Imidazole 3-oxide derivative based ACSS2 inhibitors and methods of use thereof

Abstract

To provide novel ACSS2 inhibitors having activity for anti-cancer therapy, treatment of alcoholism, and viral infection (e.g., CMV infection), composition including the inhibitors and methods of preparation the inhibitors, and to provide uses of the inhibitors for treating viral infection, alcoholism, alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), metabolic disorders including: obesity, weight gain and hepatic steatosis, neuropsychiatric diseases including: anxiety, depression, schizophrenia, autism and post-traumatic stress disorder, inflammatory / autoimmune conditions and cancer, including metastatic cancer, advanced cancer, and drug resistant cancer of various types.SOLUTION: There is provided compounds having an imidazole-3-oxide structure, such as the following structure.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to novel ACSS2 inhibitors, compositions comprising same, methods for making them, and their use for treating viral infections (e.g., CMV infection), alcoholism, alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), metabolic disorders (obesity, weight gain, fatty liver), neuropsychiatric disorders (anxiety, depression, schizophrenia, autism, post-traumatic stress disorder), inflammatory / autoimmune diseases, and cancer (metastatic cancer, advanced cancer, various types of drug-resistant cancer). [Background technology]

[0002] Cancer is the second leading cause of death in the United States, after heart disease. Cancer accounts for one in four deaths in the United States. The five-year relative survival rate for all cancer patients diagnosed between 1996 and 2003 was 66%, up from 50% between 1975 and 1977 (Cancer Facts & Figures American Cancer Society: Atlanta, GA (2008)). Between 2000 and 2009, the rate of new cancer cases decreased by an average of 0.6% per year in men but remained stable in women. Between 2000 and 2009, the rate of death from all cancers decreased by an average of 1.8% per year in men and 1.4% per year in women. This improvement in survival reflects advances in early diagnosis and improved treatment. Discovering highly effective anticancer drugs with low toxicity is a major goal of cancer research.

[0003] Cell growth and proliferation are closely linked to metabolism. Potential differences in the metabolism of normal and cancer cells have sparked renewed interest in targeting metabolic enzymes as an approach to discovering new anti-cancer therapeutics.

[0004] Cancer cells in metabolically stressed microenvironments, defined herein as hypoxic and nutrient-poor conditions (i.e., hypoxia), have recently been shown to exhibit various tumor-promoting properties, including genomic instability, altered cellular bioenergetics, and invasive behavior. Additionally, these cancer cells are often inherently resistant to cell death and are physically isolated from the tumor site's vasculature, hindering immune responses, drug delivery, and successful therapeutic efficacy, thereby promoting recurrence and metastasis and ultimately significantly reducing patient survival. Therefore, there is an urgent need to define therapeutic targets in metabolically stressed cancer cells and develop novel delivery technologies to enhance therapeutic efficacy. For example, the specific metabolic dependency of cancer cells on alternative nutrients (e.g., acetate) that support energy and biomass production may provide opportunities for the development of novel targeted therapies.

[0005] Acetyl-CoA synthase, ACSS2, as a target for cancer therapy

[0006] Acetyl-CoA is a central node in carbon metabolism that plays a key role in regulating bioenergetics, cell proliferation, and gene expression. Hyperglycolytic or hypoxic tumors require the production of this metabolite in sufficient quantities to support cell growth and survival under nutrient-limited conditions. Acetate is an important source of acetyl-CoA under hypoxic conditions. Inhibition of acetate metabolism inhibits tumor growth. ACSS2, a nucleocytoplasmic acetyl-CoA synthase, provides the primary source of acetyl-CoA for tumors by incorporating acetate as a carbon source. ACSS2-deficient adult mice exhibit significantly reduced tumor burden in two hepatocellular carcinoma models, despite not exhibiting significant growth or developmental defects. ACSS2 is expressed in the majority of human tumors, and its activity is responsible for the majority of cellular acetate incorporation into both lipids and histones. Furthermore, an unbiased functional genomic screen identified ACSS2 as an enzyme essential for the proliferation and survival of breast and prostate cancer cells cultured under hypoxic and low serum conditions. High ACSS2 expression is frequently observed in invasive ductal carcinoma, triple-negative breast cancer, glioblastoma, ovarian cancer, pancreatic cancer, and lung cancer, and is often directly correlated with increased malignancy and decreased survival compared to tumors with low ACSS2 expression. These findings suggest that ACSS2 can be considered a targetable metabolic vulnerability in a wide range of tumor types.

[0007] Due to the nature of tumorigenesis, cancer cells constantly face environments with significantly reduced nutrient and oxygen availability. To survive these harsh conditions, cancer cell transformation is often coupled with major metabolic changes to meet the energy and biomass demands imposed by continued cell proliferation. Several recent reports have discovered that some types of breast, prostate, liver, and brain tumors use acetate as an important nutrient source in an acetyl-CoA synthase 2 (ACSS2)-dependent manner. It has been shown that acetate and ACSS2 provide a significant proportion of the carbon in the fatty acid and phospholipid pools (Comerford et al. Cell 2014; Mashimo et al. Cell 2014; Schug et al. Cancer Cell 2015*). High levels of ACSS2, resulting from copy number gain or high expression, have been found to correlate with disease progression in human breast, prostate, and brain tumors. Furthermore, ACSS2, which is essential for tumor growth under hypoxic conditions, is dispensable for normal cell growth, and ACSS2-deficient mice exhibited a normal phenotype (Comerford et al. 2014). The switch to increased reliance on ACSS2 is not due to genetic alterations but rather to metabolic stress conditions in the tumor microenvironment. Under normal oxidative conditions, acetyl-CoA is typically generated from citrate via citrate lyase activity. However, under hypoxia, ACSS2 becomes essential as cells adapt to anaerobic metabolism, where acetate becomes the primary source of acetyl-CoA, effectively rendering cells synthetically lethal under hypoxic conditions (Schug et al., Cancer Cell, 2015, 27:1, pp. 57-71). Accumulating evidence from several studies suggests that ACSS2 may be a targetable metabolic vulnerability in a wide range of tumors.

[0008] Because certain tumors expressing ACSS2 are highly dependent on acetate for their growth or survival, selective inhibitors of this nonessential enzyme would provide an excellent opportunity for the development of new anticancer therapeutics. If normal human cells and tissues are not highly dependent on ACSS2 enzyme activity, such drugs may inhibit the growth of ACSS2-expressing tumors within a favorable therapeutic window.

[0009] Nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) share similar pathogenesis and histopathology but differ in etiology and epidemiology. NASH and ASH are advanced stages of nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is characterized by excessive hepatic fat accumulation (steatosis), the absence of other clear causes of chronic liver disease (e.g., viral, autoimmune, or genetic), and an alcohol intake of 20-30 g / day or less. In contrast, AFLD is defined by the presence of steatosis and an alcohol intake of more than 20-30 g / day.

[0010] Ethanol metabolism in hepatocytes produces free acetate as the end product, which can be incorporated into acetyl-coenzyme A (acetyl-CoA) for use as a substrate for Krebs cycle oxidation, fatty acid synthesis, or protein acetylation, primarily in other tissues. This conversion is catalyzed by acyl-coenzyme A synthetase short-chain family members 1 and 2 (ACSS1 and ACSS2). The role of acetyl-CoA synthesis in the control of inflammation has opened up a new field of research into the relationship between cellular energy supply and inflammatory diseases. It has been shown that ethanol promotes macrophage cytokine production by uncoupling gene transcription from its normal regulatory mechanisms through increased histone acetylation, and that the conversion of the ethanol metabolite acetate to acetyl-CoA is critical for this process.

[0011] In acute alcoholic hepatitis, increased inflammation leads to upregulation of acetyl-CoA synthase, converting the ethanol metabolite acetate into excess acetyl-CoA. This increases substrate concentrations, inhibits histone deacetylases (HDACs), and increases histone acetylation of proinflammatory cytokine genes, resulting in enhanced gene expression and perpetuation of the inflammatory response. The clinical significance of these findings is that modulation of HDAC or ACSS activity may influence the clinical course of alcoholic liver injury in humans. If inhibitors of ACSS1 and ACSS2 can modulate ethanol-related histone changes without affecting acetyl-CoA flux through normal metabolic pathways, they may represent a much-needed effective therapeutic option for acute alcoholic hepatitis. Therefore, synthesizing metabolically available acetyl-CoA from acetate is crucial for increased acetylation of proinflammatory gene histones and the resulting enhanced inflammatory response in ethanol-exposed macrophages. This mechanism represents a potential therapeutic target for acute alcoholic hepatitis.

[0012] Cytosolic acetyl-CoA is a precursor for many anabolic reactions, including de novo fatty acid (FA) synthesis. Because inhibition of FA synthesis may have a favorable impact on morbidity and mortality associated with fatty liver and metabolic syndrome (Wakil SJ, Abu-Elheiga LA. 2009. 'Fatty acid metabolism: Target for metabolic syndrome'. J. Lipid Res.), and because acetyl-CoA carboxylase (ACC) plays a pivotal role in regulating fatty acid metabolism, ACC inhibitors are being investigated as clinical targets for several metabolic disorders, including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). ACSS2 inhibitors are expected to directly reduce hepatic fatty acid accumulation by affecting acetyl-CoA flux from high levels of acetate present in the liver resulting from hepatocyte ethanol metabolism. Furthermore, ACSS2 inhibitors are expected to have a better safety profile than ACC inhibitors because they only affect the flux from acetate, which is not a major source of acetyl-CoA under normal conditions (Harriman G et. al., 2016. "Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats," PNAS). In addition, ACSS2-deficient mice showed reduced body weight and liver steatosis in a diet-induced obesity model (Z. Huang et al., ACSS2 promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism, PNAS 115, (40), E9499-E9506, 2018).

[0013] ACSS2 has also been shown to enter the nucleus under certain conditions (e.g., hypoxia, high fat), increasing the availability of acetyl-CoA and crotonyl-CoA, thereby affecting histone acetylation and crotonylation, thereby regulating gene expression. For example, reduction of ACSS2 has been shown to reduce the levels of nuclear acetyl-CoA and histone acetylation in neurons, which affects the expression of many neuronal genes. In the hippocampus, such reduction of ACSS2 affects memory and neuroplasticity (Mews P, et al., Nature, Vol. 546, 381, 2017). Such epigenetic modifications have been implicated in neuropsychiatric disorders such as anxiety, PTSD, and depression (Graff, J et al. Histone acetylation: molecular mnemonics on chromatin. Nat. Rev. Neurosci. 14, 97-111 (2013)). Therefore, ACSS2 inhibitors may be useful in treating such conditions.

[0014] Nuclear ACSS2 has also been shown to promote brain tumorigenesis by promoting lysosomal biogenesis and autophagy and affecting histone H3 acetylation (Li, X et al.: Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy, Molecular Cell 66, 1-14, 2017). Additionally, nuclear ACSS2 has been shown to activate HIF-2α through acetylation, thereby promoting the growth and metastasis of certain HIF-2α-driven cancers, such as renal cell carcinoma and glioblastoma (Chen, R. Et al. Coordinate regulation of stress signaling and epigenetic events by ACSS2 and HIF-2 in cancer cells, Plos One,12 (12) 1-31, 2017). Summary of the Invention [Means for solving the problem]

[0015] The present invention provides compounds represented by the structures of Formulas I-IX, defined herein below, and the structures listed in Table 1, or pharmaceutically acceptable salts, optical isomers, tautomers, hydrates, N-oxides, reverse amide analogs, prodrugs, isotopic variants (e.g., deuterated analogs), PROTACs, pharmaceuticals, or any combination thereof. In various embodiments, the compounds of the present invention are acyl-CoA synthetase short chain family member 2 (ACSS2) inhibitors.

[0016] The present invention further provides pharmaceutical compositions comprising a compound represented by the structures of Formulas I-IX, as defined herein below, and the structures listed in Table 1, or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof, and a pharmaceutically acceptable carrier.

[0017] The present invention further provides methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting cancer, comprising administering to a subject afflicted with cancer a compound represented by the structures of Formulas I-IX, as defined herein below, and the structures listed in Table 1, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit cancer. In various embodiments, the cancer is selected from hepatocellular carcinoma, melanoma (e.g., BRAF-mutated melanoma), glioblastoma, breast cancer (e.g., invasive ductal carcinoma, triple-negative breast cancer), prostate cancer, liver cancer, brain tumor, ovarian cancer, lung cancer, Lewis lung carcinoma (LLC), colon cancer, pancreatic cancer, renal cell carcinoma, and breast carcinoma. In various embodiments, the cancer is early stage cancer, advanced cancer, invasive cancer, metastatic cancer, drug-resistant cancer, or any combination thereof. In various embodiments, the subject has previously been treated with chemotherapy, immunotherapy, radiation therapy, biological therapy, surgical intervention, or any combination thereof. In various embodiments, the compounds of the invention are administered in combination with an anti-cancer therapy, hi various embodiments, the anti-cancer therapy is chemotherapy, immunotherapy, radiation therapy, biological therapy, surgical intervention, or any combination thereof.

[0018] The present invention further provides methods for suppressing, reducing, or inhibiting tumor growth, comprising administering to a subject suffering from cancer a compound represented by the structures of Formulas I-IX, as defined herein below, and the structures listed in Table 1, under conditions effective to suppress, reduce, or inhibit tumor growth. In various embodiments, tumor growth is promoted by increased acetate uptake by cancer cells of the cancer. In various embodiments, the increased acetate uptake is mediated by ACSS2. In various embodiments, the cancer cells are under hypoxic stress. In various embodiments, tumor growth is suppressed by inhibiting lipid (e.g., fatty acid) synthesis and / or histone synthesis induced by ACSS2-mediated acetate metabolism to acetyl-CoA. In various embodiments, tumor growth is suppressed by inhibiting the regulation of histone acetylation and function induced by ACSS2-mediated acetate metabolism to acetyl-CoA.

[0019] The present invention further provides methods for suppressing, reducing, or inhibiting lipid synthesis in a cell or modulating histone acetylation and function, comprising contacting a cell with a compound represented by the structures of Formulas I-IX, as defined herein below, and the structures listed in Table 1, under conditions effective to suppress, reduce, or inhibit lipid synthesis in the cell or modulate histone acetylation and function. In various embodiments, the cell is a cancer cell.

[0020] The present invention further provides a method of binding an ACSS2 inhibitor compound to an ACSS2 enzyme, comprising the step of contacting the ACSS2 enzyme with a compound represented by the structures of Formulas I-IX, as defined herein below, and the structures listed in Table 1, in an amount effective to bind the ACSS2 inhibitor compound to the ACSS2 enzyme.

[0021] The present invention further provides methods for suppressing, reducing, or inhibiting acetyl-CoA synthesis from acetate in a cell, comprising contacting the cell with a compound represented by the structures of Formulas I-IX, defined herein below, and the structures listed in Table 1, under conditions effective to suppress, reduce, or inhibit acetyl-CoA synthesis from acetate in the cell. In various embodiments, the cell is a cancer cell. In various embodiments, acetyl-CoA synthesis is mediated by ACSS2.

[0022] The present invention further provides methods of suppressing, reducing, or inhibiting acetate metabolism in cancer cells, comprising contacting cancer cells with a compound represented by the structures of Formulas I-IX, as defined herein below, and the structures listed in Table 1, under conditions effective to suppress, reduce, or inhibit acetate metabolism in the cancer cells. In various embodiments, acetate metabolism is mediated by ACSS2. In various embodiments, the cancer cells are under hypoxic stress.

[0023] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholism in a human, comprising administering to a subject suffering from alcoholism a compound represented by the structures of Formulas I-IX, as defined herein below, and the structures listed in Table 1, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit alcoholism.

[0024] The present invention further provides methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting a viral infection, comprising administering to a subject suffering from a viral infection a compound represented by the structures of Formulas I-IX, as defined herein below, and the structures listed in Table 1, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the viral infection. In various embodiments, the viral infection is a human cytomegalovirus (HCMV) infection.

[0025] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting non-alcoholic steatohepatitis (NASH), comprising administering to a subject afflicted with non-alcoholic steatohepatitis (NASH) a compound represented by the structures of Formulas I-IX, as defined herein below, and the structures listed in Table 1, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit non-alcoholic steatohepatitis (NASH).

[0026] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholic steatohepatitis (ASH), comprising administering to a subject afflicted with alcoholic steatohepatitis (ASH) a compound represented by the structures of Formulas I-IX, as defined herein below, and the structures listed in Table 1, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit alcoholic steatohepatitis (ASH).

[0027] The present invention further provides a method of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting a metabolic disorder, comprising administering to a subject suffering from a metabolic disorder a compound represented by the structures of Formulas I-IX, as defined herein below, and the structures listed in Table 1, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the metabolic disorder.

[0028] The present invention further provides methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting a neuropsychiatric disease or disorder, comprising administering to a subject suffering from a neuropsychiatric disease a compound represented by the structures of Formulas I-IX, as defined herein below, and the structures listed in Table 1, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is selected from anxiety, depression, schizophrenia, autism, and post-traumatic stress disorder.

[0029] The present invention further provides a method of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting an inflammatory disease, comprising administering to a subject suffering from an inflammatory disease a compound represented by the structures of Formulas I-IX, as defined herein below, and the structures listed in Table 1, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the inflammatory disease.

[0030] The present invention further provides methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting an autoimmune disease or disorder, comprising administering to a subject suffering from an autoimmune disease a compound represented by the structures of Formulas I-IX, as defined herein below, and the structures listed in Table 1, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the autoimmune disease. DETAILED DESCRIPTION OF THE INVENTION

[0031] In various embodiments, the present invention provides a compound represented by Formula I below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0032] [ka]

[0033] During the ceremony, The A and B rings may be, independently of one another, single or fused aromatic or heteroaromatic ring systems (e.g., phenyl, indole, benzofuran, 2-, 3-, or 4-pyridine, naphthalene, thiazole, thiophene, imidazole, 1-methylimidazole, benzimidazole), single or fused C3-C 10 Cycloalkyl (e.g., cyclohexyl) or single or fused C-C 10 heterocycles (e.g., benzofuran-2(3H)-one, benzo[d][1,3]dioxole, tetrahydrothiophene 1,1-dioxide, piperidine, 1-methylpiperidine, isoquinoline, 1,3-dihydroisobenzofuran); R1, R2, R 20 are, independently of one another, H, F, Cl, Br, I, OH, SH, R—OH (e.g., CH—OH), R—SH, —R—OR 10, (e.g., -CH2-O-CH3), R8-(C3-C8 cycloalkyl) (e.g., cyclohexyl), R8-(C3-C8 heterocycle) (e.g., CH2-morpholine, CH2-imidazole, CH2-indazole), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR (e.g., NH-CH3), N(R)2 (e.g., N(CH3)2), R8-N(R 10 )(R 11 ) (e.g., CH2-CH2-N(CH3)2, CH2-NH2, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ) (e.g., C≡C-CH2-NH2), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g. C(O)O-CH3, C(O)O-CH(CH3)2, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., -CH2-O-CH3), C(O)H, C(O)-R 10 (e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 linear or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR, C(O)N(R 10 )(R 11 ) (e.g., C(O)N-CH3), SO2R, SO2N(R 10 )(R 11) (e.g., SO2N(CH3)2, SO2NHC(O)CH3), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., C(H)(OH)-CH3, methyl, 2, 3, or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, butyl, t-Bu, isobutyl, pentyl, benzyl), C2-C5 straight-chain or branched, substituted or unsubstituted alkenyl (e.g., C≡C-CH2-NH2), C1-C5 straight-chain, branched, or cyclic haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, C H2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), substituted or unsubstituted C1-C5 straight or branched chain or C3-C8 cyclic alkoxy (e.g., methoxy, O-(CH2)2-pyrrolidine, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tBu), optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom (e.g., O-1-oxacyclobutyl, O-2-oxacyclobutyl ... cyclobutyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy (e.g., OCF3, OCHF2), C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperidine, piperazine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, oxadiazole, Azole, imidazole, furan, triazole, tetrazole, pyridine (2, 3, or 4-pyridine), 3-methyl-2-pyridine, pyrimidine, pyrazine, pyridazine, oxacyclobutane (1 or 2-oxacyclobutane), indole, protonated or deprotonated pyridine oxide), substituted or unsubstituted aryl (e.g., phenyl, xylyl, 2,6-difluorophenyl, 4-fluoroxylyl), substituted or unsubstituted benzyl (e.g., benzyl, 4-Cl-benzyl, 4-OH-benzyl), or CH(CF3)(NH-R10 ) is; or R2 and R1 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., pyrrole, [1,3]dioxole, furan-2(3H)-one, benzene, pyridine); R3, R4, R 40 are, independently of one another, H, F, Cl, Br, I, OH, SH, R—OH (e.g., CH—OH), R—SH, —R—OR 10 , (e.g., CH2-O-CH3)CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH2, CH2-N(CH3)2)R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, -NHCO-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g., C(O)O-CH3, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., CH2C(O)CH3), C(O)H, C(O)-R 10 (e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 straight or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R 10 )(R 11 ) (for example, C(O)N(CH3)2), C(O)N(CH3)(CH2CH3), C(O)N(CH3)(CH2CH2-O-CH3), C(S)N(R 10 )(R 11 ) (e.g., C(S)NH(CH3)), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO2R, SO2N(R10 )(R 11 ) (e.g., SO2NH(CH3), SO2N(CH3)2), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, t-Bu, isobutyl, pentyl), or substituted or unsubstituted C1-C5 straight-chain or branched or C3-C8 cyclic haloalkyl (e.g., CF3, CF2CH3, CF2-cyclobutyl, CF2-cyclopropyl, CF2-methylcyclopropyl, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2, C(OH)2CF3, cyclopropyl-CF3), C1-C5 straight-chain, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl), C1-C5 straight-chain or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., CF3-cyclopropyl, cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocycle (e.g., oxadiazole, pyrrole, N-methyloxetan-3-amine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, isoxazole, imidazole, furan, triazole, methyltriazole, pyridine (2, 3 or 4-pyridine), pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), indole), substituted or unsubstituted aryl (e.g., phenyl), or CH(CF3)(NH-R 10 ) is; or R3 and R4 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., imidazole, [1,3]dioxole, furan-2(3H)-one, benzene, cyclopentane, imidazole); R5 is H, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, CH2SH, ethyl, isopropyl), C2-C5 linear or branched, substituted or unsubstituted alkenyl, C2-C5 linear or branched, substituted or unsubstituted alkynyl (e.g., CCH), C1-C5 linear or branched haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2), CF(CH3)-CH((CH3)2), R8-aryl (e.g., CH2-Ph), C(=CH2)-R 10 (e.g., C(=CH2)-C(O)-OCH3, C(=CH2)-CN) substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted heteroaryl (2,3,4-pyridine); R6 is H, C1-C5 straight or branched alkyl (e.g., methyl), C(O)R, or S(O)2R; R 60 is H, substituted or unsubstituted C1-C5 straight or branched alkyl (e.g., methyl, CH2-OC(O)CH3, CH2-PO4H2, CH2-PO4H-tBu, CH2-OP(O)(OCH3)2), C(O)R, or S(O)2R; R8 is [CH2] p and p is 1 to 10; R9 is [CH] q , or [C] q and q is 2 to 10; R 10 and R 11 are each independently H, CN, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), R8-OR 10 (e.g., CH2CH2-O-CH3), C(O)R (e.g., C(O)(OCH3)), or S(O)2R; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., pyrrolidine, piperazine, methylpiperazine, azetidine, piperidine, morpholine); R is H, C1-C5 straight or branched alkyl (e.g., methyl, ethyl), C1-C5 straight or branched alkoxy (e.g., methoxy), phenyl, aryl, or heteroaryl; or two gemR substituents are linked together to form a five- or six-membered heterocycle; m, n, l, and k are, independently of one another, integers from 0 to 4 (e.g., 0, 1, 2); Substituents include F, Cl, Br, I, OH, C1-C5 straight or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 straight or branched alkenyl (e.g., E- or Z-propylene), C2-C5 straight or branched alkenyl (e.g., CH≡C-CH3), alkoxy, ester (e.g., OC(O)-CH3), N(R)2, CF3, aryl, Examples of alkyl phosphates include aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, or NO.

[0034] In various embodiments, the present invention provides a compound represented by Formula II below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0035] [ka]

[0036] During the ceremony, The A and B rings may be, independently of one another, single or fused aromatic or heteroaromatic ring systems (e.g., phenyl, indole, benzofuran, 2-, 3-, or 4-pyridine, naphthalene, thiazole, thiophene, imidazole, 1-methylimidazole, benzimidazole), single or fused C3-C 10 Cycloalkyl (e.g., cyclohexyl) or single or fused C-C 10 heterocycles (e.g., benzofuran-2(3H)-one, benzo[d][1,3]dioxole, tetrahydrothiophene 1,1-dioxide, piperidine, 1-methylpiperidine, isoquinoline, 1,3-dihydroisobenzofuran); R1, R2, R 20 are, independently of one another, H, F, Cl, Br, I, OH, SH, R—OH (e.g., CH—OH), R—SH, —R—OR 10 , (e.g., -CH2-O-CH3), R8-(C3-C8 cycloalkyl) (e.g., cyclohexyl), R8-(C3-C8 heterocycle) (e.g., CH2-morpholine, CH2-imidazole, CH2-indazole), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR (e.g., NH-CH3), N(R)2 (e.g., N(CH3)2), R8-N(R 10 )(R 11 ) (e.g., CH2-CH2-N(CH3)2, CH2-NH2, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ) (e.g., C≡C-CH2-NH2), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g. C(O)O-CH3, C(O)O-CH(CH3)2, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., -CH2-O-CH3), C(O)H, C(O)-R 10(e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 linear or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR, C(O)N(R 10 )(R 11 ) (e.g., C(O)N-CH3), SO2R, SO2N(R 10 )(R 11) (e.g., SO2N(CH3)2, SO2NHC(O)CH3), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., C(H)(OH)-CH3, methyl, 2, 3, or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, butyl, t-Bu, isobutyl, pentyl, benzyl), C2-C5 straight-chain or branched, substituted or unsubstituted alkenyl (e.g., C≡C-CH2-NH2), C1-C5 straight-chain, branched, or cyclic haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, C H2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), substituted or unsubstituted C1-C5 straight or branched chain or C3-C8 cyclic alkoxy (e.g., methoxy, O-(CH2)2-pyrrolidine, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tBu), optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom (e.g., O-1-oxacyclobutyl, O-2-oxacyclobutyl ... cyclobutyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy (e.g., OCF3, OCHF2), C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperidine, piperazine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, oxadiazole, Azole, imidazole, furan, triazole, tetrazole, pyridine (2, 3, or 4-pyridine), 3-methyl-2-pyridine, pyrimidine, pyrazine, pyridazine, oxacyclobutane (1 or 2-oxacyclobutane), indole, protonated or deprotonated pyridine oxide), substituted or unsubstituted aryl (e.g., phenyl, xylyl, 2,6-difluorophenyl, 4-fluoroxylyl), substituted or unsubstituted benzyl (e.g., benzyl, 4-Cl-benzyl, 4-OH-benzyl), or CH(CF3)(NH-R10 ) is; or R2 and R1 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., pyrrole, [1,3]dioxole, furan-2(3H)-one, benzene, pyridine); R3, R4, R 40 are, independently of one another, H, F, Cl, Br, I, OH, SH, R—OH (e.g., CH—OH), R—SH, —R—OR 10 , (e.g., CH2-O-CH3)CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH2, CH2-N(CH3)2)R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, -NHCO-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g., C(O)O-CH3, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., CH2C(O)CH3), C(O)H, C(O)-R 10 (e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 straight or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R 10 )(R 11 ) (for example, C(O)N(CH3)2), C(O)N(CH3)(CH2CH3), C(O)N(CH3)(CH2CH2-O-CH3), C(S)N(R 10 )(R 11 ) (e.g., C(S)NH(CH3)), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO2R, SO2N(R10 )(R 11 ) (e.g., SO2NH(CH3), SO2N(CH3)2), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, t-Bu, isobutyl, pentyl), or substituted or unsubstituted C1-C5 straight-chain or branched or C3-C8 cyclic haloalkyl (e.g., CF3, CF2CH3, CF2-cyclobutyl, CF2-cyclopropyl, CF2-methylcyclopropyl, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2, C(OH)2CF3, cyclopropyl-CF3), C1-C5 straight-chain, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl), C1-C5 straight-chain or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., CF3-cyclopropyl, cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocycle (e.g., oxadiazole, pyrrole, N-methyloxetan-3-amine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, isoxazole, imidazole, furan, triazole, methyltriazole, pyridine (2, 3 or 4-pyridine), pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), indole), substituted or unsubstituted aryl (e.g., phenyl), or CH(CF3)(NH-R 10 ) is; or R3 and R4 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., imidazole, [1,3]dioxole, furan-2(3H)-one, benzene, cyclopentane, imidazole); R5 is H, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, CH2SH, ethyl, isopropyl), C2-C5 linear or branched, substituted or unsubstituted alkenyl, C2-C5 linear or branched, substituted or unsubstituted alkynyl (e.g., CCH), C1-C5 linear or branched haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2), CF(CH3)-CH((CH3)2), R8-aryl (e.g., CH2-Ph), C(=CH2)-R 10 (e.g., C(=CH2)-C(O)-OCH3, C(=CH2)-CN) substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted heteroaryl (2,3,4-pyridine); R6 is H, C1-C5 straight or branched alkyl (e.g., methyl), C(O)R, or S(O)2R; R 60 is H, substituted or unsubstituted C1-C5 straight or branched alkyl (e.g., methyl, CH2-OC(O)CH3, CH2-PO4H2, CH2-PO4H-tBu, CH2-OP(O)(OCH3)2), C(O)R, or S(O)2R; R8 is [CH2] p and p is 1 to 10; R9 is [CH] q , or [C] q and q is 2 to 10; R 10 and R 11 are each independently H, CN, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), R8-OR 10 (e.g., CH2CH2-O-CH3), C(O)R (e.g., C(O)(OCH3)), or S(O)2R; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., pyrrolidine, piperazine, methylpiperazine, azetidine, piperidine, morpholine); R is H, C1-C5 straight or branched alkyl (e.g., methyl, ethyl), C1-C5 straight or branched alkoxy (e.g., methoxy), phenyl, aryl, or heteroaryl; or two gemR substituents are linked together to form a five- or six-membered heterocycle; X1, X2, X3, X4, and X5 are, independently of one another, C or N; m, n, l, and k are, independently of one another, integers from 0 to 4 (e.g., 0, 1, 2); Substituents include F, Cl, Br, I, OH, C1-C5 straight or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 straight or branched alkenyl (e.g., E- or Z-propylene), C2-C5 straight or branched alkenyl (e.g., CH≡C-CH3), alkoxy, ester (e.g., OC(O)-CH3), N(R)2, CF3, aryl, Examples of alkyl phosphates include aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, or NO.

[0037] In various embodiments, the present invention provides a compound represented by Formula III below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0038] [ka]

[0039] During the ceremony, R1, R2, R 20 are, independently of one another, H, F, Cl, Br, I, OH, SH, R—OH (e.g., CH—OH), R—SH, —R—OR 10 , (e.g., -CH2-O-CH3), R8-(C3-C8 cycloalkyl) (e.g., cyclohexyl), R8-(C3-C8 heterocycle) (e.g., CH2-morpholine, CH2-imidazole, CH2-indazole), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR (e.g., NH-CH3), N(R)2 (e.g., N(CH3)2), R8-N(R 10 )(R 11 ) (e.g., CH2-CH2-N(CH3)2, CH2-NH2, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ) (e.g., C≡C-CH2-NH2), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g. C(O)O-CH3, C(O)O-CH(CH3)2, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., -CH2-O-CH3), C(O)H, C(O)-R 10 (e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 linear or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR, C(O)N(R 10 )(R 11 ) (e.g., C(O)N-CH3), SO2R, SO2N(R 10 )(R 11) (e.g., SO2N(CH3)2, SO2NHC(O)CH3), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., C(H)(OH)-CH3, methyl, 2, 3, or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, butyl, t-Bu, isobutyl, pentyl, benzyl), C2-C5 straight-chain or branched, substituted or unsubstituted alkenyl (e.g., C≡C-CH2-NH2), C1-C5 straight-chain, branched, or cyclic haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, C H2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), substituted or unsubstituted C1-C5 straight or branched chain or C3-C8 cyclic alkoxy (e.g., methoxy, O-(CH2)2-pyrrolidine, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tBu), optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom (e.g., O-1-oxacyclobutyl, O-2-oxacyclobutyl ... cyclobutyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy (e.g., OCF3, OCHF2), C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperidine, piperazine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, oxadiazole, Azole, imidazole, furan, triazole, tetrazole, pyridine (2, 3, or 4-pyridine), 3-methyl-2-pyridine, pyrimidine, pyrazine, pyridazine, oxacyclobutane (1 or 2-oxacyclobutane), indole, protonated or deprotonated pyridine oxide), substituted or unsubstituted aryl (e.g., phenyl, xylyl, 2,6-difluorophenyl, 4-fluoroxylyl), substituted or unsubstituted benzyl (e.g., benzyl, 4-Cl-benzyl, 4-OH-benzyl), or CH(CF3)(NH-R10 ) is; or R2 and R1 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., pyrrole, [1,3]dioxole, furan-2(3H)-one, benzene, pyridine); R3, R4, R 40 are, independently of one another, H, F, Cl, Br, I, OH, SH, R—OH (e.g., CH—OH), R—SH, —R—OR 10 , (e.g., CH2-O-CH3)CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH2, CH2-N(CH3)2)R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, -NHCO-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g., C(O)O-CH3, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., CH2C(O)CH3), C(O)H, C(O)-R 10 (e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 straight or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R 10 )(R 11 ) (for example, C(O)N(CH3)2), C(O)N(CH3)(CH2CH3), C(O)N(CH3)(CH2CH2-O-CH3), C(S)N(R 10 )(R 11 ) (e.g., C(S)NH(CH3)), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO2R, SO2N(R10 )(R 11 ) (e.g., SO2NH(CH3), SO2N(CH3)2), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, t-Bu, isobutyl, pentyl), or substituted or unsubstituted C1-C5 straight-chain or branched or C3-C8 cyclic haloalkyl (e.g., CF3, CF2CH3, CF2-cyclobutyl, CF2-cyclopropyl, CF2-methylcyclopropyl, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2, C(OH)2CF3, cyclopropyl-CF3), C1-C5 straight-chain, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl), C1-C5 straight-chain or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., CF3-cyclopropyl, cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocycle (e.g., oxadiazole, pyrrole, N-methyloxetan-3-amine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, isoxazole, imidazole, furan, triazole, methyltriazole, pyridine (2, 3 or 4-pyridine), pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), indole), substituted or unsubstituted aryl (e.g., phenyl), or CH(CF3)(NH-R 10 ) is; or R3 and R4 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., imidazole, [1,3]dioxole, furan-2(3H)-one, benzene, cyclopentane, imidazole); R5 is H, C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, CH2SH, ethyl, isopropyl), C2-C5 linear or branched, substituted or unsubstituted alkenyl, C2-C5 linear or branched, substituted or unsubstituted alkynyl (e.g., CCH), C1-C5 linear or branched haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2), CF(CH3)-CH((CH3)2), R8-aryl (e.g., CH2-Ph), C(=CH2)-R 10 (e.g., C(=CH2)-C(O)-OCH3, C(=CH2)-CN) substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted heteroaryl (2,3,4-pyridine); R6 is H, C1-C5 straight or branched alkyl (e.g., methyl), C(O)R, or S(O)2R; R 60 is H, substituted or unsubstituted C1-C5 straight or branched alkyl (e.g., methyl, CH2-OC(O)CH3, CH2-PO4H2, CH2-PO4H-tBu, CH2-OP(O)(OCH3)2), C(O)R, or S(O)2R; R8 is [CH2] p and p is 1 to 10; R9 is [CH] q , or [C] q and q is 2 to 10; R 10 and R 11 are each independently H, CN, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), R8-OR 10 (e.g., CH2CH2-O-CH3), C(O)R (e.g., C(O)(OCH3)), or S(O)2R; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., pyrrolidine, piperazine, methylpiperazine, azetidine, piperidine, morpholine); R is H, C1-C5 straight or branched alkyl (e.g., methyl, ethyl), C1-C5 straight or branched alkoxy (e.g., methoxy), phenyl, aryl, or heteroaryl; or two gemR substituents are linked together to form a five- or six-membered heterocycle; m, n, l, and k are, independently of one another, integers from 0 to 4 (e.g., 0, 1, 2); Substituents include F, Cl, Br, I, OH, C1-C5 straight or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 straight or branched alkenyl (e.g., E- or Z-propylene), C2-C5 straight or branched alkenyl (e.g., CH≡C-CH3), alkoxy, ester (e.g., OC(O)-CH3), N(R)2, CF3, aryl, Examples of alkyl groups include aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH)), CN, or NO.

[0040] In various embodiments, the present invention provides a compound represented by formula IV below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0041] [ka]

[0042] During the ceremony, R1, R2, R 20are, independently of one another, H, F, Cl, Br, I, OH, SH, R—OH (e.g., CH—OH), R—SH, —R—OR 10 , (e.g., -CH2-O-CH3), R8-(C3-C8 cycloalkyl) (e.g., cyclohexyl), R8-(C3-C8 heterocycle) (e.g., CH2-morpholine, CH2-imidazole, CH2-indazole), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR (e.g., NH-CH3), N(R)2 (e.g., N(CH3)2), R8-N(R 10 )(R 11 ) (e.g., CH2-CH2-N(CH3)2, CH2-NH2, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ) (e.g., C≡C-CH2-NH2), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g. C(O)O-CH3, C(O)O-CH(CH3)2, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., -CH2-O-CH3), C(O)H, C(O)-R 10 (e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 linear or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR, C(O)N(R 10 )(R 11 ) (e.g., C(O)N-CH3), SO2R, SO2N(R 10 )(R 11) (e.g., SO2N(CH3)2, SO2NHC(O)CH3), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., C(H)(OH)-CH3, methyl, 2, 3, or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, butyl, t-Bu, isobutyl, pentyl, benzyl), C2-C5 straight-chain or branched, substituted or unsubstituted alkenyl (e.g., C≡C-CH2-NH2), C1-C5 straight-chain, branched, or cyclic haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, C H2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), substituted or unsubstituted C1-C5 straight or branched chain or C3-C8 cyclic alkoxy (e.g., methoxy, O-(CH2)2-pyrrolidine, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tBu), optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom (e.g., O-1-oxacyclobutyl, O-2-oxacyclobutyl ... cyclobutyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy (e.g., OCF3, OCHF2), C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperidine, piperazine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, oxadiazole, Azole, imidazole, furan, triazole, tetrazole, pyridine (2, 3, or 4-pyridine), 3-methyl-2-pyridine, pyrimidine, pyrazine, pyridazine, oxacyclobutane (1 or 2-oxacyclobutane), indole, protonated or deprotonated pyridine oxide), substituted or unsubstituted aryl (e.g., phenyl, xylyl, 2,6-difluorophenyl, 4-fluoroxylyl), substituted or unsubstituted benzyl (e.g., benzyl, 4-Cl-benzyl, 4-OH-benzyl), or CH(CF3)(NH-R10 ) is; or R2 and R1 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., pyrrole, [1,3]dioxole, furan-2(3H)-one, benzene, pyridine); R3, R4, R 40 are, independently of one another, H, F, Cl, Br, I, OH, SH, R—OH (e.g., CH—OH), R—SH, —R—OR 10 , (e.g., CH2-O-CH3)CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH2, CH2-N(CH3)2)R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, -NHCO-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g., C(O)O-CH3, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., CH2C(O)CH3), C(O)H, C(O)-R 10 (e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 straight or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R 10 )(R 11 ) (for example, C(O)N(CH3)2), C(O)N(CH3)(CH2CH3), C(O)N(CH3)(CH2CH2-O-CH3), C(S)N(R 10 )(R 11 ) (e.g., C(S)NH(CH3)), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO2R, SO2N(R10 )(R 11 ) (e.g., SO2NH(CH3), SO2N(CH3)2), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, t-Bu, isobutyl, pentyl), or substituted or unsubstituted C1-C5 straight-chain or branched or C3-C8 cyclic haloalkyl (e.g., CF3, CF2CH3, CF2-cyclobutyl, CF2-cyclopropyl, CF2-methylcyclopropyl, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2, C(OH)2CF3, cyclopropyl-CF3), C1-C5 straight-chain, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl), C1-C5 straight-chain or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., CF3-cyclopropyl, cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocycle (e.g., oxadiazole, pyrrole, N-methyloxetan-3-amine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, isoxazole, imidazole, furan, triazole, methyltriazole, pyridine (2, 3 or 4-pyridine), pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), indole), substituted or unsubstituted aryl (e.g., phenyl), or CH(CF3)(NH-R 10 ) is; or R3 and R4 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., imidazole, [1,3]dioxole, furan-2(3H)-one, benzene, cyclopentane, imidazole); R8 is [CH2] p and p is 1 to 10; R9 is [CH] q , or [C]q and q is 2 to 10; R 10 and R 11 are each independently H, CN, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), R8-OR 10 (e.g., CH2CH2-O-CH3), C(O)R (e.g., C(O)(OCH3)), or S(O)2R; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., pyrrolidine, piperazine, methylpiperazine, azetidine, piperidine, morpholine); R is H, C1-C5 straight or branched alkyl (e.g., methyl, ethyl), C1-C5 straight or branched alkoxy (e.g., methoxy), phenyl, aryl, or heteroaryl; or two gemR substituents are linked together to form a five- or six-membered heterocycle; m, n, l, and k are, independently of one another, integers from 0 to 4 (e.g., 0, 1, 2); Substituents include F, Cl, Br, I, OH, C1-C5 straight or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 straight or branched alkenyl (e.g., E- or Z-propylene), C2-C5 straight or branched alkenyl (e.g., CH≡C-CH3), alkoxy, ester (e.g., OC(O)-CH3), N(R)2, CF3, aryl, Examples of alkyl phosphates include aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, or NO.

[0043] In various embodiments, the present invention provides a compound represented by the following chemical formula V: or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0044] [ka]

[0045] During the ceremony, R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2-OH), R8-SH, -R8-OR 10 , (e.g., -CH2-O-CH3), R8-(C3-C8 cycloalkyl) (e.g., cyclohexyl), R8-(C3-C8 heterocycle) (e.g., CH2-morpholine, CH2-imidazole, CH2-indazole), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR (e.g., NH-CH3), N(R)2 (e.g., N(CH3)2), R8-N(R 10 )(R 11 ) (e.g., CH2-CH2-N(CH3)2, CH2-NH2, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ) (e.g., C≡C-CH2-NH2), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g. C(O)O-CH3, C(O)O-CH(CH3)2, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., -CH2-O-CH3), C(O)H, C(O)-R 10(e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 linear or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR, C(O)N(R 10 )(R 11 ) (e.g., C(O)N-CH3), SO2R, SO2N(R 10 )(R 11) (e.g., SO2N(CH3)2, SO2NHC(O)CH3), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., C(H)(OH)-CH3, methyl, 2, 3, or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, butyl, t-Bu, isobutyl, pentyl, benzyl), C2-C5 straight-chain or branched, substituted or unsubstituted alkenyl (e.g., C≡C-CH2-NH2), C1-C5 straight-chain, branched, or cyclic haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, C H2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), substituted or unsubstituted C1-C5 straight or branched chain or C3-C8 cyclic alkoxy (e.g., methoxy, O-(CH2)2-pyrrolidine, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tBu), optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom (e.g., O-1-oxacyclobutyl, O-2-oxacyclobutyl ... cyclobutyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy (e.g., OCF3, OCHF2), C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperidine, piperazine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, oxadiazole, Azole, imidazole, furan, triazole, tetrazole, pyridine (2, 3, or 4-pyridine), 3-methyl-2-pyridine, pyrimidine, pyrazine, pyridazine, oxacyclobutane (1 or 2-oxacyclobutane), indole, protonated or deprotonated pyridine oxide), substituted or unsubstituted aryl (e.g., phenyl, xylyl, 2,6-difluorophenyl, 4-fluoroxylyl), substituted or unsubstituted benzyl (e.g., benzyl, 4-Cl-benzyl, 4-OH-benzyl), or CH(CF3)(NH-R10 ) is; or R2 and R1 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., pyrrole, [1,3]dioxole, furan-2(3H)-one, benzene, pyridine); R3 and R4 are each independently H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2-OH), R8-SH, -R8-OR 10 , (e.g., CH2-O-CH3)CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH2, CH2-N(CH3)2)R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, -NHCO-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g., C(O)O-CH3, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., CH2C(O)CH3), C(O)H, C(O)-R 10 (e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 straight or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R 10 )(R 11 ) (for example, C(O)N(CH3)2), C(O)N(CH3)(CH2CH3), C(O)N(CH3)(CH2CH2-O-CH3), C(S)N(R 10 )(R 11 ) (e.g., C(S)NH(CH3)), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO2R, SO2N(R 10 )(R11 ) (e.g., SO2NH(CH3), SO2N(CH3)2), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, t-Bu, isobutyl, pentyl), or substituted or unsubstituted C1-C5 straight-chain or branched or C3-C8 cyclic haloalkyl (e.g., CF3, CF2CH3, CF2-cyclobutyl, CF2-cyclopropyl, CF2-methylcyclopropyl, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2, C(OH)2CF3, cyclopropyl-CF3), C1-C5 straight-chain, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl), C1-C5 straight-chain or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., CF3-cyclopropyl, cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocycle (e.g., oxadiazole, pyrrole, N-methyloxetan-3-amine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, isoxazole, imidazole, furan, triazole, methyltriazole, pyridine (2, 3 or 4-pyridine), pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), indole), substituted or unsubstituted aryl (e.g., phenyl), or CH(CF3)(NH-R 10 ) is; or R3 and R4 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., imidazole, [1,3]dioxole, furan-2(3H)-one, benzene, cyclopentane, imidazole); R8 is [CH2] p and p is 1 to 10; R9 is [CH] q , or [C] qand q is 2 to 10; R 10 and R 11 are each independently H, CN, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), R8-OR 10 (e.g., CH2CH2-O-CH3), C(O)R (e.g., C(O)(OCH3)), or S(O)2R; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., pyrrolidine, piperazine, methylpiperazine, azetidine, piperidine, morpholine); R is H, C1-C5 straight or branched alkyl (e.g., methyl, ethyl), C1-C5 straight or branched alkoxy (e.g., methoxy), phenyl, aryl, or heteroaryl; or two gemR substituents are linked together to form a five- or six-membered heterocycle; m, n, l, and k are, independently of one another, integers from 0 to 4 (e.g., 0, 1, 2); Substituents include F, Cl, Br, I, OH, C1-C5 straight or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 straight or branched alkenyl (e.g., E- or Z-propylene), C2-C5 straight or branched alkenyl (e.g., CH≡C-CH3), alkoxy, ester (e.g., OC(O)-CH3), N(R)2, CF3, aryl, Examples of alkyl phosphates include aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, or NO.

[0046] In various embodiments, the present invention provides a compound represented by formula VI below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0047] [ka]

[0048] During the ceremony, R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2-OH), R8-SH, -R8-OR 10 , (e.g., -CH2-O-CH3), R8-(C3-C8 cycloalkyl) (e.g., cyclohexyl), R8-(C3-C8 heterocycle) (e.g., CH2-morpholine, CH2-imidazole, CH2-indazole), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR (e.g., NH-CH3), N(R)2 (e.g., N(CH3)2), R8-N(R 10 )(R 11 ) (e.g., CH2-CH2-N(CH3)2, CH2-NH2, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ) (e.g., C≡C-CH2-NH2), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g. C(O)O-CH3, C(O)O-CH(CH3)2, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., -CH2-O-CH3), C(O)H, C(O)-R 10(e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 linear or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR, C(O)N(R 10 )(R 11 ) (e.g., C(O)N-CH3), SO2R, SO2N(R 10 )(R 11) (e.g., SO2N(CH3)2, SO2NHC(O)CH3), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., C(H)(OH)-CH3, methyl, 2, 3, or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, butyl, t-Bu, isobutyl, pentyl, benzyl), C2-C5 straight-chain or branched, substituted or unsubstituted alkenyl (e.g., C≡C-CH2-NH2), C1-C5 straight-chain, branched, or cyclic haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, C H2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), substituted or unsubstituted C1-C5 straight or branched chain or C3-C8 cyclic alkoxy (e.g., methoxy, O-(CH2)2-pyrrolidine, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tBu), optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom (e.g., O-1-oxacyclobutyl, O-2-oxacyclobutyl ... cyclobutyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy (e.g., OCF3, OCHF2), C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperidine, piperazine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, oxadiazole, Azole, imidazole, furan, triazole, tetrazole, pyridine (2, 3, or 4-pyridine), 3-methyl-2-pyridine, pyrimidine, pyrazine, pyridazine, oxacyclobutane (1 or 2-oxacyclobutane), indole, protonated or deprotonated pyridine oxide), substituted or unsubstituted aryl (e.g., phenyl, xylyl, 2,6-difluorophenyl, 4-fluoroxylyl), substituted or unsubstituted benzyl (e.g., benzyl, 4-Cl-benzyl, 4-OH-benzyl), or CH(CF3)(NH-R10 ) is; or R2 and R1 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., pyrrole, [1,3]dioxole, furan-2(3H)-one, benzene, pyridine); R3 is H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2-OH), R8-SH, -R8-OR 10 , (e.g., CH2-O-CH3)CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH2, CH2-N(CH3)2)R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, -NHCO-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g., C(O)O-CH3, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., CH2C(O)CH3), C(O)H, C(O)-R 10 (e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 straight or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R 10 )(R 11 ) (for example, C(O)N(CH3)2), C(O)N(CH3)(CH2CH3), C(O)N(CH3)(CH2CH2-O-CH3), C(S)N(R 10 )(R 11 ) (e.g., C(S)NH(CH3)), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO2R, SO2N(R 10 )(R 11) (e.g., SO2NH(CH3), SO2N(CH3)2), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, t-Bu, isobutyl, pentyl), or substituted or unsubstituted C1-C5 straight-chain or branched or C3-C8 cyclic haloalkyl (e.g., CF3, CF2CH3, CF2-cyclobutyl, CF2-cyclopropyl, CF2-methylcyclopropyl, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2, C(OH)2CF3, cyclopropyl-CF3), C1-C5 straight-chain, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl), C1-C5 straight-chain or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., CF3-cyclopropyl, cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocycle (e.g., oxadiazole, pyrrole, N-methyloxetan-3-amine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, isoxazole, imidazole, furan, triazole, methyltriazole, pyridine (2, 3 or 4-pyridine), pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), indole), substituted or unsubstituted aryl (e.g., phenyl), or CH(CF3)(NH-R 10 ) is; R8 is [CH2] p and p is 1 to 10; R9 is [CH] q , or [C] q and q is 2 to 10; R 10 and R 11 are each independently H, CN, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), R8-OR 10(e.g., CH2CH2-O-CH3), C(O)R (e.g., C(O)(OCH3)), or S(O)2R; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., pyrrolidine, piperazine, methylpiperazine, azetidine, piperidine, morpholine); R is H, C1-C5 straight or branched alkyl (e.g., methyl, ethyl), C1-C5 straight or branched alkoxy (e.g., methoxy), phenyl, aryl, or heteroaryl; or two gemR substituents are linked together to form a five- or six-membered heterocycle; m, n, l, and k are, independently of one another, integers from 0 to 4 (e.g., 0, 1, 2); Substituents include F, Cl, Br, I, OH, C1-C5 straight or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 straight or branched alkenyl (e.g., E- or Z-propylene), C2-C5 straight or branched alkenyl (e.g., CH≡C-CH3), alkoxy, ester (e.g., OC(O)-CH3), N(R)2, CF3, aryl, Examples of alkyl phosphates include aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, or NO.

[0049] In various embodiments, the present invention provides a compound represented by the following formula VII: or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0050] [ka]

[0051] During the ceremony, R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2-OH), R8-SH, -R8-OR 10 , (e.g., -CH2-O-CH3), R8-(C3-C8 cycloalkyl) (e.g., cyclohexyl), R8-(C3-C8 heterocycle) (e.g., CH2-morpholine, CH2-imidazole, CH2-indazole), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR (e.g., NH-CH3), N(R)2 (e.g., N(CH3)2), R8-N(R 10 )(R 11 ) (e.g., CH2-CH2-N(CH3)2, CH2-NH2, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ) (e.g., C≡C-CH2-NH2), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g. C(O)O-CH3, C(O)O-CH(CH3)2, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., -CH2-O-CH3), C(O)H, C(O)-R 10 (e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 linear or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR, C(O)N(R 10 )(R 11 ) (e.g., C(O)N-CH3), SO2R, SO2N(R 10 )(R 11) (e.g., SO2N(CH3)2, SO2NHC(O)CH3), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., C(H)(OH)-CH3, methyl, 2, 3, or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, butyl, t-Bu, isobutyl, pentyl, benzyl), C2-C5 straight-chain or branched, substituted or unsubstituted alkenyl (e.g., C≡C-CH2-NH2), C1-C5 straight-chain, branched, or cyclic haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, C H2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), substituted or unsubstituted C1-C5 straight or branched chain or C3-C8 cyclic alkoxy (e.g., methoxy, O-(CH2)2-pyrrolidine, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tBu), optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom (e.g., O-1-oxacyclobutyl, O-2-oxacyclobutyl ... cyclobutyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy (e.g., OCF3, OCHF2), C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperidine, piperazine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, oxadiazole, Azole, imidazole, furan, triazole, tetrazole, pyridine (2, 3, or 4-pyridine), 3-methyl-2-pyridine, pyrimidine, pyrazine, pyridazine, oxacyclobutane (1 or 2-oxacyclobutane), indole, protonated or deprotonated pyridine oxide), substituted or unsubstituted aryl (e.g., phenyl, xylyl, 2,6-difluorophenyl, 4-fluoroxylyl), substituted or unsubstituted benzyl (e.g., benzyl, 4-Cl-benzyl, 4-OH-benzyl), or CH(CF3)(NH-R10 ) is; or R2 and R1 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., pyrrole, [1,3]dioxole, furan-2(3H)-one, benzene, pyridine); R3 is -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R 10 )(R 11 ) (for example, C(O)N(CH3)2, C(O)N(CH3)(CH2CH3), C(O)N(CH3)(CH2CH2-O-CH3)), C(S)N(R 10 )(R 11 ) (e.g., C(S)NH(CH3)), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO2N(R 10 )(R 11 ) (e.g., SO2NH(CH3), SO2N(CH3)2), or substituted or unsubstituted C1-C5 straight or branched or C3-C8 cyclic haloalkyl (e.g., CF3, CF2CH3, CF2-cyclobutyl, CF2-cyclopropyl, CF2-methylcyclopropyl, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2, C(OH)2CF3, cyclopropyl-CF3); R8 is [CH2] p and p is 1 to 10; R9 is [CH] q , or [C] q and q is 2 to 10; R 10 and R 11 are each independently H, CN, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), R8-OR 10 (e.g., CH2CH2-O-CH3), C(O)R (e.g., C(O)(OCH3)), or S(O)2R; Or, R 10 and R 11are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., pyrrolidine, piperazine, methylpiperazine, azetidine, piperidine, morpholine); R is H, C1-C5 straight or branched alkyl (e.g., methyl, ethyl), C1-C5 straight or branched alkoxy (e.g., methoxy), phenyl, aryl, or heteroaryl; or two gemR substituents are linked together to form a five- or six-membered heterocycle; Substituents include F, Cl, Br, I, OH, C1-C5 straight or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 straight or branched alkenyl (e.g., E- or Z-propylene), C2-C5 straight or branched alkenyl (e.g., CH≡C-CH3), alkoxy, ester (e.g., OC(O)-CH3), N(R)2, CF3, aryl, Examples of alkyl phosphates include aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, or NO.

[0052] In various embodiments, the present invention provides a compound represented by Formula VIII below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0053] [ka]

[0054] During the ceremony, R1, R2, R 21 , and R 22 are, independently of one another, H, F, Cl, Br, I, OH, SH, R—OH (e.g., CH—OH), R—SH, —R—OR 10 , (e.g., -CH2-O-CH3), R8-(C3-C8 cycloalkyl) (e.g., cyclohexyl), R8-(C3-C8 heterocycle) (e.g., CH2-morpholine, CH2-imidazole, CH2-indazole), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR (e.g., NH-CH3), N(R)2 (e.g., N(CH3)2), R8-N(R 10 )(R 11 ) (e.g., CH2-CH2-N(CH3)2, CH2-NH2, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ) (e.g., C≡C-CH2-NH2), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g. C(O)O-CH3, C(O)O-CH(CH3)2, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., -CH2-O-CH3), C(O)H, C(O)-R 10 (e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 linear or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR, C(O)N(R 10 )(R 11 ) (e.g., C(O)N-CH3), SO2R, SO2N(R 10 )(R 11) (e.g., SO2N(CH3)2, SO2NHC(O)CH3), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., C(H)(OH)-CH3, methyl, 2, 3, or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, butyl, t-Bu, isobutyl, pentyl, benzyl), C2-C5 straight-chain or branched, substituted or unsubstituted alkenyl (e.g., C≡C-CH2-NH2), C1-C5 straight-chain, branched, or cyclic haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, C H2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), substituted or unsubstituted C1-C5 straight or branched chain or C3-C8 cyclic alkoxy (e.g., methoxy, O-(CH2)2-pyrrolidine, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tBu), optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom (e.g., O-1-oxacyclobutyl, O-2-oxacyclobutyl ... cyclobutyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy (e.g., OCF3, OCHF2), C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperidine, piperazine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, oxadiazole, Azole, imidazole, furan, triazole, tetrazole, pyridine (2, 3, or 4-pyridine), 3-methyl-2-pyridine, pyrimidine, pyrazine, pyridazine, oxacyclobutane (1 or 2-oxacyclobutane), indole, protonated or deprotonated pyridine oxide), substituted or unsubstituted aryl (e.g., phenyl, xylyl, 2,6-difluorophenyl, 4-fluoroxylyl), substituted or unsubstituted benzyl (e.g., benzyl, 4-Cl-benzyl, 4-OH-benzyl), or CH(CF3)(NH-R10 ) is; or R2 and R1 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., pyrrole, [1,3]dioxole, furan-2(3H)-one, benzene, pyridine); Or, R 21 and R1 combine with each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., pyrrole, [1,3]dioxole, furan-2(3H)-one, benzene, pyridine); Or, R 21 and R 22 are bonded to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., pyrrole, [1,3]dioxole, furan-2(3H)-one, benzene, pyridine); R3 is H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2-OH), R8-SH, -R8-OR 10 , (e.g., CH2-O-CH3)CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH2, CH2-N(CH3)2)R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, -NHCO-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g., C(O)O-CH3, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., CH2C(O)CH3), C(O)H, C(O)-R 10(e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 straight or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R 10 )(R 11 ) (for example, C(O)N(CH3)2), C(O)N(CH3)(CH2CH3), C(O)N(CH3)(CH2CH2-O-CH3), C(S)N(R 10 )(R 11 ) (e.g., C(S)NH(CH3)), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO2R, SO2N(R 10 )(R 11) (e.g., SO2NH(CH3), SO2N(CH3)2), C1-C5 straight or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, t-Bu, isobutyl, pentyl), or substituted or unsubstituted C1-C5 straight or branched or C3-C8 cyclic haloalkyl (e.g., CF3, CF2CH3, CF2-cyclobutyl, CF2-cyclopropyl, CF2-methylcyclopropyl). C1-C5 linear or branched alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxy (e.g., methyl, methyl, methyl)-C5 linear or branched alkoxy (e.g. ... alkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., CF3-cyclopropyl, cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocycle (e.g., oxadiazole, pyrrole, N-methyloxetan-3-amine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, isoxazole, imidazole, furan, triazole, methyltriazole, pyridine (2, 3, or 4-pyridine), pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), indole), substituted or unsubstituted aryl (e.g., phenyl) (substituents include F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof), or CH(CF3)(NH-R 10 ) is; R8 is [CH2] p and p is 1 to 10; R9 is [CH] q , or [C] q and q is 2 to 10; R 10 and R11 are each independently H, CN, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), R8-OR 10 (e.g., CH2CH2-O-CH3), C(O)R (e.g., C(O)(OCH3)), or S(O)2R; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., pyrrolidine, piperazine, methylpiperazine, azetidine, piperidine, morpholine); R is H, C1-C5 straight or branched alkyl (e.g., methyl, ethyl), C1-C5 straight or branched alkoxy (e.g., methoxy), phenyl, aryl, or heteroaryl; or two gemR substituents are linked together to form a five- or six-membered heterocycle; Substituents include F, Cl, Br, I, OH, C1-C5 straight or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 straight or branched alkenyl (e.g., E- or Z-propylene), C2-C5 straight or branched alkenyl (e.g., CH≡C-CH3), alkoxy, ester (e.g., OC(O)-CH3), N(R)2, CF3, aryl, Examples of alkyl phosphates include aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, or NO.

[0055] In some embodiments, R1 is methoxy. In some embodiments, R2 is xylyl. In some embodiments, R3 is haloalkyl. In some embodiments, R3 is CF3, CF2CH3, CF2-cyclopropyl, CH2CF3, CF2CH2CH3, C(OH)2CF3, or cyclopropyl-CF3; each represents a separate embodiment of the present invention. In some embodiments, R1 is methoxy, R2 is xylyl, and R3 is haloalkyl.

[0056] In various embodiments, the present invention provides a compound represented by formula IX below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0057] [ka]

[0058] R1, R 20 , R 21 , and R 22 are, independently of one another, H, F, Cl, Br, I, OH, SH, R—OH (e.g., CH—OH), R—SH, —R—OR 10 , (e.g., -CH2-O-CH3), R8-(C3-C8 cycloalkyl) (e.g., cyclohexyl), R8-(C3-C8 heterocycle) (e.g., CH2-morpholine, CH2-imidazole, CH2-indazole), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR (e.g., NH-CH3), N(R)2 (e.g., N(CH3)2), R8-N(R 10 )(R 11 ) (e.g., CH2-CH2-N(CH3)2, CH2-NH2, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ) (e.g., C≡C-CH2-NH2), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g. C(O)O-CH3, C(O)O-CH(CH3)2, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., -CH2-O-CH3), C(O)H, C(O)-R 10 (e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 linear or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR, C(O)N(R 10 )(R 11 ) (e.g., C(O)N-CH3), SO2R, SO2N(R 10 )(R 11) (e.g., SO2N(CH3)2, SO2NHC(O)CH3), C1-C5 straight-chain or branched, substituted or unsubstituted alkyl (e.g., C(H)(OH)-CH3, methyl, 2, 3, or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, butyl, t-Bu, isobutyl, pentyl, benzyl), C2-C5 straight-chain or branched, substituted or unsubstituted alkenyl (e.g., C≡C-CH2-NH2), C1-C5 straight-chain, branched, or cyclic haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, C H2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), substituted or unsubstituted C1-C5 straight or branched chain or C3-C8 cyclic alkoxy (e.g., methoxy, O-(CH2)2-pyrrolidine, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tBu), optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom (e.g., O-1-oxacyclobutyl, O-2-oxacyclobutyl ... cyclobutyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy (e.g., OCF3, OCHF2), C1-C5 linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperidine, piperazine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, oxadiazole, Azole, imidazole, furan, triazole, tetrazole, pyridine (2, 3, or 4-pyridine), 3-methyl-2-pyridine, pyrimidine, pyrazine, pyridazine, oxacyclobutane (1 or 2-oxacyclobutane), indole, protonated or deprotonated pyridine oxide), substituted or unsubstituted aryl (e.g., phenyl, xylyl, 2,6-difluorophenyl, 4-fluoroxylyl), substituted or unsubstituted benzyl (e.g., benzyl, 4-Cl-benzyl, 4-OH-benzyl), or CH(CF3)(NH-R10 ) is; Or, R 21 and R1 combine with each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., pyrrole, [1,3]dioxole, furan-2(3H)-one, benzene, pyridine); Or, R 21 and R 22 are bonded to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., pyrrole, [1,3]dioxole, furan-2(3H)-one, benzene, pyridine); R 201 and R 202 are, independently of each other, H, F, Cl, Br, I, CF3, or C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl); R3 is H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2-OH), R8-SH, -R8-OR 10 , (e.g., CH2-O-CH3)CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH2, CH2-N(CH3)2)R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, -NHCO-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ) (e.g., NHC(O)N(CH3)2), COOH, -C(O)Ph, C(O)OR 10 (e.g., C(O)O-CH3, C(O)O-CH2CH3), R8-C(O)-R 10 (e.g., CH2C(O)CH3), C(O)H, C(O)-R 10(e.g., C(O)-CH3, C(O)-CH2CH3, C(O)-CH2CH2CH3), C1-C5 straight or branched C(O)-haloalkyl (e.g., C(O)-CF3), -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)), C(O)N(R 10 )(R 11 ) (for example, C(O)N(CH3)2), C(O)N(CH3)(CH2CH3), C(O)N(CH3)(CH2CH2-O-CH3), C(S)N(R 10 )(R 11 ) (e.g., C(S)NH(CH3)), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO2R, SO2N(R 10 )(R 11) (e.g., SO2NH(CH3), SO2N(CH3)2), C1-C5 straight or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, t-Bu, isobutyl, pentyl), or substituted or unsubstituted C1-C5 straight or branched or C3-C8 cyclic haloalkyl (e.g., CF3, CF2CH3, CF2-cyclobutyl, CF2-cyclopropyl, CF2-methylcyclopropyl). C1-C5 linear or branched alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl), C1-C5 linear or branched thioalkoxy, C1-C5 linear or branched haloalkoxy, C1-C5 linear or branched alkoxy (e.g., methyl, methyl, methyl)-C5 linear or branched alkoxy (e.g. ... alkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., CF3-cyclopropyl, cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocycle (e.g., oxadiazole, pyrrole, N-methyloxetan-3-amine, 3-methyl-4H-1,2,4 triazole, 5-methyl-1,2,4 oxadiazole, thiophene, oxazole, isoxazole, imidazole, furan, triazole, methyltriazole, pyridine (2, 3, or 4-pyridine), pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), indole), substituted or unsubstituted aryl (e.g., phenyl) (substituents include F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof), or CH(CF3)(NH-R 10 ) is; R8 is [CH2] p and p is 1 to 10; R9 is [CH] q , or [C] q and q is 2 to 10; R 10 and R11 are each independently H, CN, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), R8-OR 10 (e.g., CH2CH2-O-CH3), C(O)R (e.g., C(O)(OCH3)), or S(O)2R; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., pyrrolidine, piperazine, methylpiperazine, azetidine, piperidine, morpholine); R is H, C1-C5 straight or branched alkyl (e.g., methyl, ethyl), C1-C5 straight or branched alkoxy (e.g., methoxy), phenyl, aryl, or heteroaryl; or two gemR substituents are linked together to form a five- or six-membered heterocycle; Substituents include F, Cl, Br, I, OH, C1-C5 straight or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 straight or branched alkenyl (e.g., E- or Z-propylene), C2-C5 straight or branched alkenyl (e.g., CH≡C-CH3), alkoxy, ester (e.g., OC(O)-CH3), N(R)2, CF3, aryl, Examples of alkyl phosphates include aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, or NO.

[0059] In various embodiments, the A ring of the compound of formula I is selected from the group consisting of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, isoquinoline, pyrazolyl, pyrrolyl, furanyl, thiophen-yl, isoquinolinyl, indolyl, 1H-indole, isoindolyl, naphthyl, anthracenyl, benzimidazolyl, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, ... H-indazole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4,5,6,7-tetrahydro-1,3-benzothiazole, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinolinyl, isoquinolinyl, 2,3-dihydroindenyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepin, benzo[d][1,3]dioxole, acridinyl, benzofuran ranyl, 1-benzofuran, isobenzofuranyl, benzofuran-2(3H)-one, benzothiophenyl, benzoxadiazole, benzo[c][1,2,5]oxadiazolyl, benzo[c]thiophenyl, benzodioxolyl, benzo[d][1,3]dioxole, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiaziolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo Oxo-6H,7H-[1,3]thiazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2-d]pyrimidin-4(3H)-one, 4-oxo-4H-thieno[3,2-d][1,3]thiazine, imidazo[1,2-a]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-imidazo[4,5-c]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazole[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrido[2,3-b]pyrazine, pyrido[2,3-b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thieno[3,2-c]pyridine, each definition represents a separate embodiment of the present invention; or the A ring is a C3-C8 cycloalkyl (e.g., cyclohexyl). Or, C3-C8 heterocycles include, but are not limited to, tetrahydropyran, piperidine, 1-methylpiperidine, tetrahydrothiophene-1,1-dioxide, 1-(piperidin-1-yl)ethanone, or morpholine. ,

[0060] In various embodiments, the B ring of the compound of formula I is selected from the group consisting of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, isoquinoline, pyrazolyl, pyrrolyl, furanyl, thiophen-yl, isoquinolinyl, indolyl, 1H-indole, isoindolyl, naphthyl, anthracenyl, benzimidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, tetrahydronaphthyl, 3,4-dihydro-1H-benzo[d]imidazolyl, tetrahydronaphthyl ... Hydro-2H-benzo[b][1,4]dioxepin, benzofuran-2(3H)-one, benzo[d][1,3]dioxole, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4,5,6,7-tetrahydro-1,3-benzothiazole, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinolinyl, Isoquinolinyl, acridinyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzothiophenyl, benzoxadiazole, benzo[c][1,2,5]oxadiazolyl, benzo[c]thiophenyl, benzodioxolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiaziolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazolyl Zolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2-d]pyrimidin-4(3H)-one, 4-oxo-4H-thieno[3,2-d][1,3]thiazine, imidazo[1,2-a]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazole[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, pyrido[2,3-b]pyrazine, pyrido[2,3-b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, 1,2,3,4-tetrahydroquinoxaline, 1-(pyridin-1(2H)-yl)ethanone, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thieno[3,2-c]pyridine, C3-C8 cycloalkyl, or C3-C8 heterocycles, including, but not limited to, tetrahydropyran, piperidine, 1-methylpiperidine, tetrahydrothiophene-1,1-dioxide, 1-(piperidin-1-yl)ethanone, or morpholine. Each definition represents a separate embodiment of the present invention.

[0061] In some embodiments, the A ring of the compound of Formula I is phenyl. In other embodiments, A is pyridinyl. In other embodiments, A is 2-pyridinyl. In other embodiments, A is 3-pyridinyl. In other embodiments, A is 4-pyridinyl. In other embodiments, A is naphthyl. In other embodiments, A is benzothiazolyl. In other embodiments, A is benzimidazolyl. In other embodiments, A is quinolinyl. In other embodiments, A is isoquinolinyl. In other embodiments, A is indolyl. In other embodiments, A is tetrahydronaphthyl. In other embodiments, A is indenyl. In other embodiments, A is benzofuran-2(3H)-one. In other embodiments, A is benzo[d][1,3]dioxole. In other embodiments, A is naphthalene. In other embodiments, A is tetrahydrothiophene 1,1-dioxide. In other embodiments, A is thiazole. In another embodiment, A is benzimidazole. In another embodiment, A is piperidine. In another embodiment, A is 1-methylpiperidine. In another embodiment, A is imidazole. In another embodiment, A is 1-methylimidazole. In another embodiment, A is thiophene. In another embodiment, A is isoquinoline. In another embodiment, A is indole. In another embodiment, A is 1,3-dihydroisobenzofuran. In another embodiment, A is benzofuran. In another embodiment, A is a single or fused C3-C 10 In another embodiment, A is a cyclohexyl ring.

[0062] In some embodiments, the B ring of the compound of Formula I is a phenyl ring. In other embodiments, B is pyridinyl. In other embodiments, B is 2-pyridinyl. In other embodiments, B is 3-pyridinyl. In other embodiments, B is 4-pyridinyl. In other embodiments, B is naphthyl. In other embodiments, B is indolyl. In other embodiments, B is benzimidazolyl. In other embodiments, B is benzothiazolyl. In other embodiments, B is quinoxalinyl. In other embodiments, B is tetrahydronaphthyl. In other embodiments, B is quinolinyl. In other embodiments, B is isoquinolinyl. In other embodiments, B is indenyl. In other embodiments, B is naphthalene. In other embodiments, B is tetrahydrothiophene 1,1-dioxide. In other embodiments, B is thiazole. In other embodiments, B is benzimidazole. In other embodiments, B is piperidine. In another embodiment, B is 1-methylpiperidine. In another embodiment, B is imidazole. In another embodiment, B is 1-methylimidazole. In another embodiment, B is thiophene. In another embodiment, B is isoquinoline. In another embodiment, B is indole. In another embodiment, B is 1,3-dihydroisobenzofuran. In another embodiment, B is benzofuran. In another embodiment, B is a single or fused C3-C 10 In another embodiment, B is a cyclohexyl ring.

[0063] In some embodiments, X 1 in the compound of formula II is C. In other embodiments, X 1 is N.

[0064] In some embodiments, X2 in the compound of formula II is C. In other embodiments, X2 is N.

[0065] In some embodiments, X3 in the compound of formula II is C. In other embodiments, X3 is N.

[0066] In some embodiments, X4 in the compound of formula II is C. In other embodiments, X4 is N.

[0067] In some embodiments, X5 in the compound of Formula II is C. In other embodiments, X5 is N.

[0068] In various embodiments, the compounds of Formulas I-IV are selected from the group consisting of R, R, and R 20 and the compound of formula V is substituted with R1 or R2. The single substituent can be in the ortho, meta, or para position.

[0069] In various embodiments, the compounds of Formulas I-V are substituted at R3 or R4. The single substituent can be at the ortho, meta, or para position. In various embodiments, the compounds of Formulas I-IV are substituted at R 40 The single substituent may be in the ortho, meta, or para position.

[0070] In some embodiments, R1 in the compound of Formula I-IX is H. In some embodiments, R1 is not H.

[0071] In another embodiment, R1 in a compound of Formulas I-IX is F. In another embodiment, R1 is Cl. In another embodiment, R1 is Br. In another embodiment, R1 is I. In another embodiment, R1 is OH. In another embodiment, R1 is R8-(C3-C8 cycloalkyl). In another embodiment, R1 is CH2-cyclohexyl. In another embodiment, R1 is R8-(C3-C8 heterocycle). In another embodiment, R1 is CH2-morpholine. In another embodiment, R1 is CH2-imidazole. In another embodiment, R1 is CH2-indazole. In another embodiment, R1 is CF3. In another embodiment, R1 is CN. In another embodiment, R1 is CF2CH2CH3. In another embodiment, R1 is CH2CH2CH3. In another embodiment, R1 is CF2CH(CH3)2. In another embodiment, R1 is CF(CH3)-CH(CH3)2. In another embodiment, R1 is OCD3. In another embodiment, R1 is NO2. In another embodiment, R1 is NH2. In another embodiment, R1 is NHR. In another embodiment, R1 is NH-CH3. In another embodiment, R1 is N(R)2. In another embodiment, R1 is N(CH3)2. In another embodiment, R1 is R8-N(R 10 )(R 11 ). In another embodiment, R1 is CH2-CH2-N(CH3)2. In another embodiment, R1 is CH2-NH2. In another embodiment, R1 is CH2-N(CH3)2. In another embodiment, R1 is R9-R8-N(R 10 )(R 11 In another embodiment, R1 is C≡C—CH2—CH2. In another embodiment, R1 is B(OH)2. In another embodiment, R1 is NHC(O)—R 10 In another embodiment, R1 is NHC(O)CH3. In another embodiment, R1 is NHCO—N(R 10 )(R 11In another embodiment, R1 is NHC(O)N(CH3)2. In another embodiment, R1 is COOH. In another embodiment, R1 is C(O)-R 10 In another embodiment, R1 is C(O)-CH3. In another embodiment, R1 is C(O)OR 10 In another embodiment, R1 is C(O)O-CH(CH3)2. In another embodiment, R1 is C(O)O-CH3. In another embodiment, R1 is SO2N(R 10 )(R 11). In another embodiment, R1 is SON(CH3)2. In another embodiment, R1 is SONHC(O)CH3. In another embodiment, R1 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In another embodiment, R1 is methyl. In another embodiment, R1 is ethyl. In another embodiment, R1 is isopropyl. In another embodiment, R1 is Bu. In another embodiment, R1 is t-Bu. In another embodiment, R1 is isobutyl. In another embodiment, R1 is pentyl. In another embodiment, R1 is propyl. In another embodiment, R1 is benzyl. In another embodiment, R1 is C(H)(OH)-CH3. In another embodiment, R1 is C2-C5 linear or branched, substituted or unsubstituted alkenyl. In another embodiment, R1 is CH=C(Ph)2. In another embodiment, R1 is 2-CH2-C6H4-Cl. In another embodiment, R1 is 3-CH2-C6H4-Cl. In another embodiment, R1 is 4-CH2-C6H4-Cl. In another embodiment, R1 is ethyl. In another embodiment, R1 is isopropyl. In another embodiment, R1 is t-Bu. In another embodiment, R1 is isobutyl. In another embodiment, R1 is pentyl. In another embodiment, R1 is substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). In another embodiment, R1 is substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy. In another embodiment, R1 is substituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy. In another embodiment, R1 is O-(CH2)2-pyrrolidine. In another embodiment, R1 is unsubstituted C1-C5 straight or branched chain, or C3-C8 cyclic alkoxy. In another embodiment, R1 is methoxy. In another embodiment, R1 is ethoxy. In another embodiment, R1 is propoxy. In another embodiment, R1 is isopropoxy. In another embodiment, R1 is O-CH2-cyclopropyl. In another embodiment, R1 is O-cyclobutyl.In another embodiment, R1 is O-cyclopentyl. In another embodiment, R1 is O-cyclohexyl. In another embodiment, R1 is O-1-oxacyclobutyl. In another embodiment, R1 is O-2-oxacyclobutyl. In another embodiment, R1 is 1-butoxy. In another embodiment, R1 is 2-butoxy. In another embodiment, R1 is O-tBu. In another embodiment, R1 is C1-C5 linear or branched, or C3-C8 cyclic alkoxy, wherein at least one methylene group (CH2) of the alkoxy is replaced with an oxygen atom (O). In another embodiment, R1 is O-1-oxacyclobutyl. In another embodiment, R1 is O-2-oxacyclobutyl. In another embodiment, R1 is C1-C5 linear or branched haloalkoxy. In another embodiment, R1 is OCF3. In another embodiment, R1 is OCHF2. In another embodiment, R1 is a substituted or unsubstituted C3-C8 cycloalkyl. In another embodiment, R1 is cyclopropyl. In another embodiment, R1 is cyclopentyl. In another embodiment, R1 is cyclohexyl. In another embodiment, R1 is a substituted or unsubstituted C3-C8 heterocycle. In another embodiment, R1 is morpholine. In another embodiment, R1 is piperidine. In another embodiment, R1 is piperazine. In another embodiment, R1 is oxazole. In another embodiment, R1 is a methyl-substituted oxazole. In another embodiment, R1 is oxadiazole. In another embodiment, R1 is a methyl-substituted oxadiazole. In another embodiment, R1 is imidazole. In another embodiment, R1 is a methyl-substituted imidazole. In another embodiment, R1 is pyridine. In another embodiment, R1 is 2-pyridine. In another embodiment, R1 is 3-pyridine. In another embodiment, R1 is 3-methyl-2-pyridine. In another embodiment, R1 is 4-pyridine. In another embodiment, R1 is tetrazole. In another embodiment, R1 is pyrimidine. In another embodiment, R1 is pyrazine. In another embodiment, R1 is pyridazine.In another embodiment, R1 is oxacyclobutane. In another embodiment, R1 is 1-oxacyclobutane. In another embodiment, R1 is 2-oxacyclobutane. In another embodiment, R1 is indole. In another embodiment, R1 is pyridine oxide. In another embodiment, R1 is protonated pyridine oxide. In another embodiment, R1 is deprotonated pyridine oxide. In another embodiment, R1 is 3-methyl-4H-1,2,4 triazole. In another embodiment, R1 is 5-methyl-1,2,4 oxadiazole. In another embodiment, R1 is substituted or unsubstituted aryl. In another embodiment, R1 is phenyl. In another embodiment, R1 is xylyl. In another embodiment, R1 is 2,6-difluorophenyl. In another embodiment, R1 is 4-fluoroxylyl. In another embodiment, R1 is bromophenyl. In another embodiment, R1 is 2-bromophenyl. In another embodiment, R1 is 3-bromophenyl. In another embodiment, R1 is 4-bromophenyl. In another embodiment, R1 is substituted or unsubstituted benzyl. In another embodiment, R1 is 4-Cl-benzyl. In another embodiment, R1 is 4-OH-benzyl. In another embodiment, R1 is benzyl. In another embodiment, R1 is R8-N(R. 10 )(R1 1). In other embodiments, R1 is CH2-NH2. In some embodiments, R1 can be further substituted with at least one selected from the following: F, Cl, Br, I, OH, C1-C5 linear or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 linear or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 linear or branched alkenyl (e.g., E- or Z-propylene), C2-C5 linear or branched alkenyl (e.g., CH≡C-CH3), C2-C5 linear or branched alkenyl (e.g., OC(O)-CH3), OH, alkoxy, ester (e.g., OC(O)-CH3). , N(R), CF, aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, and NO; each represents a separate embodiment of the present invention.

[0072] In some embodiments, R2 in the compound of Formula I-IX is H. In some embodiments, R2 is not H.

[0073] In another embodiment, R2 in a compound of Formulas I-IX is F. In another embodiment, R2 is Cl. In another embodiment, R2 is Br. In another embodiment, R2 is I. In another embodiment, R2 is OH. In another embodiment, R2 is R8-(C3-C8 cycloalkyl). In another embodiment, R2 is CH2-cyclohexyl. In another embodiment, R2 is R8-(C3-C8 heterocycle). In another embodiment, R2 is CH2-morpholine. In another embodiment, R2 is CH2-imidazole. In another embodiment, R2 is CH2-indazole. In another embodiment, R2 is CF3. In another embodiment, R2 is CN. In another embodiment, R2 is CF2CH2CH3. In another embodiment, R2 is CH2CH2CH3. In another embodiment, R2 is CF2CH(CH3)2. In other embodiments, R2 is CF(CH3)-CH(CH3)2. In other embodiments, R2 is OCD3. In other embodiments, R2 is NO2. In other embodiments, R2 is NH2. In other embodiments, R2 is NHR. In other embodiments, R2 is NH-CH3. In other embodiments, R2 is N(R)2. In other embodiments, R2 is N(CH3)2. In other embodiments, R2 is R8-N(R 10 )(R 11 ). In another embodiment, R2 is CH2-CH2-N(CH3)2. In another embodiment, R2 is CH2-NH2. In another embodiment, R2 is CH2-N(CH3)2. In another embodiment, R2 is R9-R8-N(R 10 )(R 11 ). In another embodiment, R2 is C≡C—CH2—CH2. In another embodiment, R2 is B(OH)2. In another embodiment, R2 is NHC(O)—R 10 In another embodiment, R2 is NHC(O)CH3. In another embodiment, R2 is NHCO—N(R 10 )(R 11In another embodiment, R2 is NHC(O)N(CH3)2. In another embodiment, R2 is COOH. In another embodiment, R2 is C(O)-R 10 In another embodiment, R2 is C(O)-CH3. In another embodiment, R2 is C(O)OR 10 In another embodiment, R2 is C(O)O-CH(CH3)2. In another embodiment, R2 is C(O)O-CH3. In another embodiment, R2 is SO2N(R 10 )(R 11). In another embodiment, R2 is SON(CH3)2. In another embodiment, R2 is SONHC(O)CH3. In another embodiment, R2 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In another embodiment, R2 is methyl. In another embodiment, R2 is ethyl. In another embodiment, R2 is isopropyl. In another embodiment, R2 is Bu. In another embodiment, R2 is t-Bu. In another embodiment, R2 is isobutyl. In another embodiment, R2 is pentyl. In another embodiment, R2 is propyl. In another embodiment, R2 is benzyl. In another embodiment, R2 is C(H)(OH)-CH3. In another embodiment, R2 is C2-C5 linear or branched, substituted or unsubstituted alkenyl. In another embodiment, R2 is CH=C(Ph)2. In another embodiment, R2 is 2-CH2-C6H4-Cl. In another embodiment, R2 is 3-CH2-C6H4-Cl. In another embodiment, R2 is 4-CH2-C6H4-Cl. In another embodiment, R2 is ethyl. In another embodiment, R2 is isopropyl. In another embodiment, R2 is t-Bu. In another embodiment, R2 is isobutyl. In another embodiment, R2 is pentyl. In another embodiment, R2 is substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). In another embodiment, R2 is substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy. In another embodiment, R2 is substituted C1-C5 linear or branched, or C3-C8 cyclic alkoxy. In another embodiment, R2 is O-(CH2)2-pyrrolidine. In another embodiment, R2 is unsubstituted C1-C5 straight or branched, or C3-C8 cyclic alkoxy. In another embodiment, R2 is methoxy. In another embodiment, R2 is ethoxy. In another embodiment, R2 is propoxy. In another embodiment, R2 is isopropoxy. In another embodiment, R2 is O-CH2-cyclopropyl. In another embodiment, R2 is O-cyclobutyl.In another embodiment, R2 is O-cyclopentyl. In another embodiment, R2 is O-cyclohexyl. In another embodiment, R2 is O-1-oxacyclobutyl. In another embodiment, R2 is O-2-oxacyclobutyl. In another embodiment, R2 is 1-butoxy. In another embodiment, R2 is 2-butoxy. In another embodiment, R2 is O-tBu. In another embodiment, R2 is C1-C5 linear or branched, or C3-C8 cyclic alkoxy, wherein at least one methylene group (CH2) of the alkoxy is replaced with an oxygen atom (O). In another embodiment, R2 is O-1-oxacyclobutyl. In another embodiment, R2 is O-2-oxacyclobutyl. In another embodiment, R2 is C1-C5 linear or branched haloalkoxy. In another embodiment, R2 is OCF3. In another embodiment, R2 is OCHF2. In another embodiment, R2 is a substituted or unsubstituted C3-C8 cycloalkyl. In another embodiment, R2 is cyclopropyl. In another embodiment, R2 is cyclopentyl. In another embodiment, R2 is cyclohexyl. In another embodiment, R2 is a substituted or unsubstituted C3-C8 heterocycle. In another embodiment, R2 is morpholine. In another embodiment, R2 is piperidine. In another embodiment, R2 is piperazine. In another embodiment, R2 is oxazole. In another embodiment, R2 is a methyl-substituted oxazole. In another embodiment, R2 is oxadiazole. In another embodiment, R2 is a methyl-substituted oxadiazole. In another embodiment, R2 is imidazole. In another embodiment, R2 is a methyl-substituted imidazole. In another embodiment, R2 is pyridine. In another embodiment, R2 is 2-pyridine. In another embodiment, R2 is 3-pyridine. In another embodiment, R2 is 3-methyl-2-pyridine. In another embodiment, R2 is 4-pyridine. In another embodiment, R2 is tetrazole. In another embodiment, R2 is pyrimidine. In another embodiment, R2 is pyrazine. In another embodiment, R2 is pyridazine.In another embodiment, R2 is oxacyclobutane. In another embodiment, R2 is 1-oxacyclobutane. In another embodiment, R2 is 2-oxacyclobutane. In another embodiment, R2 is indole. In another embodiment, R2 is pyridine oxide. In another embodiment, R2 is protonated pyridine oxide. In another embodiment, R2 is deprotonated pyridine oxide. In another embodiment, R2 is 3-methyl-4H-1,2,4 triazole. In another embodiment, R2 is 5-methyl-1,2,4 oxadiazole. In another embodiment, R2 is substituted or unsubstituted aryl. In another embodiment, R2 is phenyl. In another embodiment, R2 is xylyl. In another embodiment, R2 is 2,6-difluorophenyl. In another embodiment, R2 is 4-fluoroxylyl. In another embodiment, R2 is bromophenyl. In another embodiment, R2 is 2-bromophenyl. In another embodiment, R2 is 3-bromophenyl. In another embodiment, R2 is 4-bromophenyl. In another embodiment, R2 is substituted or unsubstituted benzyl. In another embodiment, R2 is 4-Cl-benzyl. In another embodiment, R2 is 4-OH-benzyl. In another embodiment, R2 is benzyl. In another embodiment, R2 is R8-N(R. 10 )(R1 1). In other embodiments, R2 is CH2-NH2. In some embodiments, R2 can be further substituted with at least one selected from the following: F, Cl, Br, I, OH, C1-C5 linear or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 linear or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 linear or branched alkenyl (e.g., E- or Z-propylene), C2-C5 linear or branched alkenyl (e.g., CH≡C-CH3), C2-C5 linear or branched alkenyl (e.g., OC(O)-CH3), OH, alkoxy, ester (e.g., OC(O)-CH3). , N(R), CF, aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, and NO; each represents a separate embodiment of the present invention.

[0074] In some embodiments, R1 and R2 of the compounds of Formulas I-VIII are bonded to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic pyrrole ring. In some embodiments, R1 and R2 are bonded to each other to form a 5- or 6-membered heterocyclic ring. In some embodiments, R1 and R2 are bonded to each other to form a 6-membered substituted aliphatic heterocyclic ring. In some embodiments, R1 and R2 are bonded to each other to form a 5-membered substituted aliphatic heterocyclic ring. In some embodiments, R1 and R2 are bonded to each other to form a 5- or 6-membered unsubstituted aliphatic heterocyclic ring. In some embodiments, R1 and R2 are bonded to each other to form a [1,3]dioxole ring. In some embodiments, R1 and R2 are bonded to each other to form a piperazine ring. In some embodiments, R1 and R2 are bonded to each other to form a morpholine ring. In some embodiments, R1 and R2 are bonded to each other to form a 5- or 6-membered unsubstituted aromatic heterocycle. In some embodiments, R1 and R2 are bonded to each other to form a pyrrole ring. In some embodiments, R1 and R2 are bonded to each other to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R1 and R2 are bonded to each other to form a pyridine ring. In some embodiments, R1 and R2 are bonded to each other to form a pyrazine ring. In some embodiments, R1 and R2 are bonded to each other to form an imidazole ring. In some embodiments, R1 and R2 are bonded to each other to form a 5- or 6-membered, substituted or unsubstituted aromatic carbocycle. In some embodiments, R1 and R2 are bonded to each other to form a benzene ring. In some embodiments, R1 and R2 are bonded to each other to form a cyclohexene ring.

[0075] In some embodiments, R of the compounds of Formulas I-IV, VIII, and / or IX 20 is H. In some embodiments, R 20 is not H.

[0076] In other embodiments, R of the compounds of Formulas I-IV, VIII, and / or IX 20 is F. In other embodiments, R 20 is Cl. In other embodiments, R 20 is Br. In other embodiments, R 20 is I. In other embodiments, R 20 is OH. In other embodiments, R 20 is R-(C-C cycloalkyl). In other embodiments, R 20 is CH-cyclohexyl. In another embodiment, R 20 is R-(C-C heterocycle). In other embodiments, R 20 is CH2-morpholine. In other embodiments, R 20 is CH2-imidazole. In another embodiment, R 20 is CH2-indazole. In another embodiment, R 20 is CF. In other embodiments, R 20 is CN. In other embodiments, R 20 is CF2CH2CH3. In other embodiments, R 20 is CH2CH2CH3. In other embodiments, R 20 is CF2CH(CH3)2. In other embodiments, R 20 is CF(CH3)-CH(CH3)2. In other embodiments, R 20 is OCD3. In other embodiments, R 20 is NO. In other embodiments, R 20 is NH. In other embodiments, R 20 is NHR. In other embodiments, R 20 is NH—CH. In other embodiments, R 20 is N(R). In other embodiments, R 20 is N(CH). In other embodiments, R 20 is R8-N(R 10 )(R 11 In other embodiments, R 20 is CH2-CH2-N(CH3)2. In other embodiments, R20 is CH-NH. In other embodiments, R 20 is CH2-N(CH3)2. In other embodiments, R 20 is R9-R8-N(R 10 )(R 11 In other embodiments, R 20 is C≡C—CH—CH. In other embodiments, R 20 is B(OH). In other embodiments, R 20 is NHC(O)-R 10 In other embodiments, R 20 is NHC(O)CH. In other embodiments, R 20 is NHCO-N(R 10 )(R 11 In other embodiments, R 20 is NHC(O)N(CH). In other embodiments, R 20 is COOH. In another embodiment, R 20 is C(O)-R 10 In other embodiments, R 20 is C(O)-CH3. In other embodiments, R 20 is C(O)OR 10 In other embodiments, R 20 is C(O)O-CH(CH). In other embodiments, R 20 is C(O)O-CH3. In other embodiments, R 20 is SO2N(R 10 )(R 11 In other embodiments, R 20 is SO2N(CH3)2. In other embodiments, R 20 is SONHC(O)CH. In other embodiments, R 20 is a C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R 20 is methyl. In another embodiment, R 20 is ethyl. In another embodiment, R 20 is isopropyl. In other embodiments, R 20 is Bu. In another embodiment, R20 is t-Bu. In another embodiment, R 20 is isobutyl. In another embodiment, R 20 is pentyl. In another embodiment, R 20 is propyl. In other embodiments, R 20 is benzyl. In another embodiment, R 20 is C(H)(OH)-CH3. In other embodiments, R 20 is a C2-C5 linear or branched, substituted or unsubstituted alkenyl. In another embodiment, R 20 is CH=C(Ph). In another embodiment, R 20 is 2-CH2-C6H4-Cl. In other embodiments, R 20 is 3-CH2-C6H4-Cl. In other embodiments, R 20 is 4-CH2-C6H4-Cl. In other embodiments, R 20 is ethyl. In another embodiment, R 20 is isopropyl. In other embodiments, R 20 is t-Bu. In another embodiment, R 20 is isobutyl. In another embodiment, R 20 is pentyl. In another embodiment, R 20 is a substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). 20 is a substituted or unsubstituted C1-C5 straight or branched chain, or C3-C8 cyclic alkoxy. 20 is a substituted C1-C5 straight or branched chain, or C3-C8 cyclic alkoxy. 20 is O—(CH)-pyrrolidine. In another embodiment, R 20 is unsubstituted C1-C5 straight or branched chain, or C3-C8 cyclic alkoxy. 20 is methoxy. In another embodiment, R 20 is ethoxy. In another embodiment, R 20is propoxy. In another embodiment, R 20 is isopropoxy. In another embodiment, R 20 is O-CH-cyclopropyl. In another embodiment, R 20 is O-cyclobutyl. In another embodiment, R 20 is O-cyclopentyl. In another embodiment, R 20 is O-cyclohexyl. In another embodiment, R 20 is O-1-oxacyclobutyl. In another embodiment, R 20 is O-2-oxacyclobutyl. In another embodiment, R 20 is 1-butoxy. In another embodiment, R 20 is 2-butoxy. In another embodiment, R 20 is O-tBu. In another embodiment, R 20 is a C1-C5 straight or branched chain or C3-C8 cyclic alkoxy, in which at least one methylene group (CH2) of the alkoxy is replaced with an oxygen atom (O). 20 is O-1-oxacyclobutyl. In another embodiment, R 20 is O-2-oxacyclobutyl. In another embodiment, R 20 is a C1-C5 straight or branched haloalkoxy. In other embodiments, R 20 is OCF3. In another embodiment, R 20 is OCHF2. In other embodiments, R 20 is a substituted or unsubstituted C-C cycloalkyl. In other embodiments, R 20 is cyclopropyl. In other embodiments, R 20 is cyclopentyl. In another embodiment, R 20 is cyclohexyl. In another embodiment, R 20 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R 20 is morpholine. In other embodiments, R 20 is piperidine. In another embodiment, R 20is piperazine. In another embodiment, R 20 is oxazole. In another embodiment, R 20 is a methyl-substituted oxazole. In other embodiments, R 20 is oxadiazole. In other embodiments, R 20 is a methyl-substituted oxadiazole. In other embodiments, R 20 is imidazole. In another embodiment, R 20 is a methyl-substituted imidazole. In other embodiments, R 20 is pyridine. In another embodiment, R 20 is 2-pyridine. In another embodiment, R 20 is 3-pyridine. In another embodiment, R 20 is 3-methyl-2-pyridine. In another embodiment, R 20 is 4-pyridine. In another embodiment, R 20 is tetrazole. In another embodiment, R 20 is pyrimidine. In other embodiments, R 20 is pyrazine. In other embodiments, R 20 is pyridazine. In another embodiment, R 20 is an oxacyclobutane In another embodiment, R 20 is 1-oxacyclobutane. In other embodiments, R 20 is 2-oxacyclobutane. In other embodiments, R 20 is indole. In another embodiment, R 20 is pyridine oxide. In another embodiment, R 20 is a protonated pyridine oxide. In another embodiment, R 20 is deprotonated pyridine oxide. In another embodiment, R 20 is 3-methyl-4H-1,2,4 triazole. In another embodiment, R 20 is 5-methyl-1,2,4 oxadiazole. In another embodiment, R 20 is substituted or unsubstituted aryl. In other embodiments, R20 is phenyl. In another embodiment, R 20 is xylyl. In another embodiment, R 20 is 2,6-difluorophenyl. In another embodiment, R 20 is 4-fluoroxylyl. In another embodiment, R 20 is bromophenyl. In another embodiment, R 20 is 2-bromophenyl. In another embodiment, R 20 is 3-bromophenyl. In another embodiment, R 20 is 4-bromophenyl. In another embodiment, R 20 is substituted or unsubstituted benzyl. In other embodiments, R 20 is 4-Cl-benzyl. In another embodiment, R 20 is 4-OH-benzyl. In another embodiment, R 20 is benzyl. In another embodiment, R 20 is R8-N(R 10 )(R 11 In other embodiments, R 20 is CH-NH. In some embodiments, R 20may be further substituted by at least one selected from the following: F, Cl, Br, I, OH, C1-C5 linear or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 linear or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 linear or branched alkenyl (e.g., E- or Z-propylene), C2-C5 linear or branched alkenyl (e.g., CH≡C-CH3), C2-C5 linear or branched alkenyl (e.g., OC(O)-CH3), OH, alkoxy, ester (e.g., OC(O)-CH3). , N(R), CF, aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, and NO; each represents a separate embodiment of the present invention.

[0077] In some embodiments, R of compounds of Formulas I-IX 21 is H. In some embodiments, R 21 is not H.

[0078] In other embodiments, R of compounds of Formulas I-IX 21 is F. In other embodiments, R 21 is Cl. In other embodiments, R 21 is Br. In other embodiments, R 21 is I. In other embodiments, R 21 is OH. In other embodiments, R 21 is R-(C-C cycloalkyl). In other embodiments, R 21 is CH-cyclohexyl. In another embodiment, R 21 is R-(C-C heterocycle). In other embodiments, R 21 is CH2-morpholine. In other embodiments, R21 is CH2-imidazole. In another embodiment, R 21 is CH2-indazole. In another embodiment, R 21 is CF. In other embodiments, R 21 is CN. In other embodiments, R 21 is CF2CH2CH3. In other embodiments, R 21 is CH2CH2CH3. In other embodiments, R 21 is CF2CH(CH3)2. In other embodiments, R 21 is CF(CH3)-CH(CH3)2. In other embodiments, R 21 is OCD3. In other embodiments, R 21 is NO. In other embodiments, R 21 is NH. In other embodiments, R 21 is NHR. In other embodiments, R 21 is NH—CH. In other embodiments, R 21 is N(R). In other embodiments, R 21 is N(CH). In other embodiments, R 21 is R8-N(R 10 )(R 11 In other embodiments, R 21 is CH2-CH2-N(CH3)2. In other embodiments, R 21 is CH-NH. In other embodiments, R 21 is CH2-N(CH3)2. In other embodiments, R 21 is R9-R8-N(R 10 )(R 11 In other embodiments, R 21 is C≡C—CH—CH. In other embodiments, R 21 is B(OH). In other embodiments, R 21 is NHC(O)-R 10 In other embodiments, R 21 is NHC(O)CH. In other embodiments, R 21 is NHCO-N(R 10 )(R 11In other embodiments, R 21 is NHC(O)N(CH). In other embodiments, R 21 is COOH. In another embodiment, R 21 is C(O)-R 10 In other embodiments, R 21 is C(O)-CH3. In other embodiments, R 21 is C(O)OR 10 In other embodiments, R 21 is C(O)O-CH(CH). In other embodiments, R 21 is C(O)O-CH3. In other embodiments, R 21 is SO2N(R 10 )(R 11 In other embodiments, R 21 is SO2N(CH3)2. In other embodiments, R 21 is SONHC(O)CH. In other embodiments, R 21 is a C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R 21 is methyl. In another embodiment, R 21 is ethyl. In another embodiment, R 21 is isopropyl. In other embodiments, R 21 is Bu. In another embodiment, R 21 is t-Bu. In another embodiment, R 21 is isobutyl. In another embodiment, R 21 is pentyl. In another embodiment, R 21 is propyl. In other embodiments, R 21 is benzyl. In another embodiment, R 21 is C(H)(OH)-CH3. In other embodiments, R 21 is a C2-C5 linear or branched, substituted or unsubstituted alkenyl. In another embodiment, R 21 is CH=C(Ph). In another embodiment, R 21 is 2-CH2-C6H4-Cl. In other embodiments, R 21is 3-CH2-C6H4-Cl. In other embodiments, R 21 is 4-CH2-C6H4-Cl. In other embodiments, R 21 is ethyl. In another embodiment, R 21 is isopropyl. In other embodiments, R 21 is t-Bu. In another embodiment, R 21 is isobutyl. In another embodiment, R 21 is pentyl. In another embodiment, R 21 is a substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). 21 is a substituted or unsubstituted C1-C5 straight or branched chain, or C3-C8 cyclic alkoxy. 21 is a substituted C1-C5 straight or branched chain or C3-C8 cyclic alkoxy. 21 is O—(CH)-pyrrolidine. In another embodiment, R 21 is unsubstituted C1-C5 straight or branched chain, or C3-C8 cyclic alkoxy. 21 is methoxy. In another embodiment, R 21 is ethoxy. In another embodiment, R 21 is propoxy. In another embodiment, R 21 is isopropoxy. In another embodiment, R 21 is O-CH-cyclopropyl. In another embodiment, R 21 is O-cyclobutyl. In another embodiment, R 21 is O-cyclopentyl. In another embodiment, R 21 is O-cyclohexyl. In another embodiment, R 21 is O-1-oxacyclobutyl. In another embodiment, R 21 is O-2-oxacyclobutyl. In another embodiment, R 21 is 1-butoxy. In another embodiment, R 21 is 2-butoxy. In another embodiment, R21 is O-tBu. In another embodiment, R 21 is a C1-C5 straight or branched chain or C3-C8 cyclic alkoxy, in which at least one methylene group (CH2) of the alkoxy is replaced with an oxygen atom (O). 21 is O-1-oxacyclobutyl. In another embodiment, R 21 is O-2-oxacyclobutyl. In another embodiment, R 21 is a C1-C5 straight or branched haloalkoxy. In other embodiments, R 21 is OCF3. In another embodiment, R 21 is OCHF2. In other embodiments, R 21 is a substituted or unsubstituted C-C cycloalkyl. In other embodiments, R 21 is cyclopropyl. In other embodiments, R 21 is cyclopentyl. In another embodiment, R 21 is cyclohexyl. In another embodiment, R 21 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R 21 is morpholine. In other embodiments, R 21 is piperidine. In another embodiment, R 21 is piperazine. In another embodiment, R 21 is oxazole. In another embodiment, R 21 is a methyl-substituted oxazole. In other embodiments, R 21 is oxadiazole. In other embodiments, R 21 is a methyl-substituted oxadiazole. In other embodiments, R 21 is imidazole. In another embodiment, R 21 is a methyl-substituted imidazole. In other embodiments, R 21 is pyridine. In another embodiment, R 21 is 2-pyridine. In another embodiment, R 21 is 3-pyridine. In another embodiment, R 21is 3-methyl-2-pyridine. In another embodiment, R 21 is 4-pyridine. In another embodiment, R 21 is tetrazole. In another embodiment, R 21 is pyrimidine. In other embodiments, R 21 is pyrazine. In other embodiments, R 21 is pyridazine. In another embodiment, R 21 is oxacyclobutane. In other embodiments, R 21 is 1-oxacyclobutane. In other embodiments, R 21 is 2-oxacyclobutane. In other embodiments, R 21 is indole. In another embodiment, R 21 is pyridine oxide. In another embodiment, R 21 is a protonated pyridine oxide. In another embodiment, R 21 is deprotonated pyridine oxide. In another embodiment, R 21 is 3-methyl-4H-1,2,4 triazole. In another embodiment, R 21 is 5-methyl-1,2,4 oxadiazole. In another embodiment, R 21 is substituted or unsubstituted aryl. In other embodiments, R 21 is phenyl. In another embodiment, R 21 is xylyl. In another embodiment, R 21 is 2,6-difluorophenyl. In another embodiment, R 21 is 4-fluoroxylyl. In another embodiment, R 21 is bromophenyl. In another embodiment, R 21 is 2-bromophenyl. In another embodiment, R 21 is 3-bromophenyl. In another embodiment, R 21 is 4-bromophenyl. In another embodiment, R 21 is substituted or unsubstituted benzyl. In other embodiments, R 21is 4-Cl-benzyl. In another embodiment, R 21 is 4-OH-benzyl. In another embodiment, R 21 is benzyl. In another embodiment, R 21 is R8-N(R 10 )(R 11 In other embodiments, R 21 is CH-NH. In some embodiments, R 21 may be further substituted by at least one selected from the following: F, Cl, Br, I, OH, C1-C5 linear or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 linear or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 linear or branched alkenyl (e.g., E- or Z-propylene), C2-C5 linear or branched alkenyl (e.g., CH≡C-CH3), C2-C5 linear or branched alkenyl (e.g., OC(O)-CH3), OH, alkoxy, ester (e.g., OC(O)-CH3). , N(R), CF, aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, and NO; each represents a separate embodiment of the present invention.

[0079] In some embodiments, R of compounds of formula VIII and / or IX 22 is H. In some embodiments, R 22 is not H.

[0080] In other embodiments, R of compounds of formula VIII and / or IX 22 is F. In other embodiments, R 22 is Cl. In other embodiments, R 22 is Br. In other embodiments, R22 is I. In other embodiments, R 22 is OH. In other embodiments, R 22 is R-(C-C cycloalkyl). In other embodiments, R 22 is CH-cyclohexyl. In another embodiment, R 22 is R-(C-C heterocycle). In other embodiments, R 22 is CH2-morpholine. In other embodiments, R 22 is CH2-imidazole. In another embodiment, R 22 is CH2-indazole. In another embodiment, R 22 is CF. In other embodiments, R 22 is CN. In other embodiments, R 22 is CF2CH2CH3. In other embodiments, R 22 is CH2CH2CH3. In other embodiments, R 22 is CF2CH(CH3)2. In other embodiments, R 22 is CF(CH3)-CH(CH3)2. In other embodiments, R 22 is OCD3. In other embodiments, R 22 is NO. In other embodiments, R 22 is NH. In other embodiments, R 22 is NHR. In other embodiments, R 22 is NH—CH. In other embodiments, R 22 is N(R). In other embodiments, R 22 is N(CH). In other embodiments, R 22 is R8-N(R 10 )(R 11 In other embodiments, R 22 is CH2-CH2-N(CH3)2. In other embodiments, R 22 is CH-NH. In other embodiments, R 22 is CH2-N(CH3)2. In other embodiments, R 22 is R9-R8-N(R 10 )(R 11In other embodiments, R 22 is C≡C—CH—CH. In other embodiments, R 22 is B(OH). In other embodiments, R 22 is NHC(O)-R 10 In other embodiments, R 22 is NHC(O)CH. In other embodiments, R 22 is NHCO-N(R 10 )(R 11 In other embodiments, R 22 is NHC(O)N(CH). In other embodiments, R 22 is COOH. In another embodiment, R 22 is C(O)-R 10 In other embodiments, R 22 is C(O)-CH3. In other embodiments, R 22 is C(O)OR 10 In other embodiments, R 22 is C(O)O-CH(CH). In other embodiments, R 22 is C(O)O-CH3. In other embodiments, R 22 is SO2N(R 10 )(R 11 In other embodiments, R 22 is SO2N(CH3)2. In other embodiments, R 22 is SONHC(O)CH. In other embodiments, R 22 is a C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R 22 is methyl. In another embodiment, R 22 is ethyl. In another embodiment, R 22 is isopropyl. In other embodiments, R 22 is Bu. In another embodiment, R 22 is t-Bu. In another embodiment, R 22 is isobutyl. In another embodiment, R 22 is pentyl. In another embodiment, R 22 is propyl. In other embodiments, R22 is benzyl. In an embodiment of 22 is C(H)(OH)-CH3. In other embodiments, R 22 is a C2-C5 linear or branched, substituted or unsubstituted alkenyl. In another embodiment, R 22 is CH=C(Ph). In another embodiment, R 22 is 2-CH2-C6H4-Cl. In other embodiments, R 22 is 3-CH2-C6H4-Cl. In other embodiments, R 22 is 4-CH2-C6H4-Cl. In other embodiments, R 22 is ethyl. In another embodiment, R 22 is isopropyl. In other embodiments, R 22 is t-Bu. In another embodiment, R 22 is isobutyl. In another embodiment, R 22 is pentyl. In another embodiment, R 22 is a substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). 22 is a substituted or unsubstituted C1-C5 straight or branched chain, or C3-C8 cyclic alkoxy. 22 is a substituted C1-C5 straight or branched chain or C3-C8 cyclic alkoxy. 22 is O—(CH)-pyrrolidine. In another embodiment, R 22 is unsubstituted C1-C5 straight or branched chain, or C3-C8 cyclic alkoxy. 22 is methoxy. In another embodiment, R 22 is ethoxy. In another embodiment, R 22 is propoxy. In another embodiment, R 22 is isopropoxy. In another embodiment, R 22 is O-CH-cyclopropyl. In another embodiment, R 22 is O-cyclobutyl. In another embodiment, R 22is O-cyclopentyl. In another embodiment, R 22 is O-cyclohexyl. In another embodiment, R 22 is O-1-oxacyclobutyl. In another embodiment, R 22 is O-2-oxacyclobutyl. In another embodiment, R 22 is 1-butoxy. In another embodiment, R 22 is 2-butoxy. In another embodiment, R 22 is O-tBu. In another embodiment, R 22 is a C1-C5 straight or branched chain or C3-C8 cyclic alkoxy, in which at least one methylene group (CH2) of the alkoxy is replaced with an oxygen atom (O). 22 is O-1-oxacyclobutyl. In another embodiment, R 22 is O-2-oxacyclobutyl. In another embodiment, R 22 is a C1-C5 straight or branched haloalkoxy. In other embodiments, R 22 is OCF3. In another embodiment, R 22 is OCHF2. In other embodiments, R 22 is a substituted or unsubstituted C-C cycloalkyl. In other embodiments, R 22 is cyclopropyl. In other embodiments, R 22 is cyclopentyl. In another embodiment, R 22 is cyclohexyl. In another embodiment, R 22 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R 22 is morpholine. In other embodiments, R 22 is piperidine. In another embodiment, R 22 is piperazine. In another embodiment, R 22 is oxazole. In another embodiment, R 22 is a methyl-substituted oxazole. In other embodiments, R 22 is oxadiazole. In other embodiments, R 22is a methyl-substituted oxadiazole. In other embodiments, R 22 is imidazole. In another embodiment, R 22 is a methyl-substituted imidazole. In other embodiments, R 22 is pyridine. In another embodiment, R 22 is 2-pyridine. In another embodiment, R 22 is 3-pyridine. In another embodiment, R 22 is 3-methyl-2-pyridine. In another embodiment, R 22 is 4-pyridine. In another embodiment, R 22 is tetrazole. In another embodiment, R 22 is pyrimidine. In other embodiments, R 22 is pyrazine. In other embodiments, R 22 is pyridazine. In another embodiment, R 22 is an oxacyclobutane. In the embodiment, R 22 is 1-oxacyclobutane. In other embodiments, R 22 is 2-oxacyclobutane. In other embodiments, R 22 is indole. In another embodiment, R 22 is pyridine oxide. In another embodiment, R 22 is a protonated pyridine oxide. In another embodiment, R 22 is deprotonated pyridine oxide. In another embodiment, R 22 is 3-methyl-4H-1,2,4 triazole. In another embodiment, R 22 is 5-methyl-1,2,4 oxadiazole. In another embodiment, R 22 is substituted or unsubstituted aryl. In other embodiments, R 22 is phenyl. In another embodiment, R 22 is xylyl. In another embodiment, R 22 is 2,6-difluorophenyl. In other embodiments, R 22is 4-fluoroxylyl. In another embodiment, R 22 is bromophenyl. In another embodiment, R 22 is 2-bromophenyl. In another embodiment, R 22 is 3-bromophenyl. In another embodiment, R 22 is 4-bromophenyl. In another embodiment, R 22 is substituted or unsubstituted benzyl. In other embodiments, R 22 is 4-Cl-benzyl. In another embodiment, R 22 is 4-OH-benzyl. In another embodiment, R 22 is benzyl. In another embodiment, R 22 is R8-N(R 10 )(R 11 In other embodiments, R 22 is CH-NH. In some embodiments, R 22 may be further substituted by at least one selected from the following: F, Cl, Br, I, OH, C1-C5 linear or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 linear or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 linear or branched alkenyl (e.g., E- or Z-propylene), C2-C5 linear or branched alkenyl (e.g., CH≡C-CH3), C2-C5 linear or branched alkenyl (e.g., OC(O)-CH3), OH, alkoxy, ester (e.g., OC(O)-CH3). , N(R), CF, aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, and NO; each represents a separate embodiment of the present invention.

[0081] In some embodiments, R and R of compounds of Formulas I-VIII 21 are joined together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic pyrrole ring. In some embodiments, R and R 21 are joined together to form a 5- or 6-membered heterocycle. In some embodiments, R and R 21 are linked together to form a 6-membered substituted aliphatic heterocycle. In some embodiments, R and R 21 are linked together to form a 5-membered substituted aliphatic heterocycle. In some embodiments, R and R 21 are bonded to each other to form a 5- or 6-membered unsubstituted aliphatic heterocycle. In some embodiments, R and R 21 are linked together to form a [1,3]dioxole ring. In some embodiments, R and R 21 are linked together to form a piperazine ring. In some embodiments, R and R 21 are linked together to form a morpholine ring. In some embodiments, R and R 21 are joined to each other to form a 5- or 6-membered unsubstituted aromatic heterocycle. In some embodiments, R and R 21 are bonded to each other to form a pyrrole ring. In some embodiments, R and R 21 are linked together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R and R 21 are bonded to each other to form a pyridine ring. In some embodiments, R and R 21 are bonded to each other to form a pyrazine ring. In some embodiments, R and R 21 are linked together to form an imidazole ring. In some embodiments, R and R 21 are joined to each other to form a 5- or 6-membered, substituted or unsubstituted, aromatic carbocyclic ring. In some embodiments, R and R 21 are bonded to each other to form a benzene ring. In some embodiments, R and R 21are bonded to each other to form a cyclohexene ring.

[0082] In some embodiments, R of Formula VIII and / or IX 21 and R 22 are joined together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic pyrrole ring. 21 and R 22 are joined together to form a 5- or 6-membered heterocycle. In some embodiments, R 21 and R 22 are joined together to form a 6-membered substituted aliphatic heterocycle. In some embodiments, R 21 and R 22 are joined together to form a 5-membered substituted aliphatic heterocycle. In some embodiments, R 21 and R 22 , which are joined together to form a 5- or 6-membered unsubstituted aliphatic heterocycle. In some embodiments, R 21 and R 22 are linked together to form a [1,3]dioxole ring. In some embodiments, R 21 and R 22 are linked together to form a piperazine ring. In some embodiments, R 21 and R 22 are linked together to form a morpholine ring. In some embodiments, R 21 and R 22 are joined together to form a 5- or 6-membered unsubstituted aromatic heterocycle. In some embodiments, R 21 and R 22 are linked together to form a pyrrole ring. In some embodiments, R 21 and R 22 are linked together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R 21 and R 22 are linked together to form a pyridine ring. In some embodiments, R 21 and R 22are linked together to form a pyrazine ring. In some embodiments, R 21 and R 22 are linked together to form an imidazole ring. In some embodiments, R 21 and R 22 are joined together to form a 5- or 6-membered, substituted or unsubstituted, aromatic carbocyclic ring. In some embodiments, R 21 and R 22 are linked together to form a benzene ring. In some embodiments, R 21 and R 22 are bonded to each other to form a cyclohexene ring.

[0083] In some embodiments, R of the compound of formula IX 201 is H. In some embodiments, R 201 is not H. In other embodiments, R 201 is F. In other embodiments, R 201 is Cl. In other embodiments, R 201 is Br. In other embodiments, R 201 is I. In other embodiments, R 201 is CF. In other embodiments, R 201 is a C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R 201 is a C1-C5 straight chain, substituted or unsubstituted alkyl. In other embodiments, R 201 is a C1-C5 straight chain unsubstituted alkyl. In other embodiments, R 201 is a C1-C5 branched, unsubstituted alkyl. In other embodiments, R 201 is a C1-C5 branched, substituted alkyl. In another embodiment, R 201 is methyl. In another embodiment, R 201 is ethyl. In another embodiment, R 201 is propyl. In other embodiments, R 201 is isopropyl. In other embodiments, R 201 is t-Bu. In another embodiment, R 201is isobutyl. In another embodiment, R 201 is pentyl.

[0084] In some embodiments, R of the compound of formula IX 202 is H. In some embodiments, R 202 is not H. In other embodiments, R 202 is F. In other embodiments, R 202 is Cl. In other embodiments, R 202 is Br. In other embodiments, R 202 is I. In other embodiments, R 202 is CF. In other embodiments, R 202 is a C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R 202 is a C1-C5 straight chain, substituted or unsubstituted alkyl. In other embodiments, R 202 is a C1-C5 straight chain unsubstituted alkyl. In other embodiments, R 202 is a C1-C5 branched, unsubstituted alkyl. In other embodiments, R 202 is a C1-C5 branched, substituted alkyl. In another embodiment, R 202 is methyl. In another embodiment, R 202 is ethyl. In another embodiment, R 202 is propyl. In other embodiments, R 202 is isopropyl. In other embodiments, R 202 is t-Bu. In another embodiment, R 202 is isobutyl. In another embodiment, R 202 is pentyl.

[0085] In some embodiments, R3 in a compound of Formulas I-IX is H. In some embodiments, R3 is not H. In other embodiments, R3 is Cl. In other embodiments, R3 is I. In other embodiments, R3 is F. In other embodiments, R3 is Br. In other embodiments, R3 is OH. In other embodiments, R3 is CD3. In other embodiments, R3 is OCD3. In other embodiments, R3 is R8-OH. In other embodiments, R3 is CH2-OH. In other embodiments, R3 is -R8-OR 10 In another embodiment, R3 is CH2-O-CH3. In another embodiment, R3 is R8-N(R 10 )(R 11 In another embodiment, R3 is CH2-NH2. In another embodiment, R3 is CH2-N(CH3)2. In another embodiment, R3 is COOH. In another embodiment, R3 is C(O)OR 10 In another embodiment, R3 is C(O)O-CH2CH3. In another embodiment, R3 is R8-C(O)-R 10 In another embodiment, R3 is CH2C(O)CH3. In another embodiment, R3 is C(O)-R 10 In another embodiment, R3 is C(O)-CH3. In another embodiment, R3 is C(O)-CH2CH3. In another embodiment, R3 is C(O)-CH2CH2CH3. In another embodiment, R3 is C1-C5 straight or branched C(O)-haloalkyl. In another embodiment, R3 is C(O)-CF3. In another embodiment, R3 is C(O)NH2. In another embodiment, R3 is C(O)NHR. In another embodiment, R3 is C(O)NH(CH3). In another embodiment, R3 is C(O)N(R 10 )(R 11 ). In another embodiment, R3 is C(O)N(CH3)2. In another embodiment, R3 is C(O)N(CH3)(CH2CH3). In another embodiment, R3 is C(O)N(CH3)(CH2CH2-O-CH3). In another embodiment, R3 is C(S)N(R10 )(R 11 ). In another embodiment, R3 is C(S)NH(CH3). In another embodiment, R3 is C(O)-pyrrolidine. In another embodiment, R3 is C(O)-azetidine. In another embodiment, R3 is C(O)-methylpiperazine. In another embodiment, R3 is C(O)-piperidine. In another embodiment, R3 is C(O)-morpholine. In another embodiment, R3 is SO2R. In another embodiment, R3 is SO2N(R 10 )(R 11). In another embodiment, R3 is SO2NH(CH3). In another embodiment, R3 is SO2N(CH3). In another embodiment, R3 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In another embodiment, R3 is methyl. In another embodiment, R3 is C(OH)(CH3)(Ph). In another embodiment, R3 is ethyl. In another embodiment, R3 is propyl. In another embodiment, R3 is isopropyl. In another embodiment, R3 is t-Bu. In another embodiment, R3 is isobutyl. In another embodiment, R3 is pentyl. In another embodiment, R3 is substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic haloalkyl. In another embodiment, R3 is CF3. In another embodiment, R3 is CF2CH3. In another embodiment, R3 is CF2-cyclobutyl. In another embodiment, R3 is CF2-cyclopropyl. In another embodiment, R3 is CF2-methylcyclopropyl. In another embodiment, R3 is CF2CH2CH3. In another embodiment, R3 is CH2CF3. In another embodiment, R3 is CF3. In another embodiment, R3 is CF2CH2CH3. In another embodiment, R3 is CH2CH2CF3. In another embodiment, R3 is CF2CH(CH3)2. In another embodiment, R3 is CF(CH3)-CH(CH3)2. In another embodiment, R3 is C(OH)2CF3. In another embodiment, R3 is cyclopropyl-CF3. In another embodiment, R3 is C1-C5 linear, branched, or cyclic alkoxy. In another embodiment, R3 is methoxy. In another embodiment, R3 is isopropoxy. In another embodiment, R3 is substituted or unsubstituted C3-C8 cycloalkyl. In another embodiment, R3 is CF3-cyclopropyl. In another embodiment, R3 is cyclopropyl. In another embodiment, R3 is cyclopentyl. In another embodiment, R3 is a substituted or unsubstituted C3-C8 heterocycle. In another embodiment, R3 is oxadiazole. In another embodiment, R3 is pyrrole.In another embodiment, R3 is N-methyloxetan-3-amine. In another embodiment, R3 is thiophene. In another embodiment, R3 is oxazole. In another embodiment, R3 is isoxazole. In another embodiment, R3 is imidazole. In another embodiment, R3 is furan. In another embodiment, R3 is triazole. In another embodiment, R3 is methyltriazole. In another embodiment, R3 is pyridine. In another embodiment, R3 is 2-pyridine. In another embodiment, R3 is 3-pyridine. In another embodiment, R3 is 4-pyridine. In another embodiment, R3 is pyrimidine. In another embodiment, R3 is pyrazine. In another embodiment, R3 is oxacyclobutane. In another embodiment, R3 is 1-oxacyclobutane. In another embodiment, R3 is 2-oxacyclobutane. In another embodiment, R3 is indole. In another embodiment, R3 is 3-methyl-4H-1,2,4 triazole. In another embodiment, R3 is 5-methyl-1,2,4 oxadiazole. In another embodiment, R3 is substituted or unsubstituted aryl. In another embodiment, R3 is phenyl. In another embodiment, R3 is CH(CF3)(NH—R. 10). In some embodiments, R3 can be further substituted with at least one selected from the following: F, Cl, Br, I, OH, C1-C5 linear or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 linear or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 linear or branched alkenyl (e.g., E- or Z-propylene), C2-C5 linear or branched alkenyl (e.g., CH≡C-CH3), C2-C5 linear or branched alkenyl (e.g., OC(O)-CH3), OH, alkoxy, ester (e.g., OC(O)-CH3). , N(R), CF, aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, and NO; each represents a separate embodiment of the present invention.

[0086] In some embodiments, R4 in the compounds of Formulas I-V is H. In some embodiments, R4 is not H. In other embodiments, R4 is Cl. In other embodiments, R4 is I. In other embodiments, R4 is F. In other embodiments, R4 is Br. In other embodiments, R4 is OH. In other embodiments, R4 is CD3. In other embodiments, R4 is OCD3. In other embodiments, R4 is R8-OH. In other embodiments, R4 is CH2-OH. In other embodiments, R4 is -R8-OR 10 In another embodiment, R4 is CH2-O-CH3. In another embodiment, R4 is R8-N(R 10 )(R 11In another embodiment, R4 is CH2-NH2. In another embodiment, R4 is CH2-N(CH3)2. In another embodiment, R4 is COOH. In another embodiment, R4 is C(O)OR 10 In another embodiment, R4 is C(O)O-CH2CH3. In another embodiment, R4 is R8-C(O)-R 10 In another embodiment, R4 is CH2C(O)CH3. In another embodiment, R4 is C(O)-R 10 In another embodiment, R4 is C(O)-CH3. In another embodiment, R4 is C(O)-CH2CH3. In another embodiment, R4 is C(O)-CH2CH2CH3. In another embodiment, R4 is C1-C5 straight or branched C(O)-haloalkyl. In another embodiment, R4 is C(O)-CF3. In another embodiment, R4 is C(O)NH2. In another embodiment, R4 is C(O)NHR. In another embodiment, R4 is C(O)NH(CH3). In another embodiment, R4 is C(O)N(R 10 )(R 11 ). In another embodiment, R4 is C(O)N(CH3)2. In another embodiment, R4 is C(O)N(CH3)(CH2CH3). In another embodiment, R4 is C(O)N(CH3)(CH2CH2-O-CH3). In another embodiment, R4 is C(S)N(R 10 )(R 11 ). In another embodiment, R4 is C(S)NH(CH3). In another embodiment, R4 is C(O)-pyrrolidine. In another embodiment, R4 is C(O)-azetidine. In another embodiment, R4 is C(O)-methylpiperazine. In another embodiment, R4 is C(O)-piperidine. In another embodiment, R4 is C(O)-morpholine. In another embodiment, R4 is SO2R. In another embodiment, R4 is SO2N(R 10 )(R 11). In another embodiment, R4 is SO2NH(CH3). In another embodiment, R4 is SO2N(CH3). In another embodiment, R4 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In another embodiment, R4 is methyl. In another embodiment, R4 is C(OH)(CH3)(Ph). In another embodiment, R4 is ethyl. In another embodiment, R4 is propyl. In another embodiment, R4 is isopropyl. In another embodiment, R4 is t-Bu. In another embodiment, R4 is isobutyl. In another embodiment, R4 is pentyl. In another embodiment, R4 is substituted or unsubstituted C1-C5 linear or branched, or C3-C8 cyclic haloalkyl. In another embodiment, R4 is CF3. In another embodiment, R4 is CF2CH3. In another embodiment, R4 is CF2-cyclobutyl. In another embodiment, R4 is CF2-cyclopropyl. In another embodiment, R4 is CF2-methylcyclopropyl. In another embodiment, R4 is CF2CH2CH3. In another embodiment, R4 is CH2CF3. In another embodiment, R4 is CF3. In another embodiment, R4 is CF2CH2CH3. In another embodiment, R4 is CH2CH2CF3. In another embodiment, R4 is CF2CH(CH3)2. In another embodiment, R4 is CF(CH3)-CH(CH3)2. In another embodiment, R4 is C(OH)2CF3. In another embodiment, R4 is cyclopropyl-CF3. In another embodiment, R4 is C1-C5 linear, branched, or cyclic alkoxy. In another embodiment, R4 is methoxy. In another embodiment, R4 is isopropoxy. In another embodiment, R4 is substituted or unsubstituted C3-C8 cycloalkyl. In another embodiment, R4 is CF3-cyclopropyl. In another embodiment, R4 is cyclopropyl. In another embodiment, R4 is cyclopentyl. In another embodiment, R4 is a substituted or unsubstituted C3-C8 heterocycle. In another embodiment, R4 is oxadiazole. In another embodiment, R4 is pyrrole.In another embodiment, R4 is thiophene. In another embodiment, R4 is oxazole. In another embodiment, R4 is isoxazole. In another embodiment, R4 is imidazole. In another embodiment, R4 is furan. In another embodiment, R4 is triazole. In another embodiment, R4 is methyltriazole. In another embodiment, R4 is pyridine. In another embodiment, R4 is 2-pyridine. In another embodiment, R4 is 3-pyridine. In another embodiment, R4 is 4-pyridine. In another embodiment, R4 is pyrimidine. In another embodiment, R4 is pyrazine. In another embodiment, R4 is oxacyclobutane. In another embodiment, R4 is 1-oxacyclobutane. In another embodiment, R4 is 2-oxacyclobutane. In another embodiment, R4 is indole. In another embodiment, R4 is 3-methyl-4H-1,2,4 triazole. In another embodiment, R4 is 5-methyl-1,2,4 oxadiazole. In another embodiment, R4 is substituted or unsubstituted aryl. In another embodiment, R4 is phenyl. In another embodiment, R4 is CH(CF3)(NH-R. 10). In some embodiments, R4 can be further substituted with at least one selected from the following: F, Cl, Br, I, OH, C1-C5 linear or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 linear or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 linear or branched alkenyl (e.g., E- or Z-propylene), C2-C5 linear or branched alkenyl (e.g., CH≡C-CH3), C2-C5 linear or branched alkenyl (e.g., OC(O)-CH3), OH, alkoxy, ester (e.g., OC(O)-CH3). , N(R), CF, aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, and NO; each represents a separate embodiment of the present invention.

[0087] In some embodiments, R3 and R4 in the compounds of Formulas I-V are bonded to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring. In some embodiments, R3 and R4 are bonded to each other to form a 5- or 6-membered carbocyclic ring. In some embodiments, R3 and R4 are bonded to each other to form a 5- or 6-membered heterocyclic ring. In some embodiments, R3 and R4 are bonded to each other to form a dioxole ring. [1,3]dioxole ring. In some embodiments, R3 and R4 are bonded to each other to form a dihydrofuran-2(3H)-one ring. In some embodiments, R3 and R4 are bonded to each other to form a furan-2(3H)-1 ring. In some embodiments, R3 and R4 are bonded to each other to form a benzene ring. In some embodiments, R3 and R4 are bonded to each other to form an imidazole ring. In some embodiments, R3 and R4 are bonded to each other to form a pyridine ring. In some embodiments, R3 and R4 are bonded to each other to form a pyrrole ring. In some embodiments, R3 and R4 are bonded to each other to form a cyclohexene ring. In some embodiments, R3 and R4 are bonded to each other to form a cyclopentene ring. In some embodiments, R3 and R4 are bonded to each other to form a dioxepine ring.

[0088] In some embodiments, R of compounds of Formulas I-V 40 is H. In some embodiments, R 40 is not H. In other embodiments, R 40 is Cl. In other embodiments, R 40 is I. In other embodiments, R 40 is F. In other embodiments, R 40 is Br. In other embodiments, R 40 is OH. In other embodiments, R 40 is CD3. In other embodiments, R 40 is OCD3. In other embodiments, R 40 is R-OH. In other embodiments, R 40is CH2-OH. In other embodiments, R 40 -R8-OR 10 In other embodiments, R 40 is CH2-O-CH3. In other embodiments, R 40 is R8-N(R 10 )(R 11 In other embodiments, R 40 is CH-NH. In other embodiments, R 40 is CH2-N(CH3)2. In other embodiments, R 40 is COOH. In another embodiment, R 40 is C(O)OR 10 In other embodiments, R 40 is C(O)O-CH2CH3. In other embodiments, R 40 is R8-C(O)-R 10 In other embodiments, R 40 is CHC(O)CH. In other embodiments, R 40 is C(O)-R 10 In other embodiments, R 40 is C(O)-CH3. In other embodiments, R 40 is C(O)-CH2CH3. In other embodiments, R 40 is C(O)-CH2CH2CH3. In other embodiments, R 40 is a C1-C5 straight or branched C(O)-haloalkyl. In another embodiment, R 40 is C(O)—CF. In other embodiments, R 40 is C(O)NH. In other embodiments, R 40 is C(O)NHR. In other embodiments, R 40 is C(O)NH(CH). In other embodiments, R 40 is C(O)N(R 10 )(R 11 In other embodiments, R 40 is C(O)N(CH). In other embodiments, R 40 is C(O)N(CH)(CHCH). In other embodiments, R 40is C(O)N(CH)(CHCH-O-CH). In other embodiments, R 40 is C(S)N(R 10 )(R 11 In other embodiments, R 40 is C(S)NH(CH). In other embodiments, R 40 is C(O)-pyrrolidine. In other embodiments, R 40 is C(O)-azetidine. In other embodiments, R 40 is C(O)-methylpiperazine. In another embodiment, R 40 is C(O)-piperidine. In another embodiment, R 40 is C(O)-morpholine. In other embodiments, R 40 is SO2R. In other embodiments, R 40 is SO2N(R 10 )(R 11 In other embodiments, R 40 is SO2NH(CH3). In other embodiments, R 40 is SO2N(CH3)2. In other embodiments, R 40 is a C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R 40 is methyl. In another embodiment, R 40 is C(OH)(CH)(Ph). In other embodiments, R 40 is ethyl. In another embodiment, R 40 is propyl. In other embodiments, R 40 is isopropyl. In other embodiments, R 40 is t-Bu. In another embodiment, R 40 is isobutyl. In another embodiment, R 40 is pentyl. In another embodiment, R 40 is a substituted or unsubstituted C1-C5 straight or branched chain, or C3-C8 cyclic haloalkyl. 40 is CF. In other embodiments, R 40 is CF2CH3. In other embodiments, R 40is CF2-cyclobutyl. In another embodiment, R 40 is CF2-cyclopropyl. In other embodiments, R 40 is CF2-methylcyclopropyl. In another embodiment, R 40 is CF2CH2CH3. In other embodiments, R 40 is CH2CF3. In other embodiments, R 40 is CF. In other embodiments, R 40 is CF2CH2CH3. In other embodiments, R 40 is CH2CH2CF3. In other embodiments, R 40 is CF2CH(CH3)2. In other embodiments, R 40 is CF(CH3)-CH(CH3)2. In other embodiments, R 40 is C(OH)CF. In other embodiments, R 40 is cyclopropyl-CF. In other embodiments, R 40 is a C1-C5 straight or branched chain, or cyclic alkoxy. In other embodiments, R 40 is methoxy. In another embodiment, R 40 is isopropoxy. In another embodiment, R 40 is a substituted or unsubstituted C-C cycloalkyl. In other embodiments, R 40 is CF3-cyclopropyl. In other embodiments, R 40 is cyclopropyl. In other embodiments, R 40 is cyclopentyl. In another embodiment, R 40 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R 40 is oxadiazole. In other embodiments, R 40 is pyrrole. In other embodiments, R 40 is thiophene. In other embodiments, R 40 is oxazole. In another embodiment, R 40 is isoxazole. In other embodiments, R 40 is imidazole. In another embodiment, R40 is furan. In another embodiment, R 40 is triazole. In another embodiment, R 40 is methyltriazole. In another embodiment, R 40 is pyridine. In another embodiment, R 40 is 2-pyridine. In another embodiment, R 40 is 3-pyridine. In another embodiment, R 40 is 4-pyridine. In another embodiment, R 40 is pyrimidine. In other embodiments, R 40 , pyrazine. In another embodiment, R 40 is oxacyclobutane. In other embodiments, R 40 is 1-oxacyclobutane. In other embodiments, R 40 is 2-oxacyclobutane. In other embodiments, R 40 is indole. In another embodiment, R 40 is 3-methyl-4H-1,2,4 triazole. In another embodiment, R 40 is 5-methyl-1,2,4 oxadiazole. In another embodiment, R 40 is substituted or unsubstituted aryl. In other embodiments, R 40 is phenyl. In another embodiment, R 40 is CH(CF3)(NH-R 10 In some embodiments, R 40may be further substituted by at least one selected from the following: F, Cl, Br, I, OH, C1-C5 linear or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 linear or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 linear or branched alkenyl (e.g., E- or Z-propylene), C2-C5 linear or branched alkenyl (e.g., CH≡C-CH3), C2-C5 linear or branched alkenyl (e.g., O-C(O)-CH3 ), OH, alkoxy, ester (e.g., OC(O)—CH), N(R), CF, aryl, phenyl, R-aryl (e.g., CHCH—Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH )2), dialkylphosphates (e.g., OP(O)(OCH3)2), CN, and NO2; each represents a separate embodiment of the present invention.

[0089] In some embodiments, R5 in the compounds of Formulas I-III is H. In some embodiments, R5 is not H. In other embodiments, R5 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R5 is methyl. In other embodiments, R5 is CH2SH. In other embodiments, R5 is ethyl. In other embodiments, R5 is isopropyl. In other embodiments, R5 is CH2SH. In other embodiments, R5 is C2-C5 linear or branched, substituted or unsubstituted alkenyl. In other embodiments, R5 is C2-C5 linear or branched, substituted or unsubstituted alkynyl. In other embodiments, R5 is C(CH). In other embodiments, R5 is C1-C5 linear or branched haloalkyl. In other embodiments, R5 is CF2CH3. In other embodiments, R5 is CH2CF3. In other embodiments, R5 is CF2CH2CH3. In other embodiments, R5 is CF3. In other embodiments, R5 is CF2CH2CH3. In other embodiments, R5 is CH2CH2CF3. In other embodiments, R5 is CF2CH(CH3)2. In other embodiments, R5 is CF(CH3)-CH(CH3)2. In other embodiments, R5 is R8-aryl. In other embodiments, R5 is CH2-Ph (i.e., benzyl). In other embodiments, R5 is substituted or unsubstituted aryl. In other embodiments, R5 is phenyl. In other embodiments, R5 is substituted or unsubstituted heteroaryl. In other embodiments, R5 is pyridine. In other embodiments, R5 is 2-pyridine. In other embodiments, R5 is 3-pyridine. In other embodiments, R5 is 4-pyridine. In some embodiments, R5 can be further substituted with at least one selected from the following:F, Cl, Br, I, OH, C1-C5 straight or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 straight or branched alkenyl (e.g., E- or Z-propylene), C2-C5 straight or branched alkenyl (e.g., CH≡C-CH3), C2-C5 straight or branched alkenyl (e.g., OC(O)-CH3), OH, alkoxy, ester (e.g., OC(O)-CH3). , N(R), CF, aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, and NO; each represents a separate embodiment of the present invention.

[0090] In some embodiments, R6 in the compounds of Formulas I-III is H. In some embodiments, R6 is not H. In other embodiments, R6 is C1-C5 linear or branched alkyl. In other embodiments, R6 is methyl. In some embodiments, R6 is ethyl. In some embodiments, R6 is C(O)R, where R is C1-C5 linear or branched alkyl, C1-C5 linear or branched alkoxy, phenyl, aryl, or heteroaryl. In some embodiments, R6 is S(O)R, where R is C1-C5 linear or branched alkyl, C1-C5 linear or branched alkoxy, phenyl, aryl, or heteroaryl.

[0091] In some embodiments, R of compounds of Formulas I-III 60 is H. In some embodiments, R 60 is not H. In other embodiments, R 60is a substituted or unsubstituted C1-C5 straight or branched alkyl. In other embodiments, R 60 is methyl. In some embodiments, R 60 is ethyl. In another embodiment, R 60 is a substituted C1-C5 straight or branched alkyl. In another embodiment, R 60 is CH2-OC(O)CH3. In other embodiments, R 60 is CH2-PO4H2. In other embodiments, R 60 is CH2-PO4H-tBu. In another embodiment, R 60 is CH2-OP(O)(OCH3)2. In some embodiments, R 60 is C(O)R, where R is C1-C5 linear or branched alkyl, C1-C5 linear or branched alkoxy, phenyl, aryl, or heteroaryl. In some embodiments, R 60 is S(O)R, where R is C1-C5 linear or branched alkyl, C1-C5 linear or branched alkoxy, phenyl, aryl, or heteroaryl. In some embodiments, R 60may be further substituted by at least one selected from the following: F, Cl, Br, I, OH, C1-C5 linear or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 linear or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 linear or branched alkenyl (e.g., E- or Z-propylene), C2-C5 linear or branched alkenyl (e.g., CH≡C-CH3), C2-C5 linear or branched alkenyl (e.g., OC(O)-CH3), OH, alkoxy, ester (e.g., OC(O)-CH3). , N(R), CF, aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, and NO; each represents a separate embodiment of the present invention.

[0092] In some embodiments, R8 in a compound of Formula I-IX is CH2. In other embodiments, R8 is CH2CH2. In other embodiments, R8 is CH2CH2CH2. In some embodiments, R8 is CH2CH2CH2CH2.

[0093] In some embodiments, p in compounds of Formulas I-IX is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 1 to 3. In some embodiments, p is 1 to 5. In some embodiments, p is 1 to 10.

[0094] In some embodiments, R9 in a compound of Formula I-IX is C≡C. In some embodiments, R9 is C≡CC≡C. In some embodiments, R9 is CH=CH. In some embodiments, R9 is CH=CH-CH=CH.

[0095] In some embodiments, q in compounds of Formulas I-IX is 2. In some embodiments, q is 4. In some embodiments, q is 6. In some embodiments, q is 8. In some embodiments, q is 2-6.

[0096] In some embodiments, R of compounds of Formulas I-IX 10 is a C1-C5 straight or branched alkyl. In other embodiments, R 10 is H. In other embodiments, R 10 is CH3. In other embodiments, R 10 is CH2CH3. In other embodiments, R 10 is CH2CH2CH3. In some embodiments, R 10 is isopropyl. In some embodiments, R 10 is butyl. In some embodiments, R 10 is isobutyl. In some embodiments, R 10 is t-butyl. In some embodiments, R 10 is cyclopropyl. In some embodiments, R 10 is pentyl. In some embodiments, R 10 is isopentyl. In some embodiments, R 10 is neopentyl. In some embodiments, R 10 is benzyl. In another embodiment, R 10 is R8-OR 10 In other embodiments, R 10 is CH2CH2-O-CH3. In other embodiments, R 10 is CN. In other embodiments, R 10 is C(O)R. In other embodiments, R10 is C(O)(OCH). In other embodiments, R 10 is S(O)R.

[0097] In some embodiments, R of compounds of Formulas I-IX 11 is a C1-C5 straight or branched alkyl. In other embodiments, R 11 is H. In other embodiments, R 11 is CH3. In other embodiments, R 11 is CH2CH3. In other embodiments, R 11 is CH2CH2CH3. In some embodiments, R 11 is isopropyl. In some embodiments, R 11 is butyl. In some embodiments, R 11 is isobutyl. In some embodiments, R 11 is t-butyl. In some embodiments, R 11 is cyclopropyl. In some embodiments, R 11 is pentyl. In some embodiments, R 11 is isopentyl. In some embodiments, R 11 is neopentyl. In some embodiments, R 11 is benzyl. In another embodiment, R 11 is R8-OR 10 In other embodiments, R 11 is CH2CH2-O-CH3. In other embodiments, R 11 is CN. In other embodiments, R 11 is C(O)R. In other embodiments, R 11 is C(O)(OCH). In other embodiments, R 11 is S(O)R.

[0098] In some embodiments, R of compounds of Formulas I-IX 10 and R 11 are joined together to form a substituted or unsubstituted C3-C8 heterocycle.10 and R 11 are linked together to form a piperazine ring. In another embodiment, R 10 and R 11 are linked together to form a piperidine ring. 10 and R 11 are linked together to form a morpholine ring. 10 and R 11 are linked together to form a pyrrolidine ring. 10 and R 11 are linked together to form a methylpiperazine ring. In another embodiment, R 10 and R 11 are linked together to form an azetidine ring. 10 and / or R 11 may be further substituted by at least one selected from the following: F, Cl, Br, I, OH, C1-C5 linear or branched alkyl (e.g., methyl, ethyl, propyl), C1-C5 linear or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C2-C5 linear or branched alkenyl (e.g., E- or Z-propylene), C2-C5 linear or branched alkenyl (e.g., CH≡C-CH3), C2-C5 linear or branched alkenyl (e.g., OC(O)-CH3), OH, alkoxy, ester (e.g., OC(O)-CH3). , N(R), CF, aryl, phenyl, R-aryl (e.g., CHCH-Ph), heteroaryl (e.g., imidazole), C-C cycloalkyl (e.g., cyclohexyl), C-C heterocycle (e.g., pyrrolidine), halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate (e.g., tBu-POH), dihydrogen phosphate (i.e., OP(O)(OH)), dialkyl phosphate (e.g., OP(O)(OCH), CN, and NO; each represents a separate embodiment of the present invention.

[0099] In some embodiments, R in a compound of Formulas I-IX is H. In some embodiments, R is not H. In other embodiments, R is C1-C5 linear or branched alkyl. In other embodiments, R is methyl. In other embodiments, R is ethyl. In other embodiments, R is C1-C5 linear or branched alkoxy. In other embodiments, R is methoxy. In other embodiments, R is phenyl. In other embodiments, R is aryl. In other embodiments, R is heteroaryl. In other embodiments, two gemR substituents are joined together to form a 5- or 6-membered heterocycle.

[0100] In various embodiments, n in the compounds of Formulas I-V is 0. In some embodiments, n is 0 or 1. In some embodiments, n is 1-3. In some embodiments, n is 1-4. In some embodiments, n is 0-2. In some embodiments, n is 0-3. In some embodiments, n is 0-4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0101] In various embodiments, m in compounds of Formulas I-V is 0. In some embodiments, m is 0 or 1. In some embodiments, m is 1-3. In some embodiments, m is 1-4. In some embodiments, m is 0-2. In some embodiments, m is 0-3. In some embodiments, m is 0-4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0102] In various embodiments, l in compounds of Formulas I-V is 0. In some embodiments, l is 0 or 1. In some embodiments, l is 1-3. In some embodiments, l is 1-4. In some embodiments, l is 0-2. In some embodiments, l is 0-3. In some embodiments, l is 0-4. In some embodiments, l is 1. In some embodiments, l is 2. In some embodiments, l is 3. In some embodiments, l is 4.

[0103] In various embodiments, k in the compounds of Formulas I-V is 0. In some embodiments, k is 0 or 1. In some embodiments, k is 1-3. In some embodiments, k is 1-4. In some embodiments, k is 0-2. In some embodiments, k is 0-3. In some embodiments, k is 0-4. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4.

[0104] In the case of a heterocycle, it should be understood that n, m, l, and / or k are limited to the number of substitutable positions, i.e., the number of CH or NH groups minus 1. Thus, when ring A and / or ring B is, for example, furanyl, thiophenyl, or pyrrolyl, n, m, l, and k are 0 to 2. When ring A and / or ring B is, for example, oxazolyl, imidazolyl, or thiazolyl, n, m, l, and k are 0 or 1. When ring A and / or ring B is, for example, oxadiazolyl or thiadiazolyl, n, m, l, and k are 0.

[0105] In various embodiments, the present invention relates to compounds set forth in Table 1, pharmaceutical compositions comprising same, and / or methods of use thereof.

[0106] [Table 1-1]

[0107] Table 1-2

[0108] Table 1-3

[0109] Table 1-4

[0110] Table 1-5

[0111] Table 1-6

[0112] Table 1-7

[0113] Table 1-8

[0114] Table 1-9

[0115] Table 1-10

[0116] Table 1-11

[0117] Table 1-12

[0118] Table 1-13

[0119] Table 1-14

[0120] Table 1-15

[0121] Table 1-16

[0122] Table 1-17

[0123] Table 1-18

[0124] Table 1-19

[0125] Table 1-20

[0126] Table 1-21

[0127] [Table 1-22]

[0128] [Table 1-23]

[0129] [Table 1-24]

[0130] [Table 1-25]

[0131] It is well understood that in the structures presented in this invention, when a carbon atom has fewer than four bonds, an H atom is present to complete the carbon valence. It is well understood that in the structures presented in this invention, when a nitrogen atom has fewer than three bonds, an H atom is present to complete the nitrogen valence.

[0132] In some embodiments, the present invention relates to compounds, pharmaceutical compositions, and / or methods of use thereof, as listed herein above. The compounds of the present invention include pharmaceutically acceptable salts, optical isomers, tautomers, hydrates, N-oxides, reverse amide analogs, prodrugs, isotopic variants (e.g., deuterated analogs), PROTACs, pharmaceuticals, or any combination thereof. In some embodiments, the compounds of the present invention are acyl-CoA synthetase short chain family member 2 (ACSS2) inhibitors.

[0133] As used herein, "monocyclic or fused ring aromatic or heteroaromatic ring system" includes, but is not limited to, phenyl, naphthyl, pyridinyl, (2-, 3-, and 4-pyridinyl), quinolinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, pyrazolyl, pyrrolyl, furanyl, thiophen-yl, quinolinyl, isoquinolinyl, 2,3-dihydroindenyl, indenyl, and tetrahydronaphthyl. , 3,4-dihydro-2H-benzo[b][1,4]dioxepine, benzodioxolyl, benzo[d][1,3]dioxole, tetrahydronaphthyl, indolyl, 1H-indole, isoindolyl, anthracenyl, benzimidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl benzo[c][1,2,5]oxadiazolyl, benzo[c]thiophenyl, benzodioxolyl, thiazole, benzo[c]thiophenyl, benzodioxolyl, benzo[c]thiazole ... Diazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiaziolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2-d]pyrimidin-4(3H)-one, 4-oxo-4H-thieno[3,2-d][1,3]thiazine, imidazo[1,2-a]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-imidazo[4,5-c]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrido[2,3-b]pyrazine, pyrido[2,3-b]pyrazine-3 (4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thieno[3,2-c]pyridine, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole, etc.

[0134] As used herein, the term "alkyl," unless otherwise specified, can be a straight or branched chain alkyl group containing up to about 30 carbons. In various embodiments, alkyl includes C1-C5 carbons. In some embodiments, alkyl includes C1-C6 carbons. In some embodiments, alkyl includes C1-C8 carbons. In some embodiments, alkyl includes C1-C 10 In some embodiments, alkyl is C-C 12 In some embodiments, alkyl is C-C 20In some embodiments, the branched alkyl is an alkyl substituted with an alkyl side chain of 1 to 5 carbons. In various embodiments, the alkyl group can be unsubstituted. In some embodiments, the alkyl group can be substituted with halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, COH, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C1-C5 straight or branched chain haloalkoxy, CF3, phenyl, halophenyl, (benzyloxy)phenyl, -CH2CN, NH2, NH-alkyl, N(alkyl)2, -OC(O)CF3, -OCH2Ph, -NHCO-alkyl, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH2, or any combination thereof.

[0135] An alkyl group can be the sole substituent or part of a larger substituent such as alkoxy, alkoxyalkyl, haloalkyl, arylalkyl, alkylamino, dialkylamino, alkylamide, alkylurea, etc. Preferred alkyl groups are methyl, ethyl, and propyl, thus halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, halopropyl, dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl, arylethyl, arylpropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylamide, acetamide, propylamide, halomethylamide, haloethylamide, halopropylamide, methyl-urea, ethyl-urea, propyl-urea, 2, 3, or 4-CH2-C6H4-Cl, C(OH)(CH3)(Ph), etc.

[0136] As used herein, the term "alkenyl" can be a straight- or branched-chain alkenyl group containing up to about 30 carbons and at least one carbon-carbon double bond, as defined herein above for the term "alkyl." Thus, the term alkenyl, as defined herein, also includes alkadienes, alkatrienes, alkatetraenes, and the like. In some embodiments, an alkenyl group contains one carbon-carbon double bond. In some embodiments, an alkenyl group contains two, three, four, five, six, seven, or eight carbon-carbon double bonds, each of which represents a separate embodiment of the present invention. Non-limiting examples of alkenyl groups include ethenyl, propenyl, butenyl (i.e., 1-butenyl, trans-2-butenyl, cis-2-butenyl, and isobutylenyl), pentene (i.e., 1-pentenyl, cis-2-pentenyl, and trans-2-pentenyl), hexene (e.g., 1-hexenyl, (E)-2-hexenyl, (Z)-2-hexenyl, (E)-3-hexenyl, (Z)-3-hexenyl, 2-methyl-1-pentene, etc.), all of which may be substituted as defined herein above for the term "alkyl."

[0137] As used herein, the term "alkynyl" can be a straight-chain or branched-chain alkynyl group containing up to about 30 carbons and at least one carbon-carbon triple bond, as defined herein above for the term "alkyl." Thus, the term alkynyl, as defined herein, also includes alkdiynes, alkatolynes, alkatetraynes, and the like. In some embodiments, an alkynyl group contains one carbon-carbon triple bond. In some embodiments, an alkynyl group contains two, three, four, five, six, seven, or eight carbon-carbon triple bonds, each of which represents a separate embodiment of the present invention. Non-limiting examples of alkynyl groups include acetylenyl, propynyl, butynyl (i.e., 1-butynyl, 2-butynyl, and isobutynyl), pentyne (i.e., 1-pentynyl, 2-pentenyl), hexyne (e.g., 1-hexynyl, 2-hexenyl, 3-hexynyl, etc.), all of which may be substituted as defined herein above for the term "alkyl."

[0138] As used herein, the term "aryl" refers to any aromatic ring directly bonded to another group and which may be either substituted or unsubstituted. An aryl group may be the only substituent or may be a component of a larger substituent, such as in an arylalkyl, arylamino, or arylamide. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, xylyl, furanyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiophen-yl, pyrrolyl, indolyl, phenylmethyl, phenylethyl, phenylamino, phenylamido, 3-methyl-4H-1,2,4-triazolyl, and 5-methyl-1,2,4-oxadiazolyl. Substituents include, but are not limited to, F, Cl, Br, I, C1-C5 straight or branched chain alkyl, C1-C5 straight or branched chain haloalkyl, C1-C5 straight or branched chain alkoxy, C1-C5 straight or branched chain haloalkoxy, CF3, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, -CH2CN, NH2, NH-alkyl, N(alkyl)2, hydroxyl, -OC(O)CF3, -OCH2Ph, -NHCO-alkyl, COOH, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH2, or combinations thereof.

[0139] As used herein, the term "alkoxy" refers to an ether group substituted with an alkyl group, as defined above. Alkoxy refers to both straight-chain and branched-chain alkoxy groups. Non-limiting examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and tert-butoxy.

[0140] As used herein, the term "aminoalkyl" refers to an amine group substituted with an alkyl group, as defined above. Aminoalkyl refers to a mono-, di-, or tri-alkylamine. Non-limiting examples of aminoalkyl groups include -N(Me)2, -nhme, and -NH3.

[0141] A "haloalkyl" group, in some embodiments, refers to an alkyl group, as defined above, substituted with one or more halogen atoms, e.g., haloalkyl by F, Cl, Br, or I. The term "haloalkyl" includes, but is not limited to, fluoroalkyl, i.e., an alkyl group having at least one fluorine atom. Non-limiting examples of haloalkyl groups are CF, CFCF, CFCH, CHCF, CFCHCH, CHCHCF, CFCH(CH), and CF(CH)-CH(CH).

[0142] A "haloalkenyl" group, in some embodiments, refers to an alkenyl group, as defined above, substituted with one or more halogen atoms, for example, F, Cl, Br, or I. The term "haloalkenyl" includes, but is not limited to, fluoroalkenyl, i.e., an alkenyl group having at least one fluorine atom, and, where applicable, each of their isomers (i.e., E, Z, cis, trans). Non-limiting examples of haloalkenyl groups are CFCF, CF=CH-CH, CFCH, CHCF, CFCHCH, CHCHCF, and CF=C-(CH) (E and Z isomers, where applicable).

[0143] A "halophenyl" group, in some embodiments, refers to a phenyl substituent that is substituted with one or more halogen atoms, such as F, Cl, Br, or I. In one embodiment, the halophenyl is 4-chlorophenyl.

[0144] An "alkoxyalkyl" group refers, in some embodiments, to an alkyl group as defined above that is substituted with an alkoxy group as defined above, e.g., methoxy, ethoxy, propoxy, i-propoxy, t-butoxy, etc. Non-limiting examples of alkoxyalkyl groups are -CH2-O-CH3, -CH2-O-CH(CH3), -CH2-OC(CH3), -CH2-CH2-O-CH3, -CH2-CH2-O-CH(CH3), -CH2-CH2-OC(CH3).

[0145] A "cycloalkyl" or "carbocyclic" group, in various embodiments, refers to a ring structure that includes carbon atoms as ring atoms, and may be saturated or unsaturated, substituted or unsubstituted, monocyclic or fused. In some embodiments, a cycloalkyl is a 3- to 10-membered ring. In some embodiments, a cycloalkyl is a 3- to 12-membered ring. In some embodiments, a cycloalkyl is a 6-membered ring. In some embodiments, a cycloalkyl is a 5- to 7-membered ring. In some embodiments, a cycloalkyl is a 3- to 8-membered ring. In some embodiments, a cycloalkyl group can be unsubstituted or substituted with halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, COH, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C-C straight or branched chain haloalkoxy, CF, phenyl, halophenyl, (benzyloxy)phenyl, —CHCN, NH, NH-alkyl, N(alkyl), —OC(O)CF, —OCHPh, —NHCO-alkyl, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH, or any combination thereof. In some embodiments, a cycloalkyl ring can be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3- to 8-membered ring. In some embodiments, the cycloalkyl ring is a saturated ring. In some embodiments, the cycloalkyl ring is an unsaturated ring. Non-limiting examples of cycloalkyl groups include cyclohexyl, cyclohexenyl, cyclopropyl, cyclopropenyl, cyclopentyl, cyclopentenyl, cyclobutyl, cyclobutenyl, cyclooctyl, cyclooctadienyl (COD), cyclooctaene (COE), and the like.

[0146] A "heterocycle" or "heterocyclic" group, in various embodiments, refers to a ring structure that, in addition to carbon atoms, includes sulfur, oxygen, nitrogen, or any combination thereof as part of the ring. A "heteroaromatic ring," in various embodiments, refers to an aromatic ring structure that, in addition to carbon atoms, includes sulfur, oxygen, nitrogen, or any combination thereof as part of the ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3- to 10-membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3- to 12-membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 6-membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 5- to 7-membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3- to 8-membered ring. In some embodiments, a heterocyclic group or heteroaromatic ring can be unsubstituted or substituted with halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, COH, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C-C straight or branched chain haloalkoxy, CF, phenyl, halophenyl, (benzyloxy)phenyl, —CHCN, NH, NH-alkyl, N(alkyl), —OC(O)CF, —OCHPh, —NHCO-alkyl, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH, or any combination thereof. In some embodiments, a heterocyclic or heteroaromatic ring can be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3- to 8-membered ring. In some embodiments, a heterocyclic ring is a saturated ring. In some embodiments, a heterocyclic ring is an unsaturated ring.Non-limiting examples of heterocyclic or heteroaromatic ring systems include pyridine, piperidine, morpholine, piperazine, thiophene, pyrrole, benzodioxole, benzofuran-2(3H)-one, benzo[d][1,3]dioxole, indole, oxazole, isoxazole, imidazole and 1-methylimidazole, furan, triazole, pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), naphthalene, tetrahydrothiophene 1,1-dioxide, thiazole, benzimidazole, piperidine, 1-methylpiperidine, isoquinoline, 1,3-dihydroisobenzofuran, benzofuran, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole, or indole.

[0147] In various embodiments, the present invention provides a compound of the present invention, or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, polymorph, crystal, or any combination thereof. In some embodiments, the present invention provides an isomer of a compound of the present invention. In some embodiments, the present invention provides a metabolite of a compound of the present invention. In some embodiments, the present invention provides a pharmaceutically acceptable salt of a compound of the present invention. In some embodiments, the present invention provides a pharmaceutical product of a compound of the present invention. In some embodiments, the present invention provides a tautomer of a compound of the present invention. In some embodiments, the present invention provides a hydrate of a compound of the present invention. In some embodiments, the present invention provides an N-oxide of a compound of the present invention. In some embodiments, the present invention provides a reverse amide analog of a compound of the present invention. In some embodiments, the present invention provides a prodrug of a compound of the present invention. In some embodiments, the present invention provides an isotopic variant of a compound of the present invention (e.g., but not limited to, a deuterated analog). In some embodiments, the present invention provides a PROTAC (proteolysis-induced chimera) of a compound of the present invention. In some embodiments, the present invention provides a polymorph of a compound of the present invention. In some embodiments, the present invention provides crystals of the compounds of the present invention. In some embodiments, the present invention provides compositions comprising a compound of the present invention described herein, or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, polymorph, crystal, or any combination thereof of a compound of the present invention.

[0148] In various embodiments, the term "isomer" includes, but is not limited to, stereoisomers, optical isomers, structural isomers, conformational isomers, and the like. In some embodiments, an isomer is an optical isomer. In some embodiments, an isomer is a stereoisomer.

[0149] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. All such compounds, including cis isomers, trans isomers, R enantiomers, S enantiomers, diastereomers, racemic mixtures thereof, and other mixtures thereof, are intended to be included within the scope of the present invention. Substituents such as alkyl groups may also have asymmetric carbon atoms. Such isomers and combinations thereof are also included in the present invention.

[0150] In various embodiments, the present invention encompasses the use of various optical isomers of the compounds of the present invention.It will be understood by those skilled in the art that the compounds of the present invention may contain at least one chiral center.Therefore, the compounds used in the method of the present invention can exist and be isolated in optically active form or racemic form. Thus, the compounds of the present invention may exist as stereoisomers or optically active isomers (e.g., enantiomers such as (R) or (S)), enantiomerically enriched mixtures, racemic mixtures, single diastereomers, diastereomeric mixtures, or any other stereoisomeric form, including, but not limited to, the (R)(R), (R)(S), (S)(S), (S)(R), (R)(R)(R), (R)(R)(S), (R)(R), (S)(R), (S)(R), (R)(S), (S)(S), (S)(R), or (S)(S)(S) stereoisomers. Some compounds may also exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically active, polymorphic, or stereoisomeric form, or combination thereof, which forms have properties useful in the treatment of the various diseases (conditions) described herein.

[0151] It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases.

[0152] The compounds of the present invention can also exist in the form of racemic mixtures containing substantially equal amounts of stereoisomers. In some embodiments, the compounds of the present invention can be prepared or otherwise isolated using known procedures to obtain stereoisomers that are substantially free of their corresponding stereoisomers (i.e., substantially pure). By substantially pure, it is intended that the stereoisomers are at least about 95% pure, more preferably at least about 98% pure, and most preferably at least about 99% pure.

[0153] The compounds of the present invention can also be in the form of hydrates, which means that the compounds further contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0154] As used herein, when a chemical functional group (eg, alkyl or aryl) is said to be "substituted," it is defined that one or more substitutions are possible.

[0155] The compounds of the present invention may exist in one or more of the possible tautomeric forms, and depending on the conditions, it is possible to separate some or all of the tautomers into separate entities. It is understood that all possible tautomers, including all additional enol and keto tautomers and / or isomers, are encompassed by the present invention. For example, but not limited to, the following tautomers are included:

[0156] [ka]

[0157] The present invention includes "pharmaceutically acceptable salts" of the compounds of the present invention prepared by reacting the compounds with an acid or base. Certain compounds, particularly those containing acidic or basic groups, may be in the form of a salt, preferably a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, even if it is not biologically or otherwise undesirable. Salts may be prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. Other salts are known to those skilled in the art and can be readily adapted for use in accordance with the present invention.

[0158] Suitable pharmaceutically acceptable salts of the amine of the compound of the present invention can be prepared from inorganic or organic acids.In various embodiments, examples of inorganic salts of amine include hydrogen sulfate, borate, bromide, chloride, hemisulfate, hydrobromide, hydrochloride, 2-hydroxyethylsulfonate (hydroxyethanesulfonate), iodate, iodide, isothionate, nitrate, persulfate, phosphate, sulfate, sulfamate, sulfanilate, sulfonic acid (alkylsulfonate, arylsulfonate, halogen-substituted alkylsulfonate, halogen-substituted arylsulfonate), sulfonate and thiocyanate.

[0159] In various embodiments, examples of organic salts of amines can be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, including acetate, arginine, aspartate, ascorbate, adipate, anthranilate, algenate, alkanecarboxylate, substituted alkanecarboxylate, alginate, benzenesulfonate, benzoate, bisulfate, butyrate, bicarbonate, bitartrate, citrate, camphorate, camphorsulfonate, cyclohexylsulfam ... Clopentanepropionate, calcium edetate, camsylate, carbonate, clavulanate, cinnamate, dicarboxylate, digluconate, dodecylsulfonate, dihydrochloride, decanoate, enanthate, ethanesulfonate, edetate, edisylate, estolate, esylate, fumarate, formate, fluoride, galacturonate, gluconate, glutamate, glycolate, glucolate, glucoheptanoate, glycerophosphate, gluceptate, glycolylarsanilate, glutarate, glutamate, heptanoate, heptanoate Xanthate, Hydroxymaleate, Hydroxycarboxylic Acid, Hexylresorcylate, Hydroxybenzoate, Hydroxynaphthoate, Hydrofluoride, Lactate, Lactobionate, Laurate, Malate, Maleate, Methylenebis(beta-oxynaphthoate), Malonate, Mandelate, Mesylate, Methanesulfonate, Methyl Bromide, Methyl Nitrate, Methanesulfonate, Monopotassium Maleate, Mucate, Monocarboxylate, Naphthalenesulfonate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Napsylate, N -Methylglucamine, oxalate, octanoate, oleate, pamoate, phenylacetate, picrate, phenylbenzoate, pivalate, propionate, phthalate, phenylacetate, pectinate, phenylpropionate, palmitate, pantothenate, polygalacturonate, pyruvate, quinate, salicylate, succinate, stearate, sulfanilate, diacetate, tartrate, theophylline acetate, p-toluenesulfonate (tosylate), trifluoroacetate, terephthalate, tannate, teoclate,These include trihaloacetates, triethiodides, tricarboxylates, undecanoates, and valerates.

[0160] In various embodiments, examples of inorganic salts of carboxylic acids or hydroxyls can be selected from alkali metals including ammonium, lithium, sodium, potassium, cesium; alkaline earth metals including calcium, magnesium, aluminum; zinc, barium, choline, quaternary ammonium.

[0161] In some embodiments, examples of organic salts of carboxylic acids or hydroxyls can be selected from arginine, organic amines (including aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathine, t-butylamine, betamin (N-benzylphenethylamine), dicyclohexylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, hydrabamine, imidazole, lysine, methylamine, meglamine, N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, nicotinamide, organic amines, ornithine, pyridine, picoline, piperazine, procaine, tris(hydroxymethyl)methylamine, triethylamine, triethanolamine, trimethylamine, tromethamine), and urea.

[0162] In various embodiments, salts can be made by conventional means, for example, by reacting the product in its free base or free acid form with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed under vacuum or by lyophilization, or by exchanging an ion of an existing salt with another ion or with a suitable ion exchange resin.

[0163] Pharmaceutical Composition

[0164] Another aspect of the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to an aspect of the present invention. The pharmaceutical composition of the present invention may contain one or more of the compounds of the present invention described above. Generally, the pharmaceutical composition of the present invention may comprise a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to any suitable adjuvant, carrier, excipient, or stabilizer, and may be in the form of a solid or liquid, such as a tablet, capsule, powder, solution, suspension, or emulsion.

[0165] Typically, the compositions of the present invention may contain about 0.01 to 99 percent, preferably about 20 to 75 percent, of the active compound, along with adjuvants, carriers, and / or excipients. While individual needs may vary, determining the optimal range of effective amounts of each component is within the skill of those in the art. A typical dosage is about 0.01 to 100 mg / kg body weight. A preferred dosage is about 0.1 to 100 mg / kg body weight. A most preferred dosage is about 1 to 100 mg / kg body weight. Furthermore, therapeutic regimens for administering the compounds of the present invention can be readily determined by those skilled in the art. That is, administration frequency and dosage can be established by routine optimization, preferably while minimizing side effects.

[0166] Solid form dosage forms can be, for example, capsules, such as ordinary gelatin types, containing a compound of the invention and a carrier such as a lubricant or inert filler (e.g., lactose, sucrose, or cornstarch). In some embodiments, the compounds are tableted in combination with a conventional tablet base such as lactose, sucrose, or cornstarch, a binder such as acacia, cornstarch, or gelatin, a disintegrating agent such as cornstarch, potato starch, or alginic acid, and a lubricant such as stearic acid or magnesium stearate.

[0167] Tablets, capsules, and the like may also contain binders such as tragacanth gum, acacia, corn starch, or gelatin, excipients such as dicalcium phosphate, disintegrating agents such as corn starch, potato starch, or alginic acid, lubricants such as magnesium stearate, and sweeteners such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0168] Various other materials can be used as coatings or to modify the physical form of the dosage unit. For example, tablets can be coated with shellac, sugar, or both. A syrup can contain, in addition to the active ingredient, sucrose as a sweetening agent, methylparaben or propylparaben as preservatives, a dye, and a flavoring such as cherry or orange flavor.

[0169] For oral therapeutic administration, these active compounds can be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage of the compound in these compositions may, of course, be varied and may conveniently be about 2-60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions according to the present invention are prepared so that an oral dosage unit contains about 1-800 mg of active compound.

[0170] The active compounds of the present invention may be administered orally, for example, with an inert diluent or an assimilable edible carrier, enclosed in a hard or soft capsule, compressed into tablets, or incorporated directly into the food of the animal.

[0171] Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the pharmaceutical form must be sterile and fluid enough to be easily injected with a syringe. It must also be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), a suitable mixture thereof, or a vegetable oil.

[0172] The compounds or pharmaceutical compositions of the present invention may also be administered in injectable dosages as a solution or suspension in a physiologically acceptable diluent with a pharmaceutical adjuvant, carrier, or excipient. Such adjuvants, carriers, and / or excipients include, but are not limited to, sterile liquids such as water and oils, with or without the addition of surfactants or other pharmaceutically and physiologically acceptable ingredients. Exemplary oils are those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose or related sugar solutions, and glycols, such as propylene glycol and polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.

[0173] These active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Exemplary oils are those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose or related sugar solutions, and glycols, such as propylene glycol and polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0174] For use as an aerosol, the compounds of the invention in solution or suspension can be packaged in a pressurized aerosol container with a suitable propellant, e.g., a conventional adjuvant and a hydrocarbon propellant such as propane, butane, or isobutane. The materials of the invention can also be administered in a non-pressurized form, such as in a nebulizer or atomizer.

[0175] In various embodiments, the compounds of the present invention are administered in combination with an anti-cancer agent. In various embodiments, the anti-cancer agent is a monoclonal antibody. In some embodiments, the monoclonal antibody is used to diagnose, monitor, or treat cancer. In various embodiments, the monoclonal antibody reacts with a specific antigen on cancer cells. In various embodiments, the monoclonal antibody acts as a cancer cell receptor antagonist. In various embodiments, the monoclonal antibody enhances a patient's immune response. In various embodiments, the monoclonal antibody acts against a cell growth factor, thereby inhibiting the proliferation of cancer cells. In various embodiments, the anti-cancer monoclonal antibody is conjugated or bound to an anti-cancer agent, a radioisotope, other biological response modifiers, other toxins, or any combination thereof. In various embodiments, the anti-cancer monoclonal antibody is conjugated or bound to a compound of the present invention as described above.

[0176] In various embodiments, the compounds of the invention are administered in combination with an agent treating an autoimmune disease.

[0177] In various embodiments, the compounds of the invention are administered in combination with an agent that treats an inflammatory disease.

[0178] In various embodiments, the compounds of the invention are administered in combination with an agent that treats a neuropsychiatric disorder.

[0179] In various embodiments, the compounds of the invention are administered in combination with an agent treating a metabolic disorder.

[0180] In various embodiments, a compound of the invention is administered in combination with an agent to treat non-alcoholic steatohepatitis (NASH).

[0181] In various embodiments, the compounds of the invention are administered in combination with an agent for treating non-alcoholic fatty liver disease (NAFLD).

[0182] In various embodiments, a compound of the invention is administered in combination with an agent to treat alcoholic steatohepatitis (ASH).

[0183] In various embodiments, the compounds of the invention are administered in combination with an agent to treat a human cytomegalovirus (HCMV) infection.

[0184] In various embodiments, the compounds of the invention are administered in combination with an antiviral agent.

[0185] In various embodiments, the compounds of the invention are administered in combination with at least one of chemotherapy, molecular targeted therapy, DNA damaging agents, hypoxia inducing agents, or immunotherapy, each representing a separate embodiment of the invention.

[0186] Yet another aspect of the invention relates to a method of treating cancer, comprising the steps of selecting a subject in need of cancer treatment and administering to the selected subject a pharmaceutical composition comprising a compound according to the first aspect of the invention and a pharmaceutically acceptable carrier under conditions effective to treat the cancer.

[0187] When administering the compounds of the present invention, the compounds of the present invention may be administered systemically or directly to the specific site where cancer cells or precancerous cells are present.Therefore, administration can be achieved by any method that is effective for delivering the compounds or pharmaceutical compositions of the present invention to cancer cells or precancerous cells.Exemplary administration modes of the compounds or compositions of the present invention include, but are not limited to, oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, intracavity, intravesical, intraocular, intraarterial, intralesional, or administration or application to mucous membranes such as the nose, throat, and bronchi.

[0188] biological activity

[0189] In various embodiments, the present invention provides compounds and compositions, including any of the embodiments described herein, for use in any of the methods of the present invention. In various embodiments, the use of the compounds of the present invention or compositions comprising same will have utility in inhibiting, suppressing, enhancing, or stimulating a desired response in a subject, as will be understood by those skilled in the art. In some embodiments, the compositions of the present invention may further comprise additional active ingredients having activities useful in the particular application for which the compounds of the present invention are administered.

[0190] Acetate is an important source of acetyl-CoA under hypoxic conditions. Inhibition of acetate metabolism inhibits tumor growth. The nucleocytoplasmic acetyl-CoA synthase ACSS2 provides the primary source of acetyl-CoA for tumors by incorporating acetate as a carbon source. ACSS2-deficient adult mice exhibit significantly reduced tumor burden in two hepatocellular carcinoma models, despite not exhibiting significant growth or developmental defects. ACSS2 is expressed in the majority of human tumors, and its activity is responsible for the majority of cellular acetate incorporation into both lipids and histones. Furthermore, an unbiased functional genomic screen identified ACSS2 as an enzyme essential for the growth and survival of breast and prostate cancer cells cultured under hypoxic and low serum conditions. Indeed, high ACSS2 expression is frequently observed in invasive ductal carcinoma, triple-negative breast cancer, glioblastoma, ovarian cancer, pancreatic cancer, and lung cancer, and is often directly correlated with increased malignancy and decreased survival compared to tumors with low ACSS2 expression. These findings suggest that ACSS2 may be considered a targetable metabolic vulnerability in a wide range of tumor types.

[0191] Thus, in various embodiments, the present invention provides methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting cancer, comprising administering to a subject suffering from cancer a compound of the present invention under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit cancer. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the cancer is an early stage cancer. In some embodiments, the cancer is an advanced cancer. In some embodiments, the cancer is an invasive cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is a drug-resistant cancer. In some embodiments, the cancer is selected from the list provided in Table 1A below.

[0192] [Table 1A-1]

[0193] [Table 1A-2]

[0194] [Table 1A-3]

[0195] [Table 1A-4]

[0196] In some embodiments, the cancer is selected from hepatocellular carcinoma, melanoma (e.g., BRAF-mutated melanoma), glioblastoma, breast cancer, prostate cancer, liver cancer, brain cancer, Lewis lung carcinoma (LLC), colon cancer, pancreatic cancer, renal cell carcinoma, and breast carcinoma. In some embodiments, the cancer is melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancer, Hodgkin's lymphoma, Merkel cell skin cancer (Merkel cell carcinoma), esophageal cancer, gastroesophageal junction cancer, liver cancer (hepatocellular carcinoma), lung cancer (small cell lung cancer: SCLC), gastric cancer, upper urinary tract cancer (urothelial carcinoma), glioblastoma multiforme, multiple myeloma, anal cancer (squamous cell carcinoma), cervical cancer, endometrial cancer, nasopharyngeal carcinoma. In some embodiments, the cancer is selected from ovarian cancer, metastatic pancreatic cancer, solid tumor cancer, adrenocortical carcinoma, HTLV-1-associated adult T-cell leukemia / lymphoma, uterine leiomyosarcoma, acute myeloid leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, uveal melanoma, meningioma, pleural mesothelioma, myelodysplasia, soft tissue sarcoma, breast cancer, colon cancer, cutaneous T-cell lymphoma, and peripheral T-cell lymphoma. In some embodiments, the cancer is selected from glioblastoma, melanoma, lymphoma, breast cancer, ovarian cancer, glioma, gastrointestinal cancer, central nervous system cancer, hepatocellular carcinoma, blood cancer, colon cancer, or any combination thereof. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0197] Glucose-independent acetate metabolism has been shown to promote melanoma cell survival and tumor growth. Glucose-starved melanoma cells are highly dependent on acetate to maintain ATP levels, cell viability, and proliferation. Conversely, depletion of ACSS1 or ACSS2 suppresses melanoma tumor growth in mice. Collectively, this data indicates that acetate metabolism contributes to melanoma.

[0198] Thus, in various embodiments, the present invention provides methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting melanoma, comprising administering a compound of the present invention to a subject afflicted with melanoma under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit melanoma. In some embodiments, the melanoma is early stage melanoma. In some embodiments, the melanoma is advanced melanoma. In some embodiments, the melanoma is invasive melanoma. In some embodiments, the melanoma is metastatic melanoma. In some embodiments, the melanoma is drug-resistant melanoma. In some embodiments, the melanoma is BRAF-mutated melanoma. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0199] Acetyl-CoA synthase, which catalyzes the conversion of acetate to acetyl-CoA, is now implicated in the growth of hepatocellular carcinoma, glioblastoma, breast cancer, and prostate cancer.

[0200] Hepatocellular carcinoma (HCC) is a deadly form of liver cancer and is currently the second leading cause of cancer-related deaths worldwide (European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer, 2012). Despite many available treatment strategies, survival rates for HCC patients are low. Given the increasing prevalence of HCC, there is a strong need for more targeted and effective treatment strategies.

[0201] In various embodiments, the present invention relates to methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting hepatocellular carcinoma (HCC), comprising administering a compound of the present invention to a subject afflicted with hepatocellular carcinoma (HCC) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit hepatocellular carcinoma (HCC). In some embodiments, the hepatocellular carcinoma (HCC) is early-stage hepatocellular carcinoma (HCC). In some embodiments, the hepatocellular carcinoma (HCC) is advanced hepatocellular carcinoma (HCC). In some embodiments, the hepatocellular carcinoma (HCC) is invasive hepatocellular carcinoma (HCC). In some embodiments, the hepatocellular carcinoma (HCC) is metastatic hepatocellular carcinoma (HCC). In some embodiments, the hepatocellular carcinoma (HCC) is drug-resistant hepatocellular carcinoma (HCC). In some embodiments, the compounds of the present invention are ACSS2 inhibitors. In some embodiments, the compounds of the present invention are selective for ACSS2. In some embodiments, the compounds of the present invention are selective for ACSS1. In some embodiments, compounds of the invention are selective for both ACSS2 and ACSS1. In some embodiments, compounds of the invention are selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, compounds of the invention are any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0202] ACSS2-mediated acetate metabolism contributes to lipid synthesis and aggressive growth in glioblastoma and breast cancer.

[0203] Nuclear ACSS2 has been shown to activate HIF-2α through acetylation, thereby promoting the growth and metastasis of HIF-2α-driven cancers, such as certain renal cell carcinomas and glioblastomas (Chen, R. Et al. Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells, Plos One,12 (12) 1-31, 2017).

[0204] Thus, in various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting glioblastoma, comprising administering a compound of the present invention to a subject afflicted with glioblastoma under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit glioblastoma. In some embodiments, the glioblastoma is an early stage glioblastoma. In some embodiments, the glioblastoma is an advanced glioblastoma. In some embodiments, the glioblastoma is an invasive glioblastoma. In some embodiments, the glioblastoma is a metastatic glioblastoma. In some embodiments, the glioblastoma is a drug-resistant glioblastoma. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0205] Thus, in various embodiments, the present invention provides methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting renal cell carcinoma, comprising administering a compound of the present invention to a subject afflicted with renal cell carcinoma under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit renal cell carcinoma. In some embodiments, the renal cell carcinoma is early stage renal cell carcinoma. In some embodiments, the renal cell carcinoma is advanced renal cell carcinoma. In some embodiments, the renal cell carcinoma is invasive renal cell carcinoma. In some embodiments, the renal cell carcinoma is metastatic renal cell carcinoma. In some embodiments, the renal cell carcinoma is drug-resistant renal cell carcinoma. In some embodiments, the compounds of the present invention are ACSS2 inhibitors. In some embodiments, the compounds of the present invention are selective for ACSS2. In some embodiments, the compounds of the present invention are selective for ACSS1. In some embodiments, the compounds of the present invention are selective for both ACSS2 and ACSS1. In some embodiments, the compounds of the present invention are selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0206] In various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting breast cancer, comprising administering a compound of the present invention to a subject afflicted with breast cancer under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit breast cancer. In some embodiments, the breast cancer is early stage breast cancer. In some embodiments, the breast cancer is advanced breast cancer. In some embodiments, the breast cancer is invasive breast cancer. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is drug-resistant breast cancer. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0207] In various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting prostate cancer, comprising administering a compound of the present invention to a subject afflicted with prostate cancer under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit prostate cancer. In some embodiments, the prostate cancer is early stage prostate cancer. In some embodiments, the prostate cancer is advanced prostate cancer. In some embodiments, the prostate cancer is invasive prostate cancer. In some embodiments, the prostate cancer is metastatic prostate cancer. In some embodiments, the prostate cancer is drug-resistant prostate cancer. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0208] In various embodiments, the present invention relates to methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting liver cancer, comprising administering a compound of the present invention to a subject afflicted with liver cancer under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit liver cancer. In some embodiments, the liver cancer is early stage liver cancer. In some embodiments, the liver cancer is advanced liver cancer. In some embodiments, the liver cancer is invasive liver cancer. In some embodiments, the liver cancer is metastatic liver cancer. In some embodiments, the liver cancer is drug-resistant liver cancer. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0209] Nuclear ACSS2 has also been shown to promote brain tumorigenesis by promoting lysosomal biogenesis and autophagy and affecting histone H3 acetylation (Li, X et al.: Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy, Molecular Cell 66, 1-14, 2017).

[0210] In various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting brain tumors, comprising administering a compound of the present invention to a subject afflicted with a brain tumor under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit brain tumors. In some embodiments, the brain tumor is an early stage brain tumor. In some embodiments, the brain tumor is an aggressive brain tumor. In some embodiments, the brain tumor is an invasive brain tumor. In some embodiments, the brain tumor is a metastatic brain tumor. In some embodiments, the brain tumor is a drug-resistant brain tumor. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0211] In various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting pancreatic cancer, comprising administering a compound of the present invention to a subject afflicted with pancreatic cancer under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit pancreatic cancer. In some embodiments, the pancreatic cancer is early stage pancreatic cancer. In some embodiments, the pancreatic cancer is advanced pancreatic cancer. In some embodiments, the pancreatic cancer is invasive pancreatic cancer. In some embodiments, the pancreatic cancer is metastatic pancreatic cancer. In some embodiments, the pancreatic cancer is drug-resistant pancreatic cancer. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0212] In various embodiments, the present invention relates to methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting Lewis lung carcinoma (LLC), comprising administering a compound of the present invention to a subject afflicted with Lewis lung carcinoma (LLC) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit Lewis lung carcinoma (LLC). In some embodiments, the Lewis lung carcinoma (LLC) is early stage Lewis lung carcinoma (LLC). In some embodiments, the Lewis lung carcinoma (LLC) is advanced Lewis lung carcinoma (LLC). In some embodiments, the Lewis lung carcinoma (LLC) is invasive Lewis lung carcinoma (LLC). In some embodiments, the Lewis lung carcinoma (LLC) is metastatic Lewis lung carcinoma (LLC). In some embodiments, the Lewis lung carcinoma (LLC) is drug-resistant Lewis lung carcinoma (LLC). In some embodiments, the compounds of the present invention are ACSS2 inhibitors. In some embodiments, the compounds of the present invention are selective for ACSS2. In some embodiments, the compounds of the present invention are selective for ACSS1. In some embodiments, compounds of the invention are selective for both ACSS2 and ACSS1. In some embodiments, compounds of the invention are selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, compounds of the invention are any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0213] In various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting colon cancer, comprising administering a compound of the present invention to a subject afflicted with colon cancer under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit colon cancer. In some embodiments, the colon cancer is early stage colon cancer. In some embodiments, the colon cancer is advanced colon cancer. In some embodiments, the colon cancer is invasive colon cancer. In some embodiments, the colon cancer is metastatic colon cancer. In some embodiments, the colon cancer is drug-resistant colon cancer. In some embodiments, the compounds of the present invention are "programmed death receptor 1" (PD-1) modulators. In some embodiments, the compounds of the present invention are ACSS2 inhibitors. In some embodiments, the compounds of the present invention are selective for ACSS2. In some embodiments, the compounds of the present invention are selective for ACSS1. In some embodiments, the compounds of the present invention are selective for both ACSS2 and ACSS1. In some embodiments, compounds of the invention are selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, compounds of the invention are any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0214] In various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting breast carcinoma, comprising administering to a subject afflicted with breast carcinoma a compound of the present invention under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit breast carcinoma. In some embodiments, the breast carcinoma is an early stage breast carcinoma. In some embodiments, the breast carcinoma is an advanced breast carcinoma. In some embodiments, the breast carcinoma is an invasive breast carcinoma. In some embodiments, the breast carcinoma is a metastatic breast carcinoma. In some embodiments, the breast carcinoma is a drug-resistant breast carcinoma. In some embodiments, the compounds of the present invention are ACSS2 inhibitors. In some embodiments, the compounds of the present invention are selective for ACSS2. In some embodiments, the compounds of the present invention are selective for ACSS1. In some embodiments, the compounds of the present invention are selective for both ACSS2 and ACSS1. In some embodiments, the compounds of the present invention are selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0215] In various embodiments, the present invention relates to methods for suppressing, reducing, or inhibiting tumor growth, comprising administering to a subject suffering from a proliferative disease (e.g., cancer) a compound of the present invention under conditions effective to suppress, reduce, or inhibit tumor growth. In some embodiments, tumor growth is promoted by increased acetate uptake by cancer cells. In some embodiments, the increased acetate uptake is mediated by ACSS2. In some embodiments, the cancer cells are under hypoxic stress. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, tumor growth is suppressed by suppressing lipid synthesis (e.g., fatty acids) induced by ACSS2-mediated acetate metabolism to acetyl-CoA. In some embodiments, tumor growth is inhibited by inhibiting the regulation of histone acetylation and function induced by ACSS2-mediated acetate metabolism to acetyl-CoA. In some embodiments, lipid synthesis is inhibited under hypoxia (hypoxic stress). In some embodiments, the compound of the invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the invention.

[0216] In various embodiments, the present invention relates to methods for suppressing, reducing, or inhibiting lipid synthesis in a cell or modulating histone acetylation and function, the methods comprising contacting a cell with a compound of the present invention under conditions effective to suppress, reduce, or inhibit lipid synthesis in the cell or modulate histone acetylation and function. In some embodiments, the methods of the present invention are performed in vitro. In some embodiments, the methods of the present invention are performed in vivo. In some embodiments, lipid synthesis is induced by ACSS2-mediated acetate metabolism to acetyl-CoA. In some embodiments, modulation of histone acetylation and function is induced by ACSS2-mediated acetate metabolism to acetyl-CoA. In some embodiments, the cell is a cancer cell. In some embodiments, the lipid is a fatty acid. In some embodiments, acetate metabolism to acetyl-CoA is performed under hypoxia (i.e., hypoxic stress). In some embodiments, the compounds of the present invention are ACSS2 inhibitors. In some embodiments, the compounds of the present invention are selective for ACSS2. In some embodiments, the compounds of the present invention are selective for ACSS1. In some embodiments, the compounds of the present invention are selective for both ACSS2 and ACSS1. In some embodiments, compounds of the invention are selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, compounds of the invention are any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0217] In various embodiments, the present invention relates to methods for suppressing, reducing, or inhibiting fatty acid accumulation in the liver, comprising administering to a subject in need thereof a compound of the present invention under conditions effective to suppress, reduce, or inhibit fatty acid accumulation in the liver. In various embodiments, fatty acid accumulation is induced by ACSS2-mediated acetate metabolism to acetyl-CoA. In various embodiments, the subject is afflicted with fatty liver. In various embodiments, acetate metabolism to acetyl-CoA in the liver occurs under hypoxia (i.e., hypoxic stress). In some embodiments, compounds of the present invention are ACSS2 inhibitors. In some embodiments, compounds of the present invention are selective for ACSS2. In some embodiments, compounds of the present invention are selective for ACSS1. In some embodiments, compounds of the present invention are selective for both ACSS2 and ACSS1. In some embodiments, compounds of the present invention are selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, compounds of the present invention are any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0218] In various embodiments, the present invention relates to a method of binding an ACSS2 inhibitor compound to an ACSS2 enzyme, comprising contacting the ACSS2 enzyme with an ACSS2 inhibitor compound of the present invention in an amount effective to bind the ACSS2 inhibitor compound to the ACSS2 enzyme. In some embodiments, the method of the present invention is performed in vitro. In some embodiments, the method of the present invention is performed in vivo. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0219] In various embodiments, the present invention relates to methods for suppressing, reducing, or inhibiting acetyl-CoA synthesis from acetate in a cell, the methods comprising contacting the cell with a compound of the present invention under conditions effective to suppress, reduce, or inhibit acetyl-CoA synthesis from acetate in the cell. In some embodiments, the cell is a cancer cell. In some embodiments, the methods of the present invention are performed in vitro. In some embodiments, the methods of the present invention are performed in vivo. In some embodiments, acetyl-CoA synthesis is mediated by ACSS2. In some embodiments, the compounds of the present invention are ACSS2 inhibitors. In some embodiments, the compounds of the present invention are selective for ACSS2. In some embodiments, the compounds of the present invention are selective for ACSS1. In some embodiments, the compounds of the present invention are selective for both ACSS2 and ACSS1. In some embodiments, the compounds of the present invention are selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the cell is under hypoxic stress. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0220] In various embodiments, the present invention relates to methods for suppressing, reducing, or inhibiting acetate metabolism in cancer cells, the methods comprising contacting cancer cells with a compound of the present invention under conditions effective to suppress, reduce, or inhibit acetate metabolism in the cancer cells. In some embodiments, acetate metabolism is mediated by ACSS2. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the cancer cells are under hypoxic stress. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0221] In various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting metastatic cancer, comprising administering to a subject afflicted with metastatic cancer a compound of the present invention, or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, polymorph, crystal, or any combination thereof. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is Lewis lung carcinoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is breast carcinoma. In some embodiments, the cancer is pancreatic cancer.

[0222] In various embodiments, the present invention relates to a method for increasing survival in a subject afflicted with metastatic cancer, the method comprising administering to the subject afflicted with metastatic cancer a compound of the present invention, and / or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, polymorph, crystal, or any combination thereof. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is Lewis lung carcinoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is breast carcinoma. In some embodiments, the cancer is pancreatic cancer.

[0223] In various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting advanced cancer, comprising administering to a subject afflicted with advanced cancer a compound of the present invention, and / or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, polymorph, crystal, or any combination thereof. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is Lewis lung carcinoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is breast carcinoma. In some embodiments, the cancer is pancreatic cancer.

[0224] In various embodiments, the present invention relates to a method for increasing the survival rate of a subject afflicted with an advanced cancer, the method comprising administering to the subject a compound of the present invention, and / or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, polymorph, crystal, or any combination thereof, of a compound of the present invention. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is Lewis lung carcinoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is breast carcinoma. In some embodiments, the cancer is pancreatic cancer.

[0225] The compounds of the present invention are useful for treating, reducing the severity of, reducing the risk of developing, or inhibiting cancer, metastatic cancer, advanced cancer, drug-resistant cancer, and various forms of cancer. In preferred embodiments, the cancer is hepatocellular carcinoma, melanoma (e.g., BRAF-mutated melanoma), glioblastoma, breast cancer, prostate cancer, liver cancer, brain cancer, pancreatic cancer, Lewis lung carcinoma (LLC), colon cancer, renal cell carcinoma, and / or breast carcinoma, each of which represents a separate embodiment of the present invention. Based on their mechanism of action, it is believed that other forms of cancer can also be treated or prevented by administering the compounds or compositions of the present invention to a patient. Preferred compounds of the present invention are preferably selectively destructive of cancer cells, rather than normal cells, causing their elimination. Importantly, because cancer cells are easily destroyed at much lower concentrations of the compounds of the present invention, harm to normal cells is minimized.

[0226] In various embodiments, other types of cancer that may be treated with the ACSS2 inhibitors of the present invention include adrenocortical carcinoma, anal cancer, bladder cancer, brain tumor, brain stem tumor, breast cancer, glioma, cerebellar astrocytoma, cerebral astrocytoma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal, pineal tumor, hypothalamic glioma, carcinoid tumor, epithelial carcinoma, cervical cancer, colon cancer, central nervous system (CNS) cancer, endometrial cancer, esophageal cancer, Extrahepatic bile duct cancer, Ewing's tumor (Pnet), extracranial germ cell tumor, eye cancer, intraocular melanoma, gallbladder cancer, gastric cancer, germ cell tumor, extragonadal tumor, gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, pancreatic islet cell carcinoma, laryngeal cancer, leukemia, acute lymphoblastic leukemia, oral cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lymphoma, AIDS-related lymphoma, central nervous system (primary), lymphoma, cutaneous T-cell lymphoma, hodgkin's lymphoma Kinesiology, non-Hodgkin's disease, malignant mesothelioma, melanoma, Merkel cell carcinoma, metastatic squamous cell carcinoma, multiple myeloma, plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myeloproliferative disorders, nasopharyngeal carcinoma, neuroblastoma, oropharyngeal carcinoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, exocrine carcinoma, pancreatic cancer, pancreatic islet cell carcinoma, paranasal and nasal sinus cancer, parathyroid cancer, penile cancer, pheochromocytoma, ptosis The cancer may be a corpus cancer, plasma cell neoplasm, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cancer, renal cell carcinoma, salivary gland cancer, Sézary syndrome, skin cancer, cutaneous T-cell lymphoma, skin cancer, Kaposi's sarcoma, melanoma, small intestine cancer, soft tissue sarcoma, testicular tumor, thymoma, malignant tumor, thyroid cancer, urethral cancer, uterine cancer, sarcoma, rare childhood cancer, vaginal cancer, vulvar cancer, Wilms' tumor, hepatocellular carcinoma, blood cancer, or any combination thereof. In some embodiments, the cancer is an invasive cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is an advanced cancer. In some embodiments, the cancer is a drug-resistant cancer.

[0227] In various embodiments, "metastatic cancer" refers to cancer that has spread (metastasized) from its original site to another area of ​​the body. Virtually all cancers have the potential to metastasize. Whether metastasis occurs depends on a complex interplay of various tumor cellular factors, including the type of cancer, the maturity (degree of differentiation) of the tumor cells, the location and duration the cancer has been present, and other factors that are not fully understood. Metastasis spreads in three ways: local extension from the tumor to surrounding tissues, metastasis to distant sites via the bloodstream, or metastasis via the lymphatic system to adjacent or distant lymph nodes. There are typical pathways for metastasis for each type of cancer. Tumors are referred to by their primary site (e.g., breast cancer that has spread to the brain is referred to as brain metastatic breast cancer).

[0228] In various embodiments, "drug-resistant cancer" refers to cancer cells that have acquired resistance to chemotherapy. Cancer cells can acquire resistance to chemotherapy through various mechanisms, including mutation or overexpression of drug targets, drug inactivation, or drug elimination from the cell. Tumors that recur after an initial response to chemotherapy may exhibit resistance to multiple drugs (multidrug resistance). The traditional view of drug resistance is that one or more cells within a tumor population acquire genetic changes that confer drug resistance. Therefore, drug resistance can occur due to, among other reasons: (a) a portion of cells that are not killed by chemotherapy mutate (change) and acquire drug resistance. As they proliferate, there are more chemotherapy-resistant cells than chemotherapy-sensitive cells; (b) gene amplification. Cancer cells produce hundreds of copies of a particular gene. This gene causes the overproduction of a protein that renders anticancer drugs ineffective; and (c) cancer cells use a molecule called p-glycoprotein to expel drugs from the cell as fast as the drugs enter the cell. (d) Cancer cells stop taking up drugs because proteins that transport drugs across the cell wall stop functioning. (e) Cancer cells learn how to repair DNA breaks caused by certain anticancer drugs. (f) Cancer cells develop mechanisms to inactivate drugs. One of the major factors behind multidrug resistance is overexpression of P-glycoprotein (P-gp). This protein is a clinically important transport protein that belongs to the ATP-binding cassette family of plasma membrane transporters. Substrates, including anticancer drugs, can be exported from tumor cells via an ATP-dependent mechanism. (g) Cells and tumors with activating RAS mutations are relatively resistant to most anticancer drugs. Therefore, resistance to anticancer drugs used in chemotherapy is a major cause of treatment failure in malignant diseases and leads to tumor resistance. Drug resistance is a major cause of chemotherapy failure in cancer.

[0229] In various embodiments, "resistant cancer" refers to a drug-resistant cancer as described above. In some embodiments, "resistant cancer" refers to cancer cells that have acquired resistance to treatments such as chemotherapy, radiation therapy, or biological therapy.

[0230] In various embodiments, the present invention relates to treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting cancer in subjects who have previously undergone chemotherapy, radiation therapy, or biological therapy.

[0231] In various embodiments, "chemotherapy" refers to the treatment of cancer, including the use of drugs that directly kill cancer cells. Such drugs are referred to as "anti-cancer" or "anti-tumor" agents. Today, chemotherapy encompasses over 100 drugs used to treat cancer. Chemotherapy is used to cure certain cancers, to control tumor growth when a cure is not possible, to shrink tumors before surgery or radiation therapy, to relieve symptoms (such as pain), or to destroy tiny cancer cells that may be present after surgical removal of a known tumor (called adjuvant therapy). Adjuvant therapy is also used to prevent cancer from recurring.

[0232] In various embodiments, "radiation therapy" (also referred to herein as "radiotherapy") refers to the treatment of cancer with high-energy x-rays or similar radiation (e.g., electrons). Many cancer patients receive radiation therapy as part of their treatment. Radiation therapy can be external, where x-rays are delivered from outside the body, or internal, where x-rays are delivered from inside the body. Radiation therapy works by destroying cancer cells in the treatment area. Normal cells can also be damaged by radiation therapy, but normal cells are usually able to repair themselves. Radiation therapy can cure some cancers and can also reduce the chance of cancer recurrence after surgery. Radiation therapy can also be used to relieve cancer symptoms.

[0233] In various embodiments, "biological therapy" refers to the treatment of cancer with substances that occur naturally in the body and destroy cancer cells. There are several types of biologic therapy, including treatment with monoclonal antibodies, cancer growth inhibitors, or vaccines, or gene therapy. Biological therapy is also called immunotherapy.

[0234] When the compounds or pharmaceutical compositions of the present invention are administered to treat, suppress, reduce the severity of, reduce the risk of, or inhibit a cancerous condition, the pharmaceutical composition may also include or be administered in combination with other therapeutic agents or treatment regimens now known or hereafter developed for the treatment of various types of cancer, including, but not limited to, radiation therapy, immunotherapy, chemotherapy, surgical intervention, and any combination thereof.

[0235] This metabolic plasticity, i.e., the ability to survive by utilizing various nutrient sources, confers resistance to many current cancer metabolic drugs as monotherapy. Interestingly, ACSS2 is highly expressed in many cancer tissues, and its upregulation due to hypoxia and low nutrient availability indicates that it is a key enzyme for coping with typical stresses within the tumor microenvironment and, therefore, a potential Achilles' heel. Furthermore, high-stress regions of tumors have been shown to select for apoptosis resistance, promoting aggressive behavior, treatment resistance, and recurrence. Thus, combining ACSS2 inhibitors with therapies (e.g., radiation therapy) that specifically target oxygen-rich regions of tumors is considered an effective regimen.

[0236] Thus, in various embodiments, the compounds of the present invention are administered in combination with anti-cancer therapies. Examples of anti-cancer therapies include, but are not limited to, chemotherapy, immunotherapy, radiation therapy, biological therapy, surgical intervention, and any combination thereof. In some embodiments, the compounds of the present invention are administered in combination with a therapy that specifically targets oxygen-rich regions of tumors. In some embodiments, the compounds of the present invention are administered in combination with radiation therapy.

[0237] In various embodiments, the compounds of the present invention are administered in combination with compounds described herein, alone or in combination with other agents, and in combination with anti-cancer agents.

[0238] In various embodiments, the cancer treatment compositions of the present invention may be used in combination with or in admixture with existing chemotherapeutic agents. Examples of such chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant-derived alkaloids, topoisomerase inhibitors, hormone therapy agents, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapeutic agents, and other anticancer agents. Furthermore, the cancer treatment compositions of the present invention may be used in combination with or in admixture with cancer treatment adjuncts, such as leukopenia (neutrophil) agents, thrombocytopenia agents, antiemetic agents, and cancer pain agents, to improve patients' quality of life.

[0239] In various embodiments, the present invention relates to a method of destroying cancer cells, the method comprising the steps of providing a compound of the present invention and contacting the compound of the present invention with cancer cells under conditions effective to destroy the cancer cells. According to various embodiments of destroying cancer cells, the cells can be destroyed in vivo or ex vivo (i.e., in culture).

[0240] In some embodiments, the cancer is selected from the group consisting of melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancer, Hodgkin's lymphoma, glioblastoma, renal cell carcinoma, Merkel cell skin cancer (Merkel cell carcinoma), and any combination thereof. In some embodiments, the cancer is melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancer, Hodgkin's lymphoma, glioblastoma, Merkel cell skin cancer (Merkel cell carcinoma), esophageal cancer, gastroesophageal junction cancer, liver cancer (hepatocellular carcinoma), lung cancer (small cell lung cancer: SCLC), gastric cancer, upper urinary tract cancer (urothelial carcinoma), glioblastoma multiforme, multiple myeloma, anal cancer (squamous cell carcinoma), cervical cancer, endometrial cancer, nasopharyngeal cancer, ovarian cancer, metastatic pancreatic cancer, The cancer is selected from the group consisting of cancer, solid tumor cancer, adrenocortical carcinoma, HTLV-1 associated adult T-cell leukemia / lymphoma, uterine leiomyosarcoma, acute myeloid leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, uveal melanoma, meningioma, pleural mesothelioma, myelodysplasia, soft tissue sarcoma, breast cancer, colon cancer, pancreatic cancer, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, or any combination thereof.

[0241] A further aspect of the invention relates to a method of treating or preventing a cancerous condition, comprising the steps of providing a compound of the invention and administering an effective amount of the compound of the invention to a patient under conditions effective to treat or prevent the cancerous condition.

[0242] In one embodiment, the patient being treated is characterized by the presence of a pre-cancerous condition, and administration of the compounds of the invention is effective to prevent the progression of the pre-cancerous condition to a cancerous condition, which can be achieved by destroying the pre-cancerous cells before or concomitantly with their further progression to a cancerous condition.

[0243] In another embodiment, the patient being treated is characterized by the presence of a cancerous condition, and administration of the compounds of the invention is effective to cause regression of the cancerous condition or inhibit the growth of the cancerous condition, i.e., to stop its growth completely or to reduce its rate of growth. This can be preferably accomplished by destroying cancer cells regardless of their location within the patient's body, i.e., whether the cancer cells are located at the primary tumor site or whether they have metastasized to form secondary tumors within the patient's body.

[0244] Recently, the ACSS2 gene has been implicated in human alcoholism and ethanol consumption. Accordingly, in various embodiments, the present invention provides methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting human alcoholism, comprising administering a compound of the present invention to a subject suffering from alcoholism under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit alcoholism. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0245] Nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) share similar pathogenesis and histopathology but differ in etiology and epidemiology. NASH and ASH are advanced stages of nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is characterized by excessive hepatic fat accumulation (steatosis), the absence of other clear causes of chronic liver disease (e.g., viral, autoimmune, or genetic), and an alcohol intake of 20-30 g / day or less. In contrast, AFLD is defined by the presence of steatosis and an alcohol intake of more than 20-30 g / day.

[0246] The synthesis of metabolically available acetyl-CoA from acetate is important for the increased acetylation of proinflammatory gene histones and the resulting enhanced inflammatory response in ethanol-exposed macrophages, a mechanism that represents a potential therapeutic target for acute alcoholic hepatitis.

[0247] Thus, in various embodiments, the present invention relates to methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholic steatohepatitis (ASH), comprising administering a compound of the present invention to a subject afflicted with alcoholic steatohepatitis (ASH) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit alcoholic steatohepatitis (ASH). In some embodiments, the compounds of the present invention are ACSS2 inhibitors. In some embodiments, the compounds of the present invention are selective for ACSS2. In some embodiments, the compounds of the present invention are selective for ACSS1. In some embodiments, the compounds of the present invention are selective for both ACSS2 and ACSS1. In some embodiments, the compounds of the present invention are selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compounds of the present invention are any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0248]

[0013] Accordingly, in various embodiments, the present invention relates to methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting non-alcoholic fatty liver disease (NAFLD), comprising administering a compound of the present invention to a subject suffering from non-alcoholic fatty liver disease (NAFLD) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit non-alcoholic fatty liver disease (NAFLD). In some embodiments, the compounds of the present invention are ACSS2 inhibitors. In some embodiments, the compounds of the present invention are selective for ACSS2. In some embodiments, the compounds of the present invention are selective for ACSS1. In some embodiments, the compounds of the present invention are selective for both ACSS2 and ACSS1. In some embodiments, the compounds of the present invention are selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compounds of the present invention are any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0249] In various embodiments, the present invention relates to methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting non-alcoholic steatohepatitis (NASH), comprising administering a compound of the present invention to a subject afflicted with non-alcoholic steatohepatitis (NASH) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit non-alcoholic steatohepatitis (NASH). In some embodiments, the compounds of the present invention are ACSS2 inhibitors. In some embodiments, the compounds of the present invention are selective for ACSS2. In some embodiments, the compounds of the present invention are selective for ACSS1. In some embodiments, the compounds of the present invention are selective for both ACSS2 and ACSS1. In some embodiments, the compounds of the present invention are selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compounds of the present invention are any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0250] ACSS2-mediated acetyl-CoA synthesis from acetate has also been shown to be required for human cytomegalovirus infection. Glucose carbons are converted to acetate and used by acetyl-CoA synthase short-chain family member 2 (ACSS2) to generate cytoplasmic acetyl-CoA, which is important for HCMV-induced lipogenesis and viral growth. Therefore, ACSS2 inhibitors are expected to be useful as antiviral therapies and in the treatment of HCMV infection.

[0251] Thus, in various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting a viral infection, comprising administering a compound of the present invention to a subject suffering from a viral infection under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the viral infection. In some embodiments, the viral infection is HCMV infection. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0252] ACSS2-deficient mice have been shown to exhibit reduced body weight and fatty liver in a diet-induced obesity model (Z. Huang et al., "ACSS2 promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism," PNAS 115, (40), E9499-E9506, 2018).

[0253] Thus, in various embodiments, the present invention provides methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting a metabolic disorder, comprising administering a compound of the present invention to a subject suffering from a metabolic disorder under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the metabolic disorder. In some embodiments, the metabolic disorder is obesity. In some embodiments, the metabolic disorder is weight gain. In some embodiments, the metabolic disorder is fatty liver. In some embodiments, the metabolic disorder is fatty liver disease. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0254] In various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting obesity, comprising administering a compound of the present invention to a subject suffering from obesity under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit obesity. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0255] In various embodiments, the present invention relates to methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting weight gain, comprising administering to a subject suffering from weight gain a compound of the present invention under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit weight gain. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0256] In various embodiments, the present invention relates to methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting liver fat, comprising administering a compound of the present invention to a subject suffering from liver fat under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit liver fat. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0257] In various embodiments, the present invention relates to methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting fatty liver disease, comprising administering a compound of the present invention to a subject suffering from fatty liver disease under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit fatty liver disease. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0258] ACSS2 has also been shown to enter the nucleus under certain conditions (e.g., hypoxia, high fat), increasing the availability of acetyl-CoA and crotonyl-CoA, thereby affecting histone acetylation and crotonylation, thereby regulating gene expression. For example, reduction of ACSS2 has been shown to reduce the levels of nuclear acetyl-CoA and histone acetylation in neurons, which affects the expression of many neuronal genes. In the hippocampus, such reduction of ACSS2 affects memory and neuroplasticity (Mews P, et al., Nature, Vol. 546, 381, 2017). Such epigenetic modifications have been implicated in neuropsychiatric disorders such as anxiety, PTSD, and depression (Graff, J et al. Histone acetylation: molecular mnemonics on chromatin. Nat. Rev. Neurosci. 14, 97-111 (2013)). Therefore, ACSS2 inhibitors may be useful in treating such conditions.

[0259] Thus, in various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting a neuropsychiatric disorder, comprising administering a compound of the present invention to a subject suffering from a neuropsychiatric disorder under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is selected from anxiety, depression, schizophrenia, autism, and / or post-traumatic stress disorder, each representing a separate embodiment of the present invention. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1, each compound representing a separate embodiment of the present invention.

[0260] In various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting anxiety, comprising administering a compound of the present invention to a subject suffering from anxiety under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit anxiety. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0261] In various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting a depressive disorder, comprising administering to a subject suffering from depression a compound of the present invention under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit depression. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0262] In various embodiments, the present invention relates to methods of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting post-traumatic stress disorder, comprising administering a compound of the present invention to a subject suffering from post-traumatic stress disorder under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit post-traumatic stress disorder. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0263] In some embodiments, the present invention relates to a method of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting an inflammatory disease, comprising administering a compound of the present invention to a subject suffering from an inflammatory disease under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the inflammatory disease. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0264] In some embodiments, the present invention relates to methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting an autoimmune disease, comprising administering a compound of the present invention to a subject suffering from an autoimmune disease under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the autoimmune disease. In some embodiments, the compound of the present invention is an ACSS2 inhibitor. In some embodiments, the compound of the present invention is selective for ACSS2. In some embodiments, the compound of the present invention is selective for ACSS1. In some embodiments, the compound of the present invention is selective for both ACSS2 and ACSS1. In some embodiments, the compound of the present invention is selective for ACSS2, ACSS1, AACS, ACSF2, and ACSL5. In some embodiments, the compound of the present invention is any one of the compounds listed in Table 1. Each compound represents a separate embodiment of the present invention.

[0265] As used herein, subject or patient refers to any mammalian patient or subject, including, but not limited to, humans and other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice, and other rodents. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, further, the methods of the present invention described herein may be useful for treating either males or females.

[0266] When administering the compounds of the present invention, the compounds of the present invention may be administered systemically or directly to the specific site where cancer cells or precancerous cells are present.Therefore, administration can be achieved by any method that is effective for delivering the compounds or pharmaceutical compositions of the present invention to cancer cells or precancerous cells.Exemplary administration modes of the compounds or compositions of the present invention include, but are not limited to, oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, intracavity, intravesical, intraocular, intraarterial, intralesional, or administration or application to mucous membranes such as the nose, throat, and bronchi.

[0267] The following examples are presented in order to more fully illustrate the preferred embodiments of the invention, but they should in no way be construed as limiting the broad scope of the invention.

[0268] Example

[0269] Example 1 Synthetic Details of the Compounds of the Invention

[0270] General Scheme

[0271] [ka]

[0272] General procedure for 3-oxo-N-phenylbutanamide (2)

[0273] To a solution of aniline 1 (1.0 equiv.) and triethylamine (1.0 equiv.) in dichloromethane was added 4-methyleneoxetan-2-one (1.1 equiv.). The solution was stirred at room temperature for 1-14 h. A simple aqueous workup afforded the product in good purity and yield. In cases where the reaction was unsuccessful, purification by reverse-phase chromatography was necessary.

[0274] General procedure for (E)-2-(hydroxyimino)-3-oxo-N-phenylbutanamide (3)

[0275] To a solution of 3-oxo-N-phenylbutanamide in acetic acid at 0 °C was added sodium nitrite (1.1 equiv.). The reaction was stirred at room temperature for 0.5 h and then concentrated in vacuo. This reaction was generally successful. The crude product was used directly in the next step without workup or purification.

[0276] General procedure for 5-methyl-2-phenyl-4-(phenylcarbamoyl)-1H-imidazole-3-oxide (5)

[0277] A mixture of (E)-2-(hydroxyimino)-3-oxo-N-phenylbutanamide (1.0 equivalent), aromatic aldehyde (1.0 equivalent), and ammonium acetate (4 equivalents) in ethanol was heated at 50° C. for 1 hour. The solution was then concentrated, and the crude product was purified by preparative HPLC to give the desired product.

[0278] Synthesis of Compound 101

[0279] Step 1: Synthesis of 4-((3-(1,1-difluoropropyl)phenyl)carbamoyl)-2-(4-methoxyphenyl)-5-methyl-1H-imidazole-3-oxide (101)

[0280] [ka]

[0281] Compound 101 was obtained from 103-G and 4-methoxybenzaldehyde by the general procedure.

[0282] LCMS: (ESI) m / z: 402.1 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ:13.77(s,1H),13.21(s,1H),8.39(d,J=8.4Hz,2H),7.93(s,1H),7.69(d,J=8.0Hz,1H),7.47(t,J= 7.6Hz,1H),7.22(d,J=7.6Hz,1H),7.13(d,J=8.8Hz,2H),3.84(s,3H),2.60(s,3H),2.27-2.17(m,2H),0.93(t,J=7.2Hz,3H).

[0283] A solution of 101-B (5.95 mmol, 1.0 equiv.) in N,N-dimethylformamide (18 mL) was added dropwise at 25 °C. The reaction mixture was then warmed to 100 °C and stirred under a nitrogen atmosphere for 1 h. After cooling to 25 °C, the reaction mixture was poured into ice water (20 mL), basified to approximately pH 10 with saturated sodium bicarbonate, and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 0.35 g (32% yield) of 101-B as a yellow solid.

[0284] LCMS: (ESI) m / z: 186.8 [M+H] + . 1 HNMR(400MHz,CDCl3-d)δ:8.52(s,1H),4.02(s,3H),2.86(s,3H).

[0285] Synthesis of Compound 100

[0286] Step 1: Synthesis of 4-methoxy-3-(3-methylpyridin-2-yl)benzaldehyde (100-A)

[0287] [ka]

[0288] To a solution of 2-bromo-3-methyl-pyridine (500 mg, 2.91 mmol, 1.0 equiv.), (5-formyl-2-methoxy-phenyl)boronic acid (628 mg, 3.49 mmol, 1.2 equiv.), and potassium carbonate (803 mg, 5.81 mmol, 2.0 equiv.) in N,N-dimethylformamide (20 mL) was added tetrakis(triphenylphosphine)palladium (168 mg, 145 μmol, 0.050 equiv.). The mixture was stirred at 100 °C under a nitrogen atmosphere for 12 h. The reaction mixture was then filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give 560 mg (85% yield) of 100-A as a colorless oil.

[0289] 1 HNMR(400MHz,CDCl3-d)δ:9.94(s,1H),8.53(dd,J=1.2,4.8Hz,1H),7.97(dd,J=2.0,8.4Hz,1H),7.83(d,J=2.4H z,1H),7.59(dd,J=0.8,8.0Hz,1H),7.24(dd,J=4.8,7.6Hz,1H),7.11(d,J=8.4Hz,1H),3.88(s,3H),2.16(s,3H).

[0290] Step 2: Synthesis of 4-((3-(1,1-difluoropropyl)phenyl)carbamoyl)-2-(4-methoxy-3-(3-methylpyridin-2-yl)phenyl)-5-methyl-1H-imidazole 3-oxide (100)

[0291] [ka]

[0292] Compound 100 was obtained from 100-A and 103-G by the general procedure.

[0293] LCMS: (ESI) m / z: 493.2 [M+H] + . 1HNMR(400MHz,MeOD-d4)δ:8.47(dd,J=2.4,8.8Hz,1H),8.42(d,J=4.0Hz,1H),8. 12(d,J=2.4Hz,1H),7.92(s,1H),7.82-7.75(m,1H),7.70(d,J=8.0Hz,1H),7.45 (t,J=8.0Hz,1H),7.38(dd,J=5.2,7.6Hz,1H),7.35(d,J=9.2Hz,1H),7.25(d,J= 7.6Hz,1H),3.89(s,3H),2.67(s,3H),2.24-2.16(m,5H),0.99(t,J=7.6Hz,3H).

[0294] Synthesis of Compound 103

[0295] Step 1: Synthesis of 3-bromo-4-(difluoromethoxy)benzaldehyde (103-A)

[0296] [ka]

[0297] To a solution of 3-bromo-4-hydroxybenzaldehyde (500 mg, 2.49 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) was added sodium carbonate (527 mg, 4.97 mmol, 2.0 equiv) and sodium 2-chloro-2,2-difluoroacetate (758 mg, 4.97 mmol, 2.0 equiv). The reaction was stirred at 100 °C for 2 h. The mixture was then diluted with water (30 mL) and the pH was adjusted to 7 with 1 M hydrochloric acid. It was then extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 450 mg (crude) of 103-A as a colorless oil.

[0298] 1 HNMR(400Hz,DMSO-d6):9.52(s,1H),8.25(s,1H),7.98(t,J=1.6Hz,1H),7.54(d,J=8.4Hz,1H),7.52(t,J=32.4Hz,1H).

[0299] Step 2: Synthesis of 6-(difluoromethoxy)-2',6'-dimethyl-[1,1'-biphenyl]-3-carbaldehyde (103-B)

[0300] [ka]

[0301] A solution of 103-A (110 mg, 438 μmol, 1.0 equiv.), (2,6-dimethylphenyl)boronic acid (98.6 mg, 657 μmol, 1.5 equiv.), tetrakis[triphenylphosphine]palladium (50.6 mg, 43.8 μmol, 0.10 equiv.), and potassium phosphate (279 mg, 1.31 mmol, 3.0 equiv.) in 1,2-dimethoxyethane (2.5 mL) and water (0.5 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 90.0 mg (74% yield) of 103-B as a pale yellow oil.

[0302] 1 HNMR(400MHz,CDCl3-d)δ:10.02(s,1H),7.94(dd,J=8.4,2.0Hz,1H),7.72(d,J=2.0Hz,1H),7.45 (d,J=8.4Hz,1H),7.21-7.25(m,1H),7.14(d,J=8.0Hz,2H),6.44(t,J=72.8Hz,1H),2.02(s,6H).

[0303] Step 3: Synthesis of 1-bromo-3-(1,1-difluoropropyl)benzene (103-C)

[0304] [ka]

[0305] A solution of 1-(3-bromophenyl)propan-1-one (25.0 g, 117 mmol, 1.0 equiv) and diethylaminosulfur trifluoride (94.6 g, 587 mmol, 78 mL, 5.0 equiv) in chloroform (400 mL) was stirred at 70 °C for 12 h under a nitrogen atmosphere. The reaction mixture was quenched with ice water (1 L), and the aqueous layer was extracted with dichloromethane (300 mL × 3). The combined organic layers were washed with brine (1.0 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to afford 21.0 g (76% yield) of 103-C as a pale yellow oil.

[0306] 1 HNMR(400MHz,CDCl3-d)δ:7.63(s,1H),7.57(dd,J=8.0,0.4Hz,1H),7.41(dd,J= 8.0,0.8Hz,1H),7.31(t,J=7.6Hz,1H),2.19-2.09(m,2H),1.00(t,J=7.6Hz,3H).

[0307] Step 4: Synthesis of tert-butyl(3-(1,1-difluoropropyl)phenyl)carbamate (103-D)

[0308] [ka]

[0309] A suspension of 103-C (21.0 g, 89.3 mmol, 1.0 equiv.), tert-butyl carbamate (15.7 g, 134 mmol, 1.5 equiv.), palladium acetate (1.00 g, 4.47 mmol, 0.050 equiv.), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane (8.52 g, 17.9 mmol, 0.20 equiv.), and cesium carbonate (58.2 g, 179 mmol, 2.0 equiv.) in dioxane (400 mL) was degassed and purged with nitrogen several times. The reaction mixture was stirred at 90 °C under a nitrogen atmosphere for 12 h. The reaction mixture was filtered, and the filtrate was diluted with water (300 mL). The aqueous layer was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 24.0 g (75% yield) of 103-D as a yellow oil.

[0310] LCMS: (ESI) m / z: 172.1 [M-Boc+H] + .

[0311] Step 5: Synthesis of 3-(1,1-difluoropropyl)aniline (103-E)

[0312] [ka]

[0313] A solution of 103-D (24.0 g, 75.2 mmol, 1.0 equiv) in hydrogen chloride in ethyl acetate (4 M, 200 mL) was stirred at 25 °C for 30 min. The pH of the mixture was adjusted to 8-9 with saturated sodium hydroxide (2.0 M). The resulting mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 14.0 g (crude) of 103-E as a yellow oil.

[0314] 1HNMR(400MHz,CDCl3-d)δ:7.20(t,J=8.0Hz,1H),6.86(d,J=7.6Hz,1H),6.80(s,1H),6.74(d,J=8.0 Hz,1H),3.49(s,2H),2.17-2.07(m,2H),0.99(t,J=7.6Hz,3H).19FNMR(376MHz,CDCl3-d)δ:-97.66.

[0315] Step 6: Synthesis of N-(3-(1,1-difluoropropyl)phenyl)-3-oxobutanamide (103-F)

[0316] [ka]

[0317] Compound 103-F was obtained from 103-E by the general procedure.

[0318] LCMS: (ESI) m / z: 256.4 [M+H] + .

[0319] Step 7: Synthesis of (E)-N-(3-(1,1-difluoropropyl)phenyl)-2-(hydroxyimino)-3-oxobutanamide (103-G)

[0320] [ka]

[0321] Compound 103-G was obtained from 103-F by the general procedure.

[0322] LCMS: (ESI) m / z: 285.2 [M+H] + .

[0323] Step 8: Synthesis of 2-(6-(difluoromethoxy)-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-4-((3-(1,1-difluoropropyl)phenyl)carbamoyl)-5-methyl-1H-imidazole 3-oxide (103)

[0324] [ka]

[0325] Compound 103 was obtained from 103-G and 103-B by the general procedure.

[0326] LCMS: (ESI) m / z: 542.2 [M+H] + . 1 HNMR(400MHz,MeOD-d4)δ:8.40(dd,J=8.8,2.0Hz,1H),8.10(d,J=2.0Hz,1H), 7.92(s,1H),7.69(d,J=9.2Hz,1H),7.51(d,J=8.8Hz,1H),7.44(t,J=7.6Hz,1 H),7.24(d,J=8.0Hz,1H),7.19-7.22(m,1H),7.13-7.14(m,2H),6.83(t,J=73 .2Hz,1H),2.67(s,3H),2.12-2.25(m,2H),2.05(s,6H),0.98(t,J=7.2Hz,3H).

[0327] Synthesis of Compound 102

[0328] Step 1: Synthesis of 6-methoxy-2',6'-dimethyl-[1,1'-biphenyl]-3-carbaldehyde (102-A)

[0329] [ka]

[0330] A mixture of 3-bromo-4-methoxybenzaldehyde (500 mg, 2.33 mmol, 1.0 equiv.), (2,6-dimethylphenyl)boronic acid (523 mg, 3.49 mmol, 1.5 equiv.), tetrakis[triphenylphosphine]palladium (672 mg, 581 μmol, 0.25 equiv.), and potassium phosphate (987 mg, 4.65 mmol, 2.0 equiv.) in 1,2-dimethoxyethane (10 mL) and water (2 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=30 / 1) to give 160 mg (yield 29%) of 102-A as a colorless oil.

[0331] 1 HNMR(400MHz,CDCl3-d)δ:9.93(s,1H),7.92(dd,J=1.6,8.8Hz,1H),7.61(d,J= 1.6Hz,1H),7.20(d,J=7.6Hz,1H),7.15-7.10(m,3H),3.85(s,3H),2.00(s,6H).

[0332] Step 2: Synthesis of 4-((3-(1,1-difluoropropyl)phenyl)carbamoyl)-2-(6-methoxy-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-5-methyl-1H-imidazole 3-oxide (102)

[0333] [ka]

[0334] Compound 102 was obtained from 103-G and 102-A by the general procedure.

[0335] LCMS: (ESI) m / z: 506.2 [M+H] + .1 HNMR(400MHz,MeOD-d4)δ:8.38(dd,J=2.4,8.8Hz,1H),7.94-7.89(m,2H),7.69(d,J=8.4Hz,1H),7.45(t,J=8.0Hz,1H),7.31(d,J=8.8Hz,1H), 7.25(d,J=7.6Hz,1H),7.17-7.12(m,1H),7.12-7.08(m,2H),3.84(s,3 H),2.66(s,3H),2.24-2.14(m,2H),2.02(s,6H),0.98(t,J=7.6Hz,3H).

[0336] Synthesis of Compound 110

[0337] Step 1: Synthesis of 3-(3-methylpyrazin-2-yl)benzaldehyde (110-A)

[0338] [ka]

[0339] A mixture of 2-chloro-3-methyl-pyrazine (200 mg, 1.56 mmol, 1.0 equiv.), (3-formylphenyl)boronic acid (233 mg, 1.56 mmol, 1.0 equiv.), tetrakis[triphenylphosphine]palladium (179 mg, 155 μmol, 0.10 equiv.), and potassium phosphate (660 mg, 3.02 mmol, 2.0 equiv.) in 1,2-dimethoxyethane (10 mL) and water (2 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5 / 1) to give 230 mg (72% yield) of 110-A as a colorless oil.

[0340] LCMS: (ESI) m / z: 199.1 [M+H] +.

[0341] Step 2: Synthesis of 4-((3-(1,1-difluoropropyl)phenyl)carbamoyl)-5-methyl-2-(3-(3-methylpyrazin-2-yl)phenyl)-1H-imidazole 3-oxide (110)

[0342] [ka]

[0343] Compound 110 was obtained from 103-G and 110-A by the general procedure.

[0344] LCMS: (ESI) m / z: 464.2 [M+H] + . 1 HNMR(400Hz,MeOD-d4)δ:8.60-8.53(m,3H),8.35-8.33(m,1H),7.92(s,1H),7.80-7.70(m,3H), 7.47-7.43(m,1H),7.24(d,J=7.6Hz,1H),2.68(s,6H),2.24-2.14(m,2H),0.98(t,J=7.2Hz,3H).

[0345] Synthesis of Compound 111

[0346] Step 1: Synthesis of 3-bromo-4-(difluoromethoxy)benzaldehyde (111-A)

[0347] [ka]

[0348] Compound 111-A was obtained from 6-bromopicolinaldehyde and (2,6-dimethylphenyl)boronic acid by the same procedure as for 102-A.

[0349] Step 2: Synthesis of 4-((3-(1,1-difluoropropyl)phenyl)carbamoyl)-2-(6-(2,6-dimethylphenyl)pyridin-2-yl)-5-methyl-1H-imidazole 3-oxide (111)

[0350] [ka]

[0351] Compound 111 was obtained from 111-A and 103-G by the general procedure.

[0352] LCMS: (ESI) m / z: 477.2 [M+H] + . 1 HNMR(400MHz,MeOD-d4)δ:9.01(d,J=8.0Hz,1H),8.10(t,J=8.0Hz,1H),7.93(s,1H),7.74(d,J=7.6Hz,1H),7.47(t,J=8.0Hz,1H),7.41(dd,J=7.6 ,0.8Hz,1H),7.27(d,J=8.0Hz,1H),7.20-7.23(m,1H),7.13(d,J=7.6Hz, 2H),2.64(s,3H),2.16-2.25(m,2H),2.06(s,6H),1.00(t,J=7.2Hz,3H).

[0353] Synthesis of Compound 106

[0354] Step 1: Synthesis of 3-(2,6-dimethylphenyl)-5-methyl-benzaldehyde (106-A)

[0355] [ka]

[0356] A mixture of 3-bromo-5-methyl-benzaldehyde (200 mg, 1.00 mmol, 1.0 equiv.), (2,6-dimethylphenyl)boronic acid (227 mg, 1.51 mmol, 1.5 equiv.), tetrakis[triphenylphosphine]palladium (581 mg, 503 μmol, 0.5 equiv.), and potassium phosphate (640 mg, 3.02 mmol, 3.0 equiv.) in 1-2-dimethoxyethane (5 mL) and water (1 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The reaction mixture was then partitioned between ethyl acetate (30 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1) to give 190 mg (crude) of 106-A as a yellow oil.

[0357] LCMS: (ESI) m / z: 225.2 [M+H] + .

[0358] Step 2: Synthesis of 4-((3-(1,1-difluoropropyl)phenyl)carbamoyl)-5-methyl-2-(2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-1H-imidazole 3-oxide (106)

[0359] [ka]

[0360] Compound 106 was obtained from 103-G and 106-A by the general procedure.

[0361] LCMS: (ESI) m / z: 490.4 [M+H] + . 1HNMR(400MHz,MeOD-d4)deruta:8.13(s,1H),7.92(s,1H),7.83(s,1H),7.69(d,J=8.0Hz,1H),7.44(t,J=8.0Hz,1H),7. 25(d,J=8.0Hz,1H),7.17-7.10(m,4H),2.67(s,3H),2.51(s,3H),2.23-2.16(m,2H),2.05(s,6H),0.98(t,J=7.6Hz,3H).

[0362] Synthesis of Compound 109

[0363] Step 1: Synthesis of 3-(5-methylpyrimidin-4-yl)benzaldehyde (109-A)

[0364] [ka]

[0365] Compound 109-A was obtained from 4-chloro-5-methyl-pyrimidine and (3-formylphenyl)boronic acid by the same procedure as for 106-A.

[0366] LCMS: (ESI) m / z: 199.2 [M+H] + .

[0367] Step 2: Synthesis of 4-((3-(1,1-difluoropropyl)phenyl)carbamoyl)-5-methyl-2-(3-(5-methylpyrimidin-4-yl)phenyl)-1H-imidazole 3-oxide (109)

[0368] [ka]

[0369] Compound 109 was obtained from 103-G and 109-A by the general procedure.

[0370] LCMS: (ESI) m / z: 464.2 [M+H] + . 1HNMR(400Hz,DMSO-d6):δ:1.58(s,2H),9.14(s,1H),8.80(s,1H),8.76(s,1H),8.54(d,J=7.6Hz,1H),7.94(s,1H),7.78(s,1H),7.7 2(t,J=8.0Hz,2H),7.48(d,J=8.0Hz,1H),7.23(d,J=7.6Hz,1H),2.62(s,3H),2.41(s,3H),2.15-2.07(m,2H),0.93(t,J=7.6Hz,3H).

[0371] Synthesis of Compound 108

[0372] Step 1: Synthesis of 6-chloro-2',6'-dimethyl-[1,1'-biphenyl]-3-carbaldehyde (108-A)

[0373] [ka]

[0374] Compound 108-A was obtained from 3-bromo-4-chlorobenzaldehyde and (2,6-dimethylphenyl)boronic acid by the same procedure as for 102-A.

[0375] LCMS: (ESI) m / z: 245.0 [M+H] + .

[0376] Step 2: Synthesis of 2-(6-chloro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-4-((3-(1,1-difluoropropyl)phenyl)carbamoyl)-5-methyl-1H-imidazole 3-oxide (108)

[0377] [ka]

[0378] Compound 108 was obtained from 103-G and 108-A by the general procedure.

[0379] LCMS: (ESI) m / z: 510.2 [M+H] + . 1 HNMR(400Hz,DMSO-d6):δ:13.49(brs,1H),13.39(brs,1H),8.53(d,J=8.8Hz,1H),8.33(s,1H),7.94(s,1H),7.82(d,J=8.4Hz,1H) ,7.70(d,J=8.4Hz,1H),7.47-7.43(m,1H),7.28-7.18(m,4H),2.59(s,3H),2.28-2.13(m,2H),1.98(s,6H),0.92(t,J=7.6Hz,3H).

[0380] Synthesis of Compound 112

[0381] Step 1: Synthesis of 3-(4,6-dimethylpyrimidin-5-yl)benzaldehyde (112-A)

[0382] [ka]

[0383] Compound 112-A was obtained from 5-bromo-4,6-dimethylpyrimidine and (3-formylphenyl)boronic acid by the same procedure as for 102-A.

[0384] LCMS: (ESI) m / z: 213.0 [M+H] + .

[0385] Step 2: Synthesis of 4-((3-(1,1-difluoropropyl)phenyl)carbamoyl)-2-(3-(4,6-dimethylpyrimidin-5-yl)phenyl)-5-methyl-1H-imidazole 3-oxide (112)

[0386] [ka]

[0387] Compound 112 was obtained from 103-G and 112-A by the general procedure.

[0388] LCMS: (ESI) m / z: 478.2 [M+H] + . 1 HNMR(400Hz,MeOD-d4)δ:8.90(s,1H),8.32(s,J=8.0Hz,1H),8.26(d,J=1.2Hz,1H),7.91(s,1H),7.78-7.69(m,2 H),7.48-7.43(m,2H),7.25(d,J=8.0Hz,1H),2.70(s,3H),2.34(s,6H),2.24-2.14(m,2H),0.98(t,J=7.2Hz,3H).

[0389] Synthesis of Compound 107

[0390] Step 1: Synthesis of 2',6'-dimethyl-[1,1'-biphenyl]-3-carbaldehyde (107-A)

[0391] [ka]

[0392] Compound 107-A was obtained from 3-bromobenzaldehyde and (2,6-dimethylphenyl)boronic acid by the same procedure as for 102-A.

[0393] LCMS: (ESI) m / z: 211.0 [M+H] + .

[0394] Step 2: Synthesis of 4-((3-(1,1-difluoropropyl)phenyl)carbamoyl)-2-(2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-5-methyl-1H-imidazole 3-oxide (107)

[0395] [ka]

[0396] Compound 107 was obtained from 103-G and 107-A by the general procedure.

[0397] LCMS: (ESI) m / z: 510.2 [M+H] + . 1 HNMR(400Hz,DMSO-d6)δ:13.63(brs,1H),13.31(brs,1H),8.48(d,J=8.0Hz,1H),8.26(s,1H),7.95(s,1H),7.72-7.65(m,2H),7 .46-7.44(m,1H),7.29(d,J=7.6Hz,1H),7.24-7.16(m,4H),2.61(s,3H),2.29-2.15(m,2H),2.02(s,6H),0.93(t,J=7.6Hz,3H).

[0398] Synthesis of Compound 104

[0399] Step 1: Synthesis of 4-((3-(cyclopropyldifluoromethyl)phenyl)carbamoyl)-2-(6-methoxy-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-5-methyl-1H-imidazole 3-oxide (104)

[0400] [ka]

[0401] Compound 107 was obtained from 161-E and 102-A by the general procedure.

[0402] LCMS: (ESI) m / z: 518.2 [M+H] + . 1 HNMR(400MHz,MeOD-d4)δ:8.38(dd,J=2.4,8.8Hz,1H),7.98(s,1H),7.91(d,J=2.4Hz,1H),7.69(d,J=8.0Hz,1H),7.44(t,J=8.0Hz,1H) ,7.33-7.29(m,2H),7.17-7.13(m,1H),7.11-7.07(m,2H),3.84(s,3H),2.66(s,3H),2.02(s,6H),1.66-1.55(m,1H),0.74-0.68(m,4H).

[0403] Synthesis of Compound 105

[0404] Step 1: Synthesis of 4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (105-A)

[0405] [ka]

[0406] To a solution of 3-bromo-4-methoxybenzaldehyde (200 mg, 930 μmol, 1.0 equiv.) in dioxane (5 mL), potassium acetate (274 mg, 2.79 mmol, 3.0 equiv.), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (69.0 mg, 94.3 μmol, 0.1 equiv.), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (354 mg, 1.40 mmol, 1.5 equiv.) were added. The reaction mixture was stirred at 90°C under a nitrogen atmosphere for 6 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The mixture was then diluted with 10 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 250 mg (crude) of 105-A as a brown oil.

[0407] LCMS: (ESI) m / z: 263.1 [M+H] + . 1 HNMR(400MHz,CDCl3-d)δ:9.91(s,1H),8.21(d,J=2.4Hz,1H),7.97(dd,J=2.0,8.4Hz,1H),6.98(d,J=8.4Hz,1H),3.93(s,3H),1.38(s,12H).

[0408] Step 2: Synthesis of 3-(3,5-dimethyl-4-pyridyl)-4-methoxy-benzaldehyde (105-B)

[0409] [ka]

[0410] To a solution of 105-A (100 mg, 381 μmol, 1.0 equiv.) and 4-bromo-3,5-dimethyl-pyridine (71.0 mg, 381 μmol, 1.0 equiv.) in dioxane (5 mL) and water (1 mL), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (28.0 mg, 38.3 μmol, 0.10 equiv.) and sodium carbonate (81.0 mg, 764 μmol, 2.0 equiv.) were added. The reaction mixture was stirred at 90° C. for 4 hours. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=2 / 1) to give 40.0 mg (43% yield) of 105-B as a yellow solid.

[0411] LCMS: (ESI) m / z: 242.2 [M+H] + .

[0412] Step 3: Synthesis of 4-((3-(cyclopropyldifluorome...

Claims

1. A compound represented by the following formula I, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, Ring A is phenyl, and ring B is selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, isoquinoline, pyrazolyl, pyrrolyl, furanyl, thiophen-yl, isoquinolinyl, indolyl, 1H-indole, isoindolyl, naphthyl, anthracenyl, benzimidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1 ,4]dioxepin, benzofuran-2(3H)-one, benzo[d][1,3]dioxole, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4,5,6,7-tetrahydro-1,3-benzothiazole, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinolinyl, isoquinolinyl, acridinyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzothiophenyl, benzoxadiazole, benzo[c][1,2,5]oxadiazolyl, benzo[c]thiophenyl, benzodioxolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiaziolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazolo[4,5-d]pyrimidine, [1,3]Thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2-d]pyrimidin-4(3H)-one, 4-oxo-4H-thieno[3,2-d][1,3]thiazine, imidazo[1,2-a]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazole[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, pyrido[2,3-b]pyrazine, pyrido[2,3-b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, 1,2,3,4-tetrahydroquinoxaline, 1-(pyridin-1(2H)-yl)ethanone, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[4,5-d]pyrimidine, thieno[3,2-c]pyridine; R ２ and R ２０ are independently H, F, Cl, Br, I, OH, SH, R ８ -OH, R ８ -SH, -R ８ -O-R １０ , R ８ -(C ３ -C ８ cycloalkyl), R ８ -(C ３ -C ８ heterocycle), CF ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , -CH ２ CN, -R ８ C.N., N.H. ２ , NHR, N(R) ２ , R ８ -N(R １０ ) (R １１ ), R ９ -R ８ -N(R １０ ) (R １１ ), B(OH) ２ , —OC(O)CF ３ , -OCH ２ Ph, NHC(O)-R １０ , NHCO-N(R １０ ) (R １１ ), COOH, -C(O)Ph, C(O)OR １０ , R ８ -C(O)-R １０ , C(O)H, C(O)-R １０ , C １ -C ５ straight-chain or branched C(O)-haloalkyl, —C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), SO ２ R, SO ２ N (R １０ ) (R １１ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl of C ２ -C ５ linear or branched, substituted or unsubstituted alkenyl of C １ -C ５ Straight-chain, branched or cyclic haloalkyl, substituted or unsubstituted C １ -C ５ Linear or branched or C ３ -C ８ cyclic alkoxy (optionally at least one methylene group in the alkoxy (CH ２ ) substituted with an oxygen atom), C １ -C ５ a straight or branched chain thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, or CH(CF ３ ) (NH-R １０ ) is; R １ are F, Cl, Br, I, OH, SH, and R ８ -OH, R ８ -SH, -R ８ -O-R １０ , R ８ -(C ３ -C ８ cycloalkyl), R ８ -(C ３ -C ８ heterocycle), CF ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , -CH ２ CN, -R ８ C.N., N.H. ２ , NHR, N(R) ２ , R ８ -N(R １０ ) (R １１ ), R ９ -R ８ -N(R １０ ) (R １１ ), B(OH) ２ , —OC(O)CF ３ , -OCH ２ Ph, NHC(O)-R １０ , NHCO-N(R １０ ) (R １１ ), COOH, -C(O)Ph, C(O)OR １０ , R ８ -C(O)-R １０ , C(O)H, C(O)-R １０ , C １ -C ５ straight-chain or branched C(O)-haloalkyl, —C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), SO ２ R, SO ２ N (R １０ ) (R １１ ), SO ２ NHC(O)CH ３ , C １ -C ５ linear or branched, substituted or unsubstituted alkyl of C ２ -C ５ linear or branched, substituted or unsubstituted alkenyl of C １ -C ５ Straight-chain, branched or cyclic haloalkyl, substituted or unsubstituted C １ -C ５ Linear or branched or C ３ -C ８ cyclic alkoxy (optionally at least one methylene group in the alkoxy (CH ２ ) substituted with an oxygen atom), C １ -C ５ a straight or branched chain thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl; Or, R ２ and R １ are joined together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; R ４ and R ４０ are independently H, F, Cl, Br, I, OH, SH, R ８ -OH, R ８ -SH, -R ８ -O-R １０ , C.F. ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , -CH ２ CN, -R ８ C.N., N.H. ２ , NHR, N(R) ２ , R ８ -N(R １０ ) (R １１ ), R ９ -R ８ -N(R １０ ) (R １１ ), B(OH) ２ , —OC(O)CF ３ , -OCH ２ Ph, -NHCO-R １０ , NHCO-N(R １０ ) (R １１ ), COOH, -C(O)Ph, C(O)OR １０ , R ８ -C(O)-R １０ , C(O)H, C(O)-R １０ , C １ -C ５ straight-chain or branched C(O)-haloalkyl, —C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), C(O)N(CH ３ ) (CH ２ CH ３ ), C(O)N(CH ３ ) (CH ２ CH ２ -O-CH ３ ), C(S)N(R １０ ) (R １１ ), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO ２ R, SO ２ N (R １０ ) (R １１ ), C １ -C ５ Linear or branched, substituted or unsubstituted alkyl, or substituted or unsubstituted C １ -C ５ Linear or branched or C ３ -C ８ Cyclic haloalkyl, C １ -C ５ linear, branched or cyclic alkoxy, C １ -C ５ a straight or branched chain thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle, or substituted or unsubstituted aryl; R ３ are F, Cl, Br, I, OH, SH, and R ８ -OH, R ８ -SH, -R ８ -O-R １０ , C.F. ３ , CDs ３ , OCD ３ , CN, -CH ２ CN, -R ８ C.N., N.H. ２ , NHR, N(R) ２ , R ８ -N(R １０ ) (R １１ ), R ９ -R ８ -N(R １０ ) (R １１ ), B(OH) ２ , —OC(O)CF ３ , -OCH ２ Ph, -NHCO-R １０ , NHCO-N(R １０ ) (R １１ ), -COOH, -C(O)Ph, C(O)OR １０ , R ８ -C(O)-R １０ ,C(O)H,C(O),C １ -C ５ straight-chain or branched C(O)-haloalkyl, —C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), C(S)N(R １０ ) (R １１ ), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO ２ R, SO ２ N (R １０ ) (R １１ ), C １ -C ５ Linear or branched, substituted or unsubstituted alkyl, substituted or unsubstituted C １ -C ５ Linear or branched or C ３ -C ８ Cyclic haloalkyl, C １ -C ５ linear, branched or cyclic alkoxy, C １ -C ５ a straight or branched chain thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle, substituted or unsubstituted aryl, or CH(CF ３ ) (NH-R １０ ) is; Or, R ３ and R ４ are joined together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; R ５ is H, C １ -C ５ linear or branched, substituted or unsubstituted alkyl of C ２ -C ５ linear or branched, substituted or unsubstituted alkenyl of C ２ -C ５ linear or branched, substituted or unsubstituted alkynyl of C １ -C ５ a straight or branched haloalkyl of R ８ -aryl, C(=CH ２ )-R １０ , substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ６ is H, C １ -C ５ straight-chain or branched alkyl, C(O)R, or S(O) ２ It is R; R ６０ is H, substituted or unsubstituted C １ -C ５ straight-chain or branched alkyl, C(O)R, or S(O) ２ It is R; R ８ is [CH ２ ] ｐ and p is 1 to 10; R ９ is [CH] ｑ , or [C] ｑ and q is 2 to 10; R １０ and R １１ are independently H, CN, C １ -C ５ a straight or branched alkyl group of R ８ -O-R １０ , C(O)R, or S(O) ２ It is R; Or, R １０ and R １１ are bonded to each other to form a substituted or unsubstituted C ３ -C ８ Forming a heterocyclic ring; Substituents include F, Cl, Br, I, OH, C １ -C ５ Straight or branched alkyl, C １ -C ５ Linear or branched alkyl-OH, C ２ -C ５ Straight or branched alkenyl, C ２ -C ５ Straight or branched alkenyl, alkoxy, ester, N(R) ２ , C.F. ３ , aryl, phenyl, R ８ -aryl, heteroaryl, C ３ -C ８ Cycloalkyl, C ３ -C ８ Heterocycle, halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate, dihydrogen phosphate (i.e., OP(O)(OH) ２ ), dialkyl phosphate, CN, or NO ２ Includes; R is H, C １ -C ５ linear or branched alkyl of C １ -C ５ is a straight or branched alkoxy, phenyl, aryl, or heteroaryl; or two gemR substituents are joined together to form a 5- or 6-membered heterocyclic ring; m, l, and k are, independently of one another, integers from 0 to 4; n is an integer from 1 to 4.

2. 2. The compound of claim 1 , A compound represented by the following chemical formula II: 【Chemistry 2】 During the ceremony, X １ is N and X ２ , X ３ , X ４ , and X ５ Each of is C.

3. 3. A compound according to claim 1 or 2, R ２ , R ２０ , R ４ , and R ４０ Each of is H.

4. A compound represented by the following formula IV, or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 R ２ and R ２０ are independently H, F, Cl, Br, I, OH, SH, R ８ -OH, R ８ -SH, -R ８ -O-R １０ , R ８ -(C ３ -C ８ cycloalkyl), R ８ -(C ３ -C ８ heterocycle), CF ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , -CH ２ CN, -R ８ C.N., N.H. ２ , NHR, N(R) ２ , R ８ -N(R １０ ) (R １１ ), R ９ -R ８ -N(R １０ ) (R １１ ), B(OH) ２ , —OC(O)CF ３ , -OCH ２ Ph, NHC(O)-R １０ , NHCO-N(R １０ ) (R １１ ), COOH, -C(O)Ph, C(O)OR １０ , R ８ -C(O)-R １０ , C(O)H, C(O)-R １０ , C １ -C ５ straight-chain or branched C(O)-haloalkyl, —C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), SO ２ R, SO ２ N (R １０ ) (R １１ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl of C ２ -C ５ linear or branched, substituted or unsubstituted alkenyl of C １ -C ５ Straight-chain, branched or cyclic haloalkyl, substituted or unsubstituted C １ -C ５ Linear or branched or C ３ -C ８ cyclic alkoxy (optionally at least one methylene group in the alkoxy (CH ２ ) substituted with an oxygen atom), C １ -C ５ a straight or branched chain thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl; R １ are F, Cl, Br, I, OH, SH, and R ８ -OH, R ８ -SH, -R ８ -O-R １０ , R ８ -(C ３ -C ８ cycloalkyl), R ８ -(C ３ -C ８ heterocycle), CF ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , -CH ２ CN, -R ８ C.N., N.H. ２ , NHR, N(R) ２ , R ８ -N(R １０ ) (R １１ ), R ９ -R ８ -N(R １０ ) (R １１ ), B(OH) ２ , —OC(O)CF ３ , -OCH ２ Ph, NHC(O)-R １０ , NHCO-N(R １０ ) (R １１ ), COOH, -C(O)Ph, C(O)OR １０ , R ８ -C(O)-R １０ , C(O)H, C(O)-R １０ , C １ -C ５ straight-chain or branched C(O)-haloalkyl, —C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), SO ２ R, SO ２ N (R １０ ) (R １１ ), SO ２ NHC(O)CH ３ , C １ -C ５ linear or branched, substituted or unsubstituted alkyl of C ２ -C ５ linear or branched, substituted or unsubstituted alkenyl of C １ -C ５ Straight-chain, branched or cyclic haloalkyl, substituted or unsubstituted C １ -C ５ Linear or branched or C ３ -C ８ cyclic alkoxy (optionally at least one methylene group in the alkoxy (CH ２ ) substituted with an oxygen atom), C １ -C ５ a straight or branched chain thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, or CH(CF ３ ) (NH-R １０ ) is; Or, R ２ and R １ are joined together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; R ４ and R ４０ are independently H, F, Cl, Br, I, OH, SH, R ８ -OH, R ８ -SH, -R ８ -O-R １０ , C.F. ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , -CH ２ CN, -R ８ C.N., N.H. ２ , NHR, N(R) ２ , R ８ -N(R １０ ) (R １１ ), R ９ -R ８ -N(R １０ ) (R １１ ), B(OH) ２ , —OC(O)CF ３ , -OCH ２ Ph, -NHCO-R １０ , NHCO-N(R １０ ) (R １１ ), COOH, -C(O)Ph, C(O)OR １０ , R ８ -C(O)-R １０ , C(O)H, C(O)-R １０ , C １ -C ５ straight-chain or branched C(O)-haloalkyl, —C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), C(S)N(R １０ ) (R １１ ), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO ２ R, SO ２ N (R １０ ) (R １１ ), C １ -C ５ Linear or branched, substituted or unsubstituted alkyl, substituted or unsubstituted C １ -C ５ Linear or branched or C ３ -C ８ Cyclic haloalkyl, C １ -C ５ linear, branched or cyclic alkoxy, C １ -C ５ a straight or branched chain thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle, substituted or unsubstituted aryl, or CH(CF ３ ) (NH-R １０ ) is; R ３ is -NHCO-R １０ , NHCO-N(R １０ ) (R １１ ), -COOH, -C(O)Ph, -C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), C(S)N(R １０ ) (R １１ ), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO ２ N (R １０ ) (R １１ ), substituted or unsubstituted C ２ -C ５ Linear or branched or C ３ -C ８ Cyclic haloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle, substituted or unsubstituted aryl, or CH(CF ３ ) (NH-R １０ ) is; Or, R ３ and R ４ are joined together to form a 5- or 6-membered, substituted or unsubstituted heterocycle; R ５ is H, C １ -C ５ linear or branched, substituted or unsubstituted alkyl of C ２ -C ５ linear or branched, substituted or unsubstituted alkenyl of C ２ -C ５ linear or branched, substituted or unsubstituted alkynyl of C １ -C ５ a straight or branched haloalkyl of R ８ -aryl, C(=CH ２ )-R １０ , substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ６ is H, C １ -C ５ straight-chain or branched alkyl, C(O)R, or S(O) ２ It is R; R ６０ is H, substituted or unsubstituted C １ -C ５ straight-chain or branched alkyl, C(O)R, or S(O) ２ It is R; R ８ is [CH ２ ] ｐ and p is 1 to 10; R ９ is [CH] ｑ , or [C] ｑ and q is 2 to 10; R １０ and R １１ are independently H, CN, C １ -C ５ a straight or branched alkyl group of R ８ -O-R １０ , C(O)R, or S(O) ２ It is R; Or, R １０ and R １１ are bonded to each other to form a substituted or unsubstituted C ３ -C ８ Forming a heterocyclic ring; Substituents include F, Cl, Br, I, OH, C １ -C ５ Straight or branched alkyl, C １ -C ５ Linear or branched alkyl-OH, C ２ -C ５ Straight or branched alkenyl, C ２ -C ５ Straight or branched alkenyl, alkoxy, ester, N(R) ２ , C.F. ３ , aryl, phenyl, R ８ -aryl, heteroaryl, C ３ -C ８ Cycloalkyl, C ３ -C ８ Heterocycle, halophenyl, (benzyloxy)phenyl, alkyl-hydrogen phosphate, dihydrogen phosphate (i.e., OP(O)(OH) ２ ), dialkyl phosphate, CN, or NO ２ Includes; R is H, C １ -C ５ linear or branched alkyl of C １ -C ５ is a straight or branched alkoxy, phenyl, aryl, or heteroaryl; or two gemR substituents are joined together to form a 5- or 6-membered heterocyclic ring; k is an integer from 0 to 4; l is an integer from 1 to 4; n is an integer from 1 to 4; m is 1.

5. 5. The compound of claim 4, A compound represented by the following chemical formula VI: 【Transformation 6】

6. 6. The compound of claim 5, A compound represented by the following formula VII: 【Transformation 7】 During the ceremony, R ３ is -C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), C(S)N(R １０ ) (R １１ ), C(O)-pyrrolidine, C(O)-azetidine, C(O)-methylpiperazine, C(O)-piperidine, C(O)-morpholine, SO ２ N (R １０ ) (R １１ ), or substituted or unsubstituted C １ -C ５ Linear or branched or C ３ -C ８ It is a cyclic haloalkyl.

7. 5. The compound of claim 4, A compound represented by the following chemical formula VIII: 【Transformation 8】 During the ceremony, R ２１ and R ２２ are independently H, F, Cl, Br, I, OH, SH, R ８ -OH, R ８ -SH, -R ８ -O-R １０ , R ８ -(C ３ -C ８ cycloalkyl), R ８ -(C ３ -C ８ heterocycle), CF ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , -CH ２ CN, -R ８ C.N., N.H. ２ , NHR, N(R) ２ , R ８ -N(R １０ ) (R １１ ), R ９ -R ８ -N(R １０ ) (R １１ ), B(OH) ２ , —OC(O)CF ３ , -OCH ２ Ph, NHC(O)-R １０ , NHCO-N(R １０ ) (R １１ ), COOH, -C(O)Ph, C(O)OR １０ , R ８ -C(O)-R １０ , C(O)H, C(O)-R １０ , C １ -C ５ straight-chain or branched C(O)-haloalkyl, —C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), SO ２ R, SO ２ N (R １０ ) (R １１ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl of C ２ -C ５ linear or branched, substituted or unsubstituted alkenyl of C １ -C ５ Straight-chain, branched or cyclic haloalkyl, substituted or unsubstituted C １ -C ５ Linear or branched or C ３ -C ８ cyclic alkoxy (optionally at least one methylene group in the alkoxy (CH ２ ) substituted with an oxygen atom), C １ -C ５ a straight or branched chain thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, or CH(CF ３ ) (NH-R １０ )

8. 5. The compound of claim 4, A compound represented by the following formula IX: 【Chemistry 9】 During the ceremony, R １ , R ２０ , R ２１ , and R ２２ are independently H, F, Cl, Br, I, OH, SH, R ８ -OH, R ８ -SH, -R ８ -O-R １０ , R ８ -(C ３ -C ８ cycloalkyl), R ８ -(C ３ -C ８ heterocycle), CF ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , -CH ２ CN, -R ８ C.N., N.H. ２ , NHR, N(R) ２ , R ８ -N(R １０ ) (R １１ ), R ９ -R ８ -N(R １０ ) (R １１ ), B(OH) ２ , —OC(O)CF ３ , -OCH ２ Ph, NHC(O)-R １０ , NHCO-N(R １０ ) (R １１ ), COOH, -C(O)Ph, C(O)OR １０ , R ８ -C(O)-R １０ , C(O)H, C(O)-R １０ , C １ -C ５ straight-chain or branched C(O)-haloalkyl, —C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), SO ２ R, SO ２ N (R １０ ) (R １１ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl of C ２ -C ５ linear or branched, substituted or unsubstituted alkenyl of C １ -C ５ Straight-chain, branched or cyclic haloalkyl, substituted or unsubstituted C １ -C ５ Linear or branched or C ３ -C ８ cyclic alkoxy (optionally at least one methylene group in the alkoxy (CH ２ ) substituted with an oxygen atom), C １ -C ５ a straight or branched chain thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, or CH(CF ３ ) (NH-R １０ ) is; Or, R ２１ and R １ are joined together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; Or, R ２１ and R ２２ are joined together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; R ２０１ and R ２０２ are, independently of one another, H, F, Cl, Br, I, CF ３ , or C １ ~C ５ is a straight or branched, substituted or unsubstituted alkyl.

9. A compound selected from Table 1 below, or a pharmaceutically acceptable salt thereof. Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25

10. A compound according to any one of claims 1 to 3, R １ is substituted or unsubstituted aryl.

11. A compound according to any one of claims 1 to 3 and 10, R １ is phenyl, xylyl, 2,6-difluorophenyl, 4-fluoroxylyl, 2-bromophenyl, 3-bromophenyl, or 4-bromophenyl.

12. A compound according to any one of claims 1 to 3, 10 and 11, R １ is a substituted or unsubstituted C １ -C ５ Linear or branched or C ３ -C ８ A compound which is a cyclic haloalkyl.

13. A compound according to any one of claims 1 to 3 and 10 to 12, R ３ is CF ３ , C.F. ２ CH ３ , C.F. ２ -cyclobutyl, CF ２ -cyclopropyl, CF ２ -methylcyclopropyl, CF ２ CH ２ CH ３ , C.H. ２ CF ３ , C.H. ２ CH ２ CF ３ , C.F. ２ CH (CH ３ ) ２ , CF(CH ３ )-CH(CH ３ ) ２ , C(OH) ２ CF ３ or cyclopropyl-CF ３ A compound.

14. A compound according to any one of claims 1 to 13; and a pharmaceutically acceptable carrier.

15. 14. Use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for treating, inhibiting, reducing the severity of, or reducing the risk of developing cancer in a subject.

16. 16. The use according to claim 15, the cancer is an early stage cancer, an advanced cancer, an invasive cancer, a metastatic cancer, or a drug-resistant cancer; the subject has been previously treated with chemotherapy, immunotherapy, radiation therapy, biological therapy, or surgical intervention; The compound is administered in combination with an anti-cancer therapy.

17. 17. The use according to claim 16, The anti-cancer therapy is chemotherapy, immunotherapy, radiation therapy, biological therapy, or surgical intervention.

18. Suppressing, reducing, or inhibiting tumor growth in a subject afflicted with cancer; Treating, controlling, reducing the severity of, or reducing the risk of developing alcoholism in a subject; Treating, suppressing, reducing the severity of, or reducing the risk of developing a viral infection in a subject; Treating, inhibiting, reducing the severity of, or reducing the risk of developing alcoholic steatohepatitis (ASH) in a subject; Treating, inhibiting, reducing the severity of, or reducing the risk of developing non-alcoholic fatty liver disease (NAFLD) in a subject; Treating, inhibiting, reducing the severity of, or reducing the risk of developing non-alcoholic steatohepatitis (NASH) in a subject; Treating, inhibiting, reducing the severity of, or reducing the risk of developing a metabolic disorder in a subject; Treating, inhibiting, reducing the severity of, or reducing the risk of developing an inflammatory disease in a subject; Treating, inhibiting, reducing the severity of, or reducing the risk of developing an autoimmune disease or disorder in a subject; or Treating, suppressing, reducing the severity of, or reducing the risk of developing, a neuropsychiatric disease or disorder of interest; Use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for the purpose of

19. 19. The use according to claim 18, The tumor growth is promoted by increased acetate uptake by cancer cells; the cancer cells are under hypoxic stress; The tumor growth is inhibited by inhibiting the regulation of lipid synthesis and / or histone acetylation and function, which are induced by ACSS2-mediated acetate metabolism to acetyl-CoA; the viral infection is a human cytomegalovirus (HCMV) infection; the metabolic disorder is selected from obesity, weight gain, fatty liver, and fatty liver disease; or The neuropsychiatric disease or disorder is selected from anxiety, depression, schizophrenia, autism, and post-traumatic stress disorder.

20. 20. The use according to claim 19, The use, wherein the increase in acetate uptake is mediated by ACSS2.

21. 19. The use according to claim 18, A compound for use in suppressing, reducing, or inhibiting tumor growth in a subject afflicted with cancer.

22. 19. The use according to claim 18, The use, wherein the purpose is to treat, inhibit, reduce the severity of, or reduce the risk of developing alcoholism in a subject.

23. 19. The use according to claim 18, The use, wherein the purpose is to treat, suppress, reduce the severity of, or reduce the risk of developing a viral infection in a subject.

24. 19. The use according to claim 18, The use, wherein the purpose is to treat, inhibit, reduce the severity of, or reduce the risk of developing alcoholic steatohepatitis (ASH).

25. 19. The use according to claim 18, The use, wherein the purpose is to treat, inhibit, reduce the severity of, or reduce the risk of developing non-alcoholic fatty liver disease (NAFLD) in a subject.

26. 19. The use according to claim 18, The use, wherein the purpose is to treat, inhibit, reduce the severity of, or reduce the risk of developing non-alcoholic steatohepatitis (NASH) in a subject.

27. 19. The use according to claim 18, The use, wherein the purpose is to treat, inhibit, reduce the severity of, or reduce the risk of developing a metabolic disorder in a subject.

28. 19. The use according to claim 18, The use, wherein the purpose is to treat, suppress, reduce the severity of, or reduce the risk of developing an inflammatory disease in a subject.

29. 19. The use according to claim 18, The use, wherein the purpose is to treat, suppress, reduce the severity of, or reduce the risk of developing an autoimmune disease or disorder in a subject.

30. 19. The use according to claim 18, The use, wherein the purpose is to treat, inhibit, reduce the severity of, or reduce the risk of developing a neuropsychiatric disease or disorder in a subject.

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