 1-20 aliphatic, C 1-20 Haloaliphatic, -C(H)(R 6A )-N(R 7A )2, phenyl, or -CH2-phenyl, each phenyl being R 10A In certain embodiments, R 5A independently for each occurrence, C 1-20 In certain embodiments, R 5A independently for each occurrence, C 1-20 In certain embodiments, R 5A is independently for each occurrence -C(H)(R 6A )-N(R 7A )2. In certain embodiments, R 5A independently for each occurrence, represents phenyl, and each phenyl is selected from R 10A In certain embodiments, R 5A represents, independently for each occurrence, -CH-phenyl, and each phenyl is selected from R 10A In certain embodiments, R 5A is hydrogen. In certain embodiments, R 5A is C 1-20 In certain embodiments, R 5A is C 1-20 In certain embodiments, R 5A is -C(H)(R 6A )-N(R 7A )2. In certain embodiments, R 5A is phenyl, and each phenyl is R 10A In certain embodiments, R5A is -CH-phenyl, and each phenyl is R 10A In certain embodiments, R 5A is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0104] As generally described above, R 6A is C 1-6 alkyl or hydrogen, and the C 1-6 The alkyl is optionally substituted with phenyl. In certain embodiments, R 6A is C 1-6 alkyl, and the C 1-6 The alkyl is optionally substituted with phenyl. In certain embodiments, R 6A is hydrogen. In certain embodiments, R 6A is C 1-6 In certain embodiments, R 6A is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0105] As generally described above, R 7A independently for each occurrence: hydrogen, C 1-6 alkyl, —C(O)CH, —C(O)OC(CH), —C(O)O(CH)phenyl, or —C(O)O(CH)-fluorenyl. 7A independently for each occurrence, C 1-6 In certain embodiments, R 7A is hydrogen. In certain embodiments, R 7A is C 1-6 In certain embodiments, R 7A is —C(O)CH. In certain embodiments, R 7A is —C(O)O(CH)phenyl. In certain embodiments, R 7A is —C(O)O(CH)fluorenyl. In certain embodiments, R 7A independently for each occurrence, C 1-6alkyl, —C(O)CH, —C(O)OC(CH), —C(O)O(CH)phenyl, or —C(O)O(CH)fluorenyl. 7A is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0106] As generally described above, R 8A is hydrogen, halo, -CH, or -CF. In certain embodiments, R 8A is hydrogen, halo, -CH, or -CF. In certain embodiments, R 8A is halo, -CH, or -CF. In certain embodiments, R 8A is hydrogen, —CH, or —CF. In certain embodiments, R 8A is hydrogen, halo, or —CF. In certain embodiments, R 8A is hydrogen, halo, or -CH. In certain embodiments, R 8A is hydrogen. In certain embodiments, R 8A is halo. In certain embodiments, R 8A is fluoro. In certain embodiments, R 8A is -CH3. In certain embodiments, R 8A is —CF. In certain embodiments, R 8A is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0107] As generally described above, R 9A is halo, -CH, or -CF. In certain embodiments, R 9A is halo. In certain embodiments, R 9A is —CH3. In certain embodiments, R 9A is —CF. In certain embodiments, R 9A is F, Br, or Cl. In certain embodiments, R 9A is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0108] As generally described above, R 10A independently for each occurrence, C 1-6 Alkyl, C 1-6 Alkoxyl, C 1-6 In certain embodiments, R 10A independently for each occurrence, C 1-6 In certain embodiments, R 10A independently for each occurrence, C 1-6 In certain embodiments, R 10A independently for each occurrence, C 1-6 In certain embodiments, R 10A independently for each occurrence represents halo. In certain embodiments, R 10A is C 1-6 Alkyl, C 1-6 Alkoxyl, C 1-6 haloalkyl, or halo. In certain embodiments, R 10A is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0109] As generally described above, B A teeth, [ka] In certain embodiments, B A teeth, [ka] In certain embodiments, B A teeth, [ka] In certain embodiments, B A is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0110] As generally defined above, m is 0, 1, or 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 1 or 2. In certain embodiments, m is 0 or 2. In certain embodiments, m is 0 or 2. In certain embodiments, m is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0111] In certain embodiments, the compound of Formula II has the following formula, or a pharmaceutically acceptable salt thereof: [ka]

[0112] Another aspect of the present disclosure is a compound represented by formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 4 are independently -C(O)R 5 or hydrogen, with the proviso that R 1 and R 4 At least one of the groups is -C(O)R 5 provided that: R 2 is halo, hydrogen, or -OH; R 3 is halomethyl, C 1-3 aliphatic, or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium; R 5 independently for each occurrence, C 1-20 aliphatic, C 1-20 Haloaliphatic, -C(H)(R 6 )-N(R 7 )2, phenyl, -CH2-phenyl, or hydrogen, each phenyl being R 10 is replaced by m occurrences of R 6 is C 1-6 alkyl or hydrogen, and the C 1-6 alkyl is optionally substituted with phenyl; R 7 independently for each occurrence: hydrogen, C 1-6 alkyl, -C(O)CH3, -C(O)OC(CH3)3, -C(O)O(CH2)phenyl, or -C(O)O(CH2)fluorenyl; R 8 is hydrogen, halo, -CH3, or -CF3, R 9 is halo, -CH3, or -CF3, R 10 independently for each occurrence, C 1-6 Alkyl, C 1-6 Alkoxyl, C 1-6 represents haloalkyl or halo, B 1 teeth, [ka] and m is 0, 1, or 2.

[0113] The definitions of the variables in Formula II above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0114] In certain embodiments, the compound is a compound of formula II.

[0115] As generally defined above, R 1 and R 4 are independently -C(O)R 5 or hydrogen, with the proviso that R 1 and R 4At least one of the groups is -C(O)R 5 This is subject to the condition that:

[0116] In some embodiments, R 1 is -C(O)R 5 and R 4 is hydrogen. In some embodiments, R 1 is -hydrogen and R 4 is C(O)R 5 In some embodiments, R 1 and R 4 are independently -C(O)R 5 In some embodiments, R 1 and R 4 is -C(O)R 5 is.

[0117] As generally defined above, R 2 is halo, hydrogen, or —OH. In certain embodiments, R 2 is fluoro, hydrogen, or —OH. In some embodiments, R 2 is halo or hydrogen. In some embodiments, R 2 is fluoro or hydrogen. In some embodiments, R 2 is hydrogen or —OH. In some embodiments, R 2 is halo or —OH. In some embodiments, R 2 is fluoro or —OH.

[0118] In some embodiments, R 2 is halo. In certain embodiments, R 2 is fluoro. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is -OH.

[0119] As generally defined above, R 3 is halomethyl, C 1-3aliphatic, or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium. 3 is halomethyl or C 1-3 aliphatic, each of which optionally has one or more hydrogens replaced with deuterium.

[0120] In certain embodiments, R 3 is halomethyl, C 1-3 aliphatic, or cyclopropyl, each of which has one or more hydrogens replaced with deuterium. 3 is halomethyl or C 1-3 They are aliphatic, each having one or more hydrogens replaced with deuterium.

[0121] In certain embodiments, R 3 is halomethyl, C 1-3 In some embodiments, R is aliphatic, or cyclopropyl. 3 is halomethyl or C 1-3 In some embodiments, R 3 is halomethyl or cyclopropyl. In some embodiments, R 3 is C 1-3 In some embodiments, R is aliphatic or cyclopropyl. 3 is ethyl or cyclopropyl.

[0122] In some embodiments, R 3 is optionally halomethyl having one or more hydrogens replaced with deuterium. In some embodiments, R 3 is halomethyl. In some embodiments, R 3 is —CH2Cl, —CH2F, —CH2Br, —CH2I, —CHF2, or —CF3. In some embodiments, R 3 is —CH2Cl, —CH2F, —CH2Br, —CH2I, or —CF3. In some embodiments, R 3is —CHF, —CHBr, —CHI, or —CF. In some embodiments, R 3 is —CH2Cl, —CH2Br, —CH2I, or —CF3. In some embodiments, R 3 is —CH2Cl, —CH2F, —CH2I, or —CF3. In some embodiments, R 3 is —CH2Cl, —CH2F, —CH2Br, or —CF3. In some embodiments, R 3 is —CH2Cl, —CH2F, —CH2Br, or —CH2I.

[0123] In some embodiments, R 3 is —CHBr, —CHI, or —CF. In some embodiments, R 3 is —CH2Cl, —CH2I, or —CF3. In some embodiments, R 3 is —CH2Cl, —CH2F, or —CF3. In some embodiments, R 3 is —CH2Cl, —CH2F, or —CH2Br. In some embodiments, R 3 is —CHF, —CHI, or —CF. In some embodiments, R 3 is —CHF, —CHBr, or —CF. In some embodiments, R 3 is —CHF, —CHBr, or —CHI. In some embodiments, R 3 is —CH2Cl, —CH2Br, or —CF3. In some embodiments, R 3 is —CH2Cl, —CH2Br, or —CH2I. In some embodiments, R 3 is —CH2Cl, —CH2F, or —CH2I. In some embodiments, R 3 is -CH2F, -CHF2, or -CF3.

[0124] In some embodiments, R 3 is -CH2I or -CF3. In some embodiments, R 3is —CH2Cl or —CH2F. In some embodiments, R 3 is —CH2Cl or —CF3. In some embodiments, R 3 is -CHF or -CHI. In some embodiments, R 3 is —CH2Cl or —CH2Br. In some embodiments, R 3 is —CHBr or —CHI. In some embodiments, R 3 is —CHBr or —CF. In some embodiments, R 3 is —CH2Cl or —CH2I. In some embodiments, R 3 is —CHF or —CF. In some embodiments, R 3 is —CHF or —CHBr. In some embodiments, R 3 is -CHF or -CHF. In some embodiments, R 3 is -CHF2 or -CF3.

[0125] In some embodiments, R 3 is —CH2Cl. In some embodiments, R 3 is -CHF. In some embodiments, R 3 is —CHBr. In some embodiments, R 3 is -CH2I. In some embodiments, R 3 is -CHF. In some embodiments, R 3 is -CF3.

[0126] In some embodiments, R 3 is halomethyl having one or more hydrogens replaced with deuterium. In some embodiments, R 3 is -CD2Cl, -CD2F, -CD2Br, -CD2I, or -CDF2. In some embodiments, R 3 is -CD2Cl or -CD2F. In some embodiments, R 3 is -CD2Cl. In some embodiments, R3 In some embodiments, R 3 is -CDBr. In some embodiments, R 3 is -CD2I. In some embodiments, R 3 is -CDF2.

[0127] In some embodiments, R 3 is optionally C with one or more hydrogens replaced with deuterium 1-3 In some embodiments, R 3 is a C with one or more hydrogens replaced by deuterium 1-3 In some embodiments, R 3 is C 1-3 In some embodiments, R 3 is C 2-3 In some embodiments, R 3 is C 1-2 In some embodiments, R 3 is C 1-3 In some embodiments, R 3 is C 2-3 In some embodiments, R 3 is C 1-2 In some embodiments, R 3 is —CH2CH3, —C(H)═CH2, or —C(H)═C═CH2. In some embodiments, R 3 is -CH2CH3. In some embodiments, R 3 is —C(H)═CH. In some embodiments, R 3 is -C(H)=C=CH2.

[0128] In some embodiments, R 3 is cyclopropyl, optionally with one or more hydrogens replaced with deuterium. In some embodiments, R 3 is cyclopropyl having one or more hydrogens replaced with deuterium. In some embodiments, R 3is cyclopropyl.

[0129] As generally defined above, R 5 independently for each occurrence, C 1-20 aliphatic, C 1-20 Haloaliphatic, -C(H)(R 6 )-N(R 7 )2, phenyl, -CH2-phenyl, or hydrogen, each phenyl being R 10 is replaced by m occurrences of

[0130] In certain embodiments, R 5 independently for each occurrence, C 1-20 aliphatic, C 1-20 represents haloaliphatic, phenyl, or hydrogen, and the phenyl is R 10 In certain embodiments, R 5 independently for each occurrence, C 1-20 aliphatic, C 1-20 In certain embodiments, R 5 is independently for each occurrence -C(H)(R 6 )-N(R 7 )2, phenyl, or -CH2-phenyl, each phenyl being R 10 In certain embodiments, R 5 is independently for each occurrence -C(H)(R 6 )-N(R 7 )2, or R 10 represents a phenyl substituted with m occurrences of

[0131] In certain embodiments, R 5 is C 1-20 aliphatic, C 1-20 represents haloaliphatic, phenyl, or hydrogen, and the phenyl is R 10 In certain embodiments, R 5 is C 1-20 aliphatic, C 1-20 haloaliphatic, or hydrogen. In certain embodiments, R 5is -C(H)(R 6 )-N(R 7 )2, phenyl, or -CH2-phenyl, each phenyl being selected from R 10 In certain embodiments, R 5 is phenyl or -CH-phenyl, and each phenyl is R 10 In certain embodiments, R 5 is -C(H)(R 6 )-N(R 7 )2, or R 10 is phenyl substituted with m occurrences of

[0132] In certain embodiments, R 5 independently for each occurrence, C 1-20 Aliphatic or C 1-20 In certain embodiments, R 5 independently for each occurrence, C 1-8 Aliphatic or C 1-8 In certain embodiments, R 5 independently for each occurrence, C 10-20 Aliphatic or C 10-20 In certain embodiments, R 5 independently for each occurrence, C 1-20 Alkyl or C 1-20 In certain embodiments, R 5 independently for each occurrence, C 1-8 Alkyl or C 1-8 In certain embodiments, R 5 independently for each occurrence, C 10-20 Alkyl or C 10-20 represents haloalkyl.

[0133] In certain embodiments, R 5 is C 1-20 Aliphatic or C 1-20 In certain embodiments, R 5 is C 1-8 Aliphatic or C 1-8In certain embodiments, R 5 is C 10-20 Aliphatic or C 10-20 In certain embodiments, R 5 is C 1-20 Alkyl or C 1-20 In certain embodiments, R 5 is C 1-8 Alkyl or C 1-8 In certain embodiments, R 5 is C 10-20 Alkyl or C 10-20 It is haloalkyl.

[0134] In certain embodiments, R 5 independently for each occurrence, C 1-20 In certain embodiments, R 5 independently for each occurrence, C 1-8 In certain embodiments, R 5 independently for each occurrence, C 10-20 In certain embodiments, R 5 independently for each occurrence, C 1-20 In certain embodiments, R 5 independently for each occurrence, C 1-8 In certain embodiments, R 5 independently for each occurrence, C 10-20 Represents alkyl.

[0135] In certain embodiments, R 5 is C 1-20 In certain embodiments, R 5 is C 1-8 In certain embodiments, R 5 is C 10-20 In certain embodiments, R 5 is C 1-20 In certain embodiments, R 5 is C 1-8In certain embodiments, R 5 is C 1-5 In certain embodiments, R 5 is C 10-20 It is alkyl.

[0136] In some embodiments, R 5 is -CH3, -CH2CH3, -CH(CH3)2, -C(H)=CH2, -CH2C(H)=CH2, -C≡CH, -(CH2)3CH3, -(CH2)3C(H)=CH2, -(CH2)6C(H)=CH2, -(CH2)3C≡CH, -(CH2)6C≡CH, or cyclopropyl. 5 is -CH, -CHCH, -CH(CH), -C(H)=CH, -CHC(H)=CH, or -C≡CH. In some embodiments, R 5 is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R 5 is -C(H)=CH, -CHC(H)=CH, or -C≡CH. In some embodiments, R 5 is -CH3. In some embodiments, R 5 is -CH2CH3. In some embodiments, R 3 is —CH(CH). In some embodiments, R 5 is —C(H)═CH. In some embodiments, R 5 is —CHC(H)═CH. In some embodiments, R 5 is -C≡CH. In some embodiments, R 5 is —(CH)CH. In some embodiments, R 5 is —(CH)C(H)═CH. In some embodiments, R 5 is —(CH)C(H)═CH. In some embodiments, R 5 is —(CH)C≡CH. In some embodiments, R 5 is —(CH)C≡CH. In some embodiments, R 5is cyclopropyl.

[0137] In certain embodiments, R 5 independently for each occurrence, C 1-20 In certain embodiments, R 5 independently for each occurrence, C 1-8 In certain embodiments, R 5 independently for each occurrence, C 10-20 In certain embodiments, R 5 independently for each occurrence, C 1-20 In certain embodiments, R 5 independently for each occurrence, C 1-8 In certain embodiments, R 5 independently for each occurrence, C 10-20 represents haloalkyl.

[0138] In certain embodiments, R 5 is C 1-20 In certain embodiments, R 5 is C 1-8 In certain embodiments, R 5 is C 10-20 In certain embodiments, R 5 is C 1-20 In certain embodiments, R 5 is C 1-8 In certain embodiments, R 5 is C 10-20 It is haloalkyl.

[0139] In some embodiments, R 5 is independently for each occurrence -C(H)(R 6 )-N(R 7 )2. In some embodiments, R 5 is -C(H)(R 6 )-N(R 7 )2. In some embodiments, R 5independently for each occurrence, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] is.

[0140] In some embodiments, R 5 independently for each occurrence, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] is.

[0141] In some embodiments, R 5 is calculated independently for each occurrence, R 10 In some embodiments, R 5 is R 10 In some embodiments, R is phenyl substituted with m occurrences of 5 is phenyl.

[0142] In some embodiments, R 5 represents, independently for each occurrence, -CH-phenyl, wherein the phenyl is selected from R 10 In some embodiments, R 5 represents -CH2-phenyl, and the phenyl is R 10 In some embodiments, R 5 is -CH2-phenyl.

[0143] In some embodiments, R 5 is hydrogen.

[0144] As generally defined above, R 6 is C 1-6 alkyl or hydrogen, 1-6 The alkyl is optionally substituted with phenyl. In certain embodiments, R 6 is methyl, isopropyl, benzyl, or hydrogen. 6is C optionally substituted with phenyl 1-6 In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 is C 1-4 In certain embodiments, R 6 is C 2-6 In certain embodiments, R 6 is a phenyl-substituted C 1-6 In certain embodiments, R 6 is hydrogen.

[0145] As generally defined above, R 7 independently for each occurrence: hydrogen, C 1-6 It represents alkyl, -C(O)CH3, -C(O)OC(CH3)3, -C(O)O(CH2)phenyl, or -C(O)O(CH2)-fluorenyl.

[0146] In certain embodiments, R 7 One occurrence of is hydrogen or C 1-6 alkyl, and R 7 The other occurrence of is hydrogen, C 1-6 alkyl, —C(O)CH, —C(O)OC(CH), —C(O)O(CH)phenyl, or —C(O)O(CH)fluorenyl. 7 One occurrence of is hydrogen or C 1-6 alkyl, and R 7 The other occurrence of is —C(O)CH3, —C(O)OC(CH3)3, —C(O)O(CH2)phenyl, or —C(O)O(CH2)fluorenyl.

[0147] In certain embodiments, R 7 One occurrence of is hydrogen and the other occurrence of R 7 The other occurrence of is hydrogen, C 1-6alkyl, —C(O)CH, —C(O)OC(CH), —C(O)O(CH)phenyl, or —C(O)O(CH)-fluorenyl. 7 One occurrence of is hydrogen and the other occurrence of R 7 The other occurrence of is —C(O)CH3, —C(O)OC(CH3)3, —C(O)O(CH2)phenyl, or —C(O)O(CH2)fluorenyl.

[0148] In certain embodiments, R 7 is, independently for each occurrence, hydrogen or C 1-6 In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 independently for each occurrence, C 1-6 Represents alkyl.

[0149] As generally defined above, R 8 is hydrogen, halo, -CH, or -CF. In certain embodiments, R 8 is hydrogen or halo. In certain embodiments, R 8 is hydrogen or fluoro. In certain embodiments, R 8 is halo or -CF. In certain embodiments, R 8 is fluoro or -CF. In certain embodiments, R 8 is —CH or —CF. In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 is halo. In certain embodiments, R 8 is fluoro. In certain embodiments, R 8 is -CH3. In certain embodiments, R 8 is -CF3.

[0150] As generally defined above, R 9 is halo, -CH, or -CF. In certain embodiments, R 9is halo or -CF. In certain embodiments, R 9 is fluoro or -CF. In certain embodiments, R 9 is —CH or —CF. In certain embodiments, R 9 is halo. In certain embodiments, R 9 is fluoro. In certain embodiments, R 9 is —CH3. In certain embodiments, R 9 is -CF3.

[0151] As generally defined above, R 10 independently for each occurrence, C 1-6 Alkyl, C 1-6 Alkoxyl, C 1-6 In certain embodiments, R 10 represents independently for each occurrence -CH3, -OCH3, -CF3, or halo.

[0152] In certain embodiments, R 10 independently for each occurrence, C 1-6 In certain embodiments, R 10 is —CH3. In certain embodiments, R 10 independently for each occurrence, C 1-6 In certain embodiments, R 10 is —OCH. In certain embodiments, R 10 independently for each occurrence, C 1-6 In certain embodiments, R 10 is —CF. In certain embodiments, R 10 represents, independently for each occurrence, a halo.

[0153] As generally defined above, B 1 teeth, [ka] In some embodiments, B1 teeth, [ka] In some embodiments, B 1 teeth, [ka] is.

[0154] As generally defined above, m is 0, 1, or 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 0 or 1. In certain embodiments, m is 1 or 2.

[0155] The above description describes multiple embodiments for compounds of Formula II. This patent application specifically contemplates all combinations of embodiments.

[0156] Another aspect of the present disclosure is a compound represented by formula II-A: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 4 is -C(O)R 5 and R 3 is halomethyl, R 5 independently for each occurrence, C 1-20 aliphatic, C 1-20 Haloaliphatic, -C(H)(R 6 )-N(R 7 )2, phenyl, or -CH2-phenyl, each phenyl being R 10 is replaced by m occurrences of R 6 is C 1-6 alkyl or hydrogen, 1-6 alkyl is optionally substituted with phenyl; R 7 independently for each occurrence: hydrogen, C 1-6 alkyl, -C(O)CH3, -C(O)OC(CH3)3, -C(O)O(CH2)phenyl, or -C(O)O(CH2)fluorenyl; R 8 is halo, or -CF3, R 10 independently for each occurrence, C 1-6 Alkyl, C 1-6 Alkoxyl, C 1-6 represents haloalkyl or halo, m is 0, 1, or 2.

[0157] As generally described above, R 1 and R 4 is -C(O)R 5 In certain embodiments, R 1 and R 4 is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0158] As generally described above, R 3 is halomethyl. In certain embodiments, R 3 is —CH2Cl or —CH2F. In certain embodiments, R 3 is —CH2Cl. In certain embodiments, R 3 is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0159] As generally described above, R 5 independently for each occurrence, C 1-20 aliphatic, C 1-20 Haloaliphatic, -C(H)(R 6A )-N(R 7A )2, phenyl, -CH2-phenyl, or hydrogen, each phenyl being R 10A In certain embodiments, R 5 independently for each occurrence, C 1-20 aliphatic, C1-20 Haloaliphatic, -C(H)(R 6A )-N(R 7A )2, phenyl, or -CH2-phenyl, each phenyl being R 10A In certain embodiments, R 5 independently for each occurrence, C 1-20 In certain embodiments, R 5 independently for each occurrence, C 1-20 In certain embodiments, R 5 is independently for each occurrence -C(H)(R 6A )-N(R 7A )2. In certain embodiments, R 5 independently for each occurrence, represents phenyl, and each phenyl is selected from R 10A In certain embodiments, R 5 represents, independently for each occurrence, -CH-phenyl, and each phenyl is selected from R 10A In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is C 1-20 In certain embodiments, R 5 is C 1-20 In certain embodiments, R 5 is -C(H)(R 6A )-N(R 7A )2. In certain embodiments, R 5 is phenyl, and each phenyl is R 10A In certain embodiments, R 5 is -CH-phenyl, and each phenyl is R 10A In certain embodiments, R 5 is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0160] As generally described above, R 6 is C 1-6alkyl or hydrogen, 1-6 The alkyl is optionally substituted with phenyl. In certain embodiments, R 6 is C 1-6 alkyl, and the C 1-6 The alkyl is optionally substituted with phenyl. In certain embodiments, R 6 is hydrogen. In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0161] As generally described above, R 7 independently for each occurrence: hydrogen, C 1-6 alkyl, —C(O)CH, —C(O)OC(CH), —C(O)O(CH)phenyl, or —C(O)O(CH)fluorenyl. 7 independently for each occurrence, C 1-6 In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is C 1-6 In certain embodiments, R 7 is —C(O)CH. In certain embodiments, R 7 is —C(O)O(CH)phenyl. In certain embodiments, R 7 is —C(O)O(CH)fluorenyl. In certain embodiments, R 7 independently for each occurrence, C 1-6 alkyl, —C(O)CH, —C(O)OC(CH), —C(O)O(CH)phenyl, or —C(O)O(CH)fluorenyl. 7 is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0162] As generally described above, R 8is halo or -CF. In certain embodiments, R 8 is halo. In certain embodiments, R 8 is fluoro. In certain embodiments, R 8 is —CF. In certain embodiments, R 8 is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0163] As generally described above, R 10 independently for each occurrence, C 1-6 Alkyl, C 1-6 Alkoxyl, C 1-6 In certain embodiments, R 10 independently for each occurrence, C 1-6 In certain embodiments, R 10 independently for each occurrence, C 1-6 In certain embodiments, R 10 independently for each occurrence, C 1-6 In certain embodiments, R 10 independently for each occurrence represents halo. In certain embodiments, R 10 is C 1-6 Alkyl, C 1-6 Alkoxyl, C 1-6 haloalkyl, or halo. In certain embodiments, R 10 is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0164] As generally defined above, m is 0, 1, or 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 1 or 2. In certain embodiments, m is 0 or 2. In certain embodiments, m is 0 or 2. In certain embodiments, m is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0165] Another aspect of the present disclosure is a compound represented by formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is —CH2Cl, —CH2F, —CH2Br, —CH2I, —CF3, —CH2CH3, —C(H)═CH2, —C(H)═C═CH2, or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium; R 2 is fluoro or -OH, R 3 is halo, -CH3, or -CF3, B 1 teeth, [ka] is.

[0166] The definitions of the variables in Formula III above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0167] In certain embodiments, the compound is a compound of formula III.

[0168] As generally defined above, R 1 is —CH2Cl, —CH2F, —CH2Br, —CH2I, —CF3, —CH2CH3, —C(H)═CH2, —C(H)═C═CH2, or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium. 1is —CH2Cl, —CH2F, —CH2Br, —CH2I, —CH2CH3, —C(H)═CH2, —C(H)═C═CH2, or cyclopropyl, each of which has one or more hydrogens replaced with deuterium.

[0169] In some embodiments, R 1 is —CH2Cl, —CH2F, —CH2Br, —CH2I, —CF3, —CH2CH3, —C(H)═CH2, —C(H)═C═CH2, or cyclopropyl. 1 is —CH2Cl, —CH2F, —CH2Br, —CH2I, or —CF3. In some embodiments, R 1 is -CH2CH3, -C(H)=CH2, -C(H)=C=CH2, or cyclopropyl.

[0170] In some embodiments, R 1 is —CHF, —CHBr, —CHI, or —CF. In some embodiments, R 1 is —CH2Cl, —CH2Br, —CH2I, or —CF3. In some embodiments, R 1 is —CH2Cl, —CH2F, —CH2I, or —CF3. In some embodiments, R 1 is —CH2Cl, —CH2F, —CH2Br, or —CF3. In some embodiments, R 1 is —CH2Cl, —CH2F, —CH2Br, or —CH2I.

[0171] In some embodiments, R 1 is —CHBr, —CHI, or —CF. In some embodiments, R 1 is —CH2Cl, —CH2I, or —CF3. In some embodiments, R 1 is —CH2Cl, —CH2F, or —CF3. In some embodiments, R 1 is —CH2Cl, —CH2F, or —CH2Br. In some embodiments, R 1is —CHF, —CHI, or —CF. In some embodiments, R 1 is —CHF, —CHBr, or —CF. In some embodiments, R 1 is —CHF, —CHBr, or —CHI. In some embodiments, R 1 is —CH2Cl, —CH2Br, or —CF3. In some embodiments, R 1 is —CH2Cl, —CH2Br, or —CH2I. In some embodiments, R 1 is —CH2Cl, —CH2F, or —CH2I.

[0172] In some embodiments, R 1 is -CH2I or -CF3. In some embodiments, R 1 is —CH2Cl or —CH2F. In some embodiments, R 1 is —CH2Cl or —CF3. In some embodiments, R 1 is -CHF or -CHI. In some embodiments, R 1 is —CH2Cl or —CH2Br. In some embodiments, R 1 is —CHBr or —CHI. In some embodiments, R 1 is —CHBr or —CF. In some embodiments, R 1 is —CH2Cl or —CH2I. In some embodiments, R 1 is —CHF or —CF. In some embodiments, R 1 is -CH2F or -CH2Br.

[0173] In some embodiments, R 1 is —CH2Cl. In some embodiments, R 1 is -CHF. In some embodiments, R 1 is —CHBr. In some embodiments, R 1 is -CH2I. In some embodiments, R 1is -CF3.

[0174] In some embodiments, R 1 is —CH2Cl, —CH2F, —CH2Br, —CH2I, or —CF3, each of which optionally has one or more hydrogens replaced with deuterium. In some embodiments, R 1 is —CH2Cl, —CH2F, —CH2Br, or —CH2I, each of which has one or more hydrogens replaced with deuterium. In some embodiments, R 1 is -CD2Cl, -CD2F, -CD2Br, or -CD2I. In some embodiments, R 1 is -CD2Cl or -CD2F. In some embodiments, R 1 is -CD2Cl. In some embodiments, R 1 In some embodiments, R 1 is -CDBr. In some embodiments, R 1 is -CD2I.

[0175] In some embodiments, R 1 is —CH2CH3, —C(H)═CH2, or —C(H)═C═CH2. In some embodiments, R 1 is —CH2CH3 or cyclopropyl. In some embodiments, R 1 is —C(H)═CH, —C(H)═C═CH, or cyclopropyl. In some embodiments, R 1 is —C(H)═CH or —C(H)═C═CH. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is —C(H)═CH. In some embodiments, R 1 is -C(H)=C=CH2. In some embodiments, R 1 is cyclopropyl.

[0176] In some embodiments, R 1is —CH2CH3, —C(H)═CH2, —C(H)═C═CH2, or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium. In some embodiments, R 1 is —CH2CH3, —C(H)═CH2, —C(H)═C═CH2, or cyclopropyl, each of which has one or more hydrogens replaced with deuterium. 1 is —CH2CH3 with one or more hydrogens replaced with deuterium. In some embodiments, R 1 is —C(H)═CH with one or more hydrogens replaced with deuterium. In some embodiments, R 1 is —C(H)═C═CH with one or more hydrogens replaced with deuterium. In some embodiments, R 1 is a cyclopropyl having one or more hydrogens replaced with deuterium.

[0177] As generally defined above, R 2 is fluoro or —OH. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is -OH.

[0178] As generally defined above, R 3 is halo, -CH, or -CF. In some embodiments, R 3 is fluoro, chloro, -CH, or -CF. In some embodiments, R 3 is fluoro, -CH3, or -CF3.

[0179] In some embodiments, R 3 is —CH or —CF. In some embodiments, R 3 is halo or -CF. In some embodiments, R 3 is halo or -CH3.

[0180] In some embodiments, R3 is halo. In some embodiments, R 3 is fluoro or chloro. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is chloro. In some embodiments, R 3 is bromo. In some embodiments, R 3 is iodine.

[0181] In some embodiments, R 3 is -CH3. In some embodiments, R 3 is -CF3.

[0182] As generally defined above, B 1 teeth, [ka] In some embodiments, B 1 teeth, [ka] In some embodiments, B 1 teeth, [ka] is.

[0183] The above description describes multiple embodiments for compounds of formula III. This patent application specifically contemplates all combinations of embodiments.

[0184] The present invention provides a compound represented by formula III-A: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1is —CH2Cl, —CH2Br, or —CH2F, each of which optionally has one or more hydrogens replaced with deuterium; R 3 is halo, or -CF3.

[0185] In certain embodiments, the compound is of formula III-A.

[0186] As generally described above, R 1 is —CH2Cl, —CH2Br, or —CH2F, each of which optionally has one or more hydrogens replaced with deuterium. In certain embodiments, R 1 is —CH2Cl. In certain embodiments, R 1 is —CHBr. In certain embodiments, R 1 is —CHF. In certain embodiments, R 1 is —CH2Cl or —CH2F. In certain embodiments, R 1 is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0187] As generally described above, R 3 is halo or -CF. In certain embodiments, R 3 is halo. In certain embodiments, R 3 is —CF. In certain embodiments, R 3 is Cl, Br, or F. In certain embodiments, R 3 is F. In certain embodiments, R 3 is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0188] The present invention provides a compound represented by formula III-B: [ka] or a pharmaceutically acceptable salt thereof, wherein: R1 is -N3, R 3 is halo, or -CF3.

[0189] In certain embodiments, the compound is of formula III-B.

[0190] As generally described above, R 1 is -N3. In certain embodiments, R 1 is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0191] As generally described above, R 3 is halo or -CF. In certain embodiments, R 3 is halo. In certain embodiments, R 3 is —CF. In certain embodiments, R 3 is Cl, Br, or F. In certain embodiments, R 3 is F. In certain embodiments, R 3 is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0192] Another aspect of the present disclosure is a compound represented by formula IV: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is —CH2Cl, —CH2F, —CH2Br, —CH2I, —CF3, —CH2CH3, —C(H)═CH2, —C(H)═C═CH2, or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium; R 2 is hydrogen, halo, or -CF3, B 1 teeth, [ka] is.

[0193] The definitions of the variables in Formula IV above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0194] In certain embodiments, the compound is of formula IV.

[0195] As generally defined above, R 1 is —CH2Cl, —CH2F, —CH2Br, —CH2I, —CF3, —CH2CH3, —C(H)═CH2, —C(H)═C═CH2, or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium. 1 is —CH2Cl, —CH2F, —CH2Br, —CH2I, —CH2CH3, —C(H)═CH2, —C(H)═C═CH2, or cyclopropyl, each of which has one or more hydrogens replaced with deuterium.

[0196] In some embodiments, R 1 is —CH2Cl, —CH2F, —CH2Br, —CH2I, —CF3, —CH2CH3, —C(H)═CH2, —C(H)═C═CH2, or cyclopropyl. 1 is —CH2Cl, —CH2F, —CH2Br, —CH2I, or —CF3. In some embodiments, R 1 is -CH2CH3, -C(H)=CH2, -C(H)=C=CH2, or cyclopropyl.

[0197] In some embodiments, R 1 is —CHF, —CHBr, —CHI, or —CF. In some embodiments, R 1is —CH2Cl, —CH2Br, —CH2I, or —CF3. In some embodiments, R 1 is —CH2Cl, —CH2F, —CH2I, or —CF3. In some embodiments, R 1 is —CH2Cl, —CH2F, —CH2Br, or —CF3. In some embodiments, R 1 is —CH2Cl, —CH2F, —CH2Br, or —CH2I.

[0198] In some embodiments, R 1 is —CHBr, —CHI, or —CF. In some embodiments, R 1 is —CH2Cl, —CH2I, or —CF3. In some embodiments, R 1 is —CH2Cl, —CH2F, or —CF3. In some embodiments, R 1 is —CH2Cl, —CH2F, or —CH2Br. In some embodiments, R 1 is —CHF, —CHI, or —CF. In some embodiments, R 1 is —CHF, —CHBr, or —CF. In some embodiments, R 1 is —CHF, —CHBr, or —CHI. In some embodiments, R 1 is —CH2Cl, —CH2Br, or —CF3. In some embodiments, R 1 is —CH2Cl, —CH2Br, or —CH2I. In some embodiments, R 1 is —CH2Cl, —CH2F, or —CH2I.

[0199] In some embodiments, R 1 is -CH2I or -CF3. In some embodiments, R 1 is —CH2Cl or —CH2F. In some embodiments, R 1 is —CH2Cl or —CF3. In some embodiments, R 1is -CHF or -CHI. In some embodiments, R 1 is —CH2Cl or —CH2Br. In some embodiments, R 1 is —CHBr or —CHI. In some embodiments, R 1 is —CHBr or —CF. In some embodiments, R 1 is —CH2Cl or —CH2I. In some embodiments, R 1 is —CHF or —CF. In some embodiments, R 1 is -CH2F or -CH2Br.

[0200] In some embodiments, R 1 is —CH2Cl. In some embodiments, R 1 is -CHF. In some embodiments, R 1 is —CHBr. In some embodiments, R 1 is -CH2I. In some embodiments, R 1 is -CF3.

[0201] In some embodiments, R 1 is —CH2Cl, —CH2F, —CH2Br, —CH2I, or —CF3, each of which optionally has one or more hydrogens replaced with deuterium. In some embodiments, R 1 is —CH2Cl, —CH2F, —CH2Br, or —CH2I, each of which has one or more hydrogens replaced with deuterium. In some embodiments, R 1 is -CD2Cl, -CD2F, -CD2Br, or -CD2I. In some embodiments, R 1 is -CD2Cl or -CD2F. In some embodiments, R 1 is -CD2Cl. In some embodiments, R 1 In some embodiments, R 1 is -CDBr. In some embodiments, R 1is -CD2I.

[0202] In some embodiments, R 1 is —CH2CH3, —C(H)═CH2, or —C(H)═C═CH2. In some embodiments, R 1 is —CH2CH3 or cyclopropyl. In some embodiments, R 1 is —C(H)═CH, —C(H)═C═CH, or cyclopropyl. In some embodiments, R 1 is —C(H)═CH or —C(H)═C═CH. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is —C(H)═CH. In some embodiments, R 1 is -C(H)=C=CH2. In some embodiments, R 1 is cyclopropyl.

[0203] In some embodiments, R 1 is —CH2CH3, —C(H)═CH2, —C(H)═C═CH2, or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium. In some embodiments, R 1 is —CH2CH3, —C(H)═CH2, —C(H)═C═CH2, or cyclopropyl, each of which has one or more hydrogens replaced with deuterium. 1 is —CH2CH3 with one or more hydrogens replaced with deuterium. In some embodiments, R 1 is —C(H)═CH with one or more hydrogens replaced with deuterium. In some embodiments, R 1 is —C(H)═C═CH with one or more hydrogens replaced with deuterium. In some embodiments, R 1 is a cyclopropyl having one or more hydrogens replaced with deuterium.

[0204] As generally defined above, R2 is hydrogen, halo, or —CF. In some embodiments, R 2 is hydrogen or —CF. In some embodiments, R 2 is halo or -CF. In some embodiments, R 2 is halo or hydrogen. In some embodiments, R 2 is fluoro or -CF. In some embodiments, R 2 is fluoro or hydrogen.

[0205] In some embodiments, R 2 is halo. In some embodiments, R 2 is fluoro or chloro. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is chloro. In some embodiments, R 2 is bromo. In some embodiments, R 2 is iodine.

[0206] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is -CF3.

[0207] As generally defined above, B 1 teeth, [ka] In some embodiments, B 1 teeth, [ka] In some embodiments, B 1 teeth, [ka] is.

[0208] The above description describes multiple embodiments for compounds of formula IV. This patent application specifically contemplates all combinations of embodiments.

[0209] Another aspect of the present disclosure is a compound represented by formula IV-A: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is (i) —CH2Cl, —CH2F, or —CH2Br, each of which optionally has one or more hydrogens replaced with deuterium, or (ii) —N3; R 2 is hydrogen or halo.

[0210] In certain embodiments, the compound is of formula IV-A.

[0211] As generally described above, R 1 is (i) —CH2Cl, —CH2F, or —CH2Br, each of which optionally has one or more hydrogens replaced with deuterium, or (ii) —N3. In certain embodiments, R 1 is —CH2Cl, —CH2F, or —CH2Br, each of which optionally has one or more hydrogens replaced with deuterium. 1 is -N3. In certain embodiments, R 1 is —CH2Cl, —CH2F, or —CH2Br. In certain embodiments, R 1 is —CH2Cl. In certain embodiments, R 1 is —CHF. In certain embodiments, R 1 is —CHBr. In certain embodiments, R 1 is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0212] As generally described above, R 2 is hydrogen or halo. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is halo. In certain embodiments, R 2 is Cl, Br, or F. In certain embodiments, R 2 is F. In certain embodiments, R 2 is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0213] Another aspect of the present disclosure is a compound represented by formula IV-B: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is —CH2Cl, —CH2F, or —CH2Br, each of which optionally has one or more hydrogens replaced with deuterium; R 2 is F.

[0214] In certain embodiments, the compound is of formula IV-B.

[0215] As generally described above, R 1 is —CH2Cl, —CH2F, or —CH2Br, each of which optionally has one or more hydrogens replaced with deuterium. 1 is —CH2Cl. In certain embodiments, R 1 is —CHF. In certain embodiments, R 1 is —CHBr. In certain embodiments, R 1 is selected from those depicted in Tables 1, 1-A, 1-B, 1-C, and 1-D.

[0216] Another aspect of the present disclosure is a compound represented by formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein: B 1 teeth, [ka] and R 1 -H, -C(O)R 8 or -P(O)(OH)-OP(O)(OH)-OP(O)(OH)2; R 2 is —H, C1-C6 aliphatic, C1-C3 haloaliphatic, C1-C3 hydroxyalkyl, —CH2NH2, —CH2SH, —CH2S—(C1-C3 aliphatic), cyclopropyl, —CN, —C(O)NH2, —N3, —O—(C1-C3 aliphatic), —O—(C1-C3 haloaliphatic), —S—(C1-C3 aliphatic), —F, or —Cl, wherein each of the C1-C6 aliphatic, the C1-C3 haloaliphatic, and the cyclopropyl optionally has one or more hydrogens replaced with deuterium; R 3 is -H or -OH, R 4 is -OH, -Cl, -OCH3, -F, -N3, or -OC(O)R 8 and R 5 is -H or -F, R 6 is -H, -F, -Cl, C1-C6 aliphatic, C1-C4 haloaliphatic, -O-(C1-C4 aliphatic), cyclopropyl, or -OH; R 7 is hydrogen, halo, -CH3, or -CF3, R 8 independently for each occurrence, C 1-20 aliphatic, C 1-20 Haloaliphatic, -C(H)(R 9 )-N(R 10 )2, phenyl, -CH2-phenyl, or hydrogen, each phenyl being R 11 is replaced by m occurrences of R9 is C 1-6 alkyl or hydrogen, 1-6 alkyl is optionally substituted with phenyl; R 10 independently for each occurrence: hydrogen, C 1-6 alkyl, -C(O)CH3, -C(O)OC(CH3)3, -C(O)O(CH2)phenyl, or -C(O)O(CH2)fluorenyl; R 11 independently for each occurrence, C 1-6 Alkyl, C 1-6 Alkoxyl, C 1-6 represents haloalkyl or halo, m is 0, 1, or 2.

[0217] The definition of the variables in Formula V above encompasses multiple chemical groups. The present application contemplates embodiments, for example, where i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0218] In certain embodiments, the compound is of formula V:

[0219] As generally defined above, R 1 -H, -C(O)R 8 or -P(O)(OH)-OP(O)(OH)-OP(O)(OH). In certain embodiments, R 1 is -H or -C(O)R 8 In certain embodiments, R 1 is —H or —C(O)C(H)(CH). In certain embodiments, R 1 is -H or -P(O)(OH)-OP(O)(OH)-OP(O)(OH). In certain embodiments, R 1 is -C(O)R 8or -P(O)(OH)-OP(O)(OH)-OP(O)(OH). In certain embodiments, R 1 is —H. In certain embodiments, R 1 is -C(O)R 8 In certain embodiments, R 1 is -P(O)(OH)-OP(O)(OH)-OP(O)(OH)2.

[0220] As generally defined above, R 2 is —H, C1-C6 aliphatic, C1-C3 haloaliphatic, C1-C3 hydroxyalkyl, —CH2NH2, —CH2SH, —CH2S—(C1-C3 aliphatic), cyclopropyl, —CN, —C(O)NH2, —N3, —O—(C1-C3 aliphatic), —O—(C1-C3 haloaliphatic), —S—(C1-C3 aliphatic), —F, or —Cl, wherein each of the C1-C6 aliphatic, the C1-C3 haloaliphatic, and the cyclopropyl optionally has one or more hydrogens replaced with deuterium.

[0221] In some embodiments, R 2 is —H, C1-C6 aliphatic, C1-C3 haloaliphatic, C1-C3 hydroxyalkyl, —CH2NH2, —CH2SH, —CH2S—(C1-C3 aliphatic), cyclopropyl, —CN, —C(O)NH2, —N3, —O—(C1-C3 aliphatic), —O—(C1-C3 haloaliphatic), —S—(C1-C3 aliphatic), —F, or —Cl.

[0222] In certain embodiments, R 2 is C1-C6 aliphatic, C1-C3 haloaliphatic, C1-C3 hydroxyalkyl, —CH2NH2, —CH2SH, —CH2S—(C1-C3 aliphatic), cyclopropyl, —CN, —C(O)NH2, —N3, —O—(C1-C3 aliphatic), —O—(C1-C3 haloaliphatic), —S—(C1-C3 aliphatic), —F, or —Cl.

[0223] In certain embodiments, R 2is —H, C1-C6 aliphatic, C1-C3 haloaliphatic, or cyclopropyl. 2 is C1-C6 aliphatic, C1-C3 haloaliphatic, or cyclopropyl. 2 is C1-C6 aliphatic or cyclopropyl. In certain embodiments, R 2 is C1-C6 aliphatic or C1-C3 haloaliphatic.

[0224] In certain embodiments, R 2 is C1-C6 aliphatic, C1-C3 haloaliphatic, or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium. 2 is a C1-C6 aliphatic or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium. In certain embodiments, R 2 is a C1-C6 aliphatic or a C1-C3 haloaliphatic, each of which optionally has one or more hydrogens replaced with deuterium.

[0225] In certain embodiments, R 2 is C1-C6 aliphatic, C1-C3 haloaliphatic, or cyclopropyl, each of which has one or more hydrogens replaced with deuterium. 2 is a C1-C6 aliphatic or cyclopropyl, each of which has one or more hydrogens replaced with deuterium. 2 is a C1-C6 aliphatic or a C1-C3 haloaliphatic, each of which has one or more hydrogens replaced with deuterium.

[0226] In certain embodiments, R 2is C1-C3 hydroxyalkyl, —CH2NH2, —CH2SH, —CH2S—(C1-C3 aliphatic), —CN, —C(O)NH2, —N3, —O—(C1-C3 aliphatic), —O—(C1-C3 haloaliphatic), —S—(C1-C3 aliphatic), —F, or —Cl. 2 is C1-C3 hydroxyalkyl, -CH2NH2, or -CH2SH. In certain embodiments, R 2 is —CHS—(C-C aliphatic), —O—(C-C aliphatic), —O—(C-C haloaliphatic), or —S—(C-C aliphatic). In certain embodiments, R 2 is —CN, —C(O)NH, or —N. In certain embodiments, R 2 is -F or -Cl.

[0227] In certain embodiments, R 2 is C1-C3 hydroxyalkyl, -O-(C1-C3 aliphatic), or -O-(C1-C3 haloaliphatic). 2 is —CH 2 NH 2 , —CN, —C(O)NH 2 , or —N 3 . In certain embodiments, R 2 is -CH2SH, -CH2S-(C1-C3 aliphatic), or -S-(C1-C3 aliphatic).

[0228] In certain embodiments, R 2 is —H. In certain embodiments, R 2 is optionally C with one or more hydrogens replaced with deuterium 1- In certain embodiments, R 2 is a C1-C6 aliphatic having one or more hydrogens replaced with deuterium. 2 is C1-C6 aliphatic. In certain embodiments, R 2 is optionally a C1-C3 haloaliphatic having one or more hydrogens replaced with deuterium. In certain embodiments, R 2is a C1-C3 haloaliphatic having one or more hydrogens replaced with deuterium. In certain embodiments, R 2 is C1-C3 haloaliphatic. In certain embodiments, R 2 is C1-C3 hydroxyalkyl. In certain embodiments, R 2 is —CH 2 NH 2 . In certain embodiments, R 2 is -CHSH. In certain embodiments, R 2 is —CHS—(C-C aliphatic). In certain embodiments, R 2 is cyclopropyl, optionally with one or more hydrogens replaced with deuterium. In certain embodiments, R 2 is cyclopropyl having one or more hydrogens replaced with deuterium. In certain embodiments, R 2 is cyclopropyl. In certain embodiments, R 2 is -CN. In certain embodiments, R 2 is —C(O)NH. In certain embodiments, R 2 is -N3. In certain embodiments, R 2 is —O—(C1-C3 aliphatic). In certain embodiments, R 2 is —O—(C1-C3 haloaliphatic). In certain embodiments, R 2 is -S-(C1-C3 aliphatic). In certain embodiments, R 2 is -F. In certain embodiments, R 2 is -Cl.

[0229] In certain embodiments, R 2 is —CH, —CF, —N, —OCH, —CHCl, —CHF, —CHF, —CHCl, —CHClF, —CHCH, —CH═CH, cyclopropyl, or —C≡CH. In certain embodiments, R 2 is -N, -CH, -CHCl, -CHF, -CH=CH, or -C≡CH. In certain embodiments, R 2is —CH2Cl, —CH2F, or —C≡CH. In certain embodiments, R 2 is —CH2Cl or —C≡CH. In certain embodiments, R 2 is —CH2Cl or —CH2F.

[0230] In certain embodiments, R 2 is -CH, -CHCH, -CH=CH, cyclopropyl, or -C≡CH. In certain embodiments, R 2 is -CHCH, -CH=CH, cyclopropyl, or -C≡CH. In certain embodiments, R 2 is —CHCH, —CH═CH, or cyclopropyl. In certain embodiments, R 2 is —CH2CH3, —C(H)═CH2, —C(H)═C═CH2, or cyclopropyl. In some embodiments, R 2 is —CH2CH3, —C(H)═CH2, or —C(H)═C═CH2. In some embodiments, R 2 is —CH2CH3 or cyclopropyl. In some embodiments, R 2 is —C(H)═CH, —C(H)═C═CH, or cyclopropyl. In some embodiments, R 2 is -C(H)=CH2 or -C(H)=C=CH2.

[0231] In certain embodiments, R 2 is —CF, —CHCl, —CHF, —CHF, —CHCl, or —CHClF. In certain embodiments, R 2 is —CF, —CHCl, —CHF, or —CHF. In certain embodiments, R 2 is —CF, —CHF, or —CHF. In certain embodiments, R 2 is -N3 or -OCH3.

[0232] In certain embodiments, R 2is —CH3. In certain embodiments, R 2 is —CF. In certain embodiments, R 2 is -N3. In certain embodiments, R 2 is —OCH. In certain embodiments, R 2 is —CH2Cl. In certain embodiments, R 2 is —CHF. In certain embodiments, R 2 is -CHF. In certain embodiments, R 2 is —CHCl. ​​In certain embodiments, R 2 is —CHClF. In certain embodiments, R 2 is -CH2CH3. In certain embodiments, R 2 is -CH=CH2. In some embodiments, R 2 is -C(H)=C=CH2. In certain embodiments, R 2 is cyclopropyl. In certain embodiments, R 2 is -C≡CH.

[0233] In some embodiments, R 2 is —CH2Cl, —CH2F, —CH2Br, —CH2I, or —CF3, each of which optionally has one or more hydrogens replaced with deuterium. In some embodiments, R 2 is —CH2Cl, —CH2F, —CH2Br, or —CH2I, each of which has one or more hydrogens replaced with deuterium. In some embodiments, R 2 is -CD2Cl, -CD2F, -CD2Br, or -CD2I. In some embodiments, R 2 is -CD2Cl or -CD2F. In some embodiments, R 2 is -CD2Cl. In some embodiments, R 2 In some embodiments, R 2 is -CDBr. In some embodiments, R 2 is -CD2I.

[0234] As generally defined above, R 3 is —H or —OH. In certain embodiments, R 3 is —H. In certain embodiments, R 3 is -OH.

[0235] As generally defined above, R 4 is -OH, -Cl, -OCH3, -F, -N3, or -OC(O)R 8 In certain embodiments, R 4 is -OH, -OCH3, or -OC(O)R 8 In certain embodiments, R 4 is —OH or —OCH. In certain embodiments, R 4 is -OH or -OC(O)R 8 In certain embodiments, R 4 is —OH or —C(O)C(H)(CH). In certain embodiments, R 4 is -OCH3 or -OC(O)R 8 is.

[0236] In certain embodiments, R 4 is —OH. In certain embodiments, R 4 is -Cl. In certain embodiments, R 4 is —OCH. In certain embodiments, R 4 is -F. In certain embodiments, R 4 is -N3. In certain embodiments, R 4 is -OC(O)R 8 In certain embodiments, R 4 is -C(O)C(H)(CH3)2.

[0237] As generally defined above, R 5 is -H or -F. In certain embodiments, R 5 is —H. In certain embodiments, R 5 is -F.

[0238] As generally defined above, R 6 is -H, -F, -Cl, C1-C6 aliphatic, C1-C4 haloaliphatic, -O-(C1-C4 aliphatic), cyclopropyl, or -OH.

[0239] In certain embodiments, R 6 is -F or -Cl. In certain embodiments, R 6 is C1-C6 aliphatic, C1-C4 haloaliphatic, or cyclopropyl. 6 is C1-C6 aliphatic or C1-C4 haloaliphatic. In certain embodiments, R 6 is C1-C6 aliphatic or cyclopropyl. In certain embodiments, R 6 is C-C haloaliphatic or cyclopropyl. In certain embodiments, R 6 is —O—(C1-C4 aliphatic) or —OH.

[0240] In certain embodiments, R 6 is —H, —F, —Cl, or —OH. In certain embodiments, R 6 is -H, -F, or -OH. In certain embodiments, R 6 is -H or -F. In certain embodiments, R 6 is —H or —OH. In certain embodiments, R 6 is -F or -OH.

[0241] In certain embodiments, R 6 is -H, -F, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -CH=CH2, -CH2F, or -CH2Cl.

[0242] In certain embodiments, R 6 is —H. In certain embodiments, R 6 is -F. In certain embodiments, R 6is -Cl. In certain embodiments, R 6 is C1-C6 aliphatic. In certain embodiments, R 6 is -CH3. In certain embodiments, R 6 is -CH2CH3. In certain embodiments, R 6 is -CH=CH2. In certain embodiments, R 6 is C1-C4 haloaliphatic. In certain embodiments, R 6 is —CHF. In certain embodiments, R 6 is —CH2Cl. In certain embodiments, R 6 is —O—(C1-C4 aliphatic). In certain embodiments, R 6 is —OCH. In certain embodiments, R 6 is —OCH2CH3. In certain embodiments, R 6 is cyclopropyl. In certain embodiments, R 6 is -OH.

[0243] As generally defined above, R 7 is hydrogen, halo, -CH, or -CF. In certain embodiments, R 7 is hydrogen or halo. In certain embodiments, R 7 is hydrogen or fluoro. In certain embodiments, R 7 is halo or -CF. In certain embodiments, R 7 is fluoro or -CF. In certain embodiments, R 7 is —CH or —CF. In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is halo. In certain embodiments, R 7 is fluoro. In certain embodiments, R 7 is -CH3. In certain embodiments, R 7 is -CF3.

[0244] As generally defined above, R 8 independently for each occurrence, C 1-20 aliphatic, C 1-20 Haloaliphatic, -C(H)(R 9 )-N(R 10 )2, phenyl, -CH2-phenyl, or hydrogen, each phenyl being R 11 is replaced by m occurrences of

[0245] In certain embodiments, R 8 independently for each occurrence, C 1-20 aliphatic, C 1-20 represents haloaliphatic, phenyl, or hydrogen, and the phenyl is R 11 In certain embodiments, R 8 independently for each occurrence, C 1-20 aliphatic, C 1-20 In certain embodiments, R 8 is independently for each occurrence -C(H)(R 9 )-N(R 10 )2, phenyl, or -CH2-phenyl, each phenyl being R 11 In certain embodiments, R 8 represents, independently for each occurrence, phenyl or -CH-phenyl, and each phenyl is selected from R 11 is replaced by m occurrences of

[0246] In certain embodiments, R 8 is C 1-20 aliphatic, C 1-20 represents haloaliphatic, phenyl, or hydrogen, and the phenyl is R 11 In certain embodiments, R 8 is C 1-20 aliphatic, C 1-20 haloaliphatic, or hydrogen. In certain embodiments, R 8 is -C(H)(R 9 )-N(R 10 )2, or R 11 is phenyl substituted with m occurrences of

[0247] In certain embodiments, R 8 independently for each occurrence, C 1-20 Aliphatic or C 1-20 In certain embodiments, R 8 independently for each occurrence, C 1-8 Aliphatic or C 1-8 In certain embodiments, R 8 independently for each occurrence, C 10-20 Aliphatic or C 10-20 In certain embodiments, R 8 independently for each occurrence, C 1-20 Alkyl or C 1-20 In certain embodiments, R 8 independently for each occurrence, C 1-8 Alkyl or C 1-8 In certain embodiments, R 8 independently for each occurrence, C 10-20 Alkyl or C 10-20 represents haloalkyl.

[0248] In certain embodiments, R 8 is C 1-20 Aliphatic or C 1-20 In certain embodiments, R 8 is C 1-8 Aliphatic or C 1-8 In certain embodiments, R 8 is C 10-20 Aliphatic or C 10-20 In certain embodiments, R 8 is C 1-20 Alkyl or C 1-20 In certain embodiments, R 8 is C 1-8 Alkyl or C 1-8 In certain embodiments, R 8 is C 10-20 Alkyl or C 10-20It is haloalkyl.

[0249] In certain embodiments, R 8 independently for each occurrence, C 1-20 In certain embodiments, R 8 independently for each occurrence, C 1-8 In certain embodiments, R 8 independently for each occurrence, C 10-20 In certain embodiments, R 8 independently for each occurrence, C 1-20 In certain embodiments, R 8 independently for each occurrence, C 1-8 In certain embodiments, R 8 independently for each occurrence, C 10-20 Represents alkyl.

[0250] In certain embodiments, R 8 is C 1-20 In certain embodiments, R 8 is C 1-8 In certain embodiments, R 8 is C 10-20 In certain embodiments, R 8 is C 1-20 In certain embodiments, R 8 is C 1-8 In certain embodiments, R 8 is C 10-20 It is alkyl.

[0251] In some embodiments, R 8is -CH3, -CH2CH3, -CH(CH3)2, -C(H)=CH2, -CH2C(H)=CH2, -C≡CH, -CH2CH3, -C(H)=CH2, -CH2C(H)=CH2, -C≡CH, -(CH2)3CH3, -(CH2)3C(H)=CH2, -(CH2)6C(H)=CH2, -(CH2)3C≡CH, -(CH2)6C≡CH, or cyclopropyl. 8 is -CH, -CHCH, -CH(CH), -C(H)=CH, -CHC(H)=CH, or -C≡CH. In some embodiments, R 8 is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R 8 is -C(H)=CH, -CHC(H)=CH, or -C≡CH. In some embodiments, R 8 is -CH3. In some embodiments, R 8 is -CH2CH3. In some embodiments, R 3 is —CH(CH). In some embodiments, R 8 is —C(H)═CH. In some embodiments, R 8 is —CHC(H)═CH. In some embodiments, R 8 is -C≡CH. In some embodiments, R 8 is —(CH)CH. In some embodiments, R 8 is —(CH)C(H)═CH. In some embodiments, R 8 is —(CH)C(H)═CH. In some embodiments, R 8 is —(CH)C≡CH. In some embodiments, R 8 is —(CH)C≡CH. In some embodiments, R 8 is cyclopropyl.

[0252] In certain embodiments, R 8 independently for each occurrence, C 1-20 In certain embodiments, R8 independently for each occurrence, C 1-8 In certain embodiments, R 8 independently for each occurrence, C 10-20 In certain embodiments, R 8 independently for each occurrence, C 1-20 In certain embodiments, R 8 independently for each occurrence, C 1-8 In certain embodiments, R 8 independently for each occurrence, C 10-20 represents haloalkyl.

[0253] In certain embodiments, R 8 is C 1-20 In certain embodiments, R 8 is C 1-8 In certain embodiments, R 8 is C 10-20 In certain embodiments, R 8 is C 1-20 In certain embodiments, R 8 is C 1-8 In certain embodiments, R 8 is C 10-20 It is haloalkyl.

[0254] In some embodiments, R 8 is independently for each occurrence -C(H)(R 9 )-N(R 10 )2. In some embodiments, R 8 is -C(H)(R 9 )-N(R 10 )2. In some embodiments, R 8 independently for each occurrence, [ka] In some embodiments, R 8 teeth, [ka] In some embodiments, R 8 teeth, [ka] In some embodiments, R 8 teeth, [ka] In some embodiments, R 8 teeth, [ka] In some embodiments, R 8 teeth, [ka] is.

[0255] In some embodiments, R 8 independently for each occurrence, [ka] In some embodiments, R 8 teeth, [ka] In some embodiments, R 8 teeth, [ka] In some embodiments, R 8 teeth, [ka] In some embodiments, R 8 teeth, [ka] In some embodiments, R 8 teeth, [ka] is.

[0256] In some embodiments, R 8 is calculated independently for each occurrence, R 11 In some embodiments, R 8 is R 11 In some embodiments, R is phenyl substituted with m occurrences of 8 is phenyl.

[0257] In some embodiments, R 8 represents, independently for each occurrence, -CH-phenyl, wherein the phenyl is selected from R 11 In some embodiments, R 8 represents -CH2-phenyl, and the phenyl is R 11 In some embodiments, R 8 is -CH2-phenyl.

[0258] In some embodiments, R 8 is hydrogen.

[0259] As generally defined above, R 9 is C 1-6 alkyl or hydrogen, and the C 1-6 The alkyl is optionally substituted with phenyl. In certain embodiments, R 9 is methyl, isopropyl, benzyl, or hydrogen. 9 is C optionally substituted with phenyl 1-6 In certain embodiments, R 9 is C 1-6 In certain embodiments, R 9 is C 1-4In certain embodiments, R 9 is C 2-6 In certain embodiments, R 9 is a phenyl-substituted C 1-6 In certain embodiments, R 9 is hydrogen.

[0260] As generally defined above, R 10 independently for each occurrence: hydrogen, C 1-6 It represents alkyl, -C(O)CH3, -C(O)OC(CH3)3, -C(O)O(CH2)phenyl, or -C(O)O(CH2)-fluorenyl.

[0261] In certain embodiments, R 10 One occurrence of is hydrogen or C 1-6 alkyl, and R 10 The other occurrence of is hydrogen, C 1-6 alkyl, —C(O)CH, —C(O)OC(CH), —C(O)O(CH)phenyl, or —C(O)O(CH)fluorenyl. 10 One occurrence of is hydrogen or C 1-6 alkyl, and R 10 The other occurrence of is —C(O)CH3, —C(O)OC(CH3)3, —C(O)O(CH2)phenyl, or —C(O)O(CH2)fluorenyl.

[0262] In certain embodiments, R 10 One occurrence of is hydrogen and the other occurrence of R 10 The other occurrence of is hydrogen, C 1-6 alkyl, —C(O)CH, —C(O)OC(CH), —C(O)O(CH)phenyl, or —C(O)O(CH)fluorenyl. 10 One occurrence of is hydrogen and the other occurrence of R 10 The other occurrence of is —C(O)CH3, —C(O)OC(CH3)3, —C(O)O(CH2)phenyl, or —C(O)O(CH2)-fluorenyl.

[0263] In certain embodiments, R 10 is, independently for each occurrence, hydrogen or C 1-6 In certain embodiments, R 10 is hydrogen. In certain embodiments, R 10 independently for each occurrence, C 1-6 Represents alkyl.

[0264] As generally defined above, R 11 independently for each occurrence, C 1-6 Alkyl, C 1-6 Alkoxyl, C 1-6 In certain embodiments, R 11 represents independently for each occurrence -CH3, -OCH3, -CF3, or halo.

[0265] In certain embodiments, R 11 independently for each occurrence, C 1-6 In certain embodiments, R 11 is -CH3. In certain embodiments, R 11 independently for each occurrence, C 1-6 In certain embodiments, R 11 is —OCH. In certain embodiments, R 11 independently for each occurrence, C 1-6 In certain embodiments, R 11 is —CF. In certain embodiments, R 11 represents, independently for each occurrence, a halo.

[0266] As generally defined above, B 1 teeth, [ka] is.

[0267] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] is.

[0268] In certain embodiments, B 1 teeth, [ka] is.

[0269] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] is.

[0270] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] is.

[0271] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] In certain embodiments, B 1 teeth, [ka] is.

[0272] As generally defined above, m is 0, 1, or 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 0 or 1. In certain embodiments, m is 1 or 2.

[0273] The above description describes multiple embodiments for compounds of formula V. This patent application specifically contemplates all combinations of embodiments.

[0274] Another aspect of the present disclosure is a compound represented by formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 4 are independently -C(O)R 5 or hydrogen, R 2 is halo, hydrogen, or -OH; R 3 is halomethyl, C 1-3 aliphatic, or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium; R 5 independently for each occurrence, C 1-20 aliphatic, C 1-20 Haloaliphatic, -C(H)(R 6 )-N(R 7 )2, phenyl, -CH2-phenyl, or hydrogen, each phenyl being R 10 is replaced by m occurrences of R 6 is C 1-6 alkyl or hydrogen, 1-6 alkyl is optionally substituted with phenyl; R 7independently for each occurrence: hydrogen, C 1-6 alkyl, -C(O)OC(CH3)3, -C(O)O(CH2)phenyl, or -C(O)O(CH2)fluorenyl; R 8 and R 9 each independently represents hydrogen, halo, -CH3, or -CF3; R 10 independently for each occurrence, C 1-6 Alkyl, C 1-6 Alkoxyl, C 1-6 represents haloalkyl or halo, B 1 teeth, [ka] and m is 0, 1, or 2.

[0275] The definitions of the variables in Formula VI above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of variables defined by (i) or (ii).

[0276] In certain embodiments, the compound is of formula VI.

[0277] As generally defined above, R 1 and R 4 are independently -C(O)R 5 or hydrogen. In certain embodiments, R 1 and R 4 is hydrogen.

[0278] In certain embodiments, R 1 is -C(O)R 5 or hydrogen. In certain embodiments, R 1 is -C(O)R 5In certain embodiments, R 1 is hydrogen.

[0279] In certain embodiments, R 4 is -C(O)R 5 or hydrogen. In certain embodiments, R 4 is -C(O)R 5 In certain embodiments, R 4 is hydrogen.

[0280] As generally defined above, R 8 and R 9 each independently represent hydrogen, halo, —CH 3 , or —CF 3 .

[0281] In certain embodiments, R 8 is hydrogen, halo, -CH, or -CF. In certain embodiments, R 8 is hydrogen or halo. In certain embodiments, R 8 is hydrogen or fluoro. In certain embodiments, R 8 is halo or -CF. In certain embodiments, R 8 is fluoro or -CF. In certain embodiments, R 8 is —CH or —CF. In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 is halo. In certain embodiments, R 8 is fluoro. In certain embodiments, R 8 is -CH3. In certain embodiments, R 8 is -CF3.

[0282] In certain embodiments, R 9 is hydrogen, halo, -CH, or -CF. In certain embodiments, R 9 is hydrogen or halo. In certain embodiments, R 9 is hydrogen or fluoro. In certain embodiments, R 9is halo or -CF. In certain embodiments, R 9 is fluoro or -CF. In certain embodiments, R 9 is —CH or —CF. In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is halo. In certain embodiments, R 9 is fluoro. In certain embodiments, R 9 is —CH3. In certain embodiments, R 9 is -CF3.

[0283] In certain embodiments, the present invention provides a compound of formula VI, wherein the variable R 2 , R 3 , R 5 , R 6 , R 7 , R 10 , B 1 Each of R, R, and m is as defined in the description of Formula II above, and both alone and in combination, as described in embodiments herein. For example, in certain embodiments, R 2 is halo. In another example, in certain embodiments, R 2 is fluoro and R 3 is halomethyl. In yet another example, in certain embodiments, R 1 and R 4 is hydrogen and R 2 is hydrogen and R 3 is —CH2F or —CH2Cl.

[0284] The above description describes multiple embodiments for compounds of formula VI. This patent application specifically contemplates all combinations of embodiments.

[0285] II. Methods of Treating Medical Disorders and / or Inhibiting Reverse Transcriptase The compounds of Section I above (e.g., compounds of Formula I described above, or pharmaceutically acceptable salts thereof) or other compounds in Section III below are contemplated to provide therapeutic benefit to subjects suffering from cancer, autoimmune disorders, and / or neurological disorders.

[0286] Thus, one aspect of the present disclosure provides a method for treating a disorder selected from the group consisting of cancer, autoimmune disorders, and neurological disorders. The method includes administering to a subject in need of treatment a therapeutically effective amount of a compound described herein (such as a compound of Formula I, II, III, IV, V, or VI, or other compounds described in Section I or III), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing, to treat the disorder. In certain embodiments, the particular compound is a compound described with respect to any of the embodiments herein, in any and all combinations of the various embodiments and aspects of the embodiments described.

[0287] Another aspect of the present disclosure provides a method of treating a disorder selected from the group consisting of cancer, autoimmune disorders, and neurological disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, a pharmaceutically acceptable salt thereof, or any of the foregoing pharmaceutical compositions, wherein the compound of Formula I is as described for any of embodiments 1-22 above, in any and all combinations of the various embodiments and aspects of the embodiments described.

[0288] Another aspect of the present disclosure provides a method for treating a disorder selected from the group consisting of cancer, autoimmune disorders, and neurological disorders. The method comprises administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula I or a compound described herein, such as a compound in Tables 1, 1-A, 1-B, 2, and / or 2-A, to treat the disorder. In certain embodiments, the particular compound is a compound described for any of the embodiments herein, in any and all combinations of the various embodiments and aspects of the embodiments described.

[0289] Yet another aspect of the present disclosure provides a method for treating a viral infection. The method includes administering to a subject in need of treatment a therapeutically effective amount of a compound described herein (such as a compound of Formula I, II, III, IV, V, or VI, or other compounds described in Section I or III), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing, to treat the viral infection. In certain embodiments, the particular compound is a compound described with respect to any of the embodiments herein, in any and all combinations of the various embodiments and aspects of the embodiments described.

[0290] In certain embodiments of each of the foregoing methods, the compound is a compound of Table 1, 1-A, 1-B, 1-C, ID, 2, 2-A, 2-B, or 2-C, or a pharmaceutically acceptable salt thereof. In certain embodiments of each of the foregoing methods, the compound is a compound of Table 1, 1-A, 1-B, 1-C, 2, 2-A, 2-B, or 2-C, or a pharmaceutically acceptable salt thereof. In certain embodiments of each of the foregoing methods, the compound is a compound of Table 1, 1-A, 1-B, 1-C, ID, 2, 2-A, 2-B, or 2-C. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 1-C, 2, 2-A, 2-B, or 2-C. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-C, 2, 2-A, 2-B, or 2-C. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-C, 2, 2-A, or 2-C, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-C, 2, 2-A, or 2-C. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 2, 2-A, or 2-B, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 2, 2-A, or 2-B. In certain embodiments, the compound is a compound of Table 1, 1-A, 2, or 2-A, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 2, or 2-A. In certain embodiments, the compound is a compound of Table 1-B or 2-B, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1-B or 2-B. In certain embodiments, the compound is a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1 or Table 2.

[0291] In certain embodiments, the compound is administered in a pharmaceutical composition comprising the compound and a carrier, excipient, and / or vehicle, as further described in Section V below.

[0292] In certain embodiments, the methods further comprise administering an effective amount of one or more additional therapeutic agents, as further described in Section IV below.

[0293] cancer In certain embodiments, the disorder is cancer. In certain embodiments, the cancer is a solid tumor or leukemia. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a carcinoma or melanoma. In certain embodiments, the cancer is a carcinoma. In certain embodiments, the cancer is a sarcoma. In certain embodiments, the cancer is a melanoma. In certain embodiments, the cancer is a lymphoma. In certain embodiments, the cancer is a leukemia.

[0294] In certain embodiments, 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, gastric cancer, bile duct cancer, cholangiocarcinoma, 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.

[0295] In certain embodiments, 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, gastric cancer, bile duct cancer, gallbladder cancer, or bladder cancer.

[0296] In certain embodiments, the cancer has (i) expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide, (ii) LINE1 reverse transcriptase activity, (iii) expression of HERV-K RNA, and / or (iv) HERV-K reverse transcriptase activity.

[0297] In certain embodiments, the cancer has (i) expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide, and / or (ii) LINE1 reverse transcriptase activity. In certain embodiments, the cancer has expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide. In certain embodiments, the cancer has expression of LINE1 RNA. In certain embodiments, the cancer has expression of LINE1 ORF1 polypeptide. In certain embodiments, the cancer has expression of LINE1 ORF2 polypeptide. In certain embodiments, the cancer has LINE1 reverse transcriptase activity.

[0298] In certain embodiments, the cancer has (i) HERV-K RNA expression and / or (ii) HERV-K reverse transcriptase activity. In certain embodiments, the cancer has HERV-K RNA expression. In certain embodiments, the cancer has HERV-K reverse transcriptase activity.

[0299] In certain embodiments, the cancer has elevated (i) levels of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide, (ii) LINE1 reverse transcriptase activity, (iii) levels of HERV-K RNA, and / or (iv) HERV-K reverse transcriptase activity.

[0300] In certain embodiments, the cancer has (i) elevated levels of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide, and / or (ii) elevated LINE1 reverse transcriptase activity. In certain embodiments, 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.

[0301] 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. In certain embodiments, the cancer has elevated activity of HERV-K reverse transcriptase.

[0302] In certain embodiments, the cancer is an epithelial cancer. In certain embodiments, the epithelial cancer is pancreatic cancer, colon cancer, breast cancer, prostate cancer, esophageal cancer, head and neck cancer, kidney cancer, ovarian cancer, or lung cancer. In certain embodiments, the cancer is pancreatic cancer, colon cancer, breast cancer, prostate cancer, kidney cancer, ovarian cancer, or lung cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is pancreatic adenocarcinoma. In certain embodiments, the cancer is colon cancer. In certain embodiments, the cancer comprises microsatellite instability (MSI) colon cancer or microsatellite stable (MSS) colon cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is esophageal cancer. In certain embodiments, the cancer is head and neck cancer. In certain embodiments, the cancer is kidney cancer. In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the lung cancer is non-small cell lung cancer or small cell lung cancer. In certain embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is small cell lung cancer.

[0303] In certain embodiments, the cancer is a precancerous or early cancerous lesion. In certain embodiments, the cancer is intraductal papillary mucinous neoplasm (IPMN), pancreatic intraepithelial neoplasia (PanIN), ductal carcinoma in situ (DCIS), or Barrett's esophagus. In certain embodiments, the cancer is intraductal papillary mucinous neoplasm (IPMN). In certain embodiments, the cancer is pancreatic intraepithelial neoplasia (PanIN). In certain embodiments, the cancer is ductal carcinoma in situ (DCIS). In certain embodiments, the cancer is Barrett's esophagus.

[0304] In certain embodiments, the cancer has elevated levels of pericentromeric human satellite II (HSATII) RNA. In some embodiments, the cancer is a microsatellite unstable (MSI) cancer. In some embodiments, the cancer is a microsatellite stable (MSS) cancer.

[0305] In some aspects of the embodiments, 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.

[0306] In certain embodiments, the cancer is a B-cell lymphoma (e.g., B-cell chronic lymphocytic leukemia, B-cell non-Hodgkin's lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma), basal cell carcinoma, bladder cancer, blastoma, brain metastasis, breast cancer, Burkitt's lymphoma, carcinoma (e.g., adenocarcinoma (e.g., of the gastroesophageal junction)), cervical cancer, colon cancer, colorectal cancer (colon and rectal cancer), endometrial cancer, esophageal cancer, Ewin's lymphoma, Cancers of the lung, lung cancer, esophageal junction cancer, gastrointestinal cancer, glioblastoma (e.g., newly diagnosed or recurrent, e.g., glioblastoma multiforme), glioma, head and neck cancer (e.g., head and neck squamous cell carcinoma), liver metastases, Hodgkin's lymphoma and non-Hodgkin's lymphoma, kidney cancer (e.g., renal cell carcinoma and Wilms' tumor), laryngeal cancer, leukemia (e.g., chronic myeloid leukemia, hairy cell leukemia), liver cancer (e.g., liver cirrhosis, liver metastases, liver ulcers, liver cirrhosis ... pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), prostate cancer (e.g., hormone-resistant (e.g., castration-resistant), metastatic, metastatic hormone-resistant (e.g., castration-resistant), lymphoblastic lymphoma, lymphoma, mantle cell lymphoma, metastatic brain tumor, metastatic carcinoma, myeloma (e.g., multiple myeloma), neuroblastoma, ocular melanoma, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), prostate cancer (e.g., hormone-resistant (e.g., castration-resistant), metastatic, metastatic hormone-resistant (e.g., castration-resistant), androgen-independent), renal cell carcinoma (e.g., metastatic), salivary gland carcinoma, sarcoma (e.g., rhabdomyosarcoma), skin cancer (e.g., melanoma (e.g., metastatic melanoma)), soft tissue sarcoma, solid tumor, squamous cell carcinoma, synovial sarcoma, testicular cancer, thyroid cancer, transitional cell carcinoma (urothelial cell carcinoma), uveal melanoma (e.g., metastatic), verrucous carcinoma, vulvar carcinoma, and Waldenstrom's macroglobulinemia.

[0307] In some embodiments, the cancer is a virus-associated cancer. As used herein, the term "virus-associated cancer" refers to any cancer in which a virus is known to play a role. For example, Epstein-Barr virus (EBV) has been reported to be associated with endemic variants of Burkitt's lymphoma and certain other lymphomas. Infection with human papillomavirus (HPV) is thought to be involved in certain types of cervical cancer and / or genital cancer. Human T-cell leukemia virus 1 (HTLV-1) has been reported to be associated with adult T-cell leukemia / lymphoma (ATLL). Human T-cell leukemia virus 2 (HTLV-2) has been reported to be associated with cutaneous T-cell lymphoma. Human herpesvirus 8 (HHV-8) is thought to cause Kaposi's sarcoma in patients with AIDS. In certain embodiments, the cancer is associated with EBV, HPV, HTLV-1, HTLV-2, or HHV-8. In certain embodiments, the cancer is Burkitt's lymphoma, cervical cancer, reproductive cancer, adult T-cell leukemia / lymphoma, cutaneous T-cell lymphoma, or Kaposi's sarcoma.

[0308] In some embodiments, the cancer is a cancer other than a virus-associated cancer. In certain embodiments, the cancer is a cancer other than a cancer associated with EBV, HPV, HTLV-1, HTLV-2, or HHV-8. In certain embodiments, the cancer is a cancer other than Burkitt's lymphoma, cervical cancer, reproductive 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.

[0309] In some embodiments, the cancer is renal cell carcinoma, or kidney cancer, mesothelioma, hepatobiliary (liver and bile duct), bone cancer, rhabdomyosarcoma, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal cancer (stomach, colorectum, and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, adrenal cortical carcinoma, sarcoma of soft tissue, sarcoma of soft tissue and bone synovium, urethral cancer, penile cancer, prostate cancer, adenocarcinoma, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axis tumor, brain stem glioma, pituitary adenocarcinoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, squamous cell carcinoma of the head and neck (SCCHN), salivary gland cancer, neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST), and medulloblastoma, or a combination of one or more of the foregoing cancers.

[0310] In some embodiments, 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 carcinoma. In some embodiments, the cancer is fallopian tube carcinoma. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine serous adenocarcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. 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 carcinoma. 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 tumor (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0311] In certain embodiments, the cancer is leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, or heavy chain disease. In one embodiment, the cancer is a sarcoma or carcinoma (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial tumor, lymphangiosarcoma, lymphangioendothelial tumor, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, and solid tumors such as liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

[0312] In some embodiments, the cancer is a glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0313] In some embodiments, the cancer is acoustic neuroma, astrocytoma (e.g., Grade I—pilocytic astrocytoma, Grade II—low-grade astrocytoma, Grade III—anaplastic astrocytoma, or Grade IV—glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal tumor (PNET), or schwannoma. In some embodiments, the cancer is a type more commonly found in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic glioma, pineal tumor, primitive neuroectodermal tumor (PNET), or rhabdoid tumor.

[0314] Autoimmune Diseases and Disorders In certain embodiments, the disorder is an autoimmune disorder. As used herein, the terms "autoimmune disorder" and "autoimmune disease" are used interchangeably and include diseases and disorders traditionally classified as autoimmune disorders, as well as inflammatory and immune disorders (excluding viral infections). The terms "autoimmune disease" and "autoimmune disorder" are intended to include all diseases and disorders caused by innate immune responses and adaptive immune responses that initiate certain innate immune inflammatory responses. It is the applicant's intention that the terms "autoimmune disease" and "autoimmune disorder" include the full range of diseases and disorders caused by innate inflammation, excluding viral infections.

[0315] In certain embodiments, the present invention provides treatment for autoimmune disorders. Classical autoimmune disorders generally occur when the immune system attacks normal cells and / or tissues within the body. Inflammatory disorders often exhibit chronic inflammation (among other symptoms) in the absence of infection. Autoimmune disorders also include conditions that occur when the cellular immune system reacts against the body's self-antigens. Autoimmune and / or inflammatory manifestations associated with a range of primary immunodeficiency diseases may also be present. In further aspects of these embodiments, the autoimmune disease or disorder is associated with elevated levels of LINE-1 and / or HERV-K RNA protein expression.

[0316] One embodiment of the present invention is a method of treating type I interferonopathy. In one aspect of this embodiment, type I interferonopathy is a congenital disorder associated with overexpression of type I interferons. In one aspect of this embodiment, the congenital type I interferonopathy is selected from Aicardi-Goutières syndrome (AGS), Singleton-Merten syndrome, proteasome-associated autoinflammatory syndrome, chronic atypical neutrophilic dermatosis with lipodystrophy and hypertension (CANDLE), STING-associated vasculopathy with early childhood onset (SAVI), Japanese autoinflammatory syndrome with lipodystrophy (JASL), spinal enchondrodysplasia (SPENCD), ISG15 deficiency, ubiquitin-specific peptidase 18 deficiency (pseudo-TORCH syndrome), chronic atypical neurotropic dermatitis with lipodystrophy, DNA II deficiency, hair-liver-bowel syndrome 2, retinal vasculopathy with cerebral leukodystrophy, familial lupus pernio, and X-linked reticular pigmentopathy (XLPDR). In another embodiment, the type I interferonopathy is an acquired disorder in the IFN system.

[0317] In one embodiment, the invention provides a method of treating an autoimmune disease resulting in the overproduction of interferon. In one aspect of this embodiment, the expressed interferon comprises a type I interferon. In another aspect of this embodiment, the autoimmune disease is associated with increased LINE-1 activity and / or expression. In another aspect of this embodiment, the autoimmune disease is associated with increased HERV-K RNA activity and / or expression.

[0318] In certain embodiments, the autoimmune disorder is achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuroneuropathy (AMAN), Baro's disease, Behcet's disease, benign mucous membrane pemphigoid, bullous rheumatoid arthritis, orthostatic hypoplasia (THP). Pemphigus, Castleman's disease (CD), celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifactorial osteomyelitis (CRMO), Churg-Strauss syndrome or eosinophilic granulomatosis, cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, complex regional pain syndrome (formerly called reflex sympathetic dystrophy), congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, cutaneous lupus erythematosus (CLE), dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, fetal Endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, graft-versus-host disease, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (acne inversa), inflammatory bowel disease, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenia Intravesical purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, lichen planus, lichen sclerosus, lignified conjunctivitis, linear IgA disease (LAD), lupus nephritis, Lyme disease (chronic), Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myelin oligodendrocyte glycoprotein antibody disorder, myositis, narcolepsy, neonatal lupus, neutropenia, ocular cicatricial pemphigoid, optic neuritis,Relapsing rheumatoid arthritis, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), paraneoplastic cerebellar degeneration (PCD), pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, rheumatic polyarteritis, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cholangitis, primary sclerosing cholangitis, progesterone dermatitis, progressive hemifacial atrophy (Parry-Romberg syndrome), psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive joints inflammatory bowel disease, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis (RA), sarcoidosis, Schmidt's syndrome (autoimmune polyendocrine syndrome type II), scleritis, scleroderma, Sjogren's disease, stiff-person syndrome, Susac's syndrome, sympathetic ophthalmia, systemic lupus erythematosus (SLE), Takayasu's arteritis, thrombotic thrombocytopenic purpura, thyroid eye disease, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and warm autoimmune hemolytic anemia.

[0319] In certain embodiments, the autoimmune disorder is selected from Aicardi-Goutieres syndrome, rheumatoid arthritis, psoriasis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), graft-versus-host disease, scleroderma, type 1 diabetes, dermatomyositis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, vasculitis, and Sjogren's syndrome.

[0320] In certain embodiments, the autoimmune disorder is Aicardi-Goutieres syndrome (AGS). In another embodiment, the autoimmune disorder is systemic lupus erythematosus (SLE). In another embodiment, 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.

[0321] In certain embodiments, the autoimmune disorder is type 1 interferonopathy. In certain embodiments, the autoimmune disorder is type 1 diabetes, Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), familial pernio lupus, systemic sclerosis, STING-associated vasculopathy with early childhood onset (SAVI), Sjögren's syndrome, or dermatomyositis. In certain embodiments, the immune disorder is type 1 interferonopathy, type 1 diabetes, Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), dermatomyositis, or Sjögren's syndrome. In certain embodiments, the autoimmune disorder is systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), or familial pernio lupus. In certain embodiments, the immune disorder is systemic lupus erythematosus (SLE).

[0322] In certain embodiments, the autoimmune disorder is type 1 diabetes. In certain embodiments, the autoimmune disorder is familial pernio lupus. In certain embodiments, the autoimmune disorder is systemic sclerosis. In certain embodiments, the autoimmune disorder is STING-associated vasculopathy with early childhood onset (SAVI). In certain embodiments, the autoimmune disorder is Sjogren's syndrome.

[0323] 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. In one embodiment, the autoimmune disorder is drug-induced colitis, such as colitis associated with the administration of checkpoint inhibitors to cancer patients.

[0324] In certain embodiments, the autoimmune disorder is osteoarthritis, non-alcoholic 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.

[0325] In certain embodiments, 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), oophoritis, primary biliary cirrhosis, myasthenia gravis, hypogonadism, hypoparathyroidism, alopecia, malabsorption syndrome, pernicious anemia, hepatitis, hypopituitarism, diabetes insipidus, or sicca syndrome.

[0326] Neuropathy In certain embodiments, the disorder is a neurological disorder. In certain embodiments, 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-Jakob disease, stroke, prion disease, frontotemporal dementia, Pick's disease, progressive supranuclear palsy, spinocerebellar ataxia, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, or major depression. In certain embodiments, 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.

[0327] In certain embodiments, the neurological disorder is peripheral neuropathy, age-related macular degeneration, Creutzfeldt-Jakob disease, stroke, prion disease, frontotemporal dementia, Pick's disease, progressive supranuclear palsy, spinocerebellar ataxia, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, or major depression.

[0328] In certain embodiments, the neurological disorder is Alzheimer's disease. In other embodiments, 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.

[0329] Viral infections In certain embodiments, the viral infection is an infection with human immunodeficiency virus 1 or 2 (HIV-1 or HIV-2), human T-cell leukemia virus 1 or 2 (HTLV-1 or HTLV-2), respiratory syncytial virus (RSV), human papillomavirus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), cytomegalovirus (CMV), herpes simplex virus 1 or 2 (HSV-1 or HSV-2), human herpesvirus 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.

[0330] In certain embodiments, the viral infection is an infection by human immunodeficiency virus 1 or 2 (HIV-1 or HIV-2). In certain embodiments, the viral infection is an infection by human immunodeficiency virus 1 (HIV-1). In certain embodiments, the viral infection is an infection by human immunodeficiency virus 2 (HIV-2). In certain embodiments, the viral infection is an infection by human T-cell leukemia virus 1 or 2 (HTLV-1 or HTLV-2). In certain embodiments, the viral infection is an infection by respiratory syncytial virus (RSV). In certain embodiments, the viral infection is an infection by human papillomavirus (HPV). In certain embodiments, the viral infection is an infection by adenovirus. In certain embodiments, 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 with varicella-zoster virus (VZV). In certain embodiments, the viral infection is an infection with cytomegalovirus (CMV). In certain embodiments, the viral infection is an infection with herpes simplex virus 1 or 2 (HSV-1 or HSV-2). In certain embodiments, the viral infection is an infection with human herpesvirus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus). In certain embodiments, the viral infection is an infection with a flavivirus selected from yellow fever virus, dengue virus, Japanese encephalitis, and West Nile virus.

[0331] In certain embodiments, the viral infection is an infection caused by an adenovirus. In certain embodiments, the viral infection is an infection caused by a herpesvirus. In certain embodiments, the viral infection is an infection caused by a poxvirus. In certain embodiments, the viral infection is an infection caused by a parvovirus. In certain embodiments, the viral infection is an infection caused by a reovirus. In certain embodiments, the viral infection is an infection caused by a picornavirus. In certain embodiments, the viral infection is an infection caused by a rhinovirus or an enterovirus. In certain embodiments, the viral infection is an infection caused by a togavirus. In certain embodiments, the viral infection is an infection caused by an orthomyxovirus. In certain embodiments, the viral infection is an infection caused by a rhabdovirus. In certain embodiments, the viral infection is an infection caused by a retrovirus. In certain embodiments, the viral infection is an infection caused by a hepadnavirus.

[0332] 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. In certain embodiments, the viral infection is an infection by a coronavirus selected from 229E (alphacoronavirus), NL63 (alphacoronavirus), OC43 (betacoronavirus), HKU1 (betacoronavirus), MERS-CoV (betacoronavirus), SARS-CoV (betacoronavirus), and SARS-CoV-2 (coronavirus disease 2019 or COVID-19).

[0333] In certain embodiments, the viral infection is an infection with an influenza virus. In certain embodiments, the viral infection is an infection with an influenza virus type A or B. In certain embodiments, the viral infection is an infection with an influenza virus selected from H5N1, H1N1, and H3N2.

[0334] In certain embodiments, the viral infection is an infection by poliovirus. In certain embodiments, the viral infection is an infection by type 1 poliovirus. In certain embodiments, the viral infection is an infection by type 2 poliovirus. In certain embodiments, the viral infection is an infection by type 3 poliovirus.

[0335] subject In certain embodiments, the subject has (i) expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide, (ii) LINE1 reverse transcriptase activity, (iii) expression of HERV-K RNA, and / or (iv) HERV-K reverse transcriptase activity.

[0336] In certain embodiments, the subject has (i) expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide, and / or (ii) LINE1 reverse transcriptase activity. In certain embodiments, the subject has (i) elevated expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide, and / or (ii) elevated LINE1 reverse transcriptase activity. In certain embodiments, the subject has expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide. In certain embodiments, the subject has expression of LINE1 RNA. In certain embodiments, 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 LINE1 reverse transcriptase activity.

[0337] In certain embodiments, the subject has (i) HERV-K RNA expression and / or (ii) HERV-K reverse transcriptase activity. In certain embodiments, the subject has HERV-K RNA expression. In certain embodiments, the subject has HERV-K reverse transcriptase activity.

[0338] In certain embodiments, the subject has elevated (i) levels of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide, (ii) LINE1 reverse transcriptase activity, (iii) levels of HERV-K RNA, and / or (iv) HERV-K reverse transcriptase activity.

[0339] In certain embodiments, the subject has (i) elevated levels of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide, and / or (ii) elevated LINE1 reverse transcriptase activity. In certain embodiments, 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.

[0340] In certain embodiments, the subject has (i) elevated levels of HERV-K RNA and / or (ii) elevated activity of HERV-K reverse transcriptase. In certain embodiments, the subject has elevated levels of HERV-K RNA. In certain embodiments, the subject has elevated activity of HERV-K reverse transcriptase.

[0341] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult. In certain embodiments, the subject is a child. In certain embodiments, the subject is a companion animal. In certain embodiments, the subject is a dog, cat, or horse.

[0342] Use of the compound Another aspect of the present disclosure provides the use of a compound described herein (such as a compound of Formula I, or other compound in Section III) for treating a medical disorder, such as a medical disorder described herein.

[0343] Another aspect of the disclosure provides the use of a compound described herein (such as a compound of Formula I, or other compounds in Section III) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disorder described herein, such as cancer, an autoimmune disorder, and / or a neurological disorder. In certain embodiments, the disorder is aging or an aging-related disease.

[0344] Methods for inhibiting LINE1 and / or HERV-K reverse transcriptase activity in a subject Another embodiment of the present invention provides a method for inhibiting LINE1 reverse transcriptase activity in a subject suffering from a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder. The method comprises contacting LINE1 reverse transcriptase with an effective amount of a compound of Formula I, wherein the compound of Formula I is as described in any of Embodiments 1-22 above, to inhibit the activity of the LINE1 reverse transcriptase. Additional compounds useful in the method are further described in Section III. In certain embodiments, the method comprises administering any of the compounds in Tables 1 and 2, or pharmaceutically acceptable salts thereof, and / or pharmaceutical compositions comprising same.

[0345] Another embodiment of the present invention provides a method of inhibiting LINE1 reverse transcriptase activity in a subject, comprising contacting the LINE1 reverse transcriptase with an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound according to Formula I, to inhibit the activity of the LINE1 reverse transcriptase.

[0346] In certain embodiments, the disorder is a disorder defined by one of the embodiments described above, such as cancer, an autoimmune disorder, and / or a neurological disorder, hi certain embodiments, the disorder is aging or an aging-related disease.

[0347] In certain embodiments, the method further comprises inhibiting HERV-K reverse transcriptase activity in the subject.

[0348] Another embodiment of the present invention provides a method for inhibiting LINE1 reverse transcriptase activity in a subject suffering from a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder, comprising contacting the LINE1 reverse transcriptase with an effective amount of a compound of Formula I or a compound described herein, such as a compound of Table 1, 1-A, 1-B, 2, 2-A, or 2-B, to inhibit the activity of the LINE1 reverse transcriptase.

[0349] In certain embodiments, the disorder is a disorder defined by one of the embodiments described above, such as cancer, an autoimmune disorder, and / or a neurological disorder.

[0350] In certain embodiments, the method further comprises inhibiting HERV-K reverse transcriptase activity in the subject.

[0351] In certain embodiments, the particular compound is a compound described for any of the embodiments herein, in any and all combinations of the various embodiments and aspects of the embodiments described. For example, in certain embodiments, the compound is a compound of Formula II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 1-C, 2, 2-A, 2-B, or 2-C, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 1-C, 1-D, 2, 2-A, 2-B, or 2-C, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 1-C, 2, 2-A, 2-B, or 2-C. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 1-C, 2, 2-A, 2-B, or 2-C. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-C, 2, 2-A, or 2-C, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-C, 2, 2-A, or 2-C. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 2, 2-A, or 2-B, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 2, 2-A, or 2-B. In certain embodiments, the compound is a compound of Table 1, 1-A, 2, or 2-A, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 2, or 2-A. In certain embodiments, the compound is a compound of Table 1-B or 2-B, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1-B or 2-B. In certain embodiments, the compound is a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1 or Table 2.

[0352] In certain embodiments, the compound is administered in a pharmaceutical composition comprising the compound and a carrier, excipient, and / or vehicle, as further described in Section V below.

[0353] Another embodiment of the present invention provides a method for inhibiting LINE1 reverse transcriptase activity. The method comprises contacting a LINE1 reverse transcriptase with a therapeutically effective amount of a compound described herein, such as a compound in Table 1, 1-A, or 1-B, to inhibit the activity of the LINE1 reverse transcriptase. In certain embodiments, the particular compound is a compound described for any of the embodiments herein, in any and all combinations of the various embodiments and aspects of the embodiments described. For example, in certain embodiments, the compound is a compound of Formula I, II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula II, III, or IV, or a pharmaceutically acceptable salt thereof.

[0354] In certain embodiments, the compound is administered in a pharmaceutical composition comprising the compound and a carrier, excipient, and / or vehicle, as further described in Section V below.

[0355] Another aspect of the present disclosure provides a method for inhibiting HERV-K reverse transcriptase activity in a subject suffering from a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder. The method comprises contacting a HERV-K reverse transcriptase with an effective amount of a compound of Formula I, wherein the compound of Formula I is as described in any of Embodiments 1-22 above, to inhibit the activity of the HERV-K reverse transcriptase. Additional compounds useful in the method are further described in Section III. In certain embodiments, the method comprises administering any of the compounds in Tables 1 and 2, or pharmaceutically acceptable salts thereof, and / or pharmaceutical compositions comprising same.

[0356] Another aspect of the present disclosure provides a method for inhibiting HERV-K reverse transcriptase activity in a subject, comprising contacting the HERV-K reverse transcriptase with an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula I, to inhibit the activity of the HERV-K reverse transcriptase.

[0357] In certain embodiments, the disorder is a disorder defined by one of the embodiments described in Section I above, such as cancer, an autoimmune disorder, and / or a neurological disorder. In certain embodiments, the disorder is aging or an aging-related disease.

[0358] In certain embodiments, the method further comprises inhibiting LINE1 reverse transcriptase activity in the subject.

[0359] Another embodiment of the present invention provides a method for inhibiting HERV-K reverse transcriptase activity in a subject suffering from a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder, comprising contacting the HERV-K reverse transcriptase with an effective amount of a compound of Formula I or a compound described herein, such as a compound of Table 1, 1-A, 1-B, 2, or 2-A, to inhibit the activity of the HERV-K reverse transcriptase.

[0360] In certain embodiments, the disorder is a disorder defined by one of the embodiments described above, such as cancer, an autoimmune disorder, and / or a neurological disorder.

[0361] In certain embodiments, the method further comprises inhibiting LINE1 reverse transcriptase activity in the subject.

[0362] In certain embodiments, the particular compound is a compound described for any of the embodiments herein, in any and all combinations of the various embodiments and aspects of the embodiments described. For example, in certain embodiments, the compound is a compound of Formula II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 1-C, 2, 2-A, 2-B, or 2-C, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 1-C, 1-D, 2, 2-A, 2-B, or 2-C, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 1-C, 2, 2-A, 2-B, or 2-C. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 1-C, 2, 2-A, 2-B, or 2-C. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-C, 2, 2-A, or 2-C, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-C, 2, 2-A, or 2-C. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 2, 2-A, or 2-B, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 1-B, 2, 2-A, or 2-B. In certain embodiments, the compound is a compound of Table 1, 1-A, 2, or 2-A, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1, 1-A, 2, or 2-A. In certain embodiments, the compound is a compound of Table 1-B or 2-B, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1-B or 2-B. In certain embodiments, the compound is a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1 or Table 2.

[0363] In certain embodiments, the compound is administered in a pharmaceutical composition comprising the compound and a carrier, excipient, and / or vehicle, as further described in Section V below.

[0364] Another embodiment of the present invention provides a method for inhibiting HERV-K reverse transcriptase activity. The method comprises contacting a HERV-K reverse transcriptase with a therapeutically effective amount of a compound described herein, such as a compound in Table 1, 1-A, or 1-B, to inhibit the activity of the HERV-K reverse transcriptase. In certain embodiments, the particular compound is a compound described for any of the embodiments herein, in any and all combinations of the various embodiments and aspects of the embodiments described. For example, in certain embodiments, the compound is a compound of Formula I, II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula II, III, or IV, or a pharmaceutically acceptable salt thereof.

[0365] One aspect of the present disclosure provides compounds that possess a combination of excellent properties, including potent inhibitory activity toward LINE1 reverse transcriptase, selectivity for inhibiting LINE1 reverse transcriptase, and excellent physical properties that make the compounds suitable for use as orally administered drugs. Selectivity for inhibiting LINE1 reverse transcriptase can be characterized according to the compound's ability to inhibit LINE1 reverse transcriptase while having substantially less inhibitory activity toward DNA polymerases (e.g., α, β, and γ). In part, because inhibition of DNA polymerases, such as DNA polymerase gamma, can result in toxicity in the form of mitochondrial toxicity, compounds that exhibit potent inhibitory activity toward LINE1 reverse transcriptase while having substantially less inhibitory activity toward DNA polymerases represent an important discovery and a significant scientific advance. Potent inhibitory activity toward LINE1 reverse transcriptase combined with low inhibitory activity toward DNA polymerases contributes to the subject compound's high therapeutic index, thereby providing a superior performance profile for the compound in medical therapy. Experimental results herein demonstrate these advantages.

[0366] Another aspect of the present disclosure provides compounds that have a combination of excellent properties, including potent inhibitory activity toward LINE1 reverse transcriptase, selectivity for inhibiting LINE1 reverse transcriptase, potent inhibition of pathogenic interferon responses in inflamed tissues, and excellent physical properties that make the compounds suitable for use as orally administered drugs. As described above, selectivity for inhibiting LINE1 reverse transcriptase can be characterized according to the compound's ability to inhibit LINE1 reverse transcriptase while having substantially less inhibitory activity toward DNA polymerases (e.g., α, β, and γ). In part, because inhibition of DNA polymerases such as DNA polymerase gamma can result in toxicity in the form of mitochondrial toxicity, compounds that exhibit potent inhibitory activity toward LINE1 reverse transcriptase while having substantially less inhibitory activity toward DNA polymerases would be an important discovery and a significant scientific advance. Compounds with potent inhibition of pathogenic interferon responses in inflamed tissues are useful for treating cancer, autoimmune diseases (e.g., SLE and CLE), neurological disorders, aging, and age-related diseases. The potent inhibitory activity towards LINE1 reverse transcriptase combined with low inhibitory activity towards DNA polymerases (e.g., α, β, and γ) contributes to the high therapeutic index of the subject compounds, thereby providing them with an excellent performance profile in medical therapy.

[0367] Another aspect of the present disclosure provides compounds that have a combination of excellent properties, including potent inhibitory activity toward HERV-K reverse transcriptase, selectivity for inhibiting HERV-K reverse transcriptase, and excellent physical properties that make the compounds suitable for use as orally administered drugs. Selectivity for inhibiting HERV-K reverse transcriptase can be characterized according to the compound's ability to inhibit HERV-K reverse transcriptase while having substantially less inhibitory activity toward DNA polymerases (e.g., α, β, and γ). In part, because inhibition of DNA polymerases, such as DNA polymerase gamma, can result in toxicity in the form of mitochondrial toxicity, compounds that exhibit potent inhibitory activity toward HERV-K reverse transcriptase while having substantially less inhibitory activity toward DNA polymerases represent an important scientific advance. Compounds that are potent inhibitors of HERV-K reverse transcriptase are useful for treating HERV-K reverse transcriptase-associated disorders. Potent inhibitory activity toward HERV-K reverse transcriptase combined with low inhibitory activity toward DNA polymerases contributes to the compound's high therapeutic index, thereby providing a superior performance profile for the compound in medical therapy.

[0368] In certain embodiments, the compound is administered in a pharmaceutical composition comprising the compound and a carrier, excipient, and / or vehicle, as further described in Section V below.

[0369] Compounds can be tested for their ability to inhibit LINE1 reverse transcriptase activity, for example, as described in the Examples. Compounds can be tested for their ability to inhibit HERV-K reverse transcriptase activity, for example, as described in the Examples.

[0370] III. Additional Compounds The methods described in Section II above can be further characterized according to the compounds used in the methods. Additional exemplary compounds for use in the methods are described below, along with exemplary procedures for making the compounds.

[0371] In certain embodiments, the compound for use in the methods described above is a compound of formula I found in Table 2. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6]

[0372] In certain embodiments, the compound for use in the methods described above is a compound in Table 2, 2-A, 2-B, or 2-C herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound for use in the methods described above is a compound in Table 2, 2-A, 2-B, or 2-C herein. In certain embodiments, the compound for use in the methods described above is a compound in Table 2, 2-A, or 2-B herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound for use in the methods described above is a compound in Table 2, 2-A, or 2-B herein. In certain embodiments, the compound for use in the methods described above is a compound in Table 2 or 2-A herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound for use in the methods described above is a compound in Table 2 or 2-A herein. In certain embodiments, the compound for use in the methods described above is a compound in Table 2-A below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound for use in the methods described above is a compound in Table 2-A below. In certain embodiments, the compound for use in the methods described above is a compound in Table 2-B below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound for use in the methods described above is a compound in Table 2-B below. In certain embodiments, the compound for use in the methods described above is a compound in Table 2-C below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound for use in the methods described above is a compound in Table 2-C below. [Table 7-1] [Table 7-2] [Table 7-3] [Table 8] [Table 9-1] [Table 9-2]

[0373] In certain embodiments, the compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, excludes all of the compounds listed in Table 2. In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, excludes all of the compounds listed in Tables 2, 2-A, and 2-B. In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound listed in Table 1, Table 1-A, Table 1-B, or Table 1-C. In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound listed in Table 1, Table 1-A, Table 1-B, Table 1-C, or Table 1-D. In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound listed in Table 1. In any of these embodiments, the compound is a compound of Formula I.

[0374] IV. Combination Therapy Another aspect of the present disclosure provides a combination therapy.In certain embodiments, the method described herein above further comprises administering one or more additional therapeutic agents for treating a medical disorder (for example, according to the method described in Section II).Thus, in some embodiments, the method of the present invention further comprises administering an effective amount of one or more additional therapeutic agents.

[0375] Each of the methods described herein for treating disease using combination therapy can be further characterized according to the additional therapeutic agent used in this method.For example, in certain embodiments, the additional therapeutic agent is the second compound provided herein or its pharmaceutically acceptable salt.In certain embodiments, the additional therapeutic agent is the second compound provided herein.

[0376] In certain embodiments, the additional therapeutic agent is stavudine, a prodrug thereof, or a pharmaceutically acceptable salt of any of the foregoing. In certain embodiments, the additional therapeutic agent is stavudine, stampidine, or a pharmaceutically acceptable salt of any of the foregoing. In certain embodiments, the additional therapeutic agent is stavudine or stampidine.

[0377] In certain embodiments, the additional therapeutic agent is tenofovir, a prodrug thereof, or a pharmaceutically acceptable salt of any of the foregoing. In certain embodiments, the additional therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibuphenamide, tenofovir disoproxil, or tenofovir exalidex, or a pharmaceutically acceptable salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibuphenamide, tenofovir disoproxil, or tenofovir exalidex.

[0378] In certain embodiments, the additional therapeutic agent is tenofovir or a pharmaceutically acceptable salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir. In certain embodiments, the additional therapeutic agent is tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir alafenamide. In certain embodiments, the additional therapeutic agent is tenofovir amibuphenamide or a pharmaceutically acceptable salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir amibuphenamide. In certain embodiments, the additional therapeutic agent is tenofovir disoproxil or a pharmaceutically acceptable salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir disoproxil, or its fumarate, succinate, maleate, orotate, aspartate, or phosphate salt. In certain embodiments, the additional therapeutic agent is tenofovir disoproxil, or its fumarate, succinate, or maleate salt. In certain embodiments, the additional therapeutic agent is tenofovir disoproxil. In certain embodiments, the additional therapeutic agent is tenofovir exalidex, or a pharmaceutically acceptable salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir exalidex, or a potassium salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir exalidex.

[0379] In some embodiments, the present invention provides methods of treating a disclosed disease or condition, comprising administering to a patient in need of treatment an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and simultaneously, separately, or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of a disclosed compound and an additional therapeutic agent(s) acts synergistically.

[0380] One or more other therapeutic agents may be administered separately from the compounds or compositions of the present invention as part of a multiple dose regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with the compounds of the present invention in a single composition. When administered as a multiple dose regimen, one or more other therapeutic agents and the compounds or compositions of the present invention may be administered simultaneously, sequentially, or separately within a certain period of time, for example, within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours of each other. In some embodiments, one or more other therapeutic agents and the compounds or compositions of the present invention are administered as a multiple dose regimen more than 24 hours apart.

[0381] The dosage and dosing schedule of the active ingredients used in the combination therapy can be determined by the attending clinician. In certain embodiments, the compound described herein, such as the compound of Formula I, including other compounds in Section III, and the additional therapeutic agent(s) (e.g., the second, third, or fourth, or fifth anti-cancer agents described below) are administered at doses typically employed when such agents are used as monotherapy to treat a disorder. In other embodiments, the compound described herein, such as the compound of Formula I, including other compounds in Section III, and the additional therapeutic agent(s) (e.g., the second, third, or fourth, or fifth anti-cancer agents described below) are administered at doses lower than those typically employed when such agents are used as monotherapy to treat a disorder. In certain embodiments, the compound described herein, such as the compound of Formula I, including other compounds in Section III, and the additional therapeutic agent(s) (e.g., the second, third, or fourth, or fifth anti-cancer agents described below) are present in the same pharmaceutical composition suitable for oral administration.

[0382] In certain embodiments, the compounds described herein, such as compounds of Formula I, including other compounds in Section III, and the additional therapeutic agent(s) (e.g., a second, third, or fourth or fifth anticancer agent described below) may act additively or synergistically. A synergistic combination may allow for lower dosages of one or more agents of the combination therapy and / or less frequent administration of one or more agents. Lower dosages or less frequent administration of one or more agents may reduce the toxicity of the therapy without reducing the efficacy of the therapy.

[0383] Another aspect of the invention is a kit comprising a therapeutically effective amount of a compound described herein, such as a compound of Formula I, including other compounds in Section III, a pharmaceutically acceptable carrier, adjuvant, or vehicle, and, optionally, at least one additional therapeutic agent listed below.

[0384] cancer Accordingly, another aspect of the present disclosure provides a method of treating cancer in a patient. The method comprises administering to a subject in need of treatment (i) a therapeutically effective amount of a compound of Formula I, including a compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof, and (ii) a second anti-cancer agent, to treat the cancer. In certain embodiments, the method comprises administering to a subject in need of treatment (i) a therapeutically effective amount of a compound described herein (such as a compound of Formula I, II, III, IV, V, or VI), or a pharmaceutically acceptable salt thereof, and (ii) a second anti-cancer agent, to treat the cancer.

[0385] In certain embodiments, the second anti-cancer agent is radiation therapy.

[0386] In certain embodiments, the second anti-cancer agent is a therapeutic antibody. In certain embodiments, the therapeutic antibody targets one of the following: CD20, CD30, CD33, CD52, EpCAM, CEA, gpA33, mucin, TAG-72, CAIX, PSMA, folate-binding protein, ganglioside, Le, VEGF, VEGFR, VEGFR2, integrin αVβ3, integrin α5β1, EGFR, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, tenascin, CD19, KIR, NKG2A, CD47, CEACAM1, c-MET, VISTA, CD73, CD38, BAFF, interleukin-1 beta, B4GALNT1, interleukin-6, and interleukin-6 receptor. In certain embodiments, the therapeutic antibody targets VEGFR3 or TRAILR3.

[0387] In certain embodiments, the second anticancer agent is rituximab, ibritumomab tiuxetan, tositumomab, obinutuzumab, ofatumumab, brentuximab vedotin, gemtuzumab ozogamicin, alemtuzumab, IGN101, adecatumumab, labetuzumab, huA33, pemtumomab, oregovomab, minetumomab, cG250, J591, Mov18, faretuzumab, 3F8, ch14. 18, KW-2871, hu3S193, lgN311, bevacizumab, IM-2C6, pazopanib, sorafenib, axitinib, CDP791, lenvatinib, ramucirumab, etaracizumab, volociximab, cetuximab, panitumumab, nimotuzumab, 806, afatinib, erlotinib, gefitinib, osimertinib, vandetanib, trastuzumab, pertuzumab, MM-121, AMG 102, METMAB, SCH 900105, AVE1642, IMC-A12, MK-0646, R1507, CP 751871, KB004, IIIA-4, mapatumumab, HGS-ETR2, CS-1008, denosumab, sibrotuzumab, F19, 81C6, MEDI551, lirilumab, MEDI9447, daratumumab, belimumab, canakinumab, dinutuximab, siltuximab, and tocilizumab.In certain embodiments, the second anticancer agent is selected from the group consisting of rituximab, ibritumomab tiuxetan, tositumomab, obinutuzumab, ofatumumab, brentuximab vedotin, gemtuzumab ozogamicin, alemtuzumab, IGN101, adecatumumab, labetuzumab, huA33, pemtumomab, oregovomab, minetumomab, cG 250, J591, Mov18, faretuzumab, 3F8, ch14.18, KW-2871, hu3S193, lgN311, bevacizumab, IM-2C6, CDP791, ramucirumab, etaracizumab, volociximab, cetuximab, panitumumab, nimotuzumab, 806, trastuzumab, pertuzumab, MM-121, AMG 102, METMAB, SCH 900105, AVE 1642, IMC-A12, MK-0646, R1507, CP 751871, KB004, IIIA-4, mapatumumab, HGS-ETR2, CS-1008, denosumab, sibrotuzumab, F19, 81C6, MEDI551, lirilumab, MEDI9447, daratumumab, belimumab, canakinumab, dinutuximab, siltuximab, and tocilizumab.

[0388] In certain embodiments, the second anti-cancer agent is a cytokine, hi certain embodiments, the cytokine is IL-12, IL-15, GM-CSF, or G-CSF.

[0389] In certain embodiments, the second anticancer agent is sipuleucel-T, aldesleukin (human recombinant interleukin-2 product having the chemical name desalanyl-1, serine-125 human interleukin-2), dabrafenib (kinase inhibitor having the chemical name N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide), vemurafenib (kinase inhibitor having the chemical name propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide), or 2-chloro-deoxyadenosine. In certain embodiments, the second anticancer agent is pazopanib, sorafenib, axitinib, lenvatinib, afatinib, erlotinib, gefitinib, osimertinib, or vandetanib.

[0390] In certain embodiments, the second anti-cancer drug is a placental growth factor, an antibody-drug conjugate, an oncolytic virus, or an anti-cancer vaccine. In certain embodiments, the second anti-cancer drug is a placental growth factor. In certain embodiments, the second anti-cancer drug is a placental growth factor comprising ziv-aflibercept. In certain embodiments, the second anti-cancer drug is an antibody-drug conjugate. In certain embodiments, the second anti-cancer drug is an antibody-drug conjugate selected from the group consisting of brentuximab vedotin and trastuzumab emtransin.

[0391] In certain embodiments, the second anti-cancer agent is an oncolytic virus. In certain embodiments, the second anti-cancer agent is the oncolytic virus talimogene laherparepvec. In certain embodiments, the second anti-cancer agent is an anti-cancer vaccine. In certain embodiments, the second anti-cancer agent is an anti-cancer vaccine selected from the group consisting of a GM-CSF tumor vaccine, a STING / GM-CSF tumor vaccine, and NY-ESO-1. In certain embodiments, the second anti-cancer agent is a cytokine selected from IL-12, IL-15, GM-CSF, and G-CSF.

[0392] In certain embodiments, the second anticancer agent is an immune checkpoint inhibitor (also referred to as an immune checkpoint blocker). Immune checkpoint inhibitors are a class of therapeutic agents that have the effect of blocking immune checkpoints. See, for example, Pardoll in Nature Reviews Cancer (2012) vol. 12, pages 252-264. In certain embodiments, the immune checkpoint inhibitor is an agent that inhibits one or more of: (i) cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), (ii) programmed cell death protein 1 (PD1), (iii) PDL1, (iv) LAB3, (v) B7-H3, (vi) B7-H4, and (vii) TIM3. In certain embodiments, the immune checkpoint inhibitor is ipilumumab. In certain embodiments, the immune checkpoint inhibitor is pembrolizumab. In certain embodiments, the immune checkpoint inhibitor is atezolizumab, cemiplimab, cemiplimab-rwlc, dostarimab, durvalumab, or nivolumab.

[0393] In certain embodiments, the second anti-cancer agent is a monoclonal antibody that targets a non-checkpoint target (e.g., Herceptin). In certain embodiments, the second anti-cancer agent is a non-cytotoxic agent (e.g., a kinase inhibitor).

[0394] In certain embodiments, the second anticancer agent is selected from the group consisting of mitomycin, ribomustine, vincristine, tretinoin, etoposide, cladribine, gemcitabine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, cytarabine, bicalutamide, and bicarbamate. Selected from norelbine, vesnarinone, flutamide, drogenil, butosin, carmofur, razoxane, sizofiran, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, colony-stimulating factor-1, colony-stimulating factor-2, denileukin diftitox, interleukin-2, luteinizing hormone-releasing factor, interferon alpha, interferon-2 alpha, interferon beta, and interferon gamma.

[0395] In certain embodiments, the second anticancer agent is paclitaxel, docetaxel, cisplatin, epirubicin, 5-fluorouracil, or capecitabine. In certain embodiments, the second anticancer agent is ixabepilone or eribulin. In certain embodiments, the second anticancer agent is ART558. In certain embodiments, the second anticancer agent is lapatinib, neratinib, or tucatinib. In certain embodiments, the second anticancer agent is fulvestrant. In certain embodiments, the second anticancer agent is anastrozole or exemestane. In certain embodiments, the second anticancer agent is MK2206. In certain embodiments, the second anticancer agent is dacomitinib, mobocertinib, necitumumab, or amivantamab. In certain embodiments, the second anticancer agent is pemetrexed. In certain embodiments, the second anticancer agent is brigatinib. In certain embodiments, the second anticancer agent is capmatinib or tepotinib. In certain embodiments, the second anticancer agent is entrectinib. In certain embodiments, the second anticancer agent is pralsetinib or selpercatinib. In certain embodiments, the second anticancer agent is ipilimumab. In certain embodiments, the second anticancer agent is sotorasib. In certain embodiments, the second anticancer agent is topotecan or irinotecan. In certain embodiments, the second anticancer agent is lurbinectedin, melphalan, or thiotepa. In certain embodiments, the second anticancer agent is trifluridine or tipiracil. In certain embodiments, the second anticancer agent is megestrol. In certain embodiments, the second anticancer agent is sunitinib. In certain embodiments, the second anti-cancer agent is lanreotide or lutetium. In certain embodiments, the second anti-cancer agent is belzutifan.

[0396] In certain embodiments, the second anticancer agent is an ALK inhibitor, an ATR inhibitor, an A2A antagonist, a base excision repair inhibitor, a Bcr-Abl tyrosine kinase inhibitor, a Bruton's tyrosine kinase inhibitor, a CDC7 inhibitor, a CHK1 inhibitor, a cyclin-dependent kinase inhibitor, a DNA-PK inhibitor, an inhibitor of both DNA-PK and mTOR, a DNMT1 inhibitor, a DNMT1 inhibitor plus 2-chloro-deoxyadenosine, an HDAC inhibitor, a hedgehog signaling pathway inhibitor, an IDO inhibitor, a JAK inhibitor, an mTOR inhibitor, a MEK inhibitor, a MELK inhibitor, an MTH1 inhibitor, a PARP inhibitor, a phosphonitide 3-kinase inhibitor, an inhibitor of both PARP1 and DHODH, a proteasome inhibitor, a topoisomerase-II inhibitor, a tyrosine kinase inhibitor, a VEGFR inhibitor, or a WEE1 inhibitor.

[0397] In certain embodiments, the second anticancer agent is an ALK inhibitor. In certain embodiments, the second anticancer agent is an ALK inhibitor comprising ceritinib or crizotinib. In certain embodiments, the second anticancer agent is an ALK inhibitor comprising lorlatinib. In certain embodiments, the second anticancer agent is an ATR inhibitor. In certain embodiments, the second anticancer agent is an ATR inhibitor comprising AZD6738 or VX-970. In certain embodiments, the second anticancer agent is an ATR inhibitor comprising BAY1895344 or M4344. In certain embodiments, the second anticancer agent is an A2A antagonist. In certain embodiments, the second anticancer agent is a base excision repair inhibitor comprising methoxyamine. In certain embodiments, the second anticancer agent is a base excision repair inhibitor such as methoxyamine. In certain embodiments, the second anticancer agent is a Bcr-Abl tyrosine kinase inhibitor. In certain embodiments, the second anticancer agent is a Bcr-Abl tyrosine kinase inhibitor, including dasatinib or nilotinib. In certain embodiments, the second anticancer agent is a Bruton's tyrosine kinase inhibitor. In certain embodiments, the second anticancer agent is a Bruton's tyrosine kinase inhibitor, including ibrutinib. In certain embodiments, the second anticancer agent is a CDC7 inhibitor. In certain embodiments, the second anticancer agent is a CDC7 inhibitor, including RXDX-103 or AS-141.

[0398] In certain embodiments, the second anticancer agent is a CHK1 inhibitor. In certain embodiments, the second anticancer agent is a CHK1 inhibitor comprising MK-8776, ARRY-575, or SAR-020106. In certain embodiments, the second anticancer agent is a CHK1 inhibitor comprising AZD7762. In certain embodiments, the second anticancer agent is a cyclin-dependent kinase inhibitor. In certain embodiments, the second anticancer agent is a cyclin-dependent kinase inhibitor comprising palbociclib. In certain embodiments, the second anticancer agent is a cyclin-dependent kinase inhibitor comprising abemaciclib or ribociclib. In certain embodiments, the second anticancer agent is a DNA-PK inhibitor. In certain embodiments, the second anticancer agent is a DNA-PK inhibitor comprising MSC2490484A. In certain embodiments, the second anticancer agent is an inhibitor of both DNA-PK and mTOR. In certain embodiments, the second anticancer agent comprises CC-115.

[0399] In certain embodiments, the second anticancer agent is a DNMT1 inhibitor. In certain embodiments, the second anticancer agent is a DNMT1 inhibitor comprising decitabine, RX-3117, guadecitabine, NUC-8000, or azacitidine. In certain embodiments, the second anticancer agent comprises a DNMT1 inhibitor and 2-chloro-deoxyadenosine. In certain embodiments, the second anticancer agent comprises ASTX-727.

[0400] In certain embodiments, the second anticancer drug is a HDAC inhibitor.In certain embodiments, the second anticancer drug is a HDAC inhibitor, including OBP-801, CHR-3996, echinostate, resminostate, pracinostat, CG-200745, panobinostat, romidepsin, mocetinostat, belinostat, AR-42, ricolinostat, KA-3000 or ACY-241.

[0401] In certain embodiments, the second anticancer agent is a hedgehog signaling pathway inhibitor. In certain embodiments, the second anticancer agent is a hedgehog signaling pathway inhibitor comprising sonidegib or vismodegib. In certain embodiments, the second anticancer agent is an IDO inhibitor. In certain embodiments, the second anticancer agent is an IDO inhibitor comprising INCB024360. In certain embodiments, the second anticancer agent is a JAK inhibitor. In certain embodiments, the second anticancer agent is a JAK inhibitor comprising ruxolitinib or tofacitinib. In certain embodiments, the second anticancer agent is an mTOR inhibitor. In certain embodiments, the second anticancer agent is an mTOR inhibitor comprising everolimus or temsirolimus. In certain embodiments, the second anticancer agent is a MEK inhibitor. In certain embodiments, the second anticancer agent is a MEK inhibitor comprising cobimetinib or trametinib. In certain embodiments, the second anticancer drug is a MELK inhibitor. In certain embodiments, the second anticancer drug is a MELK inhibitor comprising ARN-7016, APTO-500, or OTS-167. In certain embodiments, the second anticancer drug is an MTH1 inhibitor. In certain embodiments, the second anticancer drug is an MTH1 inhibitor comprising (S)-crizotinib, TH287, or TH588.

[0402] In certain embodiments, the second anticancer agent is a PARP inhibitor. In certain embodiments, the second anticancer agent is a PARP inhibitor including MP-124, olaparib, BGB-290, talazoparib, veliparib, niraparib, E7449, rucaparib, or ABT-767. In certain embodiments, the second anticancer agent is a phosphoinositide 3-kinase inhibitor. In certain embodiments, the second anticancer agent is a phosphoinositide 3-kinase inhibitor including idelalisib. In certain embodiments, the second anticancer agent is a phosphoinositide 3-kinase inhibitor including alpelisib. In certain embodiments, the second anticancer agent is an inhibitor of both PARP1 and DHODH (i.e., an agent that inhibits both poly ADP-ribose polymerase 1 and dihydroorotate dehydrogenase).

[0403] In certain embodiments, the second anticancer drug is a proteasome inhibitor. In certain embodiments, the second anticancer drug is a proteasome inhibitor comprising bortezomib or carfilzomib. In certain embodiments, the second anticancer drug is a topoisomerase II inhibitor. In certain embodiments, the second anticancer drug is a topoisomerase II inhibitor comprising vosaroxin.

[0404] In certain embodiments, the second anticancer agent is a tyrosine kinase inhibitor. In certain embodiments, the second anticancer agent is a tyrosine kinase inhibitor comprising bosutinib, cabozantinib, imatinib, or ponatinib. In certain embodiments, the second anticancer agent is a VEGFR inhibitor. In certain embodiments, the second anticancer agent is a VEGFR inhibitor comprising regorafenib. In certain embodiments, the second anticancer agent is a WEE1 inhibitor. In certain embodiments, the second anticancer agent is a WEE1 inhibitor comprising AZD1775.

[0405] In certain embodiments, the second anti-cancer agent is an agonist of OX40, CD137, CD40, GITR, CD27, HVEM, TNFRSF25 or ICOS.In certain embodiments, the second anti-cancer agent is an agonist of OX40, CD137, CD40 or GITR.In certain embodiments, the second anti-cancer agent is an agonist of CD27, HVEM, TNFRSF25 or ICOS.

[0406] In certain embodiments, the second anti-cancer agent is a second compound provided herein or a pharmaceutically acceptable salt thereof. In certain embodiments, the second anti-cancer agent is a second compound provided herein.

[0407] In certain embodiments, the second anti-cancer drug is stavudine, its prodrug, or any of the aforementioned pharmaceutically acceptable salts.In certain embodiments, the second anti-cancer drug is stavudine, stampidine, or any of the aforementioned pharmaceutically acceptable salts.In certain embodiments, the second anti-cancer drug is stavudine or stampidine.

[0408] In certain embodiments, the second anticancer drug is tenofovir, its prodrug, or any of the pharmaceutically acceptable salts thereof.In certain embodiments, the second anticancer drug is tenofovir, tenofovir alafenamide, tenofovir amibuphenamide, tenofovir disoproxil, or tenofovir exalidex, or a pharmaceutically acceptable salt thereof.In certain embodiments, the second anticancer drug is tenofovir, tenofovir alafenamide, tenofovir amibuphenamide, tenofovir disoproxil, or tenofovir exalidex.

[0409] In certain embodiments, the second anti-cancer agent is tenofovir or a pharmaceutically acceptable salt thereof. In certain embodiments, the second anti-cancer agent is tenofovir. In certain embodiments, the second anti-cancer agent is tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In certain embodiments, the second anti-cancer agent is tenofovir alafenamide. In certain embodiments, the second anti-cancer agent is tenofovir amibuphenamide or a pharmaceutically acceptable salt thereof. In certain embodiments, the second anti-cancer agent is tenofovir amibuphenamide. In certain embodiments, the second anti-cancer agent is tenofovir disoproxil or a pharmaceutically acceptable salt thereof. In certain embodiments, the second anti-cancer agent is tenofovir disoproxil, or its fumarate, succinate, maleate, orotate, aspartate, or phosphate salt. In certain embodiments, the second anticancer drug is tenofovir disoproxil, or its fumarate, succinate, or maleate salt. In certain embodiments, the second anticancer drug is tenofovir disoproxil. In certain embodiments, the second anticancer drug is tenofovir exalidex, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second anticancer drug is tenofovir exalidex, or a potassium salt thereof. In certain embodiments, the second anticancer drug is tenofovir exalidex.

[0410] In certain embodiments, the method further comprises administering to the subject a third anti-cancer agent. In certain embodiments, the method further comprises administering to the subject a fourth anti-cancer agent. In certain embodiments, the method further comprises administering to the subject a fifth anti-cancer agent.

[0411] In certain embodiments, the third anticancer drug is one of the second anticancer drugs described above. In certain embodiments, the fourth anticancer drug is one of the second anticancer drugs described above. In certain embodiments, the fifth anticancer drug is one of the second anticancer drugs described above.

[0412] Autoimmune disorders Another aspect of the present disclosure provides a method of treating an autoimmune disorder in a patient. The method comprises administering to a subject in need of treatment (i) a therapeutically effective amount of a compound according to Formula I, including a compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof, and (ii) a second therapeutic agent, to treat the autoimmune disorder. In certain embodiments, the method comprises administering to a subject in need of treatment (i) a therapeutically effective amount of a compound described herein (such as a compound of Formula I, II, III, IV, V, or VI), or a pharmaceutically acceptable salt thereof, and (ii) a second therapeutic agent, to treat the autoimmune disorder.

[0413] In certain embodiments, the second therapeutic agent is a small molecule or a recombinant biological agent. In certain embodiments, the second therapeutic agent is a nonsteroidal anti-inflammatory drug (NSAIDS) such as acetaminophen, aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib; a corticosteroid such as colchicine (Colcrys®), prednisone, prednisolone, methylprednisolone, hydrocortisone; a steroid such as probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), benzodiazepine (Bordeaux ... Antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®, Neoral®), tacrolimus, sirolimus, mycophenolate, leflunomide (Arava®), as well as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), and adalimumab (Humira®). "Anti-TNF" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), "anti-IL-1" agents such as thymoglobulin, IV immunoglobulin (IVIg), anti-T cell antibodies such as canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), tocilizumab (Actemra®), diclofenac, cortisone,"Anti-IL-6" agents such as hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil® and loperamide (Imodium®)), cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), bile acid binders such as benzodiazepines (Bile Acid Binding Agents), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®, Dulcolax®), Correctol®, and Senokot®, anticholinergics or anticonvulsants such as dicyclomine (Bentyl®), Singulair®, albuterol (Ventolin® HFA, Proventil® HFA), levartrol (Xopenex®), metaproterenol (Alupent®), beta-2 agonists such as pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®); anticholinergics such as ipratropium bromide (Atrovent® and tiotropium (Spiriva®); beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®); Inhaled corticosteroids such as liamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®,Methylxanthines such as Theo-24® and aminophylline, IgE antibodies such as omalizumab (Xolair®), zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combi nucleoside reverse transcriptase inhibitors such as delavirdine (Delavirdine), efavirenz (Sustiva), nevirapine (Viramune), and etravirine (Intelence); nucleotide reverse transcriptase inhibitors such as tenofovir (Viread); amprenavir (Agenerase), atazanavir (Reyataz); (R), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and protease inhibitors such as tipranavir (Aptivus®), enfuvirtide (Fuzeon® and entry inhibitors such as maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone Decadron® in combination with lenalidomide (Revlimid®), anti-IL36 agents such as BI655130, dihydroorotate oxidase inhibitors such as IMU-838,Anti-OX40 agents such as KHK-4083, microbiota agents such as RBX2660 and SER-287, narrow-spectrum kinase inhibitors such as TOP-1288, anti-CD40 agents such as BI-655064 and FFP-104, guanylate cyclase agonists such as dolucanatide, sphingosine kinase inhibitors such as opaganib, anti-IL-12 / IL-23 agents such as AK-101, ubiquitin protein ligase complex inhibitors such as BBT-401, and BMS-986 Sphingosine receptor modulators such as 166, P38MAPK / PDE4 inhibitors such as CBS-3595, CCR9 antagonists such as CCX-507, FimH antagonists such as EB-8018, HIF-PH inhibitors such as FG-6874, HIF-1α stabilizers such as GB-004, MAP3K8 protein inhibitors such as GS-4875, LAG-3 antibodies such as GSK-2831781, and RIP2 inhibitors such as GSK-2983559. kinase inhibitors, farnesoid X receptor agonists such as MET-409, CCK2 antagonists such as PNB-001, IL-23 receptor antagonists such as PTG-200, purinergic P2X7 receptor antagonists such as SGM-1019, PDE4 inhibitors such as apremilast, ICAM-1 inhibitors such as alicaforsen sodium, anti-IL23 agents such as guselkumab, brazikumab, and mirquizumab, AMG-714, etc. anti-IL-15 agents such as BMS-986165, TYK-2 inhibitors such as BMS-986165, NK cell activators such as CNDO-201, RIP-1 kinase inhibitors such as GSK-2982772, anti-NKGD2 agents such as JNJ-4500, CXCL-10 antibodies such as JT-02, IL-22 receptor agonists such as RG-7880, GATA-3 antagonists such as SB-012, and colony-stimulating factor-1 receptor inhibitors such as edicotinib.

[0414] In certain embodiments, the second therapeutic agent is selected from the group consisting of pentoxifylline, propentofylline, torbafillin, cyclosporine, methotrexate, tamoxifen, forskolin and its analogs, tar derivatives, steroids, vitamin A and its derivatives, vitamin D and its derivatives, cytokines, chemokines, stem cell growth factors, lymphotoxins, hematopoietic factors, colony-stimulating factors (CSFs), erythropoietin, thrombopoietin, tumor necrosis factor-α (TNF), TNF-θ, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-α, interferon-β, interferon-γ, interferon-λ, stem cell growth factors designated "S1 factor," human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxine, insulin, proinsulin, relaxin, prolepsy hormone, steroids, and the like. Laxin, follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, Müllerian inhibitory substance, mouse gonadotropin-related peptide, inhibin, activin, vascular endothelial growth factor, integrin, NGF-β, platelet growth factor, TGF-α, TGF-β, insulin-like growth factor I, insulin-like The antibody is selected from growth factor II, macrophage-CSF (M-CSF), IL-1, IL-1a, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21, IL-25, LIF, FLT-3, angiostatin, thrombospondin, endostatin, or lymphotoxin.

[0415] In certain embodiments, the second therapeutic agent is a second compound provided herein or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is a second compound provided herein.

[0416] In certain embodiments, the second therapeutic agent is stavudine, a prodrug thereof, or a pharmaceutically acceptable salt of any of the foregoing. In certain embodiments, the second therapeutic agent is stavudine, stampidine, or a pharmaceutically acceptable salt of any of the foregoing. In certain embodiments, the second therapeutic agent is stavudine or stampidine.

[0417] In certain embodiments, the second therapeutic agent is tenofovir, a prodrug thereof, or a pharmaceutically acceptable salt of any of the foregoing. In certain embodiments, the second therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibuphenamide, tenofovir disoproxil, or tenofovir exalidex, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibuphenamide, tenofovir disoproxil, or tenofovir exalidex.

[0418] In certain embodiments, the second therapeutic agent is tenofovir or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir. In certain embodiments, the second therapeutic agent is tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir alafenamide. In certain embodiments, the second therapeutic agent is tenofovir amibuphenamide or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir amibuphenamide. In certain embodiments, the second therapeutic agent is tenofovir disoproxil or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or its fumarate, succinate, maleate, orotate, aspartate, or phosphate salt. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or its fumarate, succinate, or maleate salt. In certain embodiments, the second therapeutic agent is tenofovir disoproxil. In certain embodiments, the second therapeutic agent is tenofovir exalidex or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir exalidex or a potassium salt thereof. In certain embodiments, the second therapeutic agent is tenofovir exalidex.

[0419] In certain embodiments, the method further comprises administering to the subject a third therapeutic agent. In certain embodiments, the method further comprises administering to the subject a fourth therapeutic agent. In certain embodiments, the method further comprises administering to the subject a fifth therapeutic agent.

[0420] In certain embodiments, the third therapeutic agent is one of the second therapeutic agents described above. In certain embodiments, the fourth therapeutic agent is one of the second therapeutic agents described above. In certain embodiments, the fifth therapeutic agent is one of the second therapeutic agents described above.

[0421] Viral infections Another aspect of the present disclosure provides a method for treating an immune disorder in a patient, the immune disorder being a viral infection. The method includes administering to a subject in need of treatment (i) a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I, II, III, IV, V, or VI), or a pharmaceutically acceptable salt thereof, and (ii) a second therapeutic agent, to treat the immune disorder being a viral infection. In certain embodiments, the immune disorder is a viral infection other than an influenza virus infection.

[0422] In certain embodiments, the second therapeutic agent is an anti-HIV agent. In certain embodiments, the second therapeutic agent is a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, or a fusion inhibitor. In certain embodiments, the second therapeutic agent is 3TC (lamivudine), AZT (zidovudine), (-)-FTC, ddI (didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (stavudine), rasvir, L-FddC, L-FD4C, NVP (nevirapine), DLV (delavirdine), EFV (efavirenz), SQVM (saquinavir mesylate), RTV (ritonavir), IDV (indinavir), SQV (saquinavir), NFV (nelfinavir), APV (amprenavir), LPV (lopinavir), or the fusion inhibitor T20.

[0423] In certain embodiments, the second therapeutic agent is ddC, abacavir, ddI, ddA, 3TC, AZT, D4T, FTC, FddC, Fd4C, atazanavir, adefovir dipivoxil, tenofovir disoproxil, etecavir, indinavir, KHI-227. 2-[3-[3-(S)-[[(tetrahydrofuranyloxy)carbonyl]amino]-4-phenyl-2(R)-hydroxybutyl]]-N-(1,1-dimethylethyl)decahydro-3-isoquinolinecarboxamide, VB-11,328, KNI-174, Val-Sta , CPG53820, HOEt-N2 aza-peptide isostere, 2,5-diamino-N,N'-bis(N-benzyloxycarbonylwellyl)-1,6-diphenyl-3(S),4(S)-hexanediol BzOCValPhe[diCHOH(SS)]PheValBzOC, 2,5-diamino-N,N'-bis(N-benzyloxycarbonylwellyl)-1,6-diphenyl-3(R),4(R)-hexanediol BzOCValPhe[diCHOH(RR)]PheValBzOC, [bis(SATE)ddAMP], BILA 2186 BS, Agenerase, A-98881, A-83962, A-80987, (2-Naphthalcarbonyl)Asn[decarbonylPhe-hydroxyethyl]proOtertButyl, A-81525, XM323, Tipranavir, SDZ PRI 053, SD146, Tellinavir, (R)2QuinCOAsnPhe[CHOHCH2]PipCONHtBu, Saquinavir, R-87366, DMP 460, L685,434, L685,434-OEtNMe2, L689,502, Lacinavir, Aluviran P9941, parinavir, or penicillin. In certain embodiments, the second therapeutic agent is ddC, abacavir, ddI, ddA, 3TC, AZT, D4T, FTC, FddC, or Fd4C.

[0424] In certain embodiments, the second therapeutic agent is tenofovir, a prodrug thereof, or a pharmaceutically acceptable salt of any of the foregoing. In certain embodiments, the second therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibuphenamide, tenofovir disoproxil, or tenofovir exalidex, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibuphenamide, tenofovir disoproxil, or tenofovir exalidex.

[0425] In certain embodiments, the second therapeutic agent is tenofovir or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir. In certain embodiments, the second therapeutic agent is tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir alafenamide. In certain embodiments, the second therapeutic agent is tenofovir amibuphenamide or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir amibuphenamide. In certain embodiments, the second therapeutic agent is tenofovir disoproxil or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or its fumarate, succinate, maleate, orotate, aspartate, or phosphate salt. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or its fumarate, succinate, or maleate salt. In certain embodiments, the second therapeutic agent is tenofovir disoproxil. In certain embodiments, the second therapeutic agent is tenofovir exalidex or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir exalidex or a potassium salt thereof. In certain embodiments, the second therapeutic agent is tenofovir exalidex.

[0426] In certain embodiments, the method further comprises administering to the subject a third therapeutic agent. In certain embodiments, the method further comprises administering to the subject a fourth therapeutic agent. In certain embodiments, the method further comprises administering to the subject a fifth therapeutic agent.

[0427] In certain embodiments, the third therapeutic agent is one of the second therapeutic agents described above. In certain embodiments, the fourth therapeutic agent is one of the second therapeutic agents described above. In certain embodiments, the fifth therapeutic agent is one of the second therapeutic agents described above.

[0428] Neuropathy Another aspect of the present disclosure provides a method of treating a neurological disorder in a patient. The method comprises administering to a subject in need of treatment (i) a therapeutically effective amount of a compound according to Formula I, including a compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof, and (ii) a second therapeutic agent, to treat the neurological disorder. In certain embodiments, the method comprises administering to a subject in need of treatment (i) a therapeutically effective amount of a compound described herein (such as a compound of Formula I, II, III, IV, V, or VI), or a pharmaceutically acceptable salt thereof, and (ii) a second therapeutic agent, to treat the neurological disorder.

[0429] In certain embodiments, the second therapeutic agent is a dopaminergic therapy, a cholinesterase inhibitor, an antipsychotic, deep brain stimulation (e.g., to stop tremors and intractable movement disorders), riluzole, a caffeine A2A receptor antagonist, pramipexole, or rasagiline.

[0430] In certain embodiments, the second therapeutic agent is a second compound provided herein or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is a second compound provided herein.

[0431] In certain embodiments, the second therapeutic agent is stavudine, a prodrug thereof, or a pharmaceutically acceptable salt of any of the foregoing. In certain embodiments, the second therapeutic agent is stavudine, stampidine, or a pharmaceutically acceptable salt of any of the foregoing. In certain embodiments, the second therapeutic agent is stavudine or stampidine.

[0432] In certain embodiments, the second therapeutic agent is tenofovir, a prodrug thereof, or a pharmaceutically acceptable salt of any of the foregoing. In certain embodiments, the second therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibuphenamide, tenofovir disoproxil, or tenofovir exalidex, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibuphenamide, tenofovir disoproxil, or tenofovir exalidex.

[0433] In certain embodiments, the second therapeutic agent is tenofovir or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir. In certain embodiments, the second therapeutic agent is tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir alafenamide. In certain embodiments, the second therapeutic agent is tenofovir amibuphenamide or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir amibuphenamide. In certain embodiments, the second therapeutic agent is tenofovir disoproxil or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or its fumarate, succinate, maleate, orotate, aspartate, or phosphate salt. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or its fumarate, succinate, or maleate salt. In certain embodiments, the second therapeutic agent is tenofovir disoproxil. In certain embodiments, the second therapeutic agent is tenofovir exalidex or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir exalidex or a potassium salt thereof. In certain embodiments, the second therapeutic agent is tenofovir exalidex.

[0434] In certain embodiments, the method further comprises administering to the subject a third therapeutic agent. In certain embodiments, the method further comprises administering to the subject a fourth therapeutic agent. In certain embodiments, the method further comprises administering to the subject a fifth therapeutic agent.

[0435] In certain embodiments, the third therapeutic agent is one of the second therapeutic agents described above. In certain embodiments, the fourth therapeutic agent is one of the second therapeutic agents described above. In certain embodiments, the fifth therapeutic agent is one of the second therapeutic agents described above.

[0436] V. Pharmaceutical Composition and Administration Considerations As noted above, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the compounds described above, formulated with one or more pharmaceutically acceptable carriers, adjuvants, and / or vehicles. The pharmaceutical compositions can be specially formulated for administration in solid or liquid form, including those adapted for: (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and those intended for systemic absorption, boluses, powders, granules, pastes for application to the tongue, (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained-release formulation, (3) topical application, e.g., as a cream, ointment, or controlled-release patch or spray applied to the skin, (4) vaginal or rectal administration, e.g., as a suppository, cream, or foam, (5) sublingual administration, (6) ocular administration, (7) transdermal administration, or (8) nasal administration.

[0437] In certain embodiments, the present invention provides pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula I) and a pharmaceutically acceptable carrier. In certain embodiments, the present invention provides pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula I), an additional therapeutic agent (e.g., a compound described in Section IV), and a pharmaceutically acceptable carrier.

[0438] The phrase "therapeutically effective amount," as used herein, means an amount of a compound, material, or composition, including a compound of the invention, that is effective to produce a desired therapeutic effect in at least a subpopulation of cells in an animal, at a reasonable benefit / risk ratio applicable to any medical treatment.

[0439] The phrase "pharmaceutically acceptable" is employed herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0440] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0441] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0442] 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 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. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0443] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier(s), and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0444] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powder, granules, each containing a predetermined amount of a compound of the present invention as the active ingredient, or as a solution or 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 a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, etc. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0445] In the solid dosage forms of the present invention for oral administration (capsules, tablets, pills, dragees, powders, granules, lozenges, etc.), 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) excipients or fillers, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and the like. (5) disintegrating agents such as sodium carbonate, (6) solution retarders such as paraffin, (7) absorption enhancers such as quaternary ammonium compounds, and surfactants such as poloxamer and sodium lauryl sulfate, (8) wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants, (9) absorbents such as kaolin and bentonite clay, (10) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof, (11) coloring agents, and (12) controlled-release agents such as crospovidone and ethylcellulose. In the case of capsules, tablets, and pills, pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shell gelatin capsules, using additives such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0446] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0447] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide sustained or controlled release of the active ingredient therein, using, for example, hydroxypropyl methylcellulose in various proportions to provide the desired release profile, other polymer matrices, liposomes, and / or microspheres. They can also be formulated for rapid release, e.g., lyophilized. They can also be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents and can be compositions that release the active ingredient(s) only, or preferentially, in a certain portion of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0448] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form can contain the inert diluent commonly used in the art, such as water or other solvent, solubilizer, emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0449] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0450] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0451] Formulations of pharmaceutical compositions of the invention for rectal or vaginal administration may be provided as suppositories, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound(s).

[0452] 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.

[0453] Dosage forms for 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 that may be required.

[0454] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0455] Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0456] Transdermal patches have the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable 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.

[0457] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present invention.

[0458] Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0459] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0460] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action on the target compounds can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars and sodium chloride, in the compositions. In addition, prolonged absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0461] In some cases, in order to prolong the effect of a drug, it is desirable to slow down the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of the drug then depends on its dissolution rate, which in turn depends on the crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0462] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the drug-to-polymer ratio and the properties of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0463] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they may be administered as they are or, for example, in combination with a pharmaceutically acceptable carrier, as a pharmaceutical composition containing 0.1 to 99% (more preferably, 10 to 30%) of the active ingredient.

[0464] The preparations of the present invention can be administered orally, parenterally, topically, or rectally. They are naturally administered in a form suitable for each administration route. For example, they are administered in tablet or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., by injection, infusion, or inhalation, by topical administration with lotion or ointment, and by rectal administration with suppositories. Oral administration is preferred.

[0465] The phrases "parenteral administration" and "administered parenterally" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intrathecal, and intrasternal injection and infusion.

[0466] The phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally," as used herein, refer to administration of a compound, drug, or other material other than directly into the central nervous system, e.g., subcutaneous administration, so that it enters the patient's system and therefore is subject to metabolic and other similar processes.

[0467] These compounds may be administered to humans and other animals for treatment by any suitable route of administration, including orally, nasally, e.g., by spray, rectally, intravaginally, parenterally, intracisternally, and topically, including buccal and sublingually, as by powders, ointments, or drops.

[0468] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0469] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0470] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the invention employed, or its ester, salt, or amide, the route of administration, the timing of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health, and medical history of the patient being treated, and similar factors well known in the medical arts.

[0471] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian may start dosages of the compounds of the invention employed in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0472] In general, a suitable daily dose of a compound of the present invention will be that amount of compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. Preferably, the compound is administered at about 0.01 mg / kg to about 200 mg / kg, more preferably about 0.1 mg / kg to about 100 mg / kg, and even more preferably about 0.5 mg / kg to about 50 mg / kg. When a compound described herein is co-administered with another agent (e.g., as a sensitizing agent), the effective amount may be less than when the agent is used alone.

[0473] If desired, the effective daily amount 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 administration is a once-daily administration.

[0474] The present invention further provides unit dosage forms (such as tablets or capsules) comprising censavudine or related compounds described herein in a therapeutically effective amount for the treatment of the medical disorders described herein.

[0475] VI. Enumerated Embodiments Additional aspects of the invention are described in the enumerated embodiments below. Embodiment 1. A compound according to formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: B, [ka] and R 1 is -H or [ka] Alk is, independently for each occurrence, a C2-C6 aliphatic group; R 2is -H, C1-C6 aliphatic, C1-C3 haloaliphatic, C1-C3 hydroxyalkyl, cyclopropyl, -CN, -N3, -O-(C1-C3 aliphatic), -F, or -Cl; R 3 is -H, R 4 is -OH, -Cl, -OCH3, -F, -N3, or [ka] and R 5 is -H or -F, R 6 is -H, -F, -Cl, C1-C6 aliphatic, C1-C4 haloaliphatic, -O-(C1-C4 aliphatic), cyclopropyl, or -OH, or a pharmaceutically acceptable salt thereof. Embodiment 2. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Alk is, independently for each occurrence, ethyl, propyl, isopropyl, sec-butyl, tert-butyl, or iso-butyl. Embodiment 3.R 1 But -H or [ka] 3. The compound of embodiment 1 or 2, wherein: Embodiment 4.R 1

[0023] The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein is -H. Embodiment 5.R 5

[0023] The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein is -H. Embodiment 6.R 2

[0023] The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein is not -H. Embodiment 7.R 4 But -OH or [ka] or a pharmaceutically acceptable salt thereof. Embodiment 8.R 6

[0039] The compound of any one of the preceding embodiments, wherein is -H, -F, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -CH=CH2, -CH2F, or -CH2Cl, or a pharmaceutically acceptable salt thereof. Embodiment 9.R 6

[0039] The compound of any one of the preceding embodiments, wherein is -H or -F, or a pharmaceutically acceptable salt thereof. Embodiment 10.R 6

[0023] The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein is -H. Embodiment 11.R 6 The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein is —F. Embodiment 12.B is [ka] or a pharmaceutically acceptable salt thereof. Embodiment 13.B is [ka] or a pharmaceutically acceptable salt thereof. Embodiment 14.R 2 is —CH3, —CF3, —N3, —OCH3, —CH2Cl, —CH2F, —CHF2, —CHCl2, —CHClF, —CH2CH3, —CH═CH2, cyclopropyl, or —C≡CH, or a pharmaceutically acceptable salt thereof. Embodiment 15.R 2 14. The compound of any one of embodiments 1-13, wherein is -N3, -CH3, -CH2Cl, -CH2F, -CH=CH2, or -C≡CH, or a pharmaceutically acceptable salt thereof. Embodiment 16.R 214. The compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein is —CH 2 Cl, —CH 2 F, or —C≡CH. Embodiment 17.R 2 14. The compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein is —CH 2 Cl or —C≡CH. Embodiment 18.R 2

[0023] The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein is -CH2Cl. Embodiment 19. R 4 is -OH, R 5 is -H, R 6 is H, or a pharmaceutically acceptable salt thereof. Embodiment 20.R 2 is —CH 2 Cl, or a pharmaceutically acceptable salt thereof. Embodiment 21. A compound of embodiment 1 selected from the group consisting of: [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] or a pharmaceutically acceptable salt thereof. Embodiment 22. A compound of Table 1, 1-A, or 1-B herein, or a pharmaceutically acceptable salt thereof. Embodiment 23. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 21, or a pharmaceutically acceptable salt thereof, and a carrier, excipient, and / or vehicle. Embodiment 24. A pharmaceutical composition comprising a compound according to embodiment 22, or a pharmaceutically acceptable salt thereof, and a carrier, excipient, and / or vehicle. Embodiment 25. A method for treating a disorder selected from the group consisting of cancer, autoimmune disorders, and neurological disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I as described in any one of embodiments 1 to 21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in embodiment 23, to treat the disorder. Embodiment 26 The method of embodiment 25, wherein the method further comprises administering an effective amount of an additional therapeutic agent. Embodiment 27. A method for inhibiting LINE1 reverse transcriptase activity in a subject suffering from a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder, comprising contacting the LINE1 reverse transcriptase with an effective amount of a compound of formula I, as described in any one of embodiments 1 to 21, or a pharmaceutically acceptable salt thereof, or a composition as described in embodiment 23, to inhibit the activity of the LINE1 reverse transcriptase. Embodiment 28 The method of embodiment 27, wherein the method further comprises inhibiting HERV-K reverse transcriptase activity in the subject. Embodiment 29. A method for inhibiting HERV-K reverse transcriptase activity in a subject suffering from a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder, comprising contacting the HERV-K reverse transcriptase with an effective amount of a compound of formula I as described in any one of embodiments 1 to 21, or a pharmaceutically acceptable salt thereof, or a composition as described in embodiment 23, to inhibit the activity of the HERV-K reverse transcriptase. Embodiment 30. The compound is selected from the group consisting of: [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8] [Table 11-9] [Table 11-10] 30. The method of any one of embodiments 25-29, wherein said compound is selected from the group consisting of acetaminophen, ... Embodiment 31. The method of any one of embodiments 25 to 30, wherein the disorder is cancer. Embodiment 32. The method of embodiment 31, wherein 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, gastric cancer, bile duct cancer, cholangiocarcinoma, 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. Embodiment 33. The method of any one of embodiments 25 to 30, wherein the disorder is an autoimmune disorder. Embodiment 34. The method of embodiment 33, wherein the autoimmune disorder is selected from Aicardi-Goutieres syndrome, rheumatoid arthritis, psoriasis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), graft-versus-host disease, scleroderma, type 1 diabetes, dermatomyositis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, vasculitis, and Sjogren's syndrome. Embodiment 35. The method of any one of embodiments 25 to 30, wherein the disorder is a neurological disorder. Embodiment 36. The method of embodiment 35, wherein 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-Jakob disease, stroke, prion disease, frontotemporal dementia, Pick's disease, progressive supranuclear palsy, spinocerebellar ataxia, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, or major depression. Embodiment 37. The method of any one of embodiments 25 to 36, wherein 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. Embodiment 38. The method of any one of embodiments 25 to 37, wherein the subject has (i) HERV-K RNA expression and / or (ii) HERV-K reverse transcriptase activity. Embodiment 39. The method of any one of embodiments 25 to 38, wherein the subject is a human. [Example]

[0476] The invention generally described herein will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention. Starting materials described herein can be obtained from commercial sources or can be readily prepared from commercially available materials using transformations known to those skilled in the art.

[0477] Example 1 - Synthesis of Compound 44: 4-amino-1-((2R,4S,5R)-5-ethyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one [ka] Step 1: To a stirred solution of 2'-deoxyuridine (50 g, 219.1 mmol) and imidazole (149.1 g, 2191.0 mmol) in pyridine (500 mL) was added TBSCl (99.1 g, 657.3 mmol) in small portions at room temperature under a nitrogen atmosphere. The mixture was stirred at 80 °C for 15 h. LCMS showed the reaction was complete. The mixture was cooled to room temperature, diluted with EA, washed with brine, and dried over anhydrous Na2SO4. The solids were filtered off, and the combined filtrates were concentrated to give 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}oxolan-2-yl]-3H-pyrimidine-2,4-dione (98 g, 215 mmol, crude) as a pale yellow oil. Product (ES, m / z): 457(M+H + ).

[0478] Step 2: To a stirred solution of 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}oxolan-2-yl]-3H-pyrimidine-2,4-dione (90 g, 197.1 mmol) in methanol (500 mL) was added PPTS (74.3 g, 295.5 mmol) in small portions at room temperature under a nitrogen atmosphere. The mixture was stirred at 35° C. for 15 h. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was diluted with EA, washed with an aqueous solution of citric acid and brine, and dried over anhydrous Na2SO4. The solid was filtered off, and the combined filtrates were concentrated under reduced pressure to give 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (65 g, 190 mmol, crude) as a white solid. Product (ES, m / z): 343 (M+H + ).

[0479] Step 3: To a stirred solution of 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (65 g, 189.7 mmol) in CHCN (500 mL) was added IBX (159.4 g, 569.4 mmol). The mixture was stirred at 60 °C for 3 h. LCMS indicated the reaction was complete. The reaction was cooled to room temperature. The solids were filtered off, and the filtrate was concentrated to give (2S,3S,5R)-3-[(tert-butyldimethylsilyl)oxy]-5-(2,4-dioxo-3H-pyrimidin-1-yl)oxolane-2-carbaldehyde (60 g, 176 mmol, crude) as an off-white solid. Product (ES, m / z): 341(M+H + ).

[0480] Step 4: To a stirred solution of (2S,3S,5R)-3-[(tert-butyldimethylsilyl)oxy]-5-(2,4-dioxo-3H-pyrimidin-1-yl)oxolane-2-carbaldehyde (60 g, 176.2 mmol) and formaldehyde (26.4 g, 881.1 mmol) in dioxane (500 mL) was added dropwise a solution of NaOH (21.1 g, 528.7 mmol) in water (50 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 hours. LCMS showed that the starting material was consumed, and then NaBH (20 g, 528.7 mmol) was added at 0° C. The mixture was stirred at 0° C. for 30 minutes, and LCMS showed that the reaction was complete. The reaction was quenched with aqueous NH Cl and extracted with EA. The combined organics were washed with brine and dried over anhydrous Na2SO4. The solids were filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluted with methanol / dichloromethane (7 / 93) to give 1-[(2R,4S)-4-[(tert-butyldimethylsilyl)oxy]-5,5-bis(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (20 g, 53.7 mmol, 30.47%) as a white solid. Product (ES, m / z): 372 (M+H) + ).

[0481] Step 5: To a stirred solution of 1-[(2R,4S)-4-[(tert-butyldimethylsilyl)oxy]-5,5-bis(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (20 g, 53.6 mmol) in pyridine (200 mL) was added 4,4'-(chloro(phenyl)methylene)bis(methoxybenzene) (18 g, 53.6 mmol) in portions at room temperature under a nitrogen atmosphere. The mixture was stirred at 30°C for 3 hours. LCMS showed the reaction was complete. The mixture was used in the next step without further purification. Product (ES, m / z): 675 (M+H + ).

[0482] Step 6: To the above solution was added TBSCl (20 g, 133.3 mmol). The mixture was stirred at 30 °C for 15 h. LCMS showed the reaction was complete. The mixture was diluted with EA and washed with an aqueous solution of citric acid and brine. The organic layer was dried over anhydrous Na2SO4. The solid was filtered off, and the combined filtrate was concentrated under reduced pressure to give 1-[(2R,4S,5R)-5-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}oxolan-2-yl]-3H-pyrimidine-2,4-dione (40 g, 50.7 mmol, crude) as a yellow solid. Product (ES, m / z): 787 (MH + ).

[0483] Step 7: To a stirred solution of 1-[(2R,4S,5R)-5-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}oxolan-2-yl]-3H-pyrimidine-2,4-dione (40 g, 50.6 mmol) in CHCN (50 mL) was added dropwise 80% aqueous CHCOOH (200 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 hours. LCMS showed the reaction was complete. The pH of the reaction was adjusted to 8 with an aqueous solution of sodium bicarbonate and extracted with EA. The combined organics were washed with brine and dried over anhydrous NaSO. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluted with methanol / dichloromethane (3 / 97) to give 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (18 g, 37.0 mmol, 72.95%) as a pale yellow solid. Product (ES, m / z): 487 (M+H + ).

[0484] Step 8: A solution of 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (18 g, 37.0 mmol) and IBX (31 g, 111.1 mmol) in acetonitrile (200 mL) was stirred at 60° C. for 2 hours. LCMS showed the reaction was complete. The reaction was cooled to room temperature, and the solid was filtered off. The filtrates were combined and concentrated under reduced pressure to give (2R,3S,5R)-3-[(tert-butyldimethylsilyl)oxy]-2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-(2,4-dioxo-3H-pyrimidin-1-yl)oxolane-2-carbaldehyde (17 g, 35.1 mmol, crude) as a white solid. Product (ES, m / z): 485 (M+H + ).

[0485] Step 9: To a stirred solution of methyltriphenylphosphonium bromide (37.5 g, 105.2 mmol) in THF (200 mL) was added n-BuLi (42 mL, 105.2 mmol) dropwise at −78° C. under a nitrogen atmosphere. The mixture was stirred at 0° C. for 30 minutes, and then (2R,3S,5R)-3-[(tert-butyldimethylsilyl)oxy]-2-{[(tert-butyldimethylsilyl)oxy]methyl}-5-(2,4-dioxo-3H-pyrimidin-1-yl)oxolane-2-carbaldehyde (17 g, 35.1 mmol) in THF (20 mL) was added. The mixture was stirred at room temperature for 1.5 hours. LCMS indicated the reaction was complete. The reaction was quenched with a solution of NH4Cl and extracted with EA. The combined organics were washed with brine and dried over anhydrous Na2SO4. The solid was filtered off, and the combined filtrates were concentrated. The residue was purified by silica gel column chromatography eluted with EA / PE (1 / 10) to give 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-ethenyloxolan-2-yl]-3H-pyrimidine-2,4-dione (15 g, 31.1 mmol, 88.60%) as an off-white solid. Product (ES, m / z): 483 (M+H + ).

[0486] Step 10: To a stirred solution of 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-ethenyloxolan-2-yl]-3H-pyrimidine-2,4-dione (15 g, 31.1 mmol) and DMAP (7.6 g, 62.1 mmol) in acetonitrile (200 mL) was added TEA (9.4 g, 93.2 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride (18.7 g, 62.1 mmol). The mixture was stirred at room temperature for 1 hour. LCMS indicated the reaction was complete. The reaction was purified by HCl HCl (HCl). .The mixture was quenched with HO. The mixture was then diluted with EA, washed with brine, and dried over anhydrous NaSO. The solid was filtered off, and the combined filtrates were concentrated. The residue was purified by silica gel column chromatography eluted with methanol / dichloromethane (7 / 93) to give 4-amino-1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-ethenyloxolan-2-yl]pyrimidin-2-one (14 g, 29.1 mmol, 93.52%) as a pale yellow solid. Product (ES, m / z): 482 (M+H + ).

[0487] Step 11: To a stirred solution of 4-amino-1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-ethenyloxolan-2-yl]pyrimidin-2-one (13 g, 26.9 mmol, 1 equiv.) in methanol (300 mL) was added Pd / C (2.5 g, w / w=20%). The mixture was stirred at room temperature under an H atmosphere for 15 hours. LCMS showed the reaction was complete. The solid was filtered off, and the combined filtrates were concentrated under reduced pressure to give 4-amino-1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-ethyloxolan-2-yl]pyrimidin-2-one (10 g, 20.7 mmol, crude) as a pale yellow solid. LC-MS (ES, m / z): 484 (M+H). + ).

[0488] Step 12: To a stirred solution of 4-amino-1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-ethyloxolan-2-yl]pyrimidin-2-one (7 g, 14.4 mmol) in MeOH (300 mL) was added NHF (16.1 g, 434.0 mmol). The mixture was stirred at 60 °C for 15 hours. LCMS showed the reaction was complete. The reaction was cooled to room temperature. The solid was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative SFC using the following conditions: (Column: CHIRAL ART Amylose-SA, 7 × 25 cm, 10 μm; Mobile phase A: CO, Mobile phase B: MeOH (0.1% 2M NH-MeOH); Flow rate: 250 mL / min; Gradient: Isocratic 50% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220 nm; RT1 (min): 3.998; Sample solvent: MeOH-preparative; Injection volume: 2 mL; Number of runs: 30) to give 4-amino-1-[(2R,4S,5R)-5-ethyl-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one (1.0023 g, 3.9 mmol, 26.89%) as a white solid. LC-MS (ES, m / z): 256 (M+H + ), 99.1% purity. LCMS conditions: (Column: Shim Pack Scepter C18, 33 x 3.0 mm, 3.0 μm; Mobile phase A: Water / 6.5 mM NH4HCO3, Mobile phase B: ACN; Flow rate: 1.200 mL / min; Gradient: 10% B to 95% B in 1.2 min, 95% B to 95% B in 1.80 min, 95% B to 10% B in 1.82 min; Wavelength: 254 / 220 nm; RT1 (min): 1.033). 1H NMR(300MHz,DMSO-d6)δ 7.86(d,J=7.4Hz,1H),7.11(d,J=20.2Hz,2H),6.08(t,J=6.6Hz,1H),5.70(d,J=7.4Hz,1H),5.05(d,J=4.8Hz,1H),4.96(t,J=5.2Hz,1H) ,4.23(dt,J=5.8,4.1Hz,1H),3.41(h,J=5.9,5.4Hz,2H),2.23-1.98(m,2H),1.54(ddq,J=28.8,14.5,7.3Hz,2H),0.86(t,J=7.5Hz,3H).

[0489] Example 2 - Synthesis of Compound 14: 4-amino-1-((2R,4S,5R)-5-(chloromethyl)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-fluoropyrimidin-2(1H)-one [ka] Step 1: To a stirred mixture of fluoxuridine (4 g, 16.247 mmol) in pyridine (40 mL) was added 1-[chloro(4-methoxyphenyl)phenylmethyl]-4-methoxybenzene (6.06 g, 17.872 mmol) in small portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and concentrated in vacuo. The crude product was recrystallized from petroleum ether / EtOAc (10:1) to give 1-[(2R,4S,5R)-5-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-4-hydroxyoxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (8 g, 89.8%) as a yellow solid. Product (ES, m / z): 549 (M+H + ).

[0490] Step 2: To a stirred mixture of 1-[(2R,4S,5R)-5-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-4-hydroxyoxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (11 g, 20.052 mmol) and imidazole (16.38 g, 240.624 mmol) in DMF (200 mL) was added TBSCl (12.09 g, 80.208 mmol) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and then quenched by the addition of saturated aqueous NaHCO. The resulting mixture was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. This resulted in 1-[(2R,4S,5R)-5-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-4-[(tert-butyldimethylsilyl)oxy]oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (11 g, 82.76%) as a yellow solid. Product (ES, m / z): 663 (M+H + ).

[0491] Step 3: A mixture of 1-[(2R,4S,5R)-5-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-4-[(tert-butyldimethylsilyl)oxy]oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (8 g, 12.069 mmol) in AcOH (80 mL) was stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. This afforded 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-(hydroxymethyl)oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (4 g, 91.94%) as a white solid. Product (ES, m / z): 361(M+H + ).

[0492] Step 4: To a mixture of 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-(hydroxymethyl)oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (5 g, 13.871 mmol) in ACN (100 mL) was added IBX (7.77 g, 27.742 mmol). The reaction mixture was stirred at 60 °C for 2 hours. The resulting mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated in vacuo. This gave (2S,3S,5R)-3-[(tert-butyldimethylsilyl)oxy]-5-(5-fluoro-2,4-dioxo-3H-pyrimidin-1-yl)oxolane-2-carbaldehyde (4.5 g, 90.51%) as a yellow solid. Product (ES, m / z): 359(M+H + ).

[0493] Step 5: To a stirred mixture of (2S,3S,5R)-3-[(tert-butyldimethylsilyl)oxy]-5-(5-fluoro-2,4-dioxo-3H-pyrimidin-1-yl)oxolane-2-carbaldehyde (5.0 g, 0.330 mmol) and aqueous NaOH (5 mL, 2 M) in 1,4-dioxane (50 mL) was added formaldehyde (2.5 mL, 37%) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then adjusted to pH 7 with AcOH. Following this, EtOH (7.5 mL) and NaBH (2.22 g, 58.586 mmol) were added at 0 °C. The resulting mixture was stirred at room temperature for 30 minutes and quenched by the addition of saturated aqueous NH Cl. The aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. This gave 1-[(2R,4S)-4-[(tert-butyldimethylsilyl)oxy]-5,5-bis(hydroxymethyl)oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (4 g, 73.44%) as a white solid. Product (ES, m / z): 391 (M+H + ).

[0494] Step 6: To a mixture of 1-[(2R,4S)-4-[(tert-butyldimethylsilyl)oxy]-5,5-bis(hydroxymethyl)oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (800 mg, 2.049 mmol) in pyridine (8 mL) was added TfO (1213.83 mg, 4.303 mmol) at −30° C. under a nitrogen atmosphere. The reaction mixture was stirred at −30° C. under a nitrogen atmosphere for 2 hours and then quenched by the addition of saturated aqueous NaHCO solution. The resulting mixture was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with petroleum ether / EtOAc (2:1) to give [(3S,5R)-3-[(tert-butyldimethylsilyl)oxy]-5-(5-fluoro-2,4-dioxo-3H-pyrimidin-1-yl)-2-[(trifluoromethanesulfonyloxy)methyl]oxolan-2-yl]methyl trifluoromethanesulfonate (1.1 g, 82.02%) as a yellow solid. Product (ES, m / z): 655 (M+H + ).

[0495] Step 7: A mixture of [(3S,5R)-3-[(tert-butyldimethylsilyl)oxy]-5-(5-fluoro-2,4-dioxo-3H-pyrimidin-1-yl)-2-[(trifluoromethanesulfonyloxy)methyl]oxolan-2-yl]methyl trifluoromethanesulfonate (800 mg, 1.222 mmol) and TEA (247.34 mg, 2.444 mmol) in THF (8 mL) was stirred overnight at room temperature under a nitrogen atmosphere. Then, lithium chloride (155.42 mg, 3.666 mmol) was added to the above mixture. The resulting mixture was stirred at 60° C. for another 2 hours. The desired product could be detected by LCMS. The crude resulting mixture was used directly in the next step without further purification. Product (ES, m / z): 391 (M+H + ).

[0496] Step 8: The solution from the previous step was diluted with HO (8 mL), followed by the addition of NaOH (245.56 mg, 6.141 mmol). The reaction mixture was stirred at room temperature overnight and then quenched by the addition of saturated aqueous NHCl. The resulting mixture was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with petroleum ether / EtOAc (1:1) to afford 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-(chloromethyl)-5-(hydroxymethyl)oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (600 mg, 71.70%) as a white solid. Product (ES, m / z): 409 (M+H + ).

[0497] Step 9: To a stirred mixture of 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-(chloromethyl)-5-(hydroxymethyl)oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (500 mg, 1.223 mmol) and imidazole (166.48 mg, 2.446 mmol) in DMF (10 mL) was added TBSCl (276.43 mg, 1.835 mmol) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and then quenched by the addition of saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. This resulted in 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-(chloromethyl)oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (600 mg, 93.79%) as a yellow solid. Product (ES, m / z): 523 (M+H + ).

[0498] Step 10: To a stirred mixture of 1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-(chloromethyl)oxolan-2-yl]-5-fluoro-3H-pyrimidine-2,4-dione (500 mg, 0.956 mmol), DMAP (350.27 mg, 2.868 mmol), and TEA (290.12 mg, 2.868 mmol) in ACN (20 mL) was added 2,4,6-tris(propan-2-yl)benzene-1-sulfonyl chloride (868.31 mg, 2.868 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. NH 3 .HO (10.00 mL) was then added dropwise to the above mixture. The resulting mixture was stirred at room temperature for an additional hour and then concentrated under vacuum. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water, 0% to 100% gradient in 15 minutes; detector, UV 254 nm. This yielded 4-amino-1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-(chloromethyl)oxolan-2-yl]-5-fluoropyrimidin-2-one (400 mg, 80.15%) as a white solid. Product (ES, m / z): 522 (M+H + ).

[0499] Step 11: To a mixture of 4-amino-1-[(2R,4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-(chloromethyl)oxolan-2-yl]-5-fluoropyrimidin-2-one (400 mg, 0.766 mmol) in MeOH (4 mL) was added NHF (851.08 mg, 22.980 mmol). The reaction mixture was stirred at 60 °C overnight. The resulting mixture was filtered, and the filter cake was washed with ethanol. The combined filtrates were concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (2% to a maximum of 15% ACN in 7 min); detector, UV 254 nm. This resulted in 4-amino-1-[(2R,4S,5R)-5-(chloromethyl)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-fluoropyrimidin-2-one (71.4 mg, 31.58%) as a white solid. Compound 14 (ES, m / z): 294 (M+H) + ). 1 H NMR(400MHz,DMSO-d6)δ 8.02(d,J=7.2Hz,1H),7.77(s,1H),7.53(s,1H),6.22-6.18(m,1H),5.45(d,J=4.4Hz,1H),5.30(t,J=5.2Hz, 1H),4.38-4.36(m,1H),3.78(d,J=11.6Hz,1H),3.71(d,J=11.6Hz,1H),3.66-3.56(m,2H),2.24-2.17(m,2H).

[0500] Example 3 - Synthesis of Compound 40: 4-amino-1-((2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one [ka] Step 1: To a stirred solution of 1-[(2R,3S,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (60 g, 243.7 mmol) and imidazole (166 g, 2437.1 mmol) in DMF (500 mL) was added TBSCl (110 g, 731.1 mmol) in portions at room temperature under a nitrogen atmosphere. The mixture was stirred at 80 °C for 15 h. LCMS indicated the reaction was complete. The mixture was cooled to room temperature, diluted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. The solid was filtered off and the filtrate was concentrated to give 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluorooxolan-2-yl]-3H-pyrimidine-2,4-dione (110 g, 231.7 mmol, crude) as a white solid. Product (ES, m / z): 475 (M+H + ).

[0501] Step 2: To a stirred solution of 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluorooxolan-2-yl]-3H-pyrimidine-2,4-dione (110 g, 231.7 mmol, 1 equiv.) in MeOH (500 mL) was added PPTS (175 g, 695.1 mmol) in small portions at room temperature under a nitrogen atmosphere. The mixture was stirred at 50° C. for 15 hours. LCMS showed the reaction was complete. The mixture was cooled to room temperature and concentrated. The residue was diluted with EA, washed with brine, and dried over anhydrous Na2SO4. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with methanol / dichloromethane = 3 / 97 to give 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-3-fluoro-5-(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (66 g, 183.3 mmol, 79.02%) as an off-white solid. Product (ES, m / z): 361 (M+H+ ).

[0502] Step 3: To a stirred solution of 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-3-fluoro-5-(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (66 g, 183.3 mmol) in CHCN (500 mL) was added IBX (47 g, 166.4 mmol) in portions at room temperature under a nitrogen atmosphere. The mixture was stirred at 60° C. for 5 hours. LCMS showed the reaction was complete. The mixture was cooled to room temperature. The solid was filtered off and the filtrate was concentrated to give (2S,3R,4S,5R)-3-[(tert-butyldimethylsilyl)oxy]-5-(2,4-dioxo-3H-pyrimidin-1-yl)-4-fluorooxolane-2-carbaldehyde (60 g, 167.5 mmol, crude) as a white solid. Product (ES, m / z): 359 (M+H + ).

[0503] Step 4: To a stirred solution of (2S,3R,4S,5R)-3-[(tert-butyldimethylsilyl)oxy]-5-(2,4-dioxo-3H-pyrimidin-1-yl)-4-fluorooxolane-2-carbaldehyde (60 g, 167.5 mmol) and HCHO (33 g, 1089.3 mmol, 6.5 equiv) in dioxane (1000 mL) was added a solution of NaOH (20 g, 502.7 mmol, 3 equiv) in water (50 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. To the above mixture was added NaBH (29 g, 754.1 mmol) in small portions at 0 °C. The resulting mixture was stirred for an additional 30 min. The mixture was quenched with aqueous NH Cl. The resulting mixture was extracted with EA. The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (4.9% MeOH) to give 1-[(2R,3S,4R)-4-[(tert-butyldimethylsilyl)oxy]-3-fluoro-5,5-bis(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (35 g, 89.7 mmol, 53.55%) as a white solid. Product (ES, m / z): 391 (M+H + ).

[0504] Step 5: To a stirred solution of 1-[(2R,3S,4R)-4-[(tert-butyldimethylsilyl)oxy]-3-fluoro-5,5-bis(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (31 g, 79.4 mmol) in DCM (500 mL) was added pyridine (31 g, 396.9 mmol) and trifluoromethanesulfonic anhydride (49 g, 174.6 mmol) dropwise at −35° C. under a nitrogen atmosphere. The mixture was stirred at 0° C. for 30 min, and LCMS showed the reaction was complete. The mixture was quenched with water and extracted with EA. The combined organics were washed with brine and dried over anhydrous NaSO. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluted with EA / PE (1 / 1) to give [(3R,4S,5R)-3-[(tert-butyldimethylsilyl)oxy]-5-(2,4-dioxo-3H-pyrimidin-1-yl)-4-fluoro-2-[(trifluoromethanesulfonyloxy)methyl]oxolan-2-yl]methyl trifluoromethanesulfonate (30 g, 45.8 mmol, 57.05%) as an off-white solid. Product (ES, m / z): 655 (M+H + ).

[0505] Step 6: To a stirred solution of [(3R,4S,5R)-3-[(tert-butyldimethylsilyl)oxy]-5-(2,4-dioxo-3H-pyrimidin-1-yl)-4-fluoro-2-[(trifluoromethanesulfonyloxy)methyl]oxolan-2-yl]methyl trifluoromethanesulfonate (30 g, 45.8 mmol) in THF (500 mL) was added dropwise TEA (46 g, 458.3 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at 60° C. for 15 hours. LCMS showed that the starting material was consumed, and then lithium chloride (19 g, 458.3 mmol) was added. The resulting mixture was stirred at 60° C. for 2 hours, and LCMS showed that the reaction was complete. The mixture was used in the next reaction without further purification. Product (ES, m / z): 391 (M+H + ).

[0506] Step 7: To the above solution was slowly added a solution of NaOH (5.5 g, 136.6 mmol) in water (50 mL). The mixture was stirred at room temperature for 2 days. LCMS showed that most of the starting material was consumed. The solid was filtered off, and the filtrates were combined and concentrated. The residue was diluted with EA, washed with brine, and dried over anhydrous Na2SO4. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluted with methanol / dichloromethane (7 / 93) to give 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-(chloromethyl)-3-fluoro-5-(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (11 g, 26.9 mmol, 59.07%) as a pale yellow solid. Product (ES, m / z): 409 (M+H + ).

[0507] Step 8: To a stirred solution of 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-(chloromethyl)-3-fluoro-5-(hydroxymethyl)oxolan-2-yl]-3H-pyrimidine-2,4-dione (10 g, 24.4 mmol) and imidazole (17 g, 244.5 mmol) in dimethylformamide (200 mL) was added t-butyldimethylchlorosilane (11 g, 73.3 mmol) in portions at room temperature under a nitrogen atmosphere. The mixture was stirred at 80 °C for 15 h. LCMS showed the reaction was complete. The mixture was cooled to room temperature, diluted with EA, washed with brine, and dried over anhydrous Na2SO4. The solid was filtered off, and the filtrates were combined and concentrated. The residue was purified by silica gel column chromatography eluted with methanol / dichloromethane (7 / 93) to give 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-(chloromethyl)-3-fluorooxolan-2-yl]-3H-pyrimidine-2,4-dione (12 g, 23.0 mmol, 93.79%) as a pale yellow solid. Product (ES, m / z): 523 (M+H+ ).

[0508] Step 9: To a stirred solution of 1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-(chloromethyl)-3-fluorooxolan-2-yl]-3H-pyrimidine-2,4-dione (12 g, 22.9 mmol) and DMAP (5.6 g, 45.8 mmol) in CHCN (200 mL) was added TEA (7 g, 68.8 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride (14 g, 45.8 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at 40 °C for 15 hours. The starting material was consumed, and then NH 3 .HO (50 mL) was added slowly. The resulting mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The mixture was diluted with EA, washed with brine, and dried over anhydrous Na2SO4. The solid was filtered off, and the combined filtrates were concentrated. The residue was purified by silica gel column chromatography eluted with methanol / dichloromethane (7 / 93) to give 4-amino-1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-(chloromethyl)-3-fluorooxolan-2-yl]pyrimidin-2-one (11 g, 21.1 mmol, 91.84%) as a pale yellow solid. Product (ES, m / z): 522 (M+H + ).

[0509] Step 10: A mixture of 4-amino-1-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-5-(chloromethyl)-3-fluorooxolan-2-yl]pyrimidin-2-one (8 g, 15.4 mmol) and NHF (17 g, 461 mmol) in MeOH (200 mL) was stirred at 60 °C overnight under a nitrogen atmosphere. The resulting mixture was cooled to room temperature, the solids were filtered off, and the filter cake was washed with MeOH. The filtrates were combined and concentrated under reduced pressure. The crude product was purified by back-flush (NH4HCO3) to give 4-amino-1-[(2R,3S,4R,5R)-5-(chloromethyl)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one (2.5 g, 8.53 mmol, 55.38%) as a white solid. Compound 40 (ES, m / z): 294 (M+H) + ), 98.6% purity. 1 H NMR(400MHz,DMSO-d6)δ 7.63(dd,J=7.5,1.4Hz,1H),7.24(d,J=24.8Hz,2H),6.25(dd,J=17.9,4.0Hz,1H),6.15(d,J=5.1Hz,1H),5.74(d,J=7.4Hz,1H) ,5.34(t,J=5.5Hz,1H),5.09(dt,J=53.0,3.3Hz,1H),4.42(ddd,J=18.3,5.2,2.8Hz,1H),3.97-3.69(m,2H),3.66-3.50(m,2H).

[0510] Example 4 - Synthesis of Compound 4: 1-((2R,4S,5R)-5-(chloromethyl)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione [ka] Step 1: A mixture of thymidine (5 g, 20.6 mmol) and tert-butylchlorodimethylsilane (3.4 g, 22.7 mmol) in pyridine (30 mL) was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with brine (3 × 150 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column chromatography using dichloromethane / methyl alcohol (10 / 1) to give 1-[(2R,4S,5R)-5-{[(tert-butyldimethylsilyl)oxy]methyl}-4-hydroxyoxolan-2-yl]-5-methyl-3H-pyrimidine-2,4-dione (7 g, 19.6 mmol, 95.13%) as a white solid. LC-MS(ES,m / z):357[M+H] + .

[0511] Step 2: To a mixture of 1-[(2R,4S,5R)-5-{[(tert-butyldimethylsilyl)oxy]methyl}-4-hydroxyoxolan-2-yl]-5-methyl-3H-pyrimidine-2,4-dione (7 g, 19.6 mmol) and 2,4,6-trimethyl-pyridine (7.1 g, 58.9 mmol) in dichloromethane (50 mL), silver nitrate (6.6 g, 39.2 mmol) and 1-(chlorodiphenylmethyl)-4-methoxybenzene (6.6 g, 21.6 mmol) were added at 0 °C, and the mixture was stirred at room temperature overnight. The mixture was acidified to pH 6 with hydrochloric acid (0.1 M). The resulting mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ES, m / z): 629 [M+H] + .

[0512] Step 3: A mixture of 1-[(2R,4S,5R)-5-{[(tert-butyldimethylsilyl)oxy]methyl}-4-[(4-methoxyphenyl)diphenylmethoxy]oxolan-2-yl]-5-methyl-3H-pyrimidine-2,4-dione (12 g, 19.1 mmol) and tetrabutylammonium fluoride (22.9 mL, 22.9 mmol, 1 M in THF) in tetrahydrofuran (300 mL) was stirred at room temperature for 6 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (1:1) to give 1-[(2R,4S,5R)-5-(hydroxymethyl)-4-[(4-methoxyphenyl)diphenylmethoxy]oxolan-2-yl]-5-methyl-3H-pyrimidine-2,4-dione (8 g, 15.5 mmol, 81.47%) as a pale yellow solid. LC-MS(ES,m / z):515[M+H] + .

[0513] Step 4: A mixture of 1-[(2R,4S,5R)-5-(hydroxymethyl)-4-[(4-methoxyphenyl)diphenylmethoxy]oxolan-2-yl]-5-methyl-3H-pyrimidine-2,4-dione (8 g, 15.5 mmol) and Dess-Martin (6.5 g, 15.5 mmol) in dichloromethane (50 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:1) to give (2S,3S,5R)-3-[(4-methoxyphenyl)diphenylmethoxy]-5-(5-methyl-2,4-dioxo-3H-pyrimidin-1-yl)oxolane-2-carbaldehyde (6.8 g, 13.2 mmol, 85.33%) as an off-white solid. LC-MS(ES,m / z):513[M+H] + .

[0514] Step 5: A mixture of (2S,3S,5R)-3-[(4-methoxyphenyl)diphenylmethoxy]-5-(5-methyl-2,4-dioxo-3H-pyrimidin-1-yl)oxolane-2-carbaldehyde (6.8 g, 13.2 mmol) and HCHO (3.9 g, 132.8 mmol) in 1,4-dioxane (60 mL) and water (12 mL) was treated with sodium hydroxide (1.1 g, 26.5 mmol) at room temperature under a nitrogen atmosphere overnight, followed by the addition of NaBH (2.1 g, 53.1 mmol) in small portions at room temperature. The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with dichloromethane / methyl alcohol (10:1) to give 1-[(2R,4S)-5,5-bis(hydroxymethyl)-4-[(4-methoxyphenyl)diphenylmethoxy]oxolan-2-yl]-5-methyl-3H-pyrimidine-2,4-dione (3.5 g, 6.4 mmol, 48.44%) as a white solid. LC-MS (ES, m / z): 545 [M+H] + .

[0515] Step 6: To a mixture of 1-[(2R,4S)-5,5-bis(hydroxymethyl)-4-[(4-methoxyphenyl)diphenylmethoxy]oxolan-2-yl]-5-methyl-3H-pyrimidine-2,4-dione (3.5 g, 6.4 mmol) and pyridine (2.5 g, 32.1 mmol) in dichloromethane (50 mL) was added trifluoromethanesulfonic anhydride (3.6 g, 12 mmol) dropwise at −35° C. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give [(3S,5R)-3-[(4-methoxyphenyl)diphenylmethoxy]-5-(5-methyl-2,4-dioxo-3H-pyrimidin-1-yl)-2-[(trifluoromethanesulfonyloxy)methyl]oxolan-2-yl]methyl trifluoromethanesulfonate (2 g, 2.4 mmol, 38.48%) as a yellow solid. LC-MS (ES, m / z): 809 [M+H] + .

[0516] Step 7: A mixture of [(3S,5R)-3-[(4-methoxyphenyl)diphenylmethoxy]-5-(5-methyl-2,4-dioxo-3H-pyrimidin-1-yl)-2-[(trifluoromethanesulfonyloxy)methyl]oxolan-2-yl]methyl trifluoromethanesulfonate (2 g, 2.4 mmol) and sodium hydride (0.06 g, 2.4 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature under a nitrogen atmosphere for 4 hours. Lithium chloride (0.31 g, 7.4 mmol) was then added to the mixture, and the mixture was stirred for 1.5 hours. The reaction was quenched by adding water (1 mL) at 0 °C. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluted with dichloromethane / methanol (10:1) to give (6R,8S,9R)-9-(chloromethyl)-8-((4-methoxyphenyl)diphenylmethoxy)-3-methyl-7,8,9,10-tetrahydro-2H,6H-6,9-epoxypyrimi[2,1-b][1,3]oxazocin-2-one (1 g, 1.8 mmol, 74.19%) as a white solid. LC-MS (ES, m / z): 545 / 547 [M+H] + .

[0517] Step 8: A mixture of (6R,8S,9R)-9-(chloromethyl)-8-((4-methoxyphenyl)diphenylmethoxy)-3-methyl-7,8,9,10-tetrahydro-2H,6H-6,9-epoxypyrimido[2,1-b][1,3]oxazocin-2-one (500 mg, 0.9 mmol) and sodium hydroxide (73.3 mg, 1.8 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with dichloromethane / methanol (10:1) to give 1-[(2R,4S,5R)-5-(chloromethyl)-5-(hydroxymethyl)-4-[(4-methoxyphenyl)diphenylmethoxy]oxolan-2-yl]-5-methyl-3H-pyrimidine-2,4-dione (190 mg, 0.3 mmol, 36.78%) as a white solid. LC-MS (ES, m / z): 563 / 565 [M+H]+ .

[0518] Step 9: A mixture of 1-[(2R,4S,5R)-5-(chloromethyl)-5-(hydroxymethyl)-4-[(4-methoxyphenyl)diphenylmethoxy]oxolan-2-yl]-5-methyl-3H-pyrimidine-2,4-dione (190 mg, 0.3 mmol) in formic acid (8 mL) and HO (2 mL) was stirred at room temperature under a nitrogen atmosphere for 0.5 h. The mixture was concentrated, and the crude product (80 mg) was purified by preparative HPLC under the following conditions: (Column: XBridge Prep C18 OBD column, 30 × 100 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 38% B in 10 min; Wavelength: 254 / 220 nm; RT1 (min): 9.98) to give 1-[(2R,4S,5R)-5-(chloromethyl)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methyl-3H-pyrimidine-2,4-dione (11.4 mg, 11.45%) as a white solid. LC-MS (ES, m / z): 291 / 293 [M+H] + 98.5% purity. LCMS conditions: (Column: Shim-pack Scepter C18, 33 x 3 mm, 3 μm; Mobile phase A: water / 5 mM NH4HCO3, Mobile phase B: acetonitrile; Flow rate: 1.5000 mL / min; Gradient: 5% B to 30% B in 1.79 min, 30% B to 95% B in 0.40 min, 95% B to 95% B in 0.10 min, 95% B to 10% B in 0.30 min; Wavelength: 254 nm; RT1 (min): 1.040). 1 H NMR(400MHz,DMSO-d6)δ 11.24(s,1H),7.63(d,J=1.6Hz,1H),6.26(dd,J=8.2,5.9Hz,1H),5.48(s,1H),5.25(s,1H),4.41(dd,J=6.2,3 .0Hz,1H),3.84-3.70(m,2H),3.59(s,2H),2.33(ddd,J=13.9,8.3,6.1Hz,1H),2.20-2.06(m,1H),1.79(s,3H).

[0519] Example 5 - Synthesis of Compound 67 [ka] Step 1: To a solution of [(2R,3S,4R,5R)-3,5-bis(benzoyloxy)-4-hydroxyoxolan-2-yl]methyl benzoate (50 g, 108.1 mmol) in DCM (500 mL) was added BAST (47.8 g, 216.2 mmol) dropwise at 0 °C. The resulting mixture was stirred at 50 °C for 2 days, then cooled to 0 °C and quenched by the addition of water. The resulting solution was extracted with EtOAc. The combined organics were washed with saturated aqueous NaHCO , dried over anhydrous Na SO , and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with petroleum ether / EtOAc (2:1) to give [(2R,3R,4S,5R)-3,5-bis(benzoyloxy)-4-fluorooxolan-2-yl]methyl benzoate (40 g, 79.7%) as a white solid. LC-MS(ES,m / z):343(M-OBz) + .

[0520] Step 2: To a solut...

Claims

1. Compound according to formula IA: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, R 1A is -C(O)R 5A, hydrogen, or -P(O)(OH)-OP(O)(OH)-OP(O)(OH) 2. R 2A is (i) halomethyl, C 1-3 aliphatic, or cyclopropyl, each of which optionally has one or more hydrogens replaced by deuterium, or (ii)-N 3. R 3A is -C(O)R 5A or hydrogen, R 4A is a halo, hydrogen, or -OH. R 5A independently represents C 1-20 aliphatic, C 1-20 haloaliphatic, -C(H)(R 6A)-N(R 7A) 2, phenyl, -CH 2-phenyl, or hydrogen, and each phenyl is substituted by m occurrences of R 10A. R 6A is a C1-6 alkyl group or hydrogen, and the C1-6 alkyl group is optionally substituted with phenyl. R 7A independently represents hydrogen, C1-6 alkyl, -C(O)CH3, -C(O)OC(CH3)3, -C(O)O(CH2)phenyl, or -C(O)O(CH2)fluorenyl for each occurrence. R 8A is hydrogen, halo, -CH3, or -CF3. R 9A is Halo, -CH 3, or -CF 3. R 10A independently represents C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, or halo for each occurrence. BA, 【Chemistry 2】 And, m is 0, 1, or 2, If R 4A is hydrogen, then, provided that at least one of R 1A and R 3A is -C(O)R 5A, If R 3A is hydrogen, R 4A is halo or -OH, and R 1A is hydrogen or -P(O)(OH)-OP(O)(OH)-OP(O)(OH)2, then R 8A is halo, -CH3, or -CF3. A pharmaceutical product comprising a compound or a pharmaceutically acceptable salt thereof, for the treatment of a neurological or autoimmune disorder.

2. BA is 【Transformation 3】 The pharmaceutical product according to claim 1, wherein R 8A is fluoro.

3. The pharmaceutical product according to claim 2, wherein R 4A is -OH.

4. The pharmaceutical product according to claim 3, wherein R 2A is C 1-3 aliphatic.

5. The pharmaceutical product according to claim 4, wherein R1A is hydrogen and R3A is hydrogen.

6. The compound is 【Chemistry 4】 The pharmaceutical product according to claim 1.

7. The compound is of formula II: 【Transformation 5】 A salt of which is represented by or pharmaceutically acceptable thereof, in the formula, R1 and R4 independently represent -C(O)R5 or hydrogen, provided that at least one of R1 and R4 is -C(O)R5. R2 is a halo, hydrogen, or -OH. R3 is halomethyl, C1-3 aliphatic, or cyclopropyl, each of which optionally has one or more hydrogens replaced by deuterium. R 5 independently represents C 1-20 aliphatic, C 1-20 haloaliphatic, -C(H)(R 6)-N(R 7) 2, phenyl, -CH 2-phenyl, or hydrogen, and each phenyl is substituted by m occurrences of R 10. R 6 is a C1-6 alkyl group or hydrogen, and the C1-6 alkyl group is optionally substituted with phenyl. R 7 independently represents hydrogen, C1-6 alkyl, -C(O)CH3, -C(O)OC(CH3)3, -C(O)O(CH2)phenyl, or -C(O)O(CH2)fluorenyl for each occurrence. R8 is hydrogen, halo, -CH3, or -CF3. R 9 is Halo, -CH 3, or -CF 3. R 10 independently represents C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, or halo for each occurrence. B 1 is, 【Transformation 6】 And, m is 0, 1, or 2. The pharmaceutical product according to claim 1.

8. The pharmaceutical product according to claim 7, wherein R1 and R4 are -C(O)R5 and R5 is a C1-8 alkyl group.

9. The pharmaceutical product according to claim 8, wherein R2 is -OH and R3 is C1-3 aliphatic or cyclopropyl.

10. B 1 is, 【Transformation 7】 The pharmaceutical product according to claim 9, wherein R 8 is fluoro.

11. The pharmaceutical product according to any one of claims 1 to 10, wherein the pharmaceutical product inhibits LINE1 reverse transcriptase activity.

12. The pharmaceutical agent according to claim 11, wherein the target to be treated by the pharmaceutical agent has (i) increased expression of LINE1 RNA, LINE1 ORF1 polypeptide, and / or LINE1 ORF2 polypeptide, and / or (ii) increased activity of LINE1 reverse transcriptase.

13. The pharmacopoeia according to any one of claims 1 to 10, wherein the pharmacopoeia is for treating a neurological disorder selected from Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease, Huntington's disease, peripheral neuropathy, age-related macular degeneration, Creutzfeldt-Jakob disease, stroke, prion disease, frontotemporal dementia, Pick's disease, progressive supranuclear palsy, spinocerebellar ataxia, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, or major depressive disorder.

14. Compounds according to formula IA: 【Transformation 8】 or a pharmaceutically acceptable salt thereof, in the formula, R 1A However, -C(O)R 5A , hydrogen, or -P(O)(OH)-OP(O)(OH)-OP(O)(OH) 2 And, R 2A However, (i) halomethyl, C 1-3 They are aliphatic or cyclopropyl, each having one or more hydrogens optionally replaced by deuterium, or (ii)-N 3 And, R 3A However, -C(O)R 5A or hydrogen, R 4A is a halo, hydrogen, or -OH, and R 5A However, for each occurrence independently, C 1-20 aliphatic, C 1-20 Haloliphatic, -C(H)(R 6A )-N(R 7A ) 2 phenyl, -CH 2 - Represents phenyl or hydrogen, and each phenyl is R 10A It is replaced by m occurrences of, R 6A However, C 1-6 Alkyl or hydrogen, and the C 1-6 Alkyl is optionally substituted with phenyl, R 7A However, for each appearance, independently, hydrogen, C 1-6 Alkyl, -C(O)CH 3 -C(O)OC(CH 3 ) 3 ,-C(O)O(CH 2 ) Phenyl, or -C(O)O(CH 2 ) represents fluorenyl, R 8A However, hydrogen, halo, -CH 3 , or -CF 3 And, R 9A But, hello, -CH 3 , or -CF 3 And, R 10A However, for each occurrence independently, C 1-6 Alkyl, C 1-6 Alkoxyl, C 1-6 Represents haloalkyl or halo, B A but, 【Chemistry 9】 And, m is 0, 1, or 2, R 4A If R is hydrogen, 1A and R 3A At least one of them is -C(O)R 5A The condition is that, R 3A is hydrogen, R 4A is a halo or -OH, and R 1A is hydrogen or -P(O)(OH)-OP(O)(OH)-OP(O)(OH) 2 If R 8A Hello, -CH 3 , or -CF 3 The condition is that A compound or a pharmaceutically acceptable salt thereof.

15. The compound is, Formula II: 【Chemistry 10】 A salt of which is represented by or pharmaceutically acceptable thereof, in the formula, R 1 and R 4 However, independently, -C(O)R 5 Or it represents hydrogen, however, R 1 and R 4 At least one of them is -C(O)R 5 The condition is that, R 2 However, it is a halo, hydrogen, or -OH. R 3 However, halomethyl, C 1-3 Aliphatic or cyclopropyl, each having one or more hydrogens optionally replaced by deuterium, R 5 However, for each occurrence independently, C 1-20 aliphatic, C 1-20 Haloliphatic, -C(H)(R 6 )-N(R 7 ) 2 phenyl, -CH 2 - Represents phenyl or hydrogen, and each phenyl is R 10 It is replaced by m occurrences of, R 6 However, C 1-6 Alkyl or hydrogen, and the C 1-6 Alkyl is optionally substituted with phenyl, R 7 However, for each appearance, independently, hydrogen, C 1-6 Alkyl, -C(O)CH 3 -C(O)OC(CH 3 ) 3 ,-C(O)O(CH 2 ) Phenyl, or -C(O)O(CH 2 ) represents fluorenyl, R 8 However, hydrogen, halo, -CH 3 , or -CF 3 And, R 9 But, hello, -CH 3 , or -CF 3 And, R 10 However, for each occurrence independently, C 1-6 Alkyl, C 1-6 Alkoxyl, C 1-6 Represents haloalkyl or halo, B 1 but, 【Chemistry 11】 And, m is 0, 1, or 2. The compound according to claim 14 or a pharmaceutically acceptable salt thereof.

16. R 1 and R 4 is -C(O)R 5 where R5 is C1-8 alkyl, the compound according to claim 15 or a pharmaceutically acceptable salt thereof.

17. R 2 The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein R3 is -OH and R3 is C1-3 aliphatic or cyclopropyl.

18. B 1 but, 【Chemistry 12】 The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 8 is fluoro.

19. Compounds represented by formula IV: 【Chemistry 13】 or a pharmaceutically acceptable salt thereof, in the formula, R 1 is (i) -CH 2 Cl, -CH 2 F, -CH 2 Br, -CH 2 I, -CF 3 -, -CH 2 CH 3 -, -C(H)=CH 2 -, -C(H)=C=CH 2 -, or cyclopropyl, each of which optionally has one or more hydrogens replaced with deuterium, or (ii) -N 3 and R 2 However, hydrogen, halo, or -CF 3 And, B 1 but, 【Chemistry 14】 That is, A compound or a pharmaceutically acceptable salt thereof.

20. Compounds of Table 1, 1-A, 1-B, 1-C, or 1-D herein, or pharmaceutically acceptable salts thereof.

21. A pharmaceutical composition comprising a compound according to any one of claims 14 to 20 or a pharmaceutically acceptable salt thereof, and a carrier, an additive and / or a vehicle.

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