ACSS2 inhibitors and methods of use thereof

Abstract

The present invention relates to novel ACSS2 inhibitors, compositions and methods of preparing the same, and uses thereof, which are active as anticancer therapies, in the treatment of alcoholism and viral infections (e.g., CMV), for the treatment of viral infections, alcoholism, alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), obesity / weight gain, anxiety, depression, post-traumatic stress disorder, inflammatory / autoimmune conditions and cancers (including various types of metastatic cancers, advanced cancers and drug-resistant cancers).

Description

Technical Field

[0001] The present invention relates to novel ACSS2 inhibitors, compositions, methods for preparing the same, and uses thereof for treating viral infections (e.g., CMV), 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 various types of metastatic cancer, advanced cancer, and drug-resistant cancer). Background Art

[0002] Cancer is the second most common cause of death in the United States, second only to heart disease. Cancer accounts for one in every four deaths in the United States. The five-year relative survival rate for all cancers 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 incidence of new cancers decreased by an average of 0.6% per year in men and remained unchanged in women. From 2000 to 2009, the death rate from all cancers combined decreased by an average of 1.8% per year in men and by 1.4% per year in women. These improvements in survival reflect improvements in early diagnosis and treatment. Discovering highly effective anticancer agents with low toxicity is a major goal of cancer research.

[0003] Cell growth and proliferation are closely linked to metabolism. The potential unique metabolic differences between normal and cancer cells have stimulated interest in targeting the regeneration of metabolic enzymes as an approach to discover new anticancer therapies.

[0004] It is now understood that cancer cells in metabolically stressed microenvironments, defined herein as cells with low oxygen and low nutrient availability (i.e., a hypoxic state), have many tumor-promoting characteristics, such as genomic instability, altered cellular bioenergetics, and invasive behavior. In addition, these cancer cells are often intrinsically resistant to cell death, and their physical isolation from vasculature at the tumor site compromises successful immune responses, drug delivery, and therapeutic efficiency, thereby promoting recurrence and metastasis, ultimately leading to a sharp decline in patient survival. Therefore, there is an absolute need to define therapeutic targets in metabolically stressed cancer cells and to develop new delivery technologies to improve therapeutic efficacy. For example, the specific metabolic dependence 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 synthetase, ACSS2, as a target for cancer therapy

[0006] Acetyl-CoA represents a central node in carbon metabolism, playing a key role in the regulation of bioenergetics, cell proliferation, and gene expression. Tumors that are highly glycolytic or hypoxic must produce sufficient amounts of this metabolite to support cell growth and survival under nutrient-limited conditions. Acetate is an important source of acetyl-CoA in hypoxic conditions. Inhibition of acetate metabolism may impair tumor growth. The nuclear cytosolic acetyl-CoA synthetase, ACSS2, provides a critical source of acetyl-CoA to tumors by capturing acetate as a carbon source. Although showing no overall defects in growth or development, adult mice lacking ACSS2 exhibited a significant reduction in tumor burden in two different models of hepatocellular carcinoma. ACSS2 is expressed in a large number of human tumors, and its activity is primarily responsible for the cellular uptake of acetate into lipids and histones. Furthermore, an unbiased functional genomic screen identified ACSS2 as a key enzyme for the growth and survival of breast and prostate cancer cells cultured under hypoxic and low serum conditions. ACSS2 expression is frequently found to be high in breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, pancreatic cancer, and invasive ductal carcinoma of the lung, and is often directly associated with higher tumor grade and lower survival compared to tumors with low ACSS2 expression. These observations may make ACSS2 a targetable metabolic vulnerability in a wide variety of tumors.

[0007] Due to the nature of tumorigenesis, cancer cells constantly encounter environments where nutrient and oxygen supplies are severely compromised. To survive these harsh conditions, cancer cell transformation is often accompanied by major metabolic changes to meet the energy and biomass demands of continued cell proliferation. Recent reports have found that some types of breast, prostate, liver, and brain cancers utilize acetate as a critical nutrient source in an acetyl-CoA synthetase 2 (ACSS2)-dependent manner. Results indicate that acetate and ACSS2 contribute a significant portion of the carbon in 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, either due to copy number gain or overexpression, have been found to be associated with disease progression in human breast, prostate, and brain cancers. Furthermore, ACSS2, essential for tumor growth under hypoxic conditions, is essential for normal cell growth, and mice lacking ACSS2 exhibit a normal phenotype (Comerford et al., 2014). The switch in increased reliance on ACSS2 is not due to genetic variation, but rather to metabolic stress conditions in the tumor microenvironment. Under normal oxidative conditions, acetyl-CoA is typically produced from citrate by citrate lyase activity. However, under hypoxic conditions, when cells adapt to anaerobic metabolism, acetate becomes a key source of acetyl-CoA, and therefore ACSS2 is essential, and in fact ACSS2 is synthetically lethal under hypoxic conditions (see Schug et al., Cancer Cell, 2015, 27:1, pp. 57-71). Cumulative evidence from several studies suggests that ACSS2 may be a targetable metabolic vulnerability for a wide variety of tumors.

[0008] "Some ACSS2-expressing tumors are critically dependent on acetate for growth or survival, so selective inhibitors of this nonessential enzyme may represent an exceptionally ripe opportunity for the development of new anticancer therapies. If normal human cells and tissues are not critically dependent on the activity of the ACSS2 enzyme, such agents may be able to inhibit the growth of ACSS2-expressing tumors with a favorable therapeutic window."

[0009] Nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) have similar pathogenesis and histopathology, but different etiologies and epidemiology. NASH and ASH are advanced forms of nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is characterized by excessive fat accumulation in the liver (steatosis), the absence of any other obvious cause of chronic liver disease (viral, autoimmune, genetic, etc.), and alcohol consumption ≤20-30g / day. In contrast, AFLD is defined by the presence of steatosis and alcohol consumption >20-30g / day.

[0010] Hepatocyte ethanol metabolism produces free acetate as its end product, which is primarily incorporated into acetyl-CoA (acetyl-CoA) in other tissues for Krebs cycle oxidation, fatty acid synthesis, or as a substrate for protein acetylation. Acyl-CoA synthetases, short-chain family members 1 and 2 (ACSS1 and ACSS2), catalyze this conversion. The role of acetyl-CoA synthesis in controlling inflammation has opened up a novel area of ​​research on the relationship between cellular energy supply and inflammatory diseases. Ethanol has been shown to enhance macrophage cytokine production by disconnecting gene transcription from its normal regulatory machinery through increased histone acetylation, and the conversion of the ethanol metabolite acetate to acetyl-CoA is crucial for this process.

[0011] They show that inflammation is exacerbated in acute alcoholic hepatitis, with upregulation of acetyl-CoA synthetase and conversion of the ethanol metabolite acetate to excess acetyl-CoA. This, through elevated substrate concentrations and histone deacetylase (HDAC) inhibition, increases acetylation of proinflammatory cytokine genes, leading to enhanced gene expression and perpetuation of the inflammatory response. The clinical relevance 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 2 can modulate ethanol-related histone changes without affecting the flux of acetyl-CoA through normal metabolic pathways, they could potentially become urgently needed effective therapeutic options for acute alcoholic hepatitis. Therefore, the synthesis of metabolically available acetyl-CoA from acetate is crucial for the increased acetylation of proinflammatory genes and the consequent enhancement of the inflammatory response in ethanol-exposed macrophages. This mechanism represents a potential therapeutic target in acute alcoholic hepatitis.

[0012] Cytosolic acetyl-CoA is a precursor for a variety of anabolic reactions, including the de novo synthesis of fatty acids (FA). Inhibiting FA synthesis may favorably affect the morbidity and mortality associated with the metabolic syndrome of fatty liver disease (Wakil SJ, Abu-Elheiga LA. 2009. 'Fatty acid metabolism: a target for the metabolic syndrome'. Journal of Lipid Research (J. Lipid Res.)), and due to the key role of acetyl-CoA carboxylase (ACC) in regulating fatty acid metabolism, ACC inhibitors are being studied as clinical drug targets for several metabolic diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Inhibition of ACSS2 is expected to directly reduce fatty acid accumulation in the liver through its effect on acetyl-CoA from acetate, which is present in high levels in the liver due to hepatocyte ethanol metabolism. Furthermore, ACSS2 inhibitors are expected to have a better safety profile than ACC inhibitors because they are expected to affect only the flux from acetate, which is not the major source of Ac-CoA under normal conditions (Harriman G et al., 2016. "ND-630 inhibition of acetyl-CoA carboxylase reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats" PNAS). Furthermore, in a diet-induced obesity model, mice lacking ACSS2 exhibited weight loss and hepatic steatosis (Z. Huang et al., ACSS2 promotes systemic fat storage and utilization by selectively regulating genes involved in lipid metabolism PNAS 115, (40), E9499-E9506, 2018).

[0013] It is also shown that ACSS2 enters the nucleus under certain conditions (hypoxia, high fat, etc.), and affects the acetylation and crotonylation of histones by providing acetyl-CoA and crotonyl-CoA, and thus regulates gene expression. For example, ACSS2 reduces the reduction of nuclear acetyl-CoA and histone acetylation levels in display neurons, affecting the expression of many neuronal genes. In the hippocampus, this reduction of ACSS2 has an impact on memory and neuronal plasticity (Mews P et al., "Nature (Nature)", Vol. 546, 381, 2017). This epigenetic modification is related to neuropsychiatric diseases, such as anxiety, PTSD, depression, etc. (Graff, J et al. Histone acetylation: molecular mnemonics of chromatin. "Natural Review Neuroscience (Nat Rev. Neurosci.)" 14, 97-111 (2013)). Therefore, the inhibitor of ACSS2 can find useful applications under these conditions.

[0014] Nuclear ACSS2 has also been shown to promote lysosomal biogenesis, autophagy, and brain tumorigenesis by affecting histone H3 acetylation (Li, X et al.: Nuclear translocation of ACSS2 promotes gene transcription of lysosomal biogenesis and autophagy, Molecular Cell 66, 1-14, 2017). In addition, nuclear ACSS2 has been shown to activate HIF-2α through acetylation and thus accelerate the growth and metastasis of HIF2α-driven cancers, such as certain renal cell carcinomas and glioblastomas (Chen, R. et al. Coordinated 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

[0015] The present invention provides a compound or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, drug product, or any combination thereof, as defined below by the structures of Formula (I)-(V) and represented by the structures listed in Table 1. In various embodiments, the compound is an acyl-CoA synthetase short-chain family, member 2 (ACSS2) inhibitor.

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

[0017] The present invention further provides a method of treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing cancer, comprising administering to an individual with cancer a compound represented by the structures of Formula (I)-(V) and the structures listed in Table 1, as defined below, under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of developing, or prevent the cancer. In various embodiments, the cancer is selected from the list of: hepatocellular carcinoma, melanoma (e.g., BRAF mutant melanoma), glioblastoma, breast cancer (e.g., infiltrating ductal carcinoma, triple-negative breast cancer), prostate cancer, liver cancer, brain cancer, ovarian cancer, lung cancer, Lewis Lung Cancer (LLC), colon cancer, pancreatic cancer, renal cell carcinoma, and breast cancer. 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 individual has previously been treated with chemotherapy, immunotherapy, radiation therapy, biological therapy, surgical intervention, or any combination thereof. In various embodiments, the compound is administered in combination with an anti-cancer therapy. In 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 a method for inhibiting, reducing or preventing tumor growth in an individual, comprising administering to an individual suffering from cancer a compound represented by the structures of formula (I)-(V) and the structures listed in Table 1 as defined below, under conditions effective to inhibit, reduce or prevent the growth of the tumor in the individual. In various embodiments, tumor growth is enhanced by increasing 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 inhibited due to inhibition of ACSS2-mediated acetate metabolism to lipid (e.g., fatty acid) synthesis and / or histone synthesis induced by acetyl-CoA. In various embodiments, tumor growth is inhibited due to inhibition of ACSS2-mediated acetate metabolism to regulation of histone acetylation and function induced by acetyl-CoA.

[0019] The present invention further provides a method for inhibiting, reducing or preventing lipid synthesis and / or regulating histone acetylation and function in a cell, comprising contacting a compound represented by the structures of Formula (I)-(V) and listed in Table 1 as defined below with the cell under conditions effective to inhibit, reduce or prevent lipid synthesis and / or regulate histone acetylation and function in the cell. In various embodiments, the cell is a cancer cell.

[0020] The present invention further provides a method for binding an ACSS2 inhibitor compound to an ACSS2 enzyme, comprising the steps of contacting the ACSS2 enzyme with an ACSS2 inhibitor compound represented by the structures of Formula (I)-(V) as defined below and by 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 a method for inhibiting, reducing or preventing the synthesis of acetyl-CoA from acetate in a cell, comprising contacting the cell with a compound represented by the structures of Formula (I)-(V) and the structures listed in Table 1, as defined below, under conditions effective to inhibit, reduce or prevent the synthesis of acetyl-CoA from acetate in the cell. In various embodiments, the cell is a cancer cell. In various embodiments, the synthesis is mediated by ACSS2.

[0022] The present invention further provides a method for inhibiting, reducing or preventing acetate metabolism in cancer cells, comprising contacting a compound represented by the structures of Formula (I)-(V) and the structures listed in Table 1, as defined below, with the cancer cells under conditions effective to inhibit, reduce or prevent acetate metabolism in the 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 of treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing alcoholism in a human subject, comprising administering to a subject suffering from alcoholism a compound represented by the structures of Formulae (I)-(V) and the structures listed in Table 1, as defined below, under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of developing, or prevent alcoholism in said subject.

[0024] The present invention further provides a method of treating, inhibiting, reducing the severity of, reducing the risk of, or preventing a viral infection in a subject, comprising administering to the subject having a viral infection a compound represented by the structures of Formulae (I)-(V) and listed in Table 1, as defined below, under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent the viral infection in the subject. In various embodiments, the viral infection is human cytomegalovirus (HCMV) infection.

[0025] The present invention further provides a method of treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing non-alcoholic steatohepatitis (NASH) in a subject, comprising administering to a subject having non-alcoholic steatohepatitis (NASH) a compound represented by the structures of Formulae (I)-(V) and the structures listed in Table 1, as defined below, under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent non-alcoholic steatohepatitis (NASH) in the subject.

[0026] The present invention further provides a method of treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing alcoholic steatohepatitis (ASH) in an individual, comprising administering to an individual having alcoholic steatohepatitis (ASH) a compound represented by the structures of Formulae (I)-(V) and the structures listed in Table 1, as defined below, under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent alcoholic steatohepatitis (ASH) in the individual.

[0027] The present invention further provides a method of treating, inhibiting, reducing the severity of, reducing the risk of, or preventing a metabolic disorder in a subject, comprising administering to a subject having a metabolic disorder a compound represented by the structures of Formulae (I)-(V) and listed in Table 1, as defined below, under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent the metabolic disorder in the subject. In various embodiments, the metabolic disorder is selected from the group consisting of obesity, weight gain, hepatic steatosis, and fatty liver disease.

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

[0029] The present invention further provides a method of treating, inhibiting, reducing the severity of, reducing the risk of, or preventing an inflammatory disorder in a subject, comprising administering to a subject having an inflammatory disorder a compound represented by the structures of Formulae (I)-(V) and the structures listed in Table 1, as defined below, under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent the inflammatory disorder in the subject.

[0030] The present invention further provides a method of treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing an autoimmune disease or condition in an individual, comprising administering to an individual having an autoimmune disease or condition a compound represented by the structures of Formulae (I)-(V) and the structures listed in Table 1, as defined below, under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent the autoimmune disease or condition in the individual. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. However, the invention both as to organization and method of operation, together with objects, features, and advantages thereof, may be best understood from the following detailed description when read with the accompanying drawings in which:

[0032] Figure 1 General synthetic schemes for compounds of the invention are described.

[0033] Figure 2 A synthetic scheme for compound 204 is depicted.

[0034] Figure 3 A synthetic scheme for compound 133 is depicted.

[0035] Figure 4 Depicts an in vivo efficacy study of Compound 265 in an MDA-MB-468 breast cancer cell xenograft mouse model.

[0036] It should be understood that for simplicity and clarity of illustration, the elements shown in the drawings are not necessarily drawn to scale. For example, the dimensions of some elements may be exaggerated relative to other elements for clarity. In addition, where deemed appropriate, reference numerals may be repeated between the figures to indicate corresponding or similar elements. DETAILED DESCRIPTION

[0037] In various embodiments, the present invention is directed to compounds represented by the structure of Formula (I):

[0038]

[0039] in

[0040] Ring A and Ring B are each independently a monocyclic or fused aromatic or heteroaromatic ring system, or a monocyclic or fused C3-C 10 Cycloalkyl (e.g. cyclohexyl) or a monocyclic or fused C3-C 10 heterocycle (e.g., phenyl, 2-pyridine, 3-pyridine or 4-pyridine, benzofuran-2(3H)-1, benzo[d][1,3]dioxole, naphthalene, tetrahydrothiophene 1,1-dioxide, thiazole, benzimidazole, piperidine, 1-methylpiperidine, thiophene, imidazole, 1-methylimidazole, isoquinoline);

[0041] 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), 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 )(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. 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, C(O)N(R 10 )(R 11 )(e.g. C(O)N(CH3)2), SO2R, SO2N(R 10 )(R 11 )(e.g., SO2N(CH3)2, SO2NHC(O)CH3); C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, 2-CH2-C6H4-Cl, 3-CH2-C6H4-Cl or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, pentyl); C1-C5 linear or branched haloalkyl (e.g., CF2CH3, CH2CF3); C1-C5 linear, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tert-butyl), optionally wherein at least one methylene (CH2) group in the alkoxy group is replaced by an oxygen atom (e.g., O-1-oxetanyl, O-2-oxetanyl); C1-C5 straight chain or branched thioalkoxy, C1-C5 straight chain or branched haloalkoxy (e.g., OCF3, OCHF2), C1-C5 straight chain or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocycle (e.g., thiophene, oxazole, oxadiazole, imidazole, furan, triazole, tetrazole, pyridine (2-pyridine, 3-pyridine or 4-pyridine), pyrimidine, pyrazine, oxetane (1-oxetane or 2-oxetane), indole, protonated or deprotonated pyridine oxide), substituted or unsubstituted aryl (e.g., phenyl) (wherein the substituents include: F, Cl, Br, I, C1-C5 straight chain or branched alkyl (e.g., methyl, ethyl), OH, alkoxy, N(R)2, CF3, CN or NO2), CH(CF3)(NH-R 10 );

[0042] or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring (e.g., [1,3]dioxole, furan-2(3H)-one, benzene, pyridine);

[0043] 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, 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-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, C(O)N(R 10 )(R 11 )(e.g. C(O)N(CH3)2), SO2R, SO2N(R 10 )(R 11)(e.g., SO2N(CH3)2); C1-C5 straight or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, tert-butyl, isobutyl, pentyl); C1-C5 straight or branched haloalkyl (e.g., CF2CH3, CH2CF3, CF2CH2CH3); C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl); C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxy alkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocycle (e.g., thiophene, oxazole, isoxazole, imidazole, furan, triazole, pyridine (2-pyridine, 3-pyridine or 4-pyridine), pyrimidine, pyrazine, oxetane (1-oxetane or 2-oxetane), indole), substituted or unsubstituted aryl (e.g., phenyl), (wherein the substituents include: F, Cl, Br, I, C1-C5 straight or branched chain alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2), CH(CF3)(NH-R 10 );

[0044] or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring (e.g., [1,3]dioxole, furan-2(3H)-one, benzene, cyclopentane, imidazole);

[0045] R5 is H; C1-C5 straight or branched, substituted or unsubstituted alkyl (e.g., methyl, CH2SH, ethyl, isopropyl); C1-C5 straight or branched haloalkyl (e.g., CF3), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2-pyridine, 3-pyridine and 4-pyridine)), (wherein the substituents include: F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2);

[0046] R6 is H, C1-C5 linear or branched alkyl (e.g., methyl), C(O)R or S(O)2R;

[0047] R8 is [CH2] p

[0048] Where p is between 1 and 10;

[0049] R9 is [CH] q , [C] q

[0050] Where q is between 2 and 10;

[0051] R 10 and R 11 Each is independently H, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), C(O)R or S(O)2R;

[0052] R is H, C1-C5 straight or branched chain alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain alkoxy, phenyl, aryl, or heteroaryl, or two geminal R substituents are linked together to form a 5- or 6-membered heterocyclic ring;

[0053] m, n, l and k are each independently an integer between 0 and 4;

[0054] Q1 and Q2 are each independently S, O, N-OH, CH2, C(R)2 or N-OMe;

[0055] or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), PROTAC, drug product, or any combination thereof.

[0056] In some embodiments, A 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 quinolyl. In other embodiments, A is isoquinolyl. 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 other embodiments, A is benzimidazole. In other embodiments, A is piperidine. In other embodiments, A is 1-methylpiperidine. In other embodiments, A is imidazole. In other embodiments, A is 1-methylimidazole. In other embodiments, A is thiophene. In other embodiments, A is isoquinoline. In other embodiments, A is a monocyclic or fused C3-C 10 In other embodiments, A is cyclohexyl.

[0057] In some embodiments, B is a phenyl ring. In other embodiments, B is pyridyl. In other embodiments, B is 2-pyridyl. In other embodiments, B is 3-pyridyl. In other embodiments, B is 4-pyridyl. 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 quinolyl. In other embodiments, B is isoquinolyl. 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 other embodiments, B is 1-methylpiperidine. In other embodiments, B is imidazole. In other embodiments, B is 1-methylimidazole. In other embodiments, B is thiophene. In other embodiments, B is isoquinoline.

[0058] In some embodiments, R1 is H. In other embodiments, R1 is F. In other embodiments, R1 is Cl. In other embodiments, R1 is Br. In other embodiments, R1 is I. In other embodiments, R1 is CF3. In other embodiments, R1 is OCD3. In other embodiments, R1 is NO2. In other embodiments, R1 is NH2. In other embodiments, R1 is R8-N(R 10 )(R 11 In other embodiments, R1 is CH2-NH2. In other embodiments, R1 is CH2-N(CH3)2). In other embodiments, R1 is R9-R8-N(R 10 )(R 11 In other embodiments, R1 is C≡C-CH2-NH2. In other embodiments, R1 is B(OH)2. In other embodiments, R1 is NHC(O)-R 10 In other embodiments, R1 is NHC(O)CH3. In other embodiments, R1 is NHCO-N(R 10 )(R 11 ). In other embodiments, R1 is NHC(O)N(CH3)2. In other embodiments, R1 is COOH. In other embodiments, R1 is C(O)OR 10 In other embodiments, R1 is C(O)O-CH(CH3)2. In other embodiments, R1 is C(O)O-CH3. In other embodiments, R1 is SO2N(R 10 )(R11). In other embodiments, R1 is SO2N(CH3)2. In other embodiments, R1 is SO2NHC(O)CH3. In other embodiments, R1 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R1 is methyl. In other embodiments, R1 is 2-CH2-C6H4-Cl. In other embodiments, R1 is 3-CH2-C6H4-Cl. In other embodiments, R1 is 4-CH2-C6H4-Cl. In other embodiments, R1 is ethyl. In other embodiments, R1 is propyl. In other embodiments, R1 is isopropyl. In other embodiments, R1 is tert-butyl. In other embodiments, R1 is isobutyl. In other embodiments, R1 is pentyl. In other embodiments, R1 is substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). In other embodiments, R1 is C1-C5 linear, branched, or cyclic alkoxy. In other embodiments, R1 is methoxy. In other embodiments, R1 is ethoxy. In other embodiments, R1 is propoxy. In other embodiments, R1 is isopropoxy. In other embodiments, R1 is O-CH2-cyclopropyl. In other embodiments, R1 is O-cyclobutyl. In other embodiments, R1 is O-cyclopentyl. In other embodiments, R1 is O-cyclohexyl. In other embodiments, R1 is O-1-oxetanyl. In other embodiments, R1 is O-2-oxetanyl. In other embodiments, R1 is 1-butoxy. In other embodiments, R1 is 2-butoxy. In other embodiments, R1 is O-tert-butyl. In other embodiments, R1 is a C1-C5 linear, branched, or cyclic alkoxy group, wherein at least one methylene group (CH2) in the alkoxy group is replaced by an oxygen atom (O). In other embodiments, R1 is O-1-oxetanyl. In other embodiments, R1 is O-2-oxetanyl. In other embodiments, R1 is a C1-C5 straight or branched haloalkoxy group. In other embodiments, R1 is OCF3. In other embodiments, R1 is OCHF2. In other embodiments, R1 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R1 is oxazole. In other embodiments, R1 is a methyl-substituted oxazole. In other embodiments, R1 is oxadiazole. In other embodiments, R1 is a methyl-substituted oxadiazole. In other embodiments, R1 is imidazole. In other embodiments, R1 is a methyl-substituted imidazole. In other embodiments, R1 is pyridine. In other embodiments, R1 is 2-pyridine. In other embodiments, R1 is 3-pyridine. In other embodiments, R1 is 4-pyridine. In other embodiments, R1 is tetrazole. In other embodiments, R1 is pyrimidine. In other embodiments, R1 is pyrazine.In other embodiments, R1 is oxetane. In other embodiments, R1 is 1-oxetane. In other embodiments, R1 is 2-oxetane. In other embodiments, R1 is indole. In other embodiments, R1 is pyridine oxide. In other embodiments, R1 is a protonated pyridine oxide. In other embodiments, R1 is a deprotonated pyridine oxide. In other embodiments, R1 is a substituted or unsubstituted aryl. In other embodiments, R1 is phenyl. In other embodiments, R1 is bromophenyl. In other embodiments, R1 is 2-bromophenyl. In other embodiments, R1 is 3-bromophenyl. In other embodiments, R1 is 4-bromophenyl. In other embodiments, R1 is R8-N(R). 10 )(R 11 ). In other embodiments, R1 is CH2-NH2.

[0059] In some embodiments, R2 is H. In other embodiments, R2 is F. In other embodiments, R2 is Cl. In other embodiments, R2 is Br. In other embodiments, R2 is I. In other embodiments, R2 is CF3. In other embodiments, R2 is OCD3. In other embodiments, R2 is NO2. In other embodiments, R2 is NH2. In other embodiments, R2 is R8-N(R 10 )(R 11 In other embodiments, R2 is CH2-NH2. In other embodiments, R2 is CH2-N(CH3)2). In other embodiments, R2 is R9-R8-N(R 10 )(R 11 In other embodiments, R2 is C≡C-CH2-NH2. In other embodiments, R2 is B(OH)2. In other embodiments, R2 is NHC(O)-R 10 In other embodiments, R2 is NHC(O)CH3. In other embodiments, R2 is NHCO-N(R 10 )(R 11 In other embodiments, R2 is NHC(O)N(CH3)2. In other embodiments, R2 is COOH. In other embodiments, R2 is C(O)OR 10 In other embodiments, R2 is C(O)O-CH(CH3)2. In other embodiments, R2 is C(O)O-CH3. In other embodiments, R2 is SO2N(R 10 )(R 11). In other embodiments, R2 is SO2N(CH3)2. In other embodiments, R2 is SO2NHC(O)CH3. In other embodiments, R2 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R2 is methyl. In other embodiments, R2 is 2-CH2-C6H4-Cl. In other embodiments, R2 is 3-CH2-C6H4-Cl. In other embodiments, R2 is 4-CH2-C6H4-Cl. In other embodiments, R2 is ethyl. In other embodiments, R2 is propyl. In other embodiments, R 2is isopropyl. In other embodiments, R2 is tert-butyl. In other embodiments, R2 is isobutyl. In other embodiments, R2 is pentyl. In other embodiments, R2 is a substituted or unsubstituted C3-C8 cycloalkyl group (e.g., cyclopropyl, cyclopentyl). In other embodiments, R2 is a C1-C5 linear, branched, or cyclic alkoxy group. In other embodiments, R2 is methoxy. In other embodiments, R2 is ethoxy. In other embodiments, R2 is propoxy. In other embodiments, R2 is isopropoxy. In other embodiments, R2 is O-CH2-cyclopropyl. In other embodiments, R2 is O-cyclobutyl. In other embodiments, R2 is O-cyclopentyl. In other embodiments, R2 is O-cyclohexyl. In other embodiments, R2 is O-1-oxetanyl. In other embodiments, R2 is O-2-oxetanyl. In other embodiments, R2 is 1-butoxy. In other embodiments, R2 is 2-butoxy. In other embodiments, R2 is O-tert-butyl. In other embodiments, R2 is a C1-C5 straight or branched haloalkoxy group. In other embodiments, R2 is OCF3. In other embodiments, R2 is OCHF2. In other embodiments, R2 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R2 is oxazole or a methyl-substituted oxazole. In other embodiments, R2 is oxadiazole or a methyl-substituted oxadiazole. In other embodiments, R2 is imidazole or a methyl-substituted imidazole. In other embodiments, R2 is pyridine. In other embodiments, R2 is 2-pyridine. In other embodiments, R2 is 3-pyridine. In other embodiments, R2 is 4-pyridine. In other embodiments, R2 is tetrazole. In other embodiments, R2 is pyrimidine. In other embodiments, R2 is pyrazine. In other embodiments, R2 is oxetane. In other embodiments, R2 is 1-oxetane. In other embodiments, R2 is 2-oxetane. In other embodiments, R2 is indole. In other embodiments, R2 is pyridine oxide. In other embodiments, R2 is protonated pyridine oxide. In other embodiments, R2 is deprotonated pyridine oxide. In other embodiments, R2 is substituted or unsubstituted aryl. In other embodiments, R2 is phenyl. In other embodiments, R2 is bromophenyl. In other embodiments, R2 is 2-bromophenyl. In other embodiments, R2 is 3-bromophenyl. In other embodiments, R2 is 4-bromophenyl. In other embodiments, R2 is R8-N(R 10 )(R 11 In other embodiments, R2 is CH2-NH2.

[0060] In some embodiments, R1 and R2 are linked together to form a [1,3] dioxole ring. In some embodiments, R1 and R2 are linked together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R1 and R2 are linked together to form a benzene ring. In some embodiments, R1 and R2 are linked together to form a pyridine ring.

[0061] In some embodiments, R3 is 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 other embodiments, R3 is CH2-O-CH3. In other embodiments, R3 is CF3. In other embodiments, R3 is R8-N(R 10 )(R 11 ). In other embodiments, R3 is CH2-NH2. In other embodiments, R3 is CH2-N(CH3)2. In other embodiments, R3 is COOH. In other embodiments, R3 is C(O)OR 10 In other embodiments, R3 is C(O)O-CH2CH3. In other embodiments, R3 is R8-C(O)-R 10 In other embodiments, R3 is CH2C(O)CH3. In other embodiments, R3 is C(O)-R 10 In other embodiments, R3 is C(O)-CH3. In other embodiments, R3 is C(O)-CH2CH3. In other embodiments, R3 is C(O)-CH2CH2CH3. In other embodiments, R3 is C1-C5 straight or branched C(O)-haloalkyl. In other embodiments, R3 is C(O)-CF3. In other embodiments, R3 is C(O)N(R 10 )(R 11 In other embodiments, R3 is C(O)N(CH3)2). In other embodiments, R3 is SO2N(R 10 )(R 11). In other embodiments, R3 is SO2N(CH3)2. In other embodiments, R3 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R3 is methyl. In other embodiments, R3 is C(OH)(CH3)(Ph). In other embodiments, R3 is ethyl. In other embodiments, R3 is propyl. In other embodiments, R3 is isopropyl. In other embodiments, R3 is tert-butyl. In other embodiments, R3 is isobutyl. In other embodiments, R3 is pentyl. In other embodiments, R3 is C1-C5 linear or branched haloalkyl. In other embodiments, R3 is CF2CH3. In other embodiments, R3 is CH2CF3. In other embodiments, R3 is CF2CH2CH3. In other embodiments, R3 is C1-C5 linear, branched, or cyclic alkoxy. In other embodiments, R3 is methoxy. In other embodiments, R3 is isopropoxy. In other embodiments, R3 is a substituted or unsubstituted C3-C8 cycloalkyl. In other embodiments, R3 is a cyclopropyl. In other embodiments, R3 is a cyclopentyl. In other embodiments, R3 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R3 is a thiophene. In other embodiments, R3 is an oxazole. In other embodiments, R3 is an isoxazole. In other embodiments, R3 is an imidazole. In other embodiments, R3 is a furan. In other embodiments, R3 is a triazole. In other embodiments, R3 is a pyridine. In other embodiments, R3 is a 2-pyridine. In other embodiments, R3 is a 3-pyridine. In other embodiments, R3 is a 4-pyridine. In other embodiments, R3 is a pyrimidine. In other embodiments, R3 is a pyrazine. In other embodiments, R3 is an oxetane. In other embodiments, R3 is a 1-oxetane. In other embodiments, R3 is a 2-oxetane. In other embodiments, R3 is an indole. In other embodiments, R3 is substituted or unsubstituted aryl. In other embodiments, R3 is phenyl. In other embodiments, R3 is CH(CF3)(NH-R 10 ).

[0062] In some embodiments, R4 is 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 10In other embodiments, R4 is CH2-O-CH3. In other embodiments, R4 is CF3. In other embodiments, R4 is R8-N(R 10 )(R 11 ). In other embodiments, R4 is CH2-NH2. In other embodiments, R4 is CH2-N(CH3)2. In other embodiments, R4 is COOH. In other embodiments, R4 is C(O)OR 10 In other embodiments, R4 is C(O)O-CH2CH3. In other embodiments, R4 is R8-C(O)-R 10 In other embodiments, R4 is CH2C(O)CH3. In other embodiments, R4 is C(O)-R 10 In other embodiments, R4 is C(O)-CH3. In other embodiments, R4 is C(O)-CH2CH3. In other embodiments, R4 is C(O)-CH2CH2CH3. In other embodiments, R4 is C1-C5 straight or branched C(O)-haloalkyl. In other embodiments, R4 is C(O)-CF3. In other embodiments, R4 is C(O)N(R 10 )(R 11 In other embodiments, R4 is C(O)N(CH3)2). In other embodiments, R4 is SO2N(R 10 )(R 11). In other embodiments, R4 is SO2N(CH3)2. In other embodiments, R4 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R4 is methyl. In other embodiments, R4 is C(OH)(CH3)(Ph). In other embodiments, R4 is ethyl. In other embodiments, R4 is propyl. In other embodiments, R4 is isopropyl. In other embodiments, R4 is tert-butyl. In other embodiments, R4 is isobutyl. In other embodiments, R4 is pentyl. In other embodiments, R4 is C1-C5 linear or branched haloalkyl. In other embodiments, R4 is CF2CH3. In other embodiments, R4 is CH2CF3. In other embodiments, R4 is CF2CH2CH3. In other embodiments, R4 is C1-C5 linear, branched, or cyclic alkoxy. In other embodiments, R4 is methoxy. In other embodiments, R4 is isopropoxy. In other embodiments, R4 is a substituted or unsubstituted C3-C8 cycloalkyl. In other embodiments, R4 is a cyclopropyl. In other embodiments, R4 is a cyclopentyl. In other embodiments, R4 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R4 is a thiophene. In other embodiments, R4 is an oxazole. In other embodiments, R4 is an isoxazole. In other embodiments, R4 is an imidazole. In other embodiments, R4 is a furan. In other embodiments, R4 is a triazole. In other embodiments, R4 is a pyridine. In other embodiments, R4 is a 2-pyridine. In other embodiments, R4 is a 3-pyridine. In other embodiments, R4 is a 4-pyridine. In other embodiments, R4 is a pyrimidine. In other embodiments, R4 is a pyrazine. In other embodiments, R4 is an oxetane. In other embodiments, R4 is a 1-oxetane. In other embodiments, R4 is a 2-oxetane. In other embodiments, R4 is an indole. In other embodiments, R4 is substituted or unsubstituted aryl. In other embodiments, R4 is phenyl. In other embodiments, R4 is CH(CF3)(NH-R 10 ).

[0063] In some embodiments, R3 and R4 are linked together to form a [1,3] dioxole ring. In some embodiments, R3 and R4 are linked together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R3 and R4 are linked together to form a benzene ring. In some embodiments, R3 and R4 are linked together to form a cyclopentene ring. In some embodiments, R3 and R4 are linked together to form an imidazole ring.

[0064] In some embodiments, R5 is H. In other embodiments, R5 is C1-C5 straight 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 C1-C5 straight or branched haloalkyl. In other embodiments, R5 is CF3. 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.

[0065] In some embodiments, R6 is H. In other embodiments, R6 is C1-C5 straight or branched chain alkyl. In other embodiments, R6 is methyl.

[0066] In some embodiments, R8 is CH2. In other embodiments, R8 is CH2CH2. In other embodiments, R8 is CH2CH2CH2.

[0067] In some embodiments, p is 1. In other embodiments, p is 2. In other embodiments, p is 3.

[0068] In some embodiments, R9 is C≡C.

[0069] In some embodiments, q is 2.

[0070] In some embodiments, R 10 is a C1-C5 straight or branched chain alkyl group. 10 is H. In other embodiments, R 10 is CH3. In other embodiments, R 10 is CH2CH3. In other embodiments, R 10 It is CH2CH2CH3.

[0071] In some embodiments, R 11 is a C1-C5 straight or branched chain alkyl group. 10 is H. In other embodiments, R 11 For CH3.

[0072] In some embodiments, R is H. In other embodiments, R is a C1-C5 straight or branched chain alkyl. In other embodiments, R is methyl. In other embodiments, R is ethyl.

[0073] In some embodiments, m is 1. In other embodiments, m is 0.

[0074] In some embodiments, n is 1. In other embodiments, n is 0.

[0075] In some embodiments, k is 1. In other embodiments, k is 0.

[0076] In some embodiments, l is 1. In other embodiments, l is 0.

[0077] In some embodiments, Q1 is O.

[0078] In some embodiments, Q2 is O.

[0079] In various embodiments, the present invention is directed to compounds represented by the structure of formula (II):

[0080]

[0081] in

[0082] 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), 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 )(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. 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, C(O)N(R 10 )(R 11 )(e.g. C(O)N(CH3)2), SO2R, SO2N(R 10 )(R 11 )(e.g., SO2N(CH3)2, SO2NHC(O)CH3); C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, 2-CH2-C6H4-Cl, 3-CH2-C6H4-Cl or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, pentyl); C1-C5 linear or branched haloalkyl (e.g., CF2CH3, CH2CF3); C1-C5 linear, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tert-butyl), optionally wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom (O) (e.g., O-1-oxetanyl, O-2-oxetanyl) ), 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), substituted or unsubstituted C3-C8 heterocycle (e.g., thiophene, oxazole, oxadiazole, imidazole, furan, triazole, tetrazole, pyridine (2-pyridine, 3-pyridine or 4-pyridine), pyrimidine, pyrazine, oxetane (1-oxetane or 2-oxetane), indole, protonated or deprotonated pyridine oxide), substituted or unsubstituted aryl (e.g., phenyl) (wherein the substituents include: F, Cl, Br, I, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), OH, alkoxy, N(R)2, CF3, CN or NO2), CH(CF3)(NH-R 10 );

[0083] or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring (e.g., [1,3]dioxole, furan-2(3H)-one, benzene, pyridine);

[0084] 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, 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-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, C(O)N(R 10 )(R 11 )(e.g. C(O)N(CH3)2), SO2R, SO2N(R 10 )(R 11 )(e.g., SO2N(CH3)2); C1-C5 straight or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, tert-butyl, isobutyl, pentyl); C1-C5 straight or branched haloalkyl (e.g., CF2CH3, CH2CF3, CF2CH2CH3); C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl); C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxy alkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocycle (e.g., thiophene, oxazole, isoxazole, imidazole, furan, triazole, pyridine (2-pyridine, 3-pyridine or 4-pyridine), pyrimidine, pyrazine, oxetane (1-oxetane or 2-oxetane), indole), substituted or unsubstituted aryl (e.g., phenyl), (wherein the substituents include: F, Cl, Br, I, C1-C5 straight or branched chain alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2), CH(CF3)(NH-R10 );

[0085] or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring (e.g., [1,3]dioxole, furan-2(3H)-one, benzene, cyclopentane, imidazole);

[0086] R5 is H; C1-C5 straight or branched, substituted or unsubstituted alkyl (e.g., methyl, CH2SH, ethyl, isopropyl); C1-C5 straight or branched haloalkyl (e.g., CF3), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2-pyridine, 3-pyridine and 4-pyridine)), (wherein the substituents include: F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2);

[0087] R6 is H, C1-C5 linear or branched alkyl (e.g., methyl), C(O)R or S(O)2R;

[0088] R8 is [CH2] p

[0089] Where p is between 1 and 10;

[0090] R9 is [CH] q , [C] q

[0091] Where q is between 2 and 10;

[0092] R 10 and R 11 Each is independently H, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), C(O)R or S(O)2R;

[0093] R is H, C1-C5 straight or branched chain alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain alkoxy, phenyl, aryl, or heteroaryl, or two geminal R substituents are linked together to form a 5- or 6-membered heterocyclic ring;

[0094] m, n, l and k are each independently an integer between 0 and 4;

[0095] Q1 and Q2 are each independently S, O, N-OH, CH2, C(R)2 or N-OMe;

[0096] X1, X2, X3, X4, X5, X6, X7, X8, X9 or X 10 are each independently C or N;

[0097] or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), PROTAC, drug product, or any combination thereof.

[0098] In some embodiments, R1 is H. In other embodiments, R1 is F. In other embodiments, R1 is Cl. In other embodiments, R1 is Br. In other embodiments, R1 is I. In other embodiments, R1 is CF3. In other embodiments, R1 is OCD3. In other embodiments, R1 is NO2. In other embodiments, R1 is NH2. In other embodiments, R1 is R8-N(R 10 )(R 11 In other embodiments, R1 is CH2-NH2. In other embodiments, R1 is CH2-N(CH3)2). In other embodiments, R1 is R9-R8-N(R 10 )(R 11 In other embodiments, R1 is CC-CH2-NH2. In other embodiments, R1 is B(OH)2. In other embodiments, R1 is NHC(O)-R 10 In other embodiments, R1 is NHC(O)CH3. In other embodiments, R1 is NHCO-N(R 10 )(R 11 ). In other embodiments, R1 is NHC(O)N(CH3)2. In other embodiments, R1 is COOH. In other embodiments, R1 is C(O)OR 10 In other embodiments, R1 is C(O)O-CH(CH3)2. In other embodiments, R1 is C(O)O-CH3. In other embodiments, R1 is SO2N(R 10 )(R 11). In other embodiments, R1 is SO2N(CH3)2. In other embodiments, R1 is SO2NHC(O)CH3. In other embodiments, R1 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R1 is methyl. In other embodiments, R1 is 2-CH2-C6H4-Cl. In other embodiments, R1 is 3-CH2-C6H4-Cl. In other embodiments, R1 is 4-CH2-C6H4-Cl. In other embodiments, R1 is ethyl. In other embodiments, R1 is propyl. In other embodiments, R1 is isopropyl. In other embodiments, R1 is tert-butyl. In other embodiments, R1 is isobutyl. In other embodiments, R1 is pentyl. In other embodiments, R1 is substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). In other embodiments, R1 is C1-C5 linear, branched, or cyclic alkoxy. In other embodiments, R1 is methoxy. In other embodiments, R1 is ethoxy. In other embodiments, R1 is propoxy. In other embodiments, R1 is isopropoxy. In other embodiments, R1 is O-CH2-cyclopropyl. In other embodiments, R1 is O-cyclobutyl. In other embodiments, R1 is O-cyclopentyl. In other embodiments, R1 is O-cyclohexyl. In other embodiments, R1 is O-1-oxetanyl. In other embodiments, R1 is O-2-oxetanyl. In other embodiments, R1 is 1-butoxy. In other embodiments, R1 is 2-butoxy. In other embodiments, R1 is O-tert-butyl. In other embodiments, R1 is a C1-C5 linear, branched, or cyclic alkoxy group, wherein at least one methylene group (CH2) in the alkoxy group is replaced by an oxygen atom (O). In other embodiments, R1 is O-1-oxetanyl. In other embodiments, R1 is O-2-oxetanyl. In other embodiments, R1 is a C1-C5 straight or branched haloalkoxy group. In other embodiments, R1 is OCF3. In other embodiments, R1 is OCHF2. In other embodiments, R1 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R1 is oxazole. In other embodiments, R1 is a methyl-substituted oxazole. In other embodiments, R1 is oxadiazole. In other embodiments, R1 is a methyl-substituted oxadiazole. In other embodiments, R1 is imidazole. In other embodiments, R1 is a methyl-substituted imidazole. In other embodiments, R1 is pyridine. In other embodiments, R1 is 2-pyridine. In other embodiments, R1 is 3-pyridine. In other embodiments, R1 is 4-pyridine. In other embodiments, R1 is tetrazole. In other embodiments, R1 is pyrimidine. In other embodiments, R1 is pyrazine.In other embodiments, R1 is oxetane. In other embodiments, R1 is 1-oxetane. In other embodiments, R1 is 2-oxetane. In other embodiments, R1 is indole. In other embodiments, R1 is pyridine oxide. In other embodiments, R1 is a protonated pyridine oxide. In other embodiments, R1 is a deprotonated pyridine oxide. In other embodiments, R1 is a substituted or unsubstituted aryl. In other embodiments, R1 is phenyl. In other embodiments, R1 is bromophenyl. In other embodiments, R1 is 2-bromophenyl. In other embodiments, R1 is 3-bromophenyl. In other embodiments, R1 is 4-bromophenyl. In other embodiments, R1 is R8-N(R). 10 )(R 11 ). In other embodiments, R1 is CH2-NH2.

[0099] In some embodiments, R2 is H. In other embodiments, R2 is F. In other embodiments, R2 is Cl. In other embodiments, R2 is Br. In other embodiments, R2 is I. In other embodiments, R2 is CF3. In other embodiments, R2 is OCD3. In other embodiments, R2 is NO2. In other embodiments, R2 is NH2. In other embodiments, R2 is R8-N(R 10 )(R 11 In other embodiments, R2 is CH2-NH2. In other embodiments, R2 is CH2-N(CH3)2). In other embodiments, R2 is R9-R8-N(R 10 )(R 11 In other embodiments, R2 is C≡C-CH2-NH2. In other embodiments, R2 is B(OH)2. In other embodiments, R2 is NHC(O)-R 10 In other embodiments, R2 is NHC(O)CH3. In other embodiments, R2 is NHCO-N(R 10 )(R 11 ). In other embodiments, R2 is NHC(O)N(CH3)2. In other embodiments, R2 is COOH. In other embodiments, R2 is C(O)OR 10 In other embodiments, R2 is C(O)O-CH(CH3)2. In other embodiments, R2 is C(O)O-CH3. In other embodiments, R2 is SO2N(R 10 )(R 11). In other embodiments, R2 is SO2N(CH3)2. In other embodiments, R2 is SO2NHC(O)CH3. In other embodiments, R2 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R2 is methyl. In other embodiments, R2 is 2-CH2-C6H4-Cl. In other embodiments, R2 is 3-CH2-C6H4-Cl. In other embodiments, R2 is 4-CH2-C6H4-Cl. In other embodiments, R2 is ethyl. In other embodiments, R2 is propyl. In other embodiments, R2 is isopropyl. In other embodiments, R2 is tert-butyl. In other embodiments, R2 is isobutyl. In other embodiments, R2 is pentyl. In other embodiments, R2 is substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). In other embodiments, R2 is C1-C5 linear, branched, or cyclic alkoxy. In other embodiments, R2 is methoxy. In other embodiments, R2 is ethoxy. In other embodiments, R2 is propoxy. In other embodiments, R2 is isopropoxy. In other embodiments, R2 is O-CH2-cyclopropyl. In other embodiments, R2 is O-cyclobutyl. In other embodiments, R2 is O-cyclopentyl. In other embodiments, R2 is O-cyclohexyl. In other embodiments, R2 is O-1-oxetanyl. In other embodiments, R2 is O-2-oxetanyl. In other embodiments, R2 is 1-butoxy. In other embodiments, R2 is 2-butoxy. In other embodiments, R2 is O-tert-butyl. In other embodiments, R2 is C1-C5 straight or branched haloalkoxy. In other embodiments, R2 is OCF3. In other embodiments, R2 is OCHF2. In other embodiments, R2 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R2 is oxazole or a methyl-substituted oxazole. In other embodiments, R2 is oxadiazole or a methyl-substituted oxadiazole. In other embodiments, R2 is imidazole or a methyl-substituted imidazole. In other embodiments, R2 is pyridine. In other embodiments, R2 is 2-pyridine. In other embodiments, R2 is 3-pyridine. In other embodiments, R2 is 4-pyridine. In other embodiments, R2 is tetrazole. In other embodiments, R2 is pyrimidine. In other embodiments, R2 is pyrazine. In other embodiments, R2 is oxetane. In other embodiments, R2 is 1-oxetane. In other embodiments, R2 is 2-oxetane. In other embodiments, R2 is indole. In other embodiments, R2 is a pyridine oxide. In other embodiments, R2 is a protonated pyridine oxide. In other embodiments, R2 is a deprotonated pyridine oxide.In other embodiments, R2 is substituted or unsubstituted aryl. In other embodiments, R2 is phenyl. In other embodiments, R2 is bromophenyl. In other embodiments, R2 is 2-bromophenyl. In other embodiments, R2 is 3-bromophenyl. In other embodiments, R2 is 4-bromophenyl. In other embodiments, R2 is R8-N(R). 10 )(R 11 In other embodiments, R2 is CH2-NH2.

[0100] In some embodiments, R1 and R2 are linked together to form a [1,3]dioxole ring. In some embodiments, R1 and R2 are linked together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R1 and R2 are linked together to form a benzene ring.

[0101] In some embodiments, R3 is 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 other embodiments, R3 is CH2-O-CH3. In other embodiments, R3 is CF3. In other embodiments, R3 is R8-N(R 10 )(R 11 ). In other embodiments, R3 is CH2-NH2. In other embodiments, R3 is CH2-N(CH3)2. In other embodiments, R3 is COOH. In other embodiments, R3 is C(O)OR 10 In other embodiments, R3 is C(O)O-CH2CH3. In other embodiments, R3 is R8-C(O)-R 10 In other embodiments, R3 is CH2C(O)CH3. In other embodiments, R3 is C(O)-R 10 In other embodiments, R3 is C(O)-CH3. In other embodiments, R3 is C(O)-CH2CH3. In other embodiments, R3 is C(O)-CH2CH2CH3. In other embodiments, R3 is C1-C5 straight or branched C(O)-haloalkyl. In other embodiments, R3 is C(O)-CF3. In other embodiments, R3 is C(O)N(R 10 )(R 11In other embodiments, R3 is C(O)N(CH3)2). In other embodiments, R3 is SO2N(R 10 )(R 11 ). In other embodiments, R3 is SO2N(CH3)2. In other embodiments, R3 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R3 is methyl. In other embodiments, R3 is C(OH)(CH3)(Ph). In other embodiments, R3 is ethyl. In other embodiments, R3 is propyl. In other embodiments, R3 is isopropyl. In other embodiments, R3 is tert-butyl. In other embodiments, R3 is isobutyl. In other embodiments, R3 is pentyl. In other embodiments, R3 is C1-C5 linear or branched haloalkyl. In other embodiments, R3 is CF2CH3. In other embodiments, R3 is CH2CF3. In other embodiments, R3 is CF2CH2CH3. In other embodiments, R3 is C1-C5 linear, branched, or cyclic alkoxy. In other embodiments, R3 is methoxy. In other embodiments, R3 is isopropoxy. In other embodiments, R3 is a substituted or unsubstituted C3-C8 cycloalkyl. In other embodiments, R3 is a cyclopropyl. In other embodiments, R3 is a cyclopentyl. In other embodiments, R3 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R3 is a thiophene. In other embodiments, R3 is an oxazole. In other embodiments, R3 is an isoxazole. In other embodiments, R3 is an imidazole. In other embodiments, R3 is a furan. In other embodiments, R3 is a triazole. In other embodiments, R3 is a pyridine. In other embodiments, R3 is a 2-pyridine. In other embodiments, R3 is a 3-pyridine. In other embodiments, R3 is a 4-pyridine. In other embodiments, R3 is a pyrimidine. In other embodiments, R3 is a pyrazine. In other embodiments, R3 is an oxetane. In other embodiments, R3 is a 1-oxetane. In other embodiments, R3 is a 2-oxetane. In other embodiments, R3 is an indole. In other embodiments, R3 is substituted or unsubstituted aryl. In other embodiments, R3 is phenyl. In other embodiments, R3 is CH(CF3)(NH-R 10 ).

[0102] In some embodiments, R4 is 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 other embodiments, R4 is CH2-O-CH3. In other embodiments, R4 is CF3. In other embodiments, R4 is R8-N(R 10 )(R 11 ). In other embodiments, R4 is CH2-NH2. In other embodiments, R4 is CH2-N(CH3)2. In other embodiments, R4 is COOH. In other embodiments, R4 is C(O)OR 10 In other embodiments, R4 is C(O)O-CH2CH3. In other embodiments, R4 is R8-C(O)-R 10 In other embodiments, R4 is CH2C(O)CH3. In other embodiments, R4 is C(O)-R 10 In other embodiments, R4 is C(O)-CH3. In other embodiments, R4 is C(O)-CH2CH3. In other embodiments, R4 is C(O)-CH2CH2CH3. In other embodiments, R4 is C1-C5 straight or branched C(O)-haloalkyl. In other embodiments, R4 is C(O)-CF3. In other embodiments, R4 is C(O)N(R 10 )(R 11 In other embodiments, R4 is C(O)N(CH3)2). In other embodiments, R4 is SO2N(R 10 )(R 11). In other embodiments, R4 is SO2N(CH3)2. In other embodiments, R4 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R4 is methyl. In other embodiments, R4 is C(OH)(CH3)(Ph). In other embodiments, R4 is ethyl. In other embodiments, R4 is propyl. In other embodiments, R4 is isopropyl. In other embodiments, R4 is tert-butyl. In other embodiments, R4 is isobutyl. In other embodiments, R4 is pentyl. In other embodiments, R4 is C1-C5 linear or branched haloalkyl. In other embodiments, R4 is CF2CH3. In other embodiments, R4 is CH2CF3. In other embodiments, R4 is CF2CH2CH3. In other embodiments, R4 is C1-C5 linear, branched, or cyclic alkoxy. In other embodiments, R4 is methoxy. In other embodiments, R4 is isopropoxy. In other embodiments, R4 is a substituted or unsubstituted C3-C8 cycloalkyl. In other embodiments, R4 is a cyclopropyl. In other embodiments, R4 is a cyclopentyl. In other embodiments, R4 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R4 is a thiophene. In other embodiments, R4 is an oxazole. In other embodiments, R4 is an isoxazole. In other embodiments, R4 is an imidazole. In other embodiments, R4 is a furan. In other embodiments, R4 is a triazole. In other embodiments, R4 is a pyridine. In other embodiments, R4 is a 2-pyridine. In other embodiments, R4 is a 3-pyridine. In other embodiments, R4 is a 4-pyridine. In other embodiments, R4 is a pyrimidine. In other embodiments, R4 is a pyrazine. In other embodiments, R4 is an oxetane. In other embodiments, R4 is a 1-oxetane. In other embodiments, R4 is a 2-oxetane. In other embodiments, R4 is an indole. In other embodiments, R4 is substituted or unsubstituted aryl. In other embodiments, R4 is phenyl. In other embodiments, R4 is CH(CF3)(NH-R 10 ).

[0103] In some embodiments, R3 and R4 are linked together to form a [1,3] dioxole ring. In some embodiments, R3 and R4 are linked together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R3 and R4 are linked together to form a benzene ring. In some embodiments, R3 and R4 are linked together to form a cyclopentane ring. In some embodiments, R3 and R4 are linked together to form an imidazole ring.

[0104] In some embodiments, R5 is H. In other embodiments, R5 is C1-C5 straight 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 C1-C5 straight or branched haloalkyl. In other embodiments, R5 is CF3. 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.

[0105] In some embodiments, R6 is H. In other embodiments, R6 is C1-C5 straight or branched chain alkyl. In other embodiments, R6 is methyl.

[0106] In some embodiments, R8 is CH2. In other embodiments, R8 is CH2CH2. In other embodiments, R8 is CH2CH2CH2.

[0107] In some embodiments, p is 1. In other embodiments, p is 2. In other embodiments, p is 3.

[0108] In some embodiments, R9 is C≡C.

[0109] In some embodiments, q is 2.

[0110] In some embodiments, R 10 is a C1-C5 straight or branched chain alkyl group. 10 is CH3. In other embodiments, R 10 is CH2CH3. In other embodiments, R 10 It is CH2CH2CH3.

[0111] In some embodiments, R 11 is a C1-C5 straight or branched chain alkyl group. 11 For CH3.

[0112] In some embodiments, R is H. In other embodiments, R is a C1-C5 straight or branched chain alkyl. In other embodiments, R is methyl. In other embodiments, R is ethyl.

[0113] In some embodiments, m is 1. In other embodiments, m is 0.

[0114] In some embodiments, n is 1. In other embodiments, n is 0.

[0115] In some embodiments, k is 1. In other embodiments, k is 0.

[0116] In some embodiments, l is 1. In other embodiments, l is 0.

[0117] In some embodiments, Q1 is O.

[0118] In some embodiments, Q2 is O.

[0119] In some embodiments, X1 is C. In other embodiments, X1 is N.

[0120] In some embodiments, X2 is C. In other embodiments, X2 is N.

[0121] In some embodiments, X3 is C. In other embodiments, X3 is N.

[0122] In some embodiments, X4 is C. In other embodiments, X4 is N.

[0123] In some embodiments, X6 is C. In other embodiments, X6 is N.

[0124] In some embodiments, X7 is C. In other embodiments, X7 is N.

[0125] In some embodiments, X8 is C. In other embodiments, X8 is N.

[0126] In some embodiments, X9 is C. In other embodiments, X9 is N.

[0127] In some embodiments, X 10 is C. In other embodiments, X 10 is N.

[0128] In various embodiments, the present invention is directed to compounds represented by the structure of formula (III):

[0129]

[0130] in

[0131] 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), 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 )(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. 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, C(O)N(R 10 )(R 11 )(e.g. C(O)N(CH3)2), SO2R, SO2N(R 10 )(R 11)(e.g., SO2N(CH3)2, SO2NHC(O)CH3); C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, 2,3-CH2-C6H4-Cl or -CH2-C6H4-Cl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, pentyl); C1-C5 linear or branched haloalkyl (e.g., CF2CH3, CH2CF3); C1-C5 linear, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tert-butyl), optionally wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom (O) (e.g., O-1-oxetanyl, O-2-oxetanyl); C1-C5 a linear or branched thioalkoxy group, a C1-C5 linear or branched haloalkoxy group (e.g., OCF3, OCHF2), a C1-C5 linear or branched alkoxyalkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group (e.g., cyclopropyl, cyclopentyl), a substituted or unsubstituted C3-C8 heterocycle (e.g., thiophene, oxazole, oxadiazole, imidazole, furan, triazole, tetrazole, pyridine (2-pyridine, 3-pyridine, or 4-pyridine), pyrimidine, pyrazine, oxetane (1-oxetane or 2-oxetane), indole, a protonated or deprotonated pyridine oxide), a substituted or unsubstituted aryl group (e.g., phenyl) (wherein the substituents include: F, Cl, Br, I, a C1-C5 linear or branched alkyl group (e.g., methyl, ethyl), OH, alkoxy, N(R)2, CF3, CN, or NO2), CH(CF3)(NH—R 10 );

[0132] or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring (e.g., [1,3]dioxole, furan-2(3H)-one, benzene, pyridine);

[0133] 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, 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-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, C(O)N(R 10 )(R 11 )(e.g. C(O)N(CH3)2), SO2R, SO2N(R 10 )(R 11 )(e.g., SO2N(CH3)2); C1-C5 straight or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, tert-butyl, isobutyl, pentyl); C1-C5 straight or branched haloalkyl (e.g., CF2CH3, CH2CF3, CF2CH2CH3); C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl); C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxy oxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocycle (e.g., thiophene, oxazole, isoxazole, imidazole, furan, triazole, pyridine (2-pyridine, 3-pyridine or 4-pyridine), pyrimidine, pyrazine, oxetane (1-oxetane or 2-oxetane), indole), substituted or unsubstituted aryl (e.g., phenyl), (wherein the substituents include: F, Cl, Br, I, C1-C5 straight or branched chain alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2), CH(CF3)(NH-R 10 );

[0134] or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring (e.g., [1,3]dioxole, furan-2(3H)-one, benzene, cyclopentane, imidazole);

[0135] R5 is H; C1-C5 straight or branched, substituted or unsubstituted alkyl (e.g., methyl, CH2SH, ethyl, isopropyl); C1-C5 straight or branched haloalkyl (e.g., CF3), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2-pyridine, 3-pyridine and 4-pyridine)), (wherein the substituents include: F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2);

[0136] R6 is H, C1-C5 linear or branched alkyl (e.g., methyl), C(O)R or S(O)2R;

[0137] R8 is [CH2] p

[0138] Where p is between 1 and 10;

[0139] R9 is [CH] q , [C] q

[0140] Where q is between 2 and 10;

[0141] R 10 and R 11 Each is independently H, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), C(O)R or S(O)2R;

[0142] R is H, C1-C5 straight or branched chain alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain alkoxy, phenyl, aryl, or heteroaryl, or two geminal R substituents are linked together to form a 5- or 6-membered heterocyclic ring;

[0143] Q1 and Q2 are each independently S, O, N-OH, CH2, C(R)2 or N-OMe;

[0144] X3 and X4 are each independently C or N, wherein if X3 is N, R4 is not present.

[0145] X6, X7 and X8 are each independently C or N, wherein if X8 is N, R2 is absent;

[0146] or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), PROTAC, drug product, or any combination thereof.

[0147] In some embodiments, R1 is H. In other embodiments, R1 is F. In other embodiments, R1 is Cl. In other embodiments, R1 is Br. In other embodiments, R1 is I. In other embodiments, R1 is C(O)OR 10 In other embodiments, R1 is C(O)O-CH3. In other embodiments, R1 is CF3. In other embodiments, R1 is OCD3. In other embodiments, R1 is NO2. In other embodiments, R1 is NH2. In other embodiments, R1 is R8-N(R 10 )(R 11 In other embodiments, R1 is CH2-NH2. In other embodiments, R1 is CH2-N(CH3)2). In other embodiments, R1 is R9-R8-N(R 10 )(R 11 In other embodiments, R1 is CC-CH2-NH2. In other embodiments, R1 is B(OH)2. In other embodiments, R1 is C1-C5 straight or branched chain haloalkoxy. In other embodiments, R1 is OCF3. In other embodiments, R1 is OCHF2. In other embodiments, R1 is COOH. In other embodiments, R1 is SO2N(R 10 )(R 11). In other embodiments, R1 is SO2N(CH3)2. In other embodiments, R1 is SO2NHC(O)CH3. In other embodiments, R1 is C(O)O-CH(CH3)2. In other embodiments, R1 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R1 is pyridine. In other embodiments, R1 is 2-pyridine. In other embodiments, R1 is 3-pyridine. In other embodiments, R1 is 4-pyridine. In other embodiments, R1 is oxazole. In other embodiments, R1 is a methyl-substituted oxazole. In other embodiments, R1 is oxadiazole. In other embodiments, R1 is a methyl-substituted oxadiazole. In other embodiments, R1 is imidazole. In other embodiments, R1 is a methyl-substituted imidazole. In other embodiments, R1 is tetrazole. In other embodiments, R1 is pyrimidine. In other embodiments, R1 is pyrazine. In other embodiments, R1 is oxetane. In other embodiments, R1 is 1-oxetane. In other embodiments, R1 is 2-oxetane. In other embodiments, R1 is indole. In other embodiments, R1 is a pyridine oxide. In other embodiments, R1 is a protonated pyridine oxide. In other embodiments, R1 is a deprotonated pyridine oxide. In other embodiments, R1 is a substituted or unsubstituted aryl group. In other embodiments, R1 is phenyl. In other embodiments, R1 is bromophenyl. In other embodiments, R1 is 2-bromophenyl. In other embodiments, R1 is 3-bromophenyl. In other embodiments, R1 is 4-bromophenyl. In other embodiments, R1 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R1 is methyl. In other embodiments, R1 is 2-CH2-C6H4-Cl. In other embodiments, R1 is 3-CH2-C6H4-Cl. In other embodiments, R1 is 4-CH2-C6H4-Cl. In other embodiments, R1 is ethyl. In other embodiments, R1 is propyl. In other embodiments, R1 is isopropyl. In other embodiments, R1 is tert-butyl. In other embodiments, R1 is isobutyl. In other embodiments, R1 is pentyl. In other embodiments, R1 is substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). In other embodiments, R1 is C1-C5 linear, branched, or cyclic alkoxy. In other embodiments, R1 is methoxy. In other embodiments, R1 is ethoxy. In other embodiments, R1 is propoxy. In other embodiments, R1 is isopropoxy. In other embodiments, R1 is O-cyclobutyl. In other embodiments, R1 is O-cyclopentyl. In other embodiments, R1 is O-cyclohexyl. In other embodiments, R1 is 1-butoxy.In other embodiments, R1 is 2-butoxy. In other embodiments, R1 is O-tert-butyl. In other embodiments, R1 is a C1-C5 linear, branched, or cyclic alkoxy group, wherein at least one methylene group (CH2) in the alkoxy group is replaced by an oxygen atom (O). In other embodiments, R1 is O-1-oxetanyl. In other embodiments, R1 is O-2-oxetanyl. In other embodiments, R1 is R8-N(R). 10 )(R 11 ). In other embodiments, R1 is CH2-NH2.

[0148] In some embodiments, R2 is H. In other embodiments, R2 is F. In other embodiments, R2 is Cl. In other embodiments, R2 is Br. In other embodiments, R2 is I. In other embodiments, R2 is CF3. In other embodiments, R2 is OCD3. In other embodiments, R2 is a C1-C5 straight or branched haloalkoxy. In other embodiments, R2 is OCF3. In other embodiments, R2 is OCHF2. In other embodiments, R2 is SO2N(R 10 )(R 11 In other embodiments, R2 is SO2N(CH3)2. In other embodiments, R2 is SO2NHC(O)CH3. In other embodiments, R2 is NO2. In other embodiments, R2 is NH2. In other embodiments, R2 is R8-N(R 10 )(R 11 In other embodiments, R2 is CH2-NH2. In other embodiments, R2 is CH2-N(CH3)2). In other embodiments, R2 is R9-R8-N(R 10 )(R 11 In other embodiments, R2 is C≡C-CH2-NH2. In other embodiments, R2 is B(OH)2. In other embodiments, R2 is NHC(O)-R 10 In other embodiments, R2 is NHC(O)CH3. In other embodiments, R2 is NHCO-N(R 10 )(R 11). In other embodiments, R2 is NHC(O)N(CH3)2. In other embodiments, R2 is COOH. In other embodiments, R2 is ethoxy. In other embodiments, R2 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R2 is methyl. In other embodiments, R2 is 2-CH2-C6H4-Cl. In other embodiments, R2 is 3-CH2-C6H4-Cl. In other embodiments, R2 is 4-CH2-C6H4-Cl. In other embodiments, R2 is ethyl. In other embodiments, R2 is propyl. In other embodiments, R2 is isopropyl. In other embodiments, R2 is tert-butyl. In other embodiments, R2 is isobutyl. In other embodiments, R2 is pentyl. In other embodiments, R2 is substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). In other embodiments, R2 is a C1-C5 linear, branched, or cyclic alkoxy group. In other embodiments, R2 is methoxy. In other embodiments, R2 is ethoxy. In other embodiments, R2 is propoxy. In other embodiments, R2 is isopropoxy. In other embodiments, R2 is O-CH2-cyclopropyl. In other embodiments, R2 is O-cyclobutyl. In other embodiments, R2 is O-cyclopentyl. In other embodiments, R2 is O-cyclohexyl. In other embodiments, R2 is O-1-oxetanyl. In other embodiments, R2 is O-2-oxetanyl. In other embodiments, R2 is 1-butoxy. In other embodiments, R2 is 2-butoxy. In other embodiments, R2 is O-tert-butyl. In other embodiments, R2 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R2 is pyridine. In other embodiments, R2 is 2-pyridine. In other embodiments, R2 is 3-pyridine. In other embodiments, R2 is 4-pyridine. In other embodiments, R2 is oxazole or a methyl-substituted oxazole. In other embodiments, R2 is oxadiazole or a methyl-substituted oxadiazole. In other embodiments, R2 is imidazole or a methyl-substituted imidazole. In other embodiments, R2 is tetrazole. In other embodiments, R2 is pyrimidine. In other embodiments, R2 is pyrazine. In other embodiments, R2 is oxetane. In other embodiments, R2 is 1-oxetane. In other embodiments, R2 is 2-oxetane. In other embodiments, R2 is indole. In other embodiments, R2 is pyridine oxide. In other embodiments, R2 is a protonated pyridine oxide. In other embodiments, R2 is a deprotonated pyridine oxide. In other embodiments, R2 is a substituted or unsubstituted aryl group. In other embodiments, R2 is phenyl. In other embodiments, R2 is bromophenyl.In other embodiments, R2 is 2-bromophenyl. In other embodiments, R2 is 3-bromophenyl. In other embodiments, R2 is 4-bromophenyl. In other embodiments, R2 is R8-N(R. 10 )(R 11 In other embodiments, R2 is CH2-NH2.

[0149] In some embodiments, R1 and R2 are linked together to form a [1,3] dioxole ring. In some embodiments, R1 and R2 are linked together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R1 and R2 are linked together to form a benzene ring. In some embodiments, R1 and R2 are linked together to form a pyridine ring.

[0150] In some embodiments, R3 is H. In other embodiments, R3 is a C1-C5 straight or branched haloalkyl group. In other embodiments, R3 is CF2CH3. In other embodiments, R3 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R3 is furan. In other embodiments, R3 is thiophene. In other embodiments, R3 is pyrimidine. In other embodiments, R3 is pyrazine. In other embodiments, R3 is imidazole. In other embodiments, R3 is oxazole. In other embodiments, R3 is isoxazole. In other embodiments, R3 is triazole. In other embodiments, R3 is oxetane. In other embodiments, R3 is 1-oxetane. In other embodiments, R3 is 2-oxetane. In other embodiments, R3 is indole. In other embodiments, R3 is C(O)-R 10 In other embodiments, R3 is C(O)-CH3. In other embodiments, R3 is C(O)-CH2CH2CH3. In other embodiments, R3 is C(O)N(R 10 )(R 11 In other embodiments, R3 is C(O)N(CH3)2). In other embodiments, R3 is R8-C(O)-R 10. In other embodiments, R3 is CH2C(O)CH3. In other embodiments, R3 is a substituted or unsubstituted C3-C8 cycloalkyl group. In other embodiments, R3 is a cyclopropyl group. In other embodiments, R3 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R3 is a methyl group. In other embodiments, R3 is C(OH)(CH3)(Ph). In other embodiments, R3 is an ethyl group. In other embodiments, R3 is a propyl group. In other embodiments, R3 is an isopropyl group. In other embodiments, R3 is an isobutyl group. In other embodiments, R3 is a tert-butyl group. In other embodiments, R3 is a pentyl group. 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 C(O)OR 10 In other embodiments, R3 is C(O)O-CH2CH3. In other embodiments, R3 is -R8-OR 10 In other embodiments, R3 is CH2-O-CH3. In other embodiments, R3 is C1-C5 straight or branched chain haloalkyl. In other embodiments, R3 is CH2CF3. In other embodiments, R3 is CF2CH2CH3. In other embodiments, R3 is substituted or unsubstituted C3-C8 cycloalkyl. In other embodiments, R3 is cyclopentyl. In other embodiments, R3 is C(O)OR 10 In other embodiments, R3 is C(O)O-CH2CH3. In other embodiments, R3 is substituted or unsubstituted aryl. In other embodiments, R3 is phenyl. In other embodiments, R3 is pyridine. In other embodiments, R3 is 2-pyridine. In other embodiments, R3 is 3-pyridine. In other embodiments, R3 is 4-pyridine. In other embodiments, R3 is SO2N(R 10 )(R 11 In other embodiments, R3 is SO2N(CH3)2. In other embodiments, R3 is R8-N(R 10 )(R 11 ). In other embodiments, R3 is CH2-NH2. In other embodiments, R3 is CH2-N(CH3)2. In other embodiments, R3 is C1-C5 straight or branched C(O)-haloalkyl. In other embodiments, R3 is C(O)-CF3. In other embodiments, R3 is CH(CF3)(NH-R 10In other embodiments, R3 is R8-OH. In other embodiments, R3 is CH2-OH. In other embodiments, R3 is COOH. In other embodiments, R3 is C1-C5 linear, branched, or cyclic alkoxy. In other embodiments, R3 is methoxy.

[0151] In other embodiments, R4 is H. In other embodiments, R4 is SO2N(R 10 )(R 11 ). In other embodiments, R4 is SO2N(CH3)2. In other embodiments, R4 is methoxy. In other embodiments, R4 is F. In other embodiments, R4 is C(O)-CH3. In other embodiments, R4 is OH. In other embodiments, R4 is OH. In other embodiments, R4 is C(O)OR 10 . In other embodiments, R4 is C(O)O-CH3. In other embodiments, R4 is CD3. In other embodiments, R4 is OCD3. In other embodiments, R3 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R4 is imidazole. In other embodiments, R4 is furan. In other embodiments, R4 is oxetane. In other embodiments, R4 is 1-oxetane. In other embodiments, R4 is 2-oxetane. In other embodiments, R4 is indole. In other embodiments, R3 is a C1-C5 straight or branched chain haloalkyl. In other embodiments, R4 is CF2CH3. In other embodiments, R4 is CH2CF3. In other embodiments, R4 is CF2CH2CH3. In other embodiments, R4 is R8-OH. In other embodiments, R4 is CH2-OH. In other embodiments, R4 is a C1-C5 straight or branched chain, substituted or unsubstituted alkyl. In other embodiments, R4 is methyl. In other embodiments, R4 is C(OH)(CH3)(Ph). In other embodiments, R4 is ethyl. In other embodiments, R4 is propyl. In other embodiments, R4 is isopropyl. In other embodiments, R4 is isobutyl. In other embodiments, R4 is tert-butyl. In other embodiments, R4 is pentyl.

[0152] In some embodiments, R3 and R4 are linked together to form a [1,3] dioxole ring. In some embodiments, R3 and R4 are linked together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R3 and R4 are linked together to form a cyclopentane ring. In some embodiments, R3 and R4 are linked together to form an imidazole ring.

[0153] In some embodiments, R5 is H. In other embodiments, R5 is C1-C5 straight 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 C1-C5 straight or branched haloalkyl. In other embodiments, R5 is CF3. 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.

[0154] In some embodiments, R6 is H. In other embodiments, R6 is C1-C5 straight or branched chain alkyl. In other embodiments, R6 is methyl.

[0155] In some embodiments, R8 is CH2. In other embodiments, R8 is CH2CH2. In other embodiments, R8 is CH2CH2CH2.

[0156] In some embodiments, p is 1. In other embodiments, p is 2. In other embodiments, p is 3.

[0157] In some embodiments, R9 is C≡C.

[0158] In some embodiments, q is 2.

[0159] In some embodiments, R 10 is a C1-C5 straight or branched chain alkyl group. 10 is H. In other embodiments, R 10 is CH3. In other embodiments, R 10 is CH2CH3. In other embodiments, R 10 It is CH2CH2CH3.

[0160] In some embodiments, R 11 is a C1-C5 straight or branched chain alkyl group. 11 is H. In other embodiments, R 11 For CH3.

[0161] In some embodiments, R is H. In other embodiments, R is a C1-C5 straight or branched chain alkyl. In other embodiments, R is methyl. In other embodiments, R is ethyl.

[0162] In some embodiments, Q1 is O.

[0163] In some embodiments, Q2 is O.

[0164] In some embodiments, X3 is C. In other embodiments, X3 is N.

[0165] In some embodiments, X4 is C. In other embodiments, X4 is N.

[0166] In some embodiments, X6 is C. In other embodiments, X6 is N.

[0167] In some embodiments, X7 is C. In other embodiments, X7 is N.

[0168] In some embodiments, X8 is C. In other embodiments, X8 is N.

[0169] In various embodiments, the present invention is directed to compounds represented by the structure of formula (IV):

[0170]

[0171] in

[0172] 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), 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 )(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. 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, C(O)N(R 10 )(R 11 )(e.g. C(O)N(CH3)2), SO2R, SO2N(R 10 )(R 11 )(e.g., SO2N(CH3)2, SO2NHC(O)CH3); C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, 2-CH2-C6H4-Cl, 3-CH2-C6H4-Cl or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, pentyl); C1-C5 linear or branched haloalkyl (e.g., CF2CH3, CH2CF3); C1-C5 linear, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tert-butyl), optionally wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom (O) (e.g., O-1-oxetanyl, O-2-oxetanyl) ), 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), substituted or unsubstituted C3-C8 heterocycle (e.g., thiophene, oxazole, oxadiazole, imidazole, furan, triazole, tetrazole, pyridine (2-pyridine, 3-pyridine or 4-pyridine), pyrimidine, pyrazine, oxetane (1-oxetane or 2-oxetane), indole, protonated or deprotonated pyridine oxide), substituted or unsubstituted aryl (e.g., phenyl) (wherein the substituents include: F, Cl, Br, I, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), OH, alkoxy, N(R)2, CF3, CN or NO2), CH(CF3)(NH-R 10 );

[0173] or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring (e.g., [1,3]dioxole, furan-2(3H)-one, benzene, pyridine);

[0174] 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, 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-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, C(O)N(R 10 )(R 11 )(e.g. C(O)N(CH3)2), SO2R, SO2N(R 10 )(R 11)(e.g., SO2N(CH3)2); C1-C5 straight or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, tert-butyl, isobutyl, pentyl); C1-C5 straight or branched haloalkyl (e.g., CF2CH3, CH2CF3, CF2CH2CH3); C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl); C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxy oxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocycle (e.g., thiophene, oxazole, isoxazole, imidazole, furan, triazole, pyridine (2-pyridine, 3-pyridine or 4-pyridine), pyrimidine, pyrazine, oxetane (1-oxetane or 2-oxetane), indole), substituted or unsubstituted aryl (e.g., phenyl), (wherein the substituents include: F, Cl, Br, I, C1-C5 straight or branched chain alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2), CH(CF3)(NH-R 10 );

[0175] or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring (e.g., [1,3]dioxole, furan-2(3H)-one, benzene, cyclopentane, imidazole);

[0176] R5 is H; C1-C5 straight or branched, substituted or unsubstituted alkyl (e.g., methyl, CH2SH, ethyl, isopropyl); C1-C5 straight or branched haloalkyl (e.g., CF3), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2-pyridine, 3-pyridine and 4-pyridine)), (wherein the substituents include: F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2);

[0177] R8 is [CH2] p

[0178] Where p is between 1 and 10;

[0179] R9 is [CH] q , [C] q

[0180] Where q is between 2 and 10;

[0181] R 10 and R 11Each is independently H, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), C(O)R or S(O)2R;

[0182] R is H, C1-C5 straight or branched chain alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain alkoxy, phenyl, aryl, or heteroaryl, or two geminal R substituents are linked together to form a 5- or 6-membered heterocyclic ring;

[0183] X3 and X4 are each independently C or N, wherein if X3 is N, R4 is not present.

[0184] X7 and X8 are each independently C or N, wherein if X8 is N, R2 is absent;

[0185] or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), PROTAC, drug product, or any combination thereof.

[0186] In some embodiments, R1 is H. In other embodiments, R1 is F. In other embodiments, R1 is Cl. In other embodiments, R1 is Br. In other embodiments, R1 is I. In other embodiments, R1 is C(O)OR 10 In other embodiments, R1 is C(O)O-CH3. In other embodiments, R1 is CF3. In other embodiments, R1 is OCD3. In other embodiments, R1 is NO2. In other embodiments, R1 is NH2. In other embodiments, R1 is R8-N(R 10 )(R 11 In other embodiments, R1 is CH2-NH2. In other embodiments, R1 is CH2-N(CH3)2). In other embodiments, R1 is R9-R8-N(R 10 )(R 11 ). In other embodiments, R1 is C≡C-CH2-NH2. In other embodiments, R1 is B(OH)2. In other embodiments, R1 is C1-C5 straight or branched chain haloalkoxy. In other embodiments, R1 is OCF3. In other embodiments, R1 is OCHF2. In other embodiments, R1 is COOH. In other embodiments, R1 is SO2N(R 10 )(R 11). In other embodiments, R1 is SO2N(CH3)2. In other embodiments, R1 is SO2NHC(O)CH3. In other embodiments, R1 is C(O)O-CH(CH3)2. In other embodiments, R1 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R1 is pyridine. In other embodiments, R1 is 2-pyridine. In other embodiments, R1 is 3-pyridine. In other embodiments, R1 is 4-pyridine. In other embodiments, R1 is oxazole. In other embodiments, R1 is a methyl-substituted oxazole. In other embodiments, R1 is oxadiazole. In other embodiments, R1 is a methyl-substituted oxadiazole. In other embodiments, R1 is imidazole. In other embodiments, R1 is a methyl-substituted imidazole. In other embodiments, R1 is tetrazole. In other embodiments, R1 is pyrimidine. In other embodiments, R1 is pyrazine. In other embodiments, R1 is oxetane. In other embodiments, R1 is 1-oxetane. In other embodiments, R1 is 2-oxetane. In other embodiments, R1 is indole. In other embodiments, R1 is a pyridine oxide. In other embodiments, R1 is a protonated pyridine oxide. In other embodiments, R1 is a deprotonated pyridine oxide. In other embodiments, R1 is a substituted or unsubstituted aryl group. In other embodiments, R1 is phenyl. In other embodiments, R1 is bromophenyl. In other embodiments, R1 is 2-bromophenyl. In other embodiments, R1 is 3-bromophenyl. In other embodiments, R1 is 4-bromophenyl. In other embodiments, R1 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R1 is methyl. In other embodiments, R1 is 2-CH2-C6H4-Cl. In other embodiments, R1 is 3-CH2-C6H4-Cl. In other embodiments, R1 is 4-CH2-C6H4-Cl. In other embodiments, R1 is ethyl. In other embodiments, R1 is propyl. In other embodiments, R1 is isopropyl. In other embodiments, R1 is tert-butyl. In other embodiments, R1 is isobutyl. In other embodiments, R1 is pentyl. In other embodiments, R1 is substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). In other embodiments, R1 is C1-C5 linear, branched, or cyclic alkoxy. In other embodiments, R1 is methoxy. In other embodiments, R1 is ethoxy. In other embodiments, R1 is propoxy. In other embodiments, R1 is isopropoxy. In other embodiments, R1 is O-cyclobutyl. In other embodiments, R1 is O-cyclopentyl. In other embodiments, R1 is O-cyclohexyl. In other embodiments, R1 is 1-butoxy.In other embodiments, R1 is 2-butoxy. In other embodiments, R1 is O-tert-butyl. In other embodiments, R1 is a C1-C5 linear, branched, or cyclic alkoxy group, wherein at least one methylene group (CH2) in the alkoxy group is replaced by an oxygen atom (O). In other embodiments, R1 is O-1-oxetanyl. In other embodiments, R1 is O-2-oxetanyl. In other embodiments, R1 is R8-N(R). 10 )(R 11 ). In other embodiments, R1 is CH2-NH2.

[0187] In some embodiments, R2 is H. In other embodiments, R2 is F. In other embodiments, R2 is Cl. In other embodiments, R2 is Br. In other embodiments, R2 is I. In other embodiments, R2 is CF3. In other embodiments, R2 is OCD3. In other embodiments, R2 is a C1-C5 straight or branched haloalkoxy. In other embodiments, R2 is OCF3. In other embodiments, R2 is OCHF2. In other embodiments, R2 is SO2N(R 10 )(R 11 In other embodiments, R2 is SO2N(CH3)2. In other embodiments, R2 is SO2NHC(O)CH3. In other embodiments, R2 is NO2. In other embodiments, R2 is NH2. In other embodiments, R2 is R8-N(R 10 )(R 11 In other embodiments, R2 is CH2-NH2. In other embodiments, R2 is CH2-N(CH3)2). In other embodiments, R2 is R9-R8-N(R 10 )(R 11 In other embodiments, R2 is C≡C-CH2-NH2. In other embodiments, R2 is B(OH)2. In other embodiments, R2 is NHC(O)-R 10 In other embodiments, R2 is NHC(O)CH3. In other embodiments, R2 is NHCO-N(R 10 )(R 11). In other embodiments, R2 is NHC(O)N(CH3)2. In other embodiments, R2 is COOH. In other embodiments, R2 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R2 is methyl. In other embodiments, R2 is 2-CH2-C6H4-Cl. In other embodiments, R2 is 3-CH2-C6H4-Cl. In other embodiments, R2 is 4-CH2-C6H4-Cl. In other embodiments, R2 is ethyl. In other embodiments, R2 is propyl. In other embodiments, R2 is isopropyl. In other embodiments, R2 is tert-butyl. In other embodiments, R2 is isobutyl. In other embodiments, R2 is pentyl. In other embodiments, R2 is substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). In other embodiments, R2 is ethoxy. In other embodiments, R2 is a C1-C5 linear, branched, or cyclic alkoxy group. In other embodiments, R2 is methoxy. In other embodiments, R2 is propoxy. In other embodiments, R2 is isopropoxy. In other embodiments, R2 is O-CH2-cyclopropyl. In other embodiments, R2 is O-cyclobutyl. In other embodiments, R2 is O-cyclopentyl. In other embodiments, R2 is O-cyclohexyl. In other embodiments, R2 is 1-butoxy. In other embodiments, R2 is 2-butoxy. In other embodiments, R2 is O-tert-butyl. In other embodiments, R2 is a C1-C5 linear, branched, or cyclic alkoxy group, wherein at least one methylene group (CH2) in the alkoxy group is replaced by an oxygen atom (O). In other embodiments, R2 is O-1-oxetanyl. In other embodiments, R2 is O-2-oxetanyl. In other embodiments, R2 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R2 is pyridine. In other embodiments, R2 is 2-pyridine. In other embodiments, R2 is 3-pyridine. In other embodiments, R2 is 4-pyridine. In other embodiments, R2 is oxazole. In other embodiments, R2 is a methyl-substituted oxazole. In other embodiments, R2 is an oxadiazole. In other embodiments, R2 is a methyl-substituted oxadiazole. In other embodiments, R2 is an imidazole. In other embodiments, R2 is a methyl-substituted imidazole. In other embodiments, R2 is a tetrazole. In other embodiments, R2 is a pyrimidine. In other embodiments, R2 is pyrazine. In other embodiments, R2 is an oxetane. In other embodiments, R2 is 1-oxetane. In other embodiments, R2 is 2-oxetane. In other embodiments, R2 is an indole. In other embodiments, R2 is a pyridine oxide. In other embodiments, R2 is a protonated pyridine oxide.In other embodiments, R2 is a deprotonated pyridine oxide. In other embodiments, R2 is a substituted or unsubstituted aryl group. In other embodiments, R2 is phenyl. In other embodiments, R2 is bromophenyl. In other embodiments, R2 is 2-bromophenyl. In other embodiments, R2 is 3-bromophenyl. In other embodiments, R2 is 4-bromophenyl. In other embodiments, R2 is R8-N(R). 10 )(R 11 In other embodiments, R2 is CH2-NH2.

[0188] In some embodiments, R1 and R2 are linked together to form a [1,3] dioxole ring. In some embodiments, R1 and R2 are linked together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R1 and R2 are linked together to form a benzene ring. In some embodiments, R1 and R2 are linked together to form a pyridine ring.

[0189] In some embodiments, R3 is H. In other embodiments, R3 is a C1-C5 straight or branched haloalkyl group. In other embodiments, R3 is CF2CH3. In other embodiments, R3 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R3 is furan. In other embodiments, R3 is thiophene. In other embodiments, R3 is pyrimidine. In other embodiments, R3 is pyrazine. In other embodiments, R3 is imidazole. In other embodiments, R3 is oxazole. In other embodiments, R3 is isoxazole. In other embodiments, R3 is triazole. In other embodiments, R3 is oxetane. In other embodiments, R3 is 1-oxetane. In other embodiments, R3 is 2-oxetane. In other embodiments, R3 is indole. In other embodiments, R3 is C(O)-R 10 In other embodiments, R3 is C(O)-CH3. In other embodiments, R3 is C(O)-CH2CH2CH3. In other embodiments, R3 is C(O)N(R 10 )(R 11 In other embodiments, R3 is C(O)N(CH3)2). In other embodiments, R3 is R8-C(O)-R 10. In other embodiments, R3 is CH2C(O)CH3. In other embodiments, R3 is a substituted or unsubstituted C3-C8 cycloalkyl group. In other embodiments, R3 is a cyclopropyl group. In other embodiments, R3 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R3 is a methyl group. In other embodiments, R3 is C(OH)(CH3)(Ph). In other embodiments, R3 is an ethyl group. In other embodiments, R3 is a propyl group. In other embodiments, R3 is an isopropyl group. In other embodiments, R3 is an isobutyl group. In other embodiments, R3 is a tert-butyl group. In other embodiments, R3 is a pentyl group. 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 C(O)OR 10 In other embodiments, R3 is C(O)O-CH2CH3. In other embodiments, R3 is -R8-OR 10 In other embodiments, R3 is CH2-O-CH3. In other embodiments, R3 is C1-C5 straight or branched chain haloalkyl. In other embodiments, R3 is CH2CF3. In other embodiments, R3 is CF2CH2CH3. In other embodiments, R3 is substituted or unsubstituted C3-C8 cycloalkyl. In other embodiments, R3 is cyclopentyl. In other embodiments, R3 is C(O)OR 10 In other embodiments, R3 is C(O)O-CH2CH3. In other embodiments, R3 is substituted or unsubstituted aryl. In other embodiments, R3 is phenyl. In other embodiments, R3 is pyridine. In other embodiments, R3 is 2-pyridine. In other embodiments, R3 is 3-pyridine. In other embodiments, R3 is 4-pyridine. In other embodiments, R3 is SO2N(R 10 )(R 11 In other embodiments, R3 is SO2N(CH3)2. In other embodiments, R3 is R8-N(R 10 )(R 11 ). In other embodiments, R3 is CH2-NH2. In other embodiments, R3 is CH2-N(CH3)2. In other embodiments, R3 is C1-C5 straight or branched C(O)-haloalkyl. In other embodiments, R3 is C(O)-CF3. In other embodiments, R3 is CH(CF3)(NH-R 10In other embodiments, R3 is R8-OH. In other embodiments, R3 is CH2-OH. In other embodiments, R3 is COOH. In other embodiments, R3 is C1-C5 linear, branched, or cyclic alkoxy. In other embodiments, R3 is methoxy.

[0190] In other embodiments, R4 is H. In other embodiments, R4 is SO2N(R 10 )(R 11 ). In other embodiments, R4 is SO2N(CH3)2. In other embodiments, R4 is methoxy. In other embodiments, R4 is F. In other embodiments, R4 is C(O)-CH3. In other embodiments, R4 is OH. In other embodiments, R4 is OH. In other embodiments, R4 is C(O)OR 10 . In other embodiments, R4 is C(O)O-CH3. In other embodiments, R4 is CD3. In other embodiments, R4 is OCD3. In other embodiments, R3 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R4 is imidazole. In other embodiments, R4 is oxetane. In other embodiments, R4 is 1-oxetane. In other embodiments, R4 is 2-oxetane. In other embodiments, R4 is a C1-C5 straight or branched haloalkyl group. In other embodiments, R4 is CF2CH3. In other embodiments, R4 is CH2CF3. In other embodiments, R4 is CF2CH2CH3. In other embodiments, R4 is indole. In other embodiments, R4 is R8-OH. In other embodiments, R4 is CH2-OH. In other embodiments, R4 is a C1-C5 straight or branched, substituted or unsubstituted alkyl group. In other embodiments, R4 is methyl. In other embodiments, R4 is C(OH)(CH3)(Ph). In other embodiments, R4 is ethyl. In other embodiments, R4 is propyl. In other embodiments, R4 is isopropyl. In other embodiments, R4 is isobutyl. In other embodiments, R4 is tert-butyl. In other embodiments, R4 is pentyl.

[0191] In some embodiments, R3 and R4 are linked together to form a [1,3] dioxole ring. In some embodiments, R3 and R4 are linked together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R3 and R4 are linked together to form a cyclopentane ring. In some embodiments, R3 and R4 are linked together to form an imidazole ring.

[0192] In some embodiments, R5 is H. In other embodiments, R5 is C1-C5 straight 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 C1-C5 straight or branched haloalkyl. In other embodiments, R5 is CF3. 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.

[0193] In some embodiments, R8 is CH2. In other embodiments, R8 is CH2CH2. In other embodiments, R8 is CH2CH2CH2.

[0194] In some embodiments, p is 1. In other embodiments, p is 2. In other embodiments, p is 3.

[0195] In some embodiments, R9 is C≡C.

[0196] In some embodiments, q is 2.

[0197] In some embodiments, R 10 is a C1-C5 straight or branched chain alkyl group. 10 is H. In other embodiments, R 10 is CH3. In other embodiments, R 10 is CH2CH3. In other embodiments, R 10 It is CH2CH2CH3.

[0198] In some embodiments, R 11 is a C1-C5 straight or branched chain alkyl group. 10 is H. In other embodiments, R 11 For CH3.

[0199] In some embodiments, R is H. In other embodiments, R is a C1-C5 straight or branched chain alkyl. In other embodiments, R is methyl. In other embodiments, R is ethyl.

[0200] In some embodiments, X3 is C. In other embodiments, X3 is N.

[0201] In some embodiments, X4 is C. In other embodiments, X4 is N.

[0202] In some embodiments, X7 is C. In other embodiments, X7 is N.

[0203] In some embodiments, X8 is C. In other embodiments, X8 is N.

[0204] In various embodiments, the present invention is directed to compounds represented by the structure of Formula (V):

[0205]

[0206] in

[0207] 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), 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 )(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. 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, C(O)N(R 10 )(R 11 )(e.g. C(O)N(CH3)2), SO2R, SO2N(R10 )(R 11 )(e.g., SO2N(CH3)2, SO2NHC(O)CH3); C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, 2-CH2-C6H4-Cl, 3-CH2-C6H4-Cl or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, pentyl); C1-C5 linear or branched haloalkyl (e.g., CF2CH3, CH2CF3); C1-C5 linear, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, O-tert-butyl), optionally wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom (O) (e.g., O-1-oxetanyl, O-2-oxetanyl) ), 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), substituted or unsubstituted C3-C8 heterocycle (e.g., thiophene, oxazole, oxadiazole, imidazole, furan, triazole, tetrazole, pyridine (2-pyridine, 3-pyridine or 4-pyridine), pyrimidine, pyrazine, oxetane (1-oxetane or 2-oxetane), indole, protonated or deprotonated pyridine oxide), substituted or unsubstituted aryl (e.g., phenyl) (wherein the substituents include: F, Cl, Br, I, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), OH, alkoxy, N(R)2, CF3, CN or NO2), CH(CF3)(NH-R 10 );

[0208] or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring (e.g., [1,3]dioxole, furan-2(3H)-one, benzene, pyridine);

[0209] 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, 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-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, C(O)N(R 10 )(R 11 )(e.g. C(O)N(CH3)2), SO2R, SO2N(R 10 )(R 11 )(e.g., SO2N(CH3)2); C1-C5 straight or branched, substituted or unsubstituted alkyl (e.g., methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, tert-butyl, isobutyl, pentyl); C1-C5 straight or branched haloalkyl (e.g., CF2CH3, CH2CF3, CF2CH2CH3); C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, O-CH2-cyclopropyl); C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxy alkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl), substituted or unsubstituted C3-C8 heterocycle (e.g., thiophene, oxazole, isoxazole, imidazole, furan, triazole, pyridine (2-pyridine, 3-pyridine or 4-pyridine), pyrimidine, pyrazine, oxetane (1-oxetane or 2-oxetane), indole), substituted or unsubstituted aryl (e.g., phenyl), (wherein the substituents include: F, Cl, Br, I, C1-C5 straight or branched chain alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2), CH(CF3)(NH-R 10 );

[0210] R8 is [CH2] p

[0211] Where p is between 1 and 10;

[0212] R9 is [CH] q , [C] q

[0213] Where q is between 2 and 10;

[0214] R 10 and R 11 Each is independently H, C1-C5 linear or branched alkyl (e.g., methyl, ethyl), C(O)R or S(O)2R;

[0215] R is H, C1-C5 straight or branched chain alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain alkoxy, phenyl, aryl, or heteroaryl, or two geminal R substituents are linked together to form a 5- or 6-membered heterocyclic ring;

[0216] X3 and X7 are each independently C or N;

[0217] or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), PROTAC, drug product, or any combination thereof.

[0218] In some embodiments, R1 is H. In other embodiments, R1 is F. In other embodiments, R1 is Cl. In other embodiments, R1 is Br. In other embodiments, R1 is I. In other embodiments, R1 is C(O)OR 10 In other embodiments, R1 is C(O)O-CH3. In other embodiments, R1 is CF3. In other embodiments, R1 is OCD3. In other embodiments, R1 is R8-N(R 10 )(R 11 In other embodiments, R1 is CH2-NH2. In other embodiments, R1 is CH2-N(CH3)2). In other embodiments, R1 is R9-R8-N(R 10 )(R 11 ). In other embodiments, R1 is C≡C-CH2-NH2. In other embodiments, R1 is B(OH)2. In other embodiments, R1 is C1-C5 straight or branched chain haloalkoxy. In other embodiments, R1 is OCF3. In other embodiments, R1 is OCHF2. In other embodiments, R1 is COOH. In other embodiments, R1 is SO2N(R 10 )(R 11). In other embodiments, R1 is SO2N(CH3)2. In other embodiments, R1 is SO2NHC(O)CH3. In other embodiments, R1 is C(O)O-CH(CH3)2. In other embodiments, R1 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R1 is pyridine. In other embodiments, R1 is 2-pyridine. In other embodiments, R1 is 3-pyridine. In other embodiments, R1 is 4-pyridine. In other embodiments, R1 is oxazole. In other embodiments, R1 is a methyl-substituted oxazole. In other embodiments, R1 is oxadiazole. In other embodiments, R1 is a methyl-substituted oxadiazole. In other embodiments, R1 is imidazole. In other embodiments, R1 is a methyl-substituted imidazole. In other embodiments, R1 is tetrazole. In other embodiments, R1 is pyrimidine. In other embodiments, R1 is pyrazine. In other embodiments, R1 is oxetane. In other embodiments, R1 is 1-oxetane. In other embodiments, R1 is 2-oxetane. In other embodiments, R1 is indole. In other embodiments, R1 is a pyridine oxide. In other embodiments, R1 is a protonated pyridine oxide. In other embodiments, R1 is a deprotonated pyridine oxide. In other embodiments, R1 is a substituted or unsubstituted aryl group. In other embodiments, R1 is phenyl. In other embodiments, R1 is bromophenyl. In other embodiments, R1 is 2-bromophenyl. In other embodiments, R1 is 3-bromophenyl. In other embodiments, R1 is 4-bromophenyl. In other embodiments, R1 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R1 is methyl. In other embodiments, R1 is 2-CH2-C6H4-Cl. In other embodiments, R1 is 3-CH2-C6H4-Cl. In other embodiments, R1 is 4-CH2-C6H4-Cl. In other embodiments, R1 is ethyl. In other embodiments, R1 is propyl. In other embodiments, R1 is isopropyl. In other embodiments, R1 is tert-butyl. In other embodiments, R1 is isobutyl. In other embodiments, R1 is pentyl. In other embodiments, R1 is substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). In other embodiments, R1 is C1-C5 linear, branched, or cyclic alkoxy. In other embodiments, R1 is methoxy. In other embodiments, R1 is ethoxy. In other embodiments, R1 is propoxy. In other embodiments, R1 is isopropoxy. In other embodiments, R1 is O-cyclobutyl. In other embodiments, R1 is O-cyclopentyl. In other embodiments, R1 is O-cyclohexyl. In other embodiments, R1 is 1-butoxy.In other embodiments, R1 is 2-butoxy. In other embodiments, R1 is O-tert-butyl. In other embodiments, R1 is a C1-C5 linear, branched, or cyclic alkoxy group, wherein at least one methylene group (CH2) in the alkoxy group is replaced by an oxygen atom (O). In other embodiments, R1 is O-1-oxetanyl. In other embodiments, R1 is O-2-oxetanyl. In other embodiments, R1 is R8-N(R). 10 )(R 11 ). In other embodiments, R1 is CH2-NH2.

[0219] In some embodiments, R2 is H. In other embodiments, R2 is F. In other embodiments, R2 is Cl. In other embodiments, R2 is Br. In other embodiments, R2 is I. In other embodiments, R2 is CF3. In other embodiments, R2 is OCD3. In other embodiments, R2 is R8-N(R 10 )(R 11 In other embodiments, R2 is CH2-NH2. In other embodiments, R2 is CH2-N(CH3)2). In other embodiments, R2 is R9-R8-N(R 10 )(R 11 In other embodiments, R2 is C≡C-CH2-NH2. In other embodiments, R2 is B(OH)2. In other embodiments, R2 is C1-C5 straight or branched chain haloalkoxy. In other embodiments, R2 is OCF3. In other embodiments, R2 is OCHF2. In other embodiments, R2 is SO2N(R 10 )(R 11 In other embodiments, R2 is SO2N(CH3)2. In other embodiments, R2 is SO2NHC(O)CH3. In other embodiments, R2 is NO2. In other embodiments, R2 is NH2. In other embodiments, R2 is NHC(O)-R 10 In other embodiments, R2 is NHC(O)CH3. In other embodiments, R2 is NHCO-N(R 10 )(R 11). In other embodiments, R2 is NHC(O)N(CH3)2. In other embodiments, R2 is COOH. In other embodiments, R2 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R2 is methyl. In other embodiments, R2 is 2-CH2-C6H4-Cl. In other embodiments, R2 is 3-CH2-C6H4-Cl. In other embodiments, R2 is 4-CH2-C6H4-Cl. In other embodiments, R2 is ethyl. In other embodiments, R2 is propyl. In other embodiments, R2 is isopropyl. In other embodiments, R2 is tert-butyl. In other embodiments, R2 is isobutyl. In other embodiments, R2 is pentyl. In other embodiments, R2 is substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). In other embodiments, R2 is ethoxy. In other embodiments, R2 is a C1-C5 linear, branched, or cyclic alkoxy group. In other embodiments, R2 is methoxy. In other embodiments, R2 is propoxy. In other embodiments, R2 is isopropoxy. In other embodiments, R2 is O-CH2-cyclopropyl. In other embodiments, R2 is O-cyclobutyl. In other embodiments, R2 is O-cyclopentyl. In other embodiments, R2 is O-cyclohexyl. In other embodiments, R2 is 1-butoxy. In other embodiments, R2 is 2-butoxy. In other embodiments, R2 is O-tert-butyl. In other embodiments, R2 is a C1-C5 linear, branched, or cyclic alkoxy group, wherein at least one methylene group (CH2) in the alkoxy group is replaced by an oxygen atom (O). In other embodiments, R2 is O-1-oxetanyl. In other embodiments, R2 is O-2-oxetanyl. In other embodiments, R2 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R2 is pyridine. In other embodiments, R2 is 2-pyridine. In other embodiments, R2 is 3-pyridine. In other embodiments, R2 is 4-pyridine. In other embodiments, R2 is oxazole. In other embodiments, R2 is a methyl-substituted oxazole. In other embodiments, R2 is an oxadiazole. In other embodiments, R2 is a methyl-substituted oxadiazole. In other embodiments, R2 is an imidazole. In other embodiments, R2 is a methyl-substituted imidazole. In other embodiments, R2 is a tetrazole. In other embodiments, R2 is a pyrimidine. In other embodiments, R2 is pyrazine. In other embodiments, R2 is an oxetane. In other embodiments, R2 is 1-oxetane. In other embodiments, R2 is 2-oxetane. In other embodiments, R2 is an indole. In other embodiments, R2 is a pyridine oxide. In other embodiments, R2 is a protonated pyridine oxide.In other embodiments, R2 is a deprotonated pyridine oxide. In other embodiments, R2 is a substituted or unsubstituted aryl group. In other embodiments, R2 is phenyl. In other embodiments, R2 is bromophenyl. In other embodiments, R2 is 2-bromophenyl. In other embodiments, R2 is 3-bromophenyl. In other embodiments, R2 is 4-bromophenyl. In other embodiments, R2 is R8-N(R). 10 )(R 11 In other embodiments, R2 is CH2-NH2.

[0220] In some embodiments, R1 and R2 are linked together to form a [1,3] dioxole ring. In some embodiments, R1 and R2 are linked together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R1 and R2 are linked together to form a benzene ring. In some embodiments, R1 and R2 are linked together to form a pyridine ring.

[0221] In some embodiments, R3 is H. In other embodiments, R3 is a C1-C5 straight or branched haloalkyl group. In other embodiments, R3 is CF2CH3. In other embodiments, R3 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R3 is furan. In other embodiments, R3 is thiophene. In other embodiments, R3 is pyrimidine. In other embodiments, R3 is pyrazine. In other embodiments, R3 is imidazole. In other embodiments, R3 is oxazole. In other embodiments, R3 is isoxazole. In other embodiments, R3 is triazole. In other embodiments, R3 is oxetane. In other embodiments, R3 is 1-oxetane. In other embodiments, R3 is 2-oxetane. In other embodiments, R3 is indole. In other embodiments, R3 is C(O)-R 10 In other embodiments, R3 is C(O)-CH3. In other embodiments, R3 is C(O)-CH2CH2CH3. In other embodiments, R3 is C(O)N(R 10 )(R 11 In other embodiments, R3 is C(O)N(CH3)2). In other embodiments, R3 is R8-C(O)-R 10. In other embodiments, R3 is CH2C(O)CH3. In other embodiments, R3 is a substituted or unsubstituted C3-C8 cycloalkyl group. In other embodiments, R3 is a cyclopropyl group. In other embodiments, R3 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R3 is a methyl group. In other embodiments, R3 is C(OH)(CH3)(Ph). In other embodiments, R3 is an ethyl group. In other embodiments, R3 is a propyl group. In other embodiments, R3 is an isopropyl group. In other embodiments, R3 is an isobutyl group. In other embodiments, R3 is a tert-butyl group. In other embodiments, R3 is a pentyl group. 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 C(O)OR 10 In other embodiments, R3 is C(O)O-CH2CH3. In other embodiments, R3 is -R8-OR 10 In other embodiments, R3 is CH2-O-CH3. In other embodiments, R3 is C1-C5 straight or branched chain haloalkyl. In other embodiments, R3 is CH2CF3. In other embodiments, R3 is CF2CH2CH3. In other embodiments, R3 is substituted or unsubstituted C3-C8 cycloalkyl. In other embodiments, R3 is cyclopentyl. In other embodiments, R3 is C(O)OR 10 In other embodiments, R3 is C(O)O-CH2CH3. In other embodiments, R3 is substituted or unsubstituted aryl. In other embodiments, R3 is phenyl. In other embodiments, R3 is pyridine. In other embodiments, R3 is 2-pyridine. In other embodiments, R3 is 3-pyridine. In other embodiments, R3 is 4-pyridine. In other embodiments, R3 is SO2N(R 10 )(R 11 In other embodiments, R3 is SO2N(CH3)2. In other embodiments, R3 is R8-N(R 10 )(R 11 ). In other embodiments, R3 is CH2-NH2. In other embodiments, R3 is CH2-N(CH3)2. In other embodiments, R3 is C1-C5 straight or branched C(O)-haloalkyl. In other embodiments, R3 is C(O)-CF3. In other embodiments, R3 is CH(CF3)(NH-R 10In other embodiments, R3 is R8-OH. In other embodiments, R3 is CH2-OH. In other embodiments, R3 is COOH. In other embodiments, R3 is C1-C5 linear, branched, or cyclic alkoxy. In other embodiments, R3 is methoxy.

[0222] In some embodiments, R8 is CH2. In other embodiments, R8 is CH2CH2. In other embodiments, R8 is CH2CH2CH2.

[0223] In some embodiments, p is 1. In other embodiments, p is 2. In other embodiments, p is 3.

[0224] In some embodiments, R9 is C≡C.

[0225] In some embodiments, q is 2.

[0226] In some embodiments, R 10 is a C1-C5 straight or branched chain alkyl group. 10 is H. In other embodiments, R 10 is CH3. In other embodiments, R 10 is CH2CH3. In other embodiments, R 10 It is CH2CH2CH3.

[0227] In some embodiments, R 11 is a C1-C5 straight or branched chain alkyl group. 11 is H. In other embodiments, R 11 For CH3.

[0228] In some embodiments, R is H. In other embodiments, R is a C1-C5 straight or branched chain alkyl. In other embodiments, R is methyl. In other embodiments, R is ethyl.

[0229] In some embodiments, X3 is C. In other embodiments, X3 is N.

[0230] In some embodiments, X7 is C. In other embodiments, X7 is N.

[0231] In various embodiments, the present invention relates to the compounds, pharmaceutical compositions and / or methods of use thereof presented in Table 1:

[0232] Table 1:

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278] As is well known, in the structures presented herein, where the nitrogen atom has fewer than 3 bonds, H atoms are present to complete the valence of the nitrogen.

[0279] In some embodiments, the present invention relates to the compounds listed above, their pharmaceutical compositions and / or methods of use, wherein the compound is a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (deuterated analog), PROTAC, pharmaceutical product or any combination thereof. In some embodiments, the compound is an acyl-CoA synthetase short chain family member 2 (ACSS2) inhibitor.

[0280] In various embodiments, Ring A of Formula I is phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, isoquinoline, pyrazolyl, pyrrolyl, furanyl, thienyl, isoquinolinyl, indolyl, 1H-indole, isoindolyl, naphthyl, anthracenyl, benzimidazolyl, 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, phthalide azinyl, quinolyl, isoquinolyl, 2,3-dihydroindenyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepene, benzo[d][1,3]dioxole, acridinyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzofuran-2(3H)-one, benzothienyl, benzodiazole, benzo[c][1,2,5]oxadiazolyl, benzo[c]thienyl, benzodioxolyl, benzo[d][1,3]dioxole, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiazolyl, 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, 1 H-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, each defined as a separate embodiment according to the present invention; or A is a C3-C8 cycloalkyl (e.g., cyclohexyl) or a C3-C8 heterocycle, including but not limited to: tetrahydropyran, piperidine, 1-methylpiperidine, tetrahydrothiophene 1,1-dioxide, 1-(piperidin-1-yl)ethanone or morpholine.

[0281] In various embodiments, Ring A of Formula I is phenyl. In some embodiments, Ring A is naphthyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is pyridazinyl. In some embodiments, A is pyrazinyl. In some embodiments, Ring A is triazinyl. In some embodiments, Ring A is tetrazinyl. In some embodiments, Ring A is thiazolyl. In some embodiments, Ring A is isothiazolyl. In some embodiments, Ring A is oxazolyl. In some embodiments, Ring A is isoxazolyl. In some embodiments, Ring A is imidazolyl. In some embodiments, Ring A is 1-methylimidazole. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is pyrrolyl. In some embodiments, Ring A is furanyl. In some embodiments, Ring A is thienyl. In some embodiments, Ring A is indolyl. In some embodiments, Ring A is indenyl. In some embodiments, Ring A is 2,3-dihydroindenyl. In some embodiments, Ring A is tetrahydronaphthyl. In some embodiments, Ring A is isoindoleyl. In some embodiments, Ring A is naphthyl. In some embodiments, Ring A is anthracenyl. In some embodiments, Ring A is benzimidazolyl. In some embodiments, Ring A is indazolyl. In some embodiments, Ring A is purinyl. In some embodiments, Ring A is benzoxazolyl. In some embodiments, Ring A is benzisoxazolyl. In some embodiments, Ring A is benzothiazolyl. In some embodiments, Ring A is quinazolinyl. In some embodiments, Ring A is quinoxalinyl. In some embodiments, Ring A is cinnolinyl. In some embodiments, Ring A is phthalazinyl. In some embodiments, Ring A is quinolinyl. In some embodiments, Ring A is isoquinolinyl. In some embodiments, Ring A is 3,4-dihydro-2H-benzo[b][1,4]dioxepene. In some embodiments, Ring A is benzo[d][1,3]dioxole. In some embodiments, Ring A is benzofuran-2(3H)-one. In some embodiments, Ring A is benzodioxolyl. In some embodiments, Ring A is acridinyl. In some embodiments, Ring A is benzofuranyl. In some embodiments, Ring A is isobenzofuranyl. In some embodiments, Ring A is benzothienyl. In some embodiments, Ring A is benzo[c]thienyl. In some embodiments, Ring A is benzodioxolyl. In some embodiments, Ring A is thiadiazolyl. In some embodiments, Ring A is oxadiazolyl. In some embodiments, Ring A is 7-oxo-6H,7H-[1,3]thiazolo[4,5-d]pyrimidine. In some embodiments, Ring A is [1,3]thiazolo[5,4-b]pyridine. In some embodiments, Ring A is thieno[3,2-d]pyrimidin-4(3H)-one.In some embodiments, Ring A is 4-oxo-4H-thieno[3,2-d][1,3]thiazine. In some embodiments, Ring A is pyrido[2,3-b]pyrazine or pyrido[2,3-b]pyrazin-3(4H)-one. In some embodiments, Ring A is quinoxalin-2(1H)-one. In some embodiments, Ring A is 1H-indole. In some embodiments, Ring A is 2H-indazole. In some embodiments, Ring A is 4,5,6,7-tetrahydro-2H-indazole. In some embodiments, Ring A is 3H-indole-3-one. In some embodiments, Ring A is 1,3-benzoxazolyl. In some embodiments, Ring A is 1,3-benzothiazole. In some embodiments, Ring A is 4,5,6,7-tetrahydro-1,3-benzothiazole. In some embodiments, Ring A is 1-benzofuran. In some embodiments, Ring A is [1,3]oxazolo[4,5-b]pyridine. In some embodiments, Ring A is imidazo[2,1-b][1,3]thiazole. In some embodiments, Ring A is 4H,5H,6H-cyclopenta[d][1,3]thiazole. In some embodiments, Ring A is 5H,6H,7H,8H-imidazo[1,2-a]pyridine. In some embodiments, Ring A is 2H,3H-imidazo[2,1-b][1,3]thiazole. In some embodiments, Ring A is imidazo[1,2-a]pyridine. In some embodiments, Ring A is pyrazolo[1,5-a]pyridine. In some embodiments, Ring A is imidazo[1,2-a]pyrazine. In some embodiments, Ring A is imidazo[1,2-a]pyrimidine. In some embodiments, Ring A is 4H-thieno[3,2-b]pyrrole. In some embodiments, Ring A is 1H-pyrrolo[2,3-b]pyridine. In some embodiments, Ring A is 1H-pyrrolo[3,2-b]pyridine. In some embodiments, Ring A is 7H-pyrrolo[2,3-d]pyrimidine. In some embodiments, Ring A is oxazolo[5,4-b]pyridine. In some embodiments, Ring A is thiazolo[5,4-b]pyridine. In some embodiments, Ring A is triazolyl. In some embodiments, Ring A is benzoxadiazole. In some embodiments, Ring A is benzo[c][1,2,5]oxadiazolyl. In some embodiments, Ring A is 1H-imidazo[4,5-b]pyridine. In some embodiments, Ring A is 3H-imidazo[4,5-c]pyridine. In some embodiments, Ring A is C3-C8 cycloalkyl. In some embodiments, Ring A is a C3-C8 heterocycle. In some embodiments, Ring A is tetrahydropyran. In some embodiments, Ring A is piperidine. In some embodiments, Ring A is 1-(piperidin-1-yl)ethanone. In some embodiments, Ring A is morpholine. In some embodiments, Ring A is thieno[3,2-c]pyridine. In some embodiments, Ring A is 1-methylpiperidine.In some embodiments, Ring A is tetrahydrothiophene 1,1-dioxide.In some embodiments, Ring A is cyclohexyl.

[0282] In various embodiments, Ring B of Formula I is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, isoquinoline, pyrazolyl, pyrrolyl, furanyl, thienyl, isoquinolinyl, indolyl, 1H-indole, isoindolyl, naphthyl, anthracenyl, benzimidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepene, benzofuran-2(3H)-one, benzo[d][1,3]dioxole, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indole-3 -ketone, 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, benzo oxadiazole, benzo[c][1,2,5]oxadiazolyl, benzo[c]thienyl, benzodioxolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiazolyl, 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, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, pyrido[2,3-b]pyrazine or 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]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thieno[3,2-c]pyridine, C3-C8 cycloalkyl or C3-C8 heterocycle, including but not limited to: tetrahydropyran, piperidine, 1-methylpiperidine, tetrahydrothiophene 1,1-dioxide, 1-(piperidin-1-yl)ethanone or morpholine; each definition is a separate embodiment according to the present invention.

[0283] In various embodiments, Ring B of Formula I is phenyl. In some embodiments, Ring B is naphthyl. In some embodiments, Ring B is pyridinyl. In some embodiments, Ring B is pyrimidinyl. In some embodiments, Ring B is pyridazinyl. In some embodiments, Ring B is pyrazinyl. In some embodiments, Ring B is triazinyl. In some embodiments, Ring B is tetrazinyl. In some embodiments, Ring B is thiazolyl. In some embodiments, Ring B is isothiazolyl. In some embodiments, Ring B is oxazolyl. In some embodiments, Ring B is isoxazolyl. In some embodiments, Ring B is imidazolyl. In some embodiments, Ring B is 1-methylimidazole. In some embodiments, Ring B is pyrazolyl. In some embodiments, Ring B is pyrrolyl. In some embodiments, Ring B is furanyl. In some embodiments, Ring B is thienyl. In some embodiments, Ring B is isoquinolinyl. In some embodiments, Ring B is indolyl. In some embodiments, Ring B is isoindolyl. In some embodiments, Ring B is naphthyl. In some embodiments, Ring B is anthracenyl. In some embodiments, Ring B is benzimidazolyl. In some embodiments, Ring B is 2,3-dihydro-1H-benzo[d]imidazole. In some embodiments, Ring B is indazolyl. In some embodiments, Ring B is purinyl. In some embodiments, Ring B is benzoxazolyl. In some embodiments, Ring B is benzisoxazolyl. In some embodiments, Ring B is benzothiazolyl. In some embodiments, Ring B is quinazolinyl. In some embodiments, Ring B is quinoxalinyl. In some embodiments, Ring B is 1,2,3,4-tetrahydroquinoxaline. In other embodiments, B is 1-(pyridin-1(2H)-yl)ethanone. In some embodiments, Ring B is benzo[d][1,3]dioxole. In some embodiments, Ring B is benzofuran-2(3H)-one. In some embodiments, Ring B is benzodioxolyl. In some embodiments, Ring B is tetrahydronaphthyl. In some embodiments, Ring B is cinnolinyl. In some embodiments, Ring B is phthalazinyl. In some embodiments, Ring B is quinolyl. In some embodiments, Ring B is isoquinolyl. In some embodiments, Ring B is acridinyl. In some embodiments, Ring B is benzofuranyl. In some embodiments, Ring B is isobenzofuranyl. In some embodiments, Ring B is benzothienyl. In some embodiments, Ring B is benzo[c]thienyl. In some embodiments, Ring B is benzodioxolyl. In some embodiments, Ring B is thiadiazolyl. In some embodiments, Ring B is oxadiazolyl. In some embodiments, Ring B is 7-oxo-6H,7H-[1,3]thiazolo[4,5-d]pyrimidine. In some embodiments, Ring B is [1,3]thiazolo[5,4-b]pyridine.In some embodiments, Ring C is thieno[3,2-d]pyrimidin-4(3H)-one. In some embodiments, Ring B is 4-oxo-4H-thieno[3,2-d][1,3]thiazine. In some embodiments, Ring B is pyrido[2,3-b]pyrazine or pyrido[2,3-b]pyrazin-3(4H)-one. In some embodiments, Ring B is quinoxalin-2(1H)-one. In some embodiments, Ring B is 1H-indole. In some embodiments, Ring B is 2H-indazole. In some embodiments, Ring B is 4,5,6,7-tetrahydro-2H-indazole. In some embodiments, Ring B is 3H-indole-3-one. In some embodiments, Ring B is 1,3-benzoxazolyl. In some embodiments, Ring B is 1,3-benzothiazole. In some embodiments, Ring B is 4,5,6,7-tetrahydro-1,3-benzothiazole. In some embodiments, Ring B is 1-benzofuran. In some embodiments, Ring C is [1,3]oxazolo[4,5-b]pyridine. In some embodiments, Ring B is imidazo[2,1-b][1,3]thiazole. In some embodiments, Ring B is 4H,5H,6H-cyclopenta[d][1,3]thiazole. In some embodiments, Ring C is 5H,6H,7H,8H-imidazo[1,2-a]pyridine. In some embodiments, Ring B is 2H,3H-imidazo[2,1-b][1,3]thiazole. In some embodiments, Ring B is imidazo[1,2-a]pyridine. In some embodiments, Ring B is pyrazolo[1,5-a]pyridine. In some embodiments, Ring B is imidazo[1,2-a]pyrazine. In some embodiments, Ring B is imidazo[1,2-a]pyrimidine. In some embodiments, Ring B is 4H-thieno[3,2-b]pyrrole. In some embodiments, Ring B is 1H-pyrrolo[2,3-b]pyridine, and in some embodiments, Ring B is 1H-pyrrolo[3,2-b]pyridine. In some embodiments, Ring B is 7H-pyrrolo[2,3-d]pyrimidine. In some embodiments, Ring B is oxazolo[5,4-b]pyridine. In some embodiments, Ring B is thiazolo[5,4-b]pyridine. In some embodiments, Ring B is triazolyl. In some embodiments, Ring B is benzoxadiazole. In some embodiments, Ring B is benzo[c][1,2,5]oxadiazolyl. In some embodiments, Ring B is 1H-imidazo[4,5-b]pyridine. In some embodiments, Ring B is 3H-imidazo[4,5-c]pyridine. In some embodiments, Ring B is a C3-C8 cycloalkyl. In some embodiments, Ring B is a C3-C8 heterocycle. In some embodiments, Ring B is tetrahydropyran. In some embodiments, Ring B is piperidine. In some embodiments, Ring B is 1-(piperidin-1-yl)ethanone. In some embodiments, Ring B is morpholine.In some embodiments, Ring B is thieno[3,2-c]pyridine. In some embodiments, Ring B is 1-methylpiperidine. In some embodiments, Ring B is tetrahydrothiophene 1,1-dioxide.

[0284] In various embodiments, the compounds of Formula I are substituted with R1 and R2. A single substituent may be present in the ortho, meta, or para position.

[0285] In various embodiments, R1 of Formula IV is H. In some embodiments, R1 is F. In some embodiments, R1 is Cl. In some embodiments, R1 is Br. In some embodiments, R1 is I. In some embodiments, R1 is OH. In some embodiments, R1 is SH. In some embodiments, R1 is R8-OH. In some embodiments, R1 is CH2-OH. In some embodiments, R1 is R8-SH. In some embodiments, R1 is -R8-OR 10 In some embodiments, R1 is -CH2-O-CH3. In some embodiments, R1 is CF3. In other embodiments, R1 is CD3. In other embodiments, R1 is OCD3. In some embodiments, R1 is CN. In some embodiments, R1 is NO2. In some embodiments, R1 is -CH2CN. In some embodiments, R1 is -R8CN. In some embodiments, R1 is NH2. In some embodiments, R1 is NHR. In some embodiments, R1 is N(R)2. In some embodiments, R1 is R8-N(R 10 )(R 11 ). In other embodiments, R1 is CH2-NH2. In some embodiments, R1 is CH2-N(CH3)2. In other embodiments, R1 is R9-R8-N(R 10 )(R 11 In other embodiments, R1 is C≡C-CH2-NH2. In other embodiments, R1 is B(OH)2. In some embodiments, R1 is -OC(O)CF3. In some embodiments, R1 is -OCH2Ph. In some embodiments, R1 is NHC(O)-R 10 In some embodiments, R1 is NHC(O)CH3. In some embodiments, R1 is NHCO-N(R 10 )(R 11 In some embodiments, R1 is NHC(O)N(CH3)2. In some embodiments, R1 is COOH. In some embodiments, R1 is -C(O)Ph. In some embodiments, R1 is C(O)OR 10In some embodiments, R1 is C(O)O-CH3. In some embodiments, R1 is C(O)O-CH(CH3)2. In some embodiments, R1 is C(O)O-CH2CH3). In some embodiments, R1 is R8-C(O)-R 10 In some embodiments, R1 is CH2C(O)CH3). In some embodiments, R1 is C(O)H. In some embodiments, R1 is C(O)-R 10 In some embodiments, R1 is C(O)-CH3. In some embodiments, R1 is C(O)-CH2CH3. In some embodiments, R1 is C(O)-CH2CH2CH3). In some embodiments, R1 is C1-C5 straight or branched C(O)-haloalkyl. In some embodiments, R1 is C(O)-CF3. In some embodiments, R1 is -C(O)NH2. In some embodiments, R1 is C(O)NHR. In some embodiments, R1 is C(O)N(R 10 )(R 11 In some embodiments, R1 is C(O)N(CH3)2. In some embodiments, R1 is SO2R. In some embodiments, R1 is SO2N(R 10 )(R 11). In some embodiments, R1 is SO2N(CH3)2. In some embodiments, R1 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In some embodiments, R1 is methyl, 2-CH2-C6H4-Cl, 3-CH2-C6H4-Cl or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, tert-butyl, isobutyl or pentyl, each representing a separate embodiment according to the present invention. In some embodiments, R1 is C1-C5 linear or branched haloalkyl. In some embodiments, R1 is CF2CH3. In some embodiments, R1 is CH2CF3. In some embodiments, R1 is C1-C5 linear, branched or cyclic alkoxy. In some embodiments, R1 is methoxy, ethoxy, propoxy, isopropoxy, or O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, or O-tert-butyl, each representing a separate embodiment according to the present invention. In other embodiments, R1 is a C1-C5 linear, branched, or cyclic alkoxy group, wherein at least one methylene group (CH2) in the alkoxy group is replaced by an oxygen atom (O). In some embodiments, R1 is O-1-oxetanyl or O-2-oxetanyl, each representing a separate embodiment according to the present invention. In some embodiments, R1 is a C1-C5 linear or branched thioalkoxy group. In some embodiments, R1 is a C1-C5 linear or branched haloalkoxy group. In some embodiments, R1 is OCF3. In some embodiments, R1 is OCHF2. In some embodiments, R1 is a C1-C5 linear or branched alkoxyalkyl group. In some embodiments, R1 is a substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, R1 is a cyclopropyl. In some embodiments, R1 is a cyclopentyl. In some embodiments, R1 is a substituted or unsubstituted C3-C8 heterocycle. In some embodiments, R1 is thiophene, oxazole, oxadiazole, imidazole, furan, triazole, tetrazole, pyridine (2-pyridine, 3-pyridine, or 4-pyridine), pyrimidine, pyrazine, 1-oxetane or 2-oxetane, indole, or a protonated or deprotonated pyridine oxide, each representing a separate embodiment according to the present invention. In some embodiments, R1 is a methyl-substituted oxazole. In some embodiments, R1 is a methyl-substituted oxadiazole. In some embodiments, R1 is a methyl-substituted imidazole. In other embodiments, R1 is a tetrazole. In some embodiments, R1 is a substituted aryl. In some embodiments, R1 is phenyl. In some embodiments, the substituents include: F, Cl, Br, I, C1-C5 straight or branched alkyl (e.g., methyl, ethyl), OH, alkoxy, N(R)2, CF3, CN, or NO2. In some embodiments, R1 is CH(CF3)(NH-R 10In some embodiments, R1 is 2, 3, or 4 bromophenyl groups, each of which is a separate embodiment according to the present invention.

[0286] In some embodiments, R1 and R2 are joined together to form a 5- or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring. In some embodiments, R1 and R2 are joined together to form a 5- or 6-membered heterocyclic ring. In some embodiments, R1 and R2 are joined together to form a [1,3]dioxole ring. In some embodiments, R1 and R2 are joined together to form a furan-2(3H)-one ring. In some embodiments, R1 and R2 are joined together to form a benzene ring. In some embodiments, R1 and R2 are joined together to form a pyridine ring. In some embodiments, R1 and R2 are joined together to form a morpholine ring. In some embodiments, R1 and R2 are joined together to form a piperazine ring. In some embodiments, R1 and R2 are joined together to form an imidazole ring. In some embodiments, R1 and R2 are joined together to form a pyrrole ring. In some embodiments, R1 and R2 are joined together to form a cyclohexene ring. In some embodiments, R1 and R2 are joined together to form a pyrazine ring.

[0287] In various embodiments, R2 of Formula IV is H. In some embodiments, R2 is F. In some embodiments, R2 is Cl. In some embodiments, R2 is Br. In some embodiments, R2 is I. In some embodiments, R2 is OH. In some embodiments, R2 is SH. In some embodiments, R2 is R8-OH. In some embodiments, R2 is CH2-OH. In some embodiments, R2 is R8-SH. In some embodiments, R1 is -R8-OR 10 In some embodiments, R2 is -CH2-O-CH3. In some embodiments, R2 is CF3. In other embodiments, R2 is CD3. In other embodiments, R2 is OCD3. In some embodiments, R2 is CN. In some embodiments, R2 is NO2. In some embodiments, R2 is -CH2CN. In some embodiments, R2 is -R8CN. In some embodiments, R2 is NH2. In some embodiments, R2 is NHR. In some embodiments, R2 is N(R)2. In some embodiments, R2 is R8-N(R 10 )(R 11 In other embodiments, R2 is CH2-NH2. In some embodiments, R2 is CH2-N(CH3)2. In other embodiments, R2 is R9-R8-N(R 10 )(R 11In other embodiments, R2 is C≡C-CH2-NH2. In other embodiments, R2 is B(OH)2. In some embodiments, R2 is -OC(O)CF3. In some embodiments, R2 is -OCH2Ph. In some embodiments, R2 is NHC(O)-R 10 In some embodiments, R2 is NHC(O)CH3. In some embodiments, R2 is NHCO-N(R 10 )(R 11 In some embodiments, R2 is NHC(O)N(CH3)2. In some embodiments, R2 is COOH. In some embodiments, R2 is -C(O)Ph. In some embodiments, R2 is C(O)OR 10 In some embodiments, R2 is C(O)O-CH(CH3)2. In some embodiments, R2 is C(O)O-CH3. In some embodiments, R2 is C(O)O-CH2CH3). In some embodiments, R2 is R8-C(O)-R 10 In some embodiments, R2 is CH2C(O)CH3). In some embodiments, R2 is C(O)H. In some embodiments, R2 is C(O)-R 10 In some embodiments, R2 is C(O)-CH3. In some embodiments, R2 is C(O)-CH2CH3. In some embodiments, R2 is C(O)-CH2CH2CH3). In some embodiments, R2 is C1-C5 straight or branched C(O)-haloalkyl. In some embodiments, R2 is C(O)-CF3. In some embodiments, R2 is -C(O)NH2. In some embodiments, R2 is C(O)NHR. In some embodiments, R2 is C(O)N(R 10 )(R 11 In some embodiments, R2 is C(O)N(CH3)2. In some embodiments, R2 is SO2R. In some embodiments, R2 is SO2N(R 10 )(R 11). In some embodiments, R2 is SO2N(CH3)2. In some embodiments, R2 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In some embodiments, R2 is methyl, 2-CH2-C6H4-Cl, 3-CH2-C6H4-Cl or 4-CH2-C6H4-Cl, ethyl, propyl, isopropyl, tert-butyl, isobutyl or pentyl, each representing a separate embodiment according to the present invention. In some embodiments, R2 is C1-C5 linear or branched haloalkyl. In some embodiments, R2 is CF2CH3. In some embodiments, R2 is CH2CF3. In some embodiments, R2 is C1-C5 linear, branched or cyclic alkoxy. In some embodiments, R2 is methoxy, ethoxy, propoxy, isopropoxy, or O-CH2-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl, 1-butoxy, 2-butoxy, or O-tert-butyl, each representing a separate embodiment according to the present invention. In other embodiments, R2 is a C1-C5 straight, branched, or cyclic alkoxy group, wherein at least one methylene group (CH2) in the alkoxy group is replaced by an oxygen atom (O). In some embodiments, R2 is O-1-oxetanyl or O-2-oxetanyl, each representing a separate embodiment according to the present invention. In some embodiments, R2 is a C1-C5 straight or branched thioalkoxy group. In some embodiments, R2 is a C1-C5 straight or branched haloalkoxy group. In some embodiments, R2 is OCF3. In some embodiments, R2 is OCHF2. In some embodiments, R2 is a C1-C5 straight or branched alkoxyalkyl group. In some embodiments, R2 is a substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, R2 is a cyclopropyl. In some embodiments, R2 is a cyclopentyl. In some embodiments, R2 is a substituted or unsubstituted C3-C8 heterocycle. In some embodiments, R2 is thiophene, oxazole, oxadiazole, imidazole, furan, triazole, tetrazole, pyridine (2-pyridine, 3-pyridine, or 4-pyridine), pyrimidine, pyrazine, 1-oxetane or 2-oxetane, indole, or a protonated or deprotonated pyridine oxide, each representing a separate embodiment according to the present invention. In some embodiments, R2 is a methyl-substituted oxazole. In some embodiments, R2 is a methyl-substituted oxadiazole. In some embodiments, R2 is a methyl-substituted imidazole. In other embodiments, R2 is a tetrazole. In some embodiments, R2 is a substituted aryl. In some embodiments, R2 is phenyl. In some embodiments, the substituents include: F, Cl, Br, I, C1-C5 straight or branched alkyl (e.g., methyl, ethyl), OH, alkoxy, N(R)2, CF3, CN, or NO2. In some embodiments, R2 is CH(CF3)(NH-R 10In some embodiments, R2 is 2, 3, or 4 bromophenyl groups, each representing a separate embodiment according to the present invention.

[0288] In various embodiments, the compound of formula IV is substituted with R3 and R4. A single substituent may be present in the ortho, meta, or para position.

[0289] In various embodiments, R3 of Formula IV is H. In some embodiments, R3 is F. In some embodiments, R3 is Cl. In some embodiments, R3 is Br. In some embodiments, R3 is I. In some embodiments, R3 is OH. In some embodiments, R3 is SH. In some embodiments, R3 is R8-OH. In some embodiments, R3 is CH2-OH. In some embodiments, R3 is R8-SH. In some embodiments, R3 is -R8-OR 10 . In some embodiments, R3 is CH2-O-CH3. In some embodiments, R3 is CF3. In other embodiments, R3 is CD3. In other embodiments, R3 is OCD3. In some embodiments, R3 is CN. In some embodiments, R3 is NO2. In some embodiments, R3 is -CH2CN. In some embodiments, R3 is -R8CN. In some embodiments, R3 is NH2. In some embodiments, R3 is NHR. In some embodiments, R3 is N(R)2. In some embodiments, R3 is R8-N(R 10 )(R 11 In some embodiments, R3 is CH2-NH2. In some embodiments, R3 is CH2-N(CH3)2. In other embodiments, R3 is R9-R8-N(R 10 )(R 11 In other embodiments, R3 is C≡C-CH2-NH2. In other embodiments, R3 is B(OH)2. In some embodiments, R3 is -OC(O)CF3. In some embodiments, R3 is -OCH2Ph. In some embodiments, R3 is -NHCO-R 10 In some embodiments, R3 is NHC(O)CH3). In some embodiments, R3 is NHCO-N(R 10 )(R 11 In some embodiments, R3 is NHC(O)N(CH3)2. In some embodiments, R3 is COOH. In some embodiments, R3 is -C(O)Ph. In some embodiments, R3 is C(O)OR 10In some embodiments, R3 is C(O)O-CH3. In some embodiments, R3 is C(O)O-CH2CH3. In some embodiments, R3 is R8-C(O)-R 10 In some embodiments, R3 is CH2C(O)CH3. In some embodiments, R3 is C(O)H. In some embodiments, R3 is C1-C5 straight or branched chain C(O)-R 10 . In some embodiments, R3 is C(O)-CH3. In some embodiments, R3 is C(O)-CH2CH3. In some embodiments, R3 is C(O)-CH2CH2CH3. In some embodiments, R3 is C1-C5 straight or branched C(O)-haloalkyl. In some embodiments, R3 is C(O)-CF3. In some embodiments, R3 is -C(O)NH2. In some embodiments, R3 is C(O)NHR. In some embodiments, R3 is C(O)N(R 10 )(R 11 In some embodiments, R3 is C(O)N(CH3)2. In some embodiments, R3 is SO2R. In some embodiments, R3 is SO2N(R 10 )(R 11). In some embodiments, R3 is SO2N(CH3)2. In some embodiments, R3 is a C1-C5 straight or branched, substituted or unsubstituted alkyl group. In some embodiments, R3 is methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, tert-butyl, isobutyl, or pentyl, each representing a separate embodiment according to the present invention. In some embodiments, R3 is a C1-C5 straight or branched haloalkyl group. In some embodiments, R3 is CF2CH3. In some embodiments, R3 is CH2CF3. In other embodiments, R3 is CF2CH2CH3. In some embodiments, R3 is a C1-C5 straight, branched, or cyclic alkoxy group. In some embodiments, R3 is methoxy, ethoxy, propoxy, isopropoxy, or O-CH2-cyclopropyl; each representing a separate embodiment according to the present invention. In some embodiments, R3 is a C1-C5 straight or branched thioalkoxy group. In some embodiments, R3 is a C1-C5 straight or branched haloalkoxy group. In some embodiments, R3 is a C1-C5 straight or branched alkoxyalkyl group. In some embodiments, R3 is a substituted or unsubstituted C3-C8 cycloalkyl group. In some embodiments, R3 is a cyclopropyl group. In some embodiments, R3 is a cyclopentyl group. In some embodiments, R3 is a substituted or unsubstituted C3-C8 heterocycle. In some embodiments, R3 is thiophene, oxazole, isoxazole, imidazole, furan, triazole, tetrazole, pyridine (2-pyridine, 3-pyridine, or 4-pyridine), pyrimidine, pyrazine, oxetane (1-oxetane or 2-oxetane), or indole; each represents a separate embodiment of the present invention. In some embodiments, R3 is a substituted or unsubstituted aryl group. In some embodiments, R3 is phenyl. In some embodiments, the substituents include: F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2. In some embodiments, R3 is CH(CF3)(NH-R 10 ).

[0290] In some embodiments, R3 and R4 are joined together to form a 5- or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring. In some embodiments, R3 and R4 are joined together to form a 5- or 6-membered carbocyclic ring. In some embodiments, R3 and R4 are joined together to form a 5- or 6-membered heterocyclic ring. In some embodiments, R3 and R4 are joined together to form a dioxole ring. [1,3]dioxole ring. In some embodiments, R3 and R4 are joined together to form a dihydrofuran-2(3H)-one ring. In some embodiments, R3 and R4 are joined together to form a furan-2(3H)-one ring. In some embodiments, R3 and R4 are joined together to form a benzene ring. In some embodiments, R3 and R4 are joined together to form an imidazole ring. In some embodiments, R3 and R4 are joined together to form a pyridine ring. In some embodiments, R3 and R4 are joined together to form a pyrrole ring. In some embodiments, R3 and R4 are linked together to form a cyclohexene ring. In some embodiments, R3 and R4 are linked together to form a cyclopentene ring. In some embodiments, R4 and R3 are linked together to form a dioxepene ring.

[0291] In various embodiments, R4 of Formula IV is H. In some embodiments, R4 is F. In some embodiments, R4 is Cl. In some embodiments, R4 is Br. In some embodiments, R4 is I. In some embodiments, R4 is OH. In some embodiments, R4 is SH. In some embodiments, R4 is R8-OH. In some embodiments, R4 is CH2-OH. In some embodiments, R4 is R8-SH. In some embodiments, R4 is -R8-OR 10 In some embodiments, R4 is CH2-O-CH3. In some embodiments, R4 is CF3. In other embodiments, R4 is CD3. In other embodiments, R4 is OCD3. In some embodiments, R4 is CN. In some embodiments, R4 is NO2. In some embodiments, R4 is -CH2CN. In some embodiments, R4 is -R8CN. In some embodiments, R4 is NH2. In some embodiments, R4 is NHR. In some embodiments, R4 is N(R)2. In some embodiments, R4 is R8-N(R 10 )(R 11 In other embodiments, R4 is CH2-NH2. In some embodiments, R4 is CH2-N(CH3)2. In other embodiments, R4 is R9-R8-N(R 10 )(R 11). In other embodiments, R4 is C≡C-CH2-NH2. In other embodiments, R4 is B(OH)2. In some embodiments, R4 is -OC(O)CF3. In some embodiments, R4 is -OCH2Ph. In some embodiments, R4 is -NHCO-R 10 In some embodiments, R4 is NHC(O)CH3). In some embodiments, R4 is NHCO-N(R 10 )(R 11 In some embodiments, R4 is NHC(O)N(CH3)2. In some embodiments, R4 is COOH. In some embodiments, R4 is -C(O)Ph. In some embodiments, R4 is C(O)OR 10 In some embodiments, R4 is C(O)O-CH3. In some embodiments, R4 is C(O)O-CH2CH3. In some embodiments, R4 is R8-C(O)-R 10 In some embodiments, R4 is CH2C(O)CH3. In some embodiments, R4 is C(O)H. In some embodiments, R4 is C1-C5 straight or branched chain C(O)-R 10 . In some embodiments, R4 is C(O)-CH3. In some embodiments, R4 is C(O)-CH2CH3. In some embodiments, R4 is C(O)-CH2CH2CH3. In some embodiments, R4 is C1-C5 straight or branched C(O)-haloalkyl. In some embodiments, R4 is C(O)-CF3. In some embodiments, R4 is -C(O)NH2. In some embodiments, R4 is C(O)NHR. In some embodiments, R4 is C(O)N(R 10 )(R 11 In some embodiments, R4 is C(O)N(CH3)2. In some embodiments, R4 is SO2R. In some embodiments, R4 is SO2N(R 10 )(R 11). In some embodiments, R4 is SO2N(CH3)2. In some embodiments, R4 is a C1-C5 straight or branched, substituted or unsubstituted alkyl group. In some embodiments, R4 is methyl, C(OH)(CH3)(Ph), ethyl, propyl, isopropyl, tert-butyl, isobutyl, or pentyl, each representing a separate embodiment according to the present invention. In some embodiments, R4 is a C1-C5 straight or branched haloalkyl group. In some embodiments, R4 is CF2CH3. In some embodiments, R4 is CH2CF3. In other embodiments, R4 is CF2CH2CH3. In some embodiments, R4 is a C1-C5 straight, branched, or cyclic alkoxy group. In some embodiments, R4 is methoxy, ethoxy, propoxy, isopropoxy, or O-CH2-cyclopropyl; each representing a separate embodiment according to the present invention. In some embodiments, R4 is a C1-C5 straight or branched thioalkoxy group. In some embodiments, R4 is a C1-C5 straight or branched haloalkoxy group. In some embodiments, R4 is a C1-C5 straight or branched alkoxyalkyl group. In some embodiments, R4 is a substituted or unsubstituted C3-C8 cycloalkyl group. In some embodiments, R4 is a cyclopropyl group. In some embodiments, R4 is a cyclopentyl group. In some embodiments, R4 is a substituted or unsubstituted C3-C8 heterocycle. In some embodiments, R4 is thiophene, oxazole, isoxazole, imidazole, furan, triazole, tetrazole, pyridine (2-pyridine, 3-pyridine, or 4-pyridine), pyrimidine, pyrazine, oxetane (1-oxetane or 2-oxetane), or indole; each represents a separate embodiment of the present invention. In some embodiments, R4 is a substituted or unsubstituted aryl group. In some embodiments, R4 is phenyl. In some embodiments, the substituents include: F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2. In some embodiments, R4 is CH(CF3)(NH-R 10 ).

[0292] In various embodiments, R5 of the compounds of Formulas I-IV is H. In some embodiments, R5 is C1-C5 straight or branched, substituted or unsubstituted alkyl. In some embodiments, R5 is methyl, CH2SH, ethyl, isopropyl; each represents a separate embodiment of the invention. In some embodiments, R5 is C1-C5 straight or branched haloalkyl. In some embodiments, R5 is CF3. In some embodiments, R5 is R8-aryl. In some embodiments, R5 is CH2-Ph. In some embodiments, R5 is substituted or unsubstituted aryl. In some embodiments, R5 is phenyl. In some embodiments, R5 is substituted or unsubstituted heteroaryl. In some embodiments, R5 is pyridine. In some embodiments, R5 is 2-pyridine. In some embodiments, R5 is 3-pyridine. In some embodiments, R5 is 4-pyridine. In some embodiments, the substituents include: F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy, N(R)2, CF3, CN, or NO2.

[0293] In various embodiments, n of the compound of Formula I-II is 0. In some embodiments, n is 0 or 1. In some embodiments, n is between 1 and 3. In some embodiments, n is between 1 and 4. In some embodiments, n is between 0 and 2. In some embodiments, n is between 0 and 3. In some embodiments, n is between 0 and 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.

[0294] In various embodiments, m of the compound of Formula I-II is 0. In some embodiments, m is 0 or 1. In some embodiments, m is between 1 and 3. In some embodiments, m is between 1 and 4. In some embodiments, m is between 0 and 2. In some embodiments, m is between 0 and 3. In some embodiments, m is between 0 and 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.

[0295] In various embodiments, l of the compounds of Formula I-II is 0. In certain embodiments, l is 0 or 1. In some embodiments, l is between 1 and 3. In some embodiments, l is between 1 and 4. In some embodiments, l is between 0 and 2. In some embodiments, l is between 0 and 3. In some embodiments, l is between 0 and 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.

[0296] In various embodiments, k for compounds of Formula I-II is 0. In some embodiments, k is 0 or 1. In some embodiments, k is between 1 and 3. In some embodiments, k is between 1 and 4. In some embodiments, k is between 0 and 2. In some embodiments, k is between 0 and 3. In some embodiments, k is between 0 and 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.

[0297] It should be understood that for heterocycles, n, m, l and / or k are limited to the number of positions available for substituents, i.e., the number of CH or NH groups minus one. Thus, if the A and / or B rings are, for example, furanyl, thienyl, or pyrrolyl, then n, m, l, and k are between 0 and 2; and if the A and / or B rings are, for example, oxazolyl, imidazolyl, or thiazolyl, then n, m, l, and k are 0 or 1; and if the A and / or B rings are, for example, oxadiazolyl or thiadiazolyl, then n, m, l, and k are 0.

[0298] In various embodiments, R6 of the compounds of Formula I-III is H. In some embodiments, R6 is C1-C5 straight or branched chain alkyl. In some embodiments, R6 is methyl. In some embodiments, R6 is ethyl. In some embodiments, R6 is C(O)R, wherein R6 is C1-C5 straight or branched chain alkyl, C1-C5 straight or branched chain alkoxy, phenyl, aryl, or heteroaryl. In some embodiments, R6 is S(O)2R, wherein R6 is C1-C5 straight or branched chain alkyl, C1-C5 straight or branched chain alkoxy, phenyl, aryl, or heteroaryl.

[0299] In various embodiments, R8 of the compound of Formula IV is CH2. In some embodiments, R8 is CH2CH2. In some embodiments, R8 is CH2CH2CH2. In some embodiments, R8 is CH2CH2CH2.

[0300] In various embodiments, p 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 between 1 and 3. In some embodiments, p is between 1 and 5. In some embodiments, p is between 1 and 10.

[0301] In some embodiments, R9 of the compound of formula IV 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.

[0302] In some embodiments, q of the compound of Formula IV 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 between 2 and 6.

[0303] In various embodiments, R of the compound of Formula IV 10 is H. In some embodiments, R 10 is a C1-C5 straight or branched chain alkyl group. 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 is C(O)R. In some embodiments, R 10 is S(O)2R.

[0304] In various embodiments, R of the compound of Formula IV 11 is H. In some embodiments, R 11 is a C1-C5 straight or branched chain alkyl group. 11 In some embodiments, R 11 In some embodiments, R 10 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11In some embodiments, R 11 is C(O)R. In some embodiments, R 11 is S(O)2R.

[0305] In various embodiments, R of the compound of Formula IV is H. In other embodiments, R is a C1-C5 straight or branched chain alkyl group. In other embodiments, R is methyl. In other embodiments, R is ethyl. In other embodiments, R is a C1-C5 straight or branched chain alkoxy group. In other embodiments, R is phenyl. In other embodiments, R is aryl. In other embodiments, R is heteroaryl. In other embodiments, two geminal R substituents are linked together to form a 5- or 6-membered heterocyclic ring.

[0306] In various embodiments, Q1 of the compounds of Formula I-III is O. In other embodiments, Q1 is S. In other embodiments, Q1 is N-OH. In other embodiments, Q1 is CH2. In other embodiments, Q1 is C(R)2. In other embodiments, Q1 is N-OMe.

[0307] In various embodiments, Q2 of the compounds of Formula I-III is O. In other embodiments, Q2 is S. In other embodiments, Q2 is N-OH. In other embodiments, Q2 is CH2. In other embodiments, Q2 is C(R)2. In other embodiments, Q2 is N-OMe.

[0308] In various embodiments, X1 of the compound of Formula II is C. In other embodiments, X1 is N.

[0309] In various embodiments, X2 of the compound of Formula II is C. In other embodiments, X2 is N.

[0310] In various embodiments, X3 of the compound of Formula II-V is C. In other embodiments, X3 is N.

[0311] In various embodiments, X4 of the compound of Formula II-IV is C. In other embodiments, X4 is N.

[0312] In various embodiments, X5 of the compound of Formula II is C. In other embodiments, X5 is N.

[0313] In various embodiments, X6 of the compound of Formula II-III is C. In other embodiments, X6 is N.

[0314] In various embodiments, X7 of the compound of Formula II-V is C. In other embodiments, X7 is N.

[0315] In various embodiments, X8 of the compounds of Formula II-IV is C. In other embodiments, X8 is N.

[0316] In various embodiments, X9 of the compound of Formula II is C. In other embodiments, X9 is N.

[0317] In various embodiments, X of the compound of Formula II 10 is C. In other embodiments, X 10 is N.

[0318] As used herein, a "monocyclic or fused aromatic or heteroaromatic ring system" can be any such ring including, but not limited to, phenyl, naphthyl, pyridinyl (2-pyridinyl, 3-pyridinyl, and 4-pyridinyl), quinolyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, pyrazolyl, pyrrolyl, furanyl, thienyl, quinolyl, isoquinolyl, 2,3-dihydroindenyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepene, benzodioxolyl, benzo[d][1,3]dioxole, tetrahydronaphthyl, indolyl, 1H-indole, isoindolyl, anthracenyl, benzo[b][1,4]benzo[d][1,3]benzo[d][ ... imidazolyl, 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, 1,3-benzothiazole, 4,5,6,7-tetrahydro-1,3 -benzothiazole, quinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxaline, 1-(pyridin-1(2H)-yl)ethanone, cinnolinyl, phthalazinyl, quinolinyl, isoquinolinyl, acridinyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzofuran-2(3H)-one, benzothiophene, benzodiazole, benzo[c][1,2, 5]oxadiazolyl, benzo[c]thienyl, benzodioxolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiazolyl, 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, etc.

[0319] As used herein, unless otherwise indicated, the term "alkyl" may be any straight or branched chain alkyl group containing up to about 30 carbons. In various embodiments, the alkyl group includes C1-C5 carbons. In some embodiments, the alkyl group includes C1-C6 carbons. In some embodiments, the alkyl group includes C1-C8 carbons. In some embodiments, the alkyl group includes C1-C 10 In some embodiments, the alkyl group is C1-C 12 In some embodiments, the alkyl group is C1-C 20 In some embodiments, the branched alkyl group is an alkyl group substituted with an alkyl side chain having 1 to 5 carbon atoms. In various embodiments, the alkyl group can be unsubstituted. In some embodiments, the alkyl group can be substituted with halo, haloalkyl, hydroxy, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, sulfanyl, and / or sulfanyl.

[0320] The alkyl group may be the sole substituent or it may be a component of a larger substituent, as in alkoxy, alkoxyalkyl, haloalkyl, arylalkyl, alkylamino, dialkylamino, alkylamido, alkylurea, etc. Preferred alkyl groups are methyl, ethyl, and propyl, and thus halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, halopropyl, dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl, arylethyl, arylpropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, formamido, acetamido, propylamido, halomethylamido, haloethylamido, halopropylamido, methylurea, ethylurea, propylurea, 2, 3, or 4-CH2-C6H4-Cl, C(OH)(CH3)(Ph), and the like.

[0321] As used herein, the term "aryl" refers to any aromatic ring that is directly bonded to another group and may be substituted or unsubstituted. The aryl group may be the sole substituent, or the aryl group may be a component of a larger substituent, such as in arylalkyl, arylamino, arylamido, and the like. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, xylyl, furanyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thienyl, pyrrolyl, benzyl, phenethyl, phenethyl, phenylamino, phenylamido, and the like. Substituents include, but are not limited to, F, Cl, Br, I, C1-C5 straight or branched alkyl, C1-C5 straight or branched haloalkyl, C1-C5 straight or branched alkoxy, C1-C5 straight or branched haloalkoxy, CF3, 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 or -C(O)NH2.

[0322] As used herein, the term "alkoxy" refers to an ether group substituted with an alkyl group as defined above. Alkoxy refers to both straight and branched chain alkoxy groups. Non-limiting examples of alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, and tert-butoxy.

[0323] As used herein, the term "aminoalkyl" refers to an amine group substituted with an alkyl group as defined above. Aminoalkyl refers to a monoalkylamine, a dialkylamine, or a trialkylamine. Non-limiting examples of aminoalkyl groups are -N(Me)2, -NHMe, and -NH3.

[0324] In some embodiments, "haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halogen atoms, such as F, Cl, Br, or I. The term "haloalkyl" includes, but is not limited to, fluoroalkyl groups, i.e., alkyl groups with at least one fluorine atom. Non-limiting examples of haloalkyl groups are CF3, CF2CF3, CF2CH3, and CH2CF3.

[0325] In some embodiments, "alkoxyalkyl" refers to an alkyl group as defined above substituted with an alkoxy group as defined above, for example, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, etc. Non-limiting examples of alkoxyalkyl groups are -CH2-O-CH3, -CH2-O-CH(CH3)2, -CH2-OC(CH3)3, -CH2-CH2-O-CH3, -CH2-CH2-O-CH(CH3)2, -CH2-CH2-OC(CH3)3.

[0326] In various embodiments, a "cycloalkyl" or "carbocyclic" group refers to a ring structure containing carbon atoms as ring atoms, which can be saturated or unsaturated, substituted or unsubstituted, monocyclic or fused. In some embodiments, the cycloalkyl group is a 3-10 membered ring. In some embodiments, the cycloalkyl group is a 3-12 membered ring. In some embodiments, the cycloalkyl group is a 6 membered ring. In some embodiments, the cycloalkyl group is a 5-7 membered ring. In some embodiments, the cycloalkyl group is a 3-8 membered ring. In some embodiments, the cycloalkyl group can be unsubstituted or substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, sulfanyl, and / or sulfanyl. In some embodiments, the cycloalkyl ring can be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring. In some embodiments, the cycloalkyl ring is saturated. In some embodiments, the cycloalkyl ring is unsaturated. Non-limiting examples of cycloalkyl groups include cyclohexyl, cyclohexenyl, cyclopropyl, cyclopropenyl, cyclopentyl, cyclopentenyl, cyclobutyl, cyclobutenyl, cyclooctyl, cyclohexenyl (COD), cyclohexene (COE), and the like.

[0327] In various embodiments, a "heterocycle" or "heterocyclic" group refers to a ring structure that, in addition to carbon atoms, also includes sulfur, oxygen, nitrogen, or any combination thereof as part of the ring. In various embodiments, a "heteroaromatic ring" refers to an aromatic ring structure that, in addition to carbon atoms, also includes sulfur, oxygen, nitrogen, or any combination thereof as part of the ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3-10 membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3-12 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 5-7 membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3-8 membered ring. In some embodiments, the heterocycle or heteroaromatic ring can be unsubstituted or substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carbonyl, amide, alkylamide, dialkylamide, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, sulfanyl, and / or sulfanyl. In some embodiments, the heterocyclic or heteroaromatic ring can be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring. In some embodiments, the heterocyclic ring is a saturated ring. In some embodiments, the 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, or indole.

[0328] 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 (deuterated analog), PROTAC, polymorph or crystal or a combination thereof. In various 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 prodrug of a compound of the present invention. In some embodiments, the present invention provides an isotopic variant (including but not limited to deuterated analog) of a compound of the present invention. In some embodiments, the present invention provides a PROTAC (proteolysis targeting 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 a crystal of a compound of the present invention. In some embodiments, the present invention provides a composition comprising a compound of the invention as described herein, or in some embodiments, a combination of an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant (deuterated analog), PROTAC, polymorph, or crystal of a compound of the invention.

[0329] In various embodiments, the term "isomer" includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, etc. In some embodiments, the isomer is an optical isomer.

[0330] In various embodiments, the present invention encompasses the use of various optical isomers of the compounds of the present invention. It will be appreciated 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 methods of the present invention may exist in optically active or racemic forms and be separated in such forms. Therefore, the compounds according to the present invention may be used as optically active isomers (enantiomers or diastereomers, including but not limited to: (R), (S), (R)(R), (R)(S), (S)(S), (S)(R), (R)(R)(R), (R)(R)(S), (R)(S)(R), (S)(R)(R), (R)(S)(S), (S)(R)(S), (S)(R)(S), (S)(S)(R), or (S)(S)(S) isomers), as racemic mixtures or as enantiomeric enrichment mixtures. Some compounds may also exhibit polymorphism. It will be appreciated that the present invention encompasses any racemic, optically active, polymorphic or stereoisomeric forms or mixtures thereof, which have properties suitable for treating different conditions described herein.

[0331] It is well known in the art how to prepare optically active forms (e.g., by resolution of racemic forms using recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using chiral stationary phases).

[0332] The compounds of the present invention may also exist as racemic mixtures containing substantially equal amounts of stereoisomers. In some embodiments, the compounds of the present invention can be prepared using known procedures or otherwise isolated to obtain stereoisomers that are substantially free of their corresponding stereoisomers (i.e., substantially pure). By substantially pure, it is meant that the purity of the stereoisomers is at least about 95%, more preferably at least about 98%, and most preferably at least about 99%.

[0333] The compounds of the present invention may also be in the form of a hydrate, which means that the compound further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0334] The compounds of the present invention may exist in one or more possible tautomer forms, and depending on the specific conditions, it is possible to separate some or all tautomers into individual and distinct entities. It should be understood that all possible tautomers are encompassed herein, including all additional enol and keto tautomers and / or isomers. For example, the following tautomers are included (but are not limited to these tautomers):

[0335] Tautomerization of the imidazole ring

[0336]

[0337] Tautomerization of the pyrazolone ring:

[0338]

[0339] The present invention includes "pharmaceutically acceptable salts" of the compounds of the present invention, which can be produced by the reaction of the compounds of the present invention with an acid or base. Certain compounds, particularly those having acidic or basic groups, can also be in the form of salts, preferably pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the free base or free acid, which are not biologically or otherwise undesirable. Salts are formed by inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxoacid, 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 easily adapted for use according to the present invention.

[0340] Suitable pharmaceutically acceptable salts of the amines of the compounds of the present invention can be prepared from inorganic or organic acids. In various embodiments, examples of inorganic salts of amines are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromides, hydrochlorides, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothiosulfonates, nitrates, persulfates, phosphates, sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halo-substituted alkylsulfonates, halo-substituted arylsulfonates), sulfonates, and thiocyanates.

[0341] In various embodiments, examples of organic salts of amines can be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acid classes of organic acids, examples of which are acetic acid, arginine, aspartic acid, ascorbate, adipate, anthranilate, alginate, alkane carboxylates, substituted alkane carboxylates, alginate, benzenesulfonate, benzoate, bisulfate, butyrate, bicarbonate, bitartrate, citrate, camphorate, camphorsulfonate, cyclohexylaminosulfonate, cyclopentanepropionate, calcium edetate, dextrorotatory camphorsulfonate, carbonate, clavulanate, cinnamate, dicarboxylate, digluconate, dodecylsulfonate, dihydrochloride, decanoate, heptanoate, ethanesulfonate, edetate, edisylate, propionate dodecylsulfate, ethanesulfonate, fumarate, formate, fluoride, galacturonate, gluconate, glutamate, glycolate, glucarate, gluceptate, glycerophosphate, glucoheptanoate, glycolylaminophenylarsonic acid salt, glutarate, glutamate, Acid, heptanoate, hexanoate, hydroxymaleate, hydroxycarboxylic acid, hexylresorcinate, hydroxybenzoate, hydroxynaphthoate, hydrofluoride, lactate, lactobionate, laurate, malate, maleate, methylenebis(β-oxynaphthoate), malonate, mandelate, methanesulfonate, methanesulfonate, methylbromide, methylnitrate, methanesulfonate, monopotassium maleate, mucate, monocarboxylate, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, naphthalenesulfonate, N-methylglucamine, oxalate, octanoic acid Salt, oleate, pamoate, phenylacetate, picrate, phenylacetate, pivalate, propionate, phthalate, phenylacetate, pectinate, phenylpropionate, palmitate, pantothenate, polygalacturonate, pyruvate, quinic acid, salicylate, succinate, stearate, sulfanilate, subacetate, tartrate, theophylline acetate, p-toluenesulfonate (toluenesulfonate), trifluoroacetate, terephthalate, tannate, theocyanate, trihaloacetate, triethyl iodide, tricarboxylate, undecanoate, and valerate.

[0342] In various embodiments, examples of inorganic salts of carboxylic acids or hydroxyls can be selected from ammonium, alkali metals (including lithium, sodium, potassium, cesium), alkaline earth metals (including calcium, magnesium, aluminum, zinc, barium), choline, quaternary ammonium.

[0343] In some embodiments, examples of organic salts of carboxylic acids or hydroxyl groups can be selected from arginine, organic amines (including aliphatic organic amines, alicyclic organic amines, aromatic organic amines), benzathine, tert-butylamine, phenethylbenzylamine (N-benzylphenethylamine), dicyclohexylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, hydrazine, imidazole, lysine, methylamine, meglumine, N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, nicotinamide, organic amines, ornithine, pyridine, picoline, piperazine, procaine, tris(hydroxymethyl)methylamine, triethylamine, triethanolamine, trimethylamine, tromethamine, and urea.

[0344] In various embodiments, salts can be formed by conventional means, for example, by reacting the free base or free acid form of the product with one or more equivalents of an 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 in vacuo or by freeze drying or by exchanging the ion of the existing salt for another ion or a suitable ion exchange resin.

[0345] Pharmaceutical composition

[0346] Another aspect of the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to various aspects of the present invention. The pharmaceutical composition may contain one or more of the above-mentioned compounds of the present invention. Typically, the pharmaceutical composition of the present invention will include 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, vehicle, excipient or stabilizer, and can be in solid or liquid form, such as a tablet, capsule, powder, solution, suspension or emulsion.

[0347] Typically, the composition will contain about 0.01% to 99%, preferably about 20% to 75% of the active compound and an adjuvant, carrier and / or excipient. Although individual needs may vary, the determination of the optimal range of each component of the effective amount is within the technical scope of the art. A typical dose comprises about 0.01 to about 100 mg / kg body weight. A preferred dose comprises about 0.1 to about 100 mg / kg body weight. A most preferred dose comprises about 1 to about 100 mg / kg body weight. A person of ordinary skill in the art can also easily determine a treatment regimen for administering the compounds of the invention. That is, the frequency and dose size of administration can be determined by conventional optimization, preferably while minimizing any side effects.

[0348] Solid unit dosage forms can be conventional. Solid forms can be capsules, such as conventional gelatin-type capsules containing the compounds of the invention and carriers, such as lubricants and inert fillers, such as lactose, sucrose, or corn starch. In some embodiments, these compounds are combined with conventional tablet bases, such as lactose, sucrose, or corn starch; binders, such as acacia, corn starch, or gelatin; disintegrants, such as corn starch, potato starch, or alginic acid; and lubricants, such as stearic acid or magnesium stearate.

[0349] Tablets, capsules, etc. may also contain a binder such as tragacanth, gum arabic, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose or saccharin. When the unit dosage form is a capsule, it may contain, in addition to the above-mentioned materials, a liquid carrier such as a fatty oil.

[0350] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. In addition to the active ingredient, a syrup may contain sucrose as a sweetener, methyl and propylparabens as preservatives, dyes, and flavorings (such as cherry or orange flavor).

[0351] For oral therapeutic administration, these active compounds can be combined with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, etc. Such compositions and preparations should contain at least 0.1% active compound. Of course, the percentage of compound in these compositions can vary and can conveniently be between about 2% and about 60% of the unit weight. The amount of active compound in such therapeutically useful compositions will thereby provide a suitable dosage. Preferred compositions according to the present invention are prepared so that the oral dosage unit contains between about 1 mg and 800 mg of active compound.

[0352] The active compound of this invention may be administered orally, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in a hard or soft shell capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.

[0353] The pharmaceutical form suitable for injection purposes includes sterile aqueous solutions or dispersions and sterile powders for the temporary preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be fluid, to the extent that it can be easily injected. It should be stable under the conditions of manufacture and storage and should be preserved to avoid the contamination of microorganisms (such as bacteria and fungi). Carrier can be a solvent or dispersion medium, which contains, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), a suitable mixture thereof and vegetable oil.

[0354] Compound of the present invention or pharmaceutical composition can also be given with injectable dose by the solution or suspension of these materials in the form of physiologically acceptable diluent and pharmaceutical adjuvant, carrier or excipient.When adding or not adding surfactant and other pharmaceutically and physiologically acceptable components, this type of adjuvant, carrier and / or excipient include but are not limited to sterile liquids, such as water and oil.Exemplary oils are those oils of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil or mineral oil.In general, water, normal saline, dextrose and related sugar solutions and as the glycol of propylene glycol or polyethylene glycol are preferred liquid vehicles, especially for injectable solutions.

[0355] These active compounds can also be given parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersion liquids can also be prepared in oil in glycerol, liquid polyethylene glycol and mixtures thereof. Exemplary oils are those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil or mineral oil. In general, water, normal saline, dextrose and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, especially for injectable solutions. Under general storage and use conditions, these preparations contain preservatives to prevent microbial growth.

[0356] For use as aerosols, the compound of the present invention in solution or suspension can be packaged in a pressurized aerosol container with a suitable propellant (e.g., a hydrocarbon propellant such as propane, butane or isobutane) and conventional co-adjuvants. The material of the present invention can also be administered in a non-pressurized form, for example, in a sprayer or atomizer.

[0357] In various embodiments, the compounds of the present invention are administered in combination with an anticancer agent. In various embodiments, the anticancer agent is a monoclonal antibody. In some embodiments, monoclonal antibodies are used to diagnose, monitor, or treat cancer. In various embodiments, monoclonal antibodies react to specific antigens on cancer cells. In various embodiments, monoclonal antibodies act as cancer cell receptor antagonists. In various embodiments, monoclonal antibodies enhance the patient's immune response. In various embodiments, monoclonal antibodies act against cell growth factors, thereby hindering the growth of cancer cells. In various embodiments, anticancer monoclonal antibodies are bound to or connected to anticancer drugs, radioisotopes, other biological response modifiers, other toxins, or combinations thereof. In various embodiments, anticancer monoclonal antibodies are bound to or connected to the compounds of the present invention as described above.

[0358] In various embodiments, the compounds of the invention are administered in combination with an agent that treats Alzheimer's disease.

[0359] In various embodiments, the compounds of the invention are administered in combination with an antiviral agent.

[0360] In various embodiments, the compounds of the invention are administered in combination with at least one of chemotherapy, molecularly targeted therapy, DNA damaging agents, serotonin-inducing agents, or immunotherapy, each possibility representing a separate embodiment of the invention.

[0361] Yet another aspect of the present invention relates to a method for treating cancer, comprising selecting an individual in need of cancer treatment, and administering to the individual a pharmaceutical composition comprising a compound according to the first aspect of the present invention and a pharmaceutically acceptable carrier under conditions effective to treat the cancer.

[0362] When the compounds of this invention are administered, they can be administered systemically, or alternatively, they can be administered directly to the specific site where cancer cells or precancerous cells are present. Therefore, administration can be achieved in any manner that effectively compounds or pharmaceutical compositions are delivered to cancer cells or precancerous cells. Exemplary modes of administration include, but are not limited to, oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, by intranasal administration, by intracavitary or intravesical administration, intraocular, intraarterial, intraarterial, intralesional, or by being applied to mucous membranes, such as the mucous membranes of the nose, throat, and bronchus to administer compounds or compositions.

[0363] Biological activity

[0364] In various embodiments, the present invention provides compounds and compositions for use in any of the methods of the present invention, including any of the embodiments described herein. In various embodiments, the use of the compounds of the present invention or compositions comprising the same will have utility in preventing, inhibiting, enhancing, or stimulating a desired response in an individual, as will be understood by those skilled in the art. In some embodiments, the composition may include other active ingredients whose activity is suitable for the specific application for which the compounds of the present invention are administered.

[0365] Acetate is a critical source of acetyl-CoA during hypoxia. Inhibition of acetate metabolism may impair tumor growth. The nuclear cytosolic acetyl-CoA synthetase, ACSS2, provides a critical source of acetyl-CoA to tumors by capturing acetate as a carbon source. Although showing no overall defects in growth or development, adult mice lacking ACSS2 exhibited significantly reduced tumor burden in two different models of hepatocellular carcinoma. ACSS2 is expressed in a wide range of human tumors, and its activity is primarily responsible for cellular acetate uptake into lipids and histones. Furthermore, an unbiased functional genomic screen identified ACSS2 as a key enzyme for the growth and survival of breast and prostate cancer cells cultured under hypoxic and low-serum conditions. Indeed, ACSS2 expression is frequently found at higher levels in breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, pancreatic cancer, and invasive ductal carcinoma of the lung, and is directly associated with higher tumor grade and lower survival compared to tumors with low ACSS2 expression. These observations may make ACSS2 a targetable metabolic vulnerability in a wide variety of tumors.

[0366] Therefore, in various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing cancer, comprising administering a compound of the present invention to an individual suffering from cancer under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of developing, or prevent the cancer. In some embodiments, the compound 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 presented below:

[0367]

[0368]

[0369]

[0370] In some embodiments, the cancer is selected from the following list: hepatocellular carcinoma, melanoma (e.g., BRAF mutant melanoma), glioblastoma, breast cancer, prostate cancer, liver cancer, brain cancer, Lewis lung carcinoma (LLC), colon cancer, pancreatic cancer, renal cell carcinoma, and breast cancer. In some embodiments, the cancer is selected from the following list: melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancer, Hodgkin lymphoma, Merkel cell skin cancer (Merkel cell carcinoma), esophageal cancer, gastroesophageal junction cancer, liver cancer (hepatocellular carcinoma), lung cancer (small cell) (SCLC), gastric cancer, upper urinary tract cancer (urothelial carcinoma), glioblastoma multiforme, multiple myeloma, anal cancer (squamous cell), cervical cancer, endometrial cancer, nasopharyngeal cancer, 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 the following list: glioblastoma, melanoma, lymphoma, breast cancer, ovarian cancer, glioma, digestive system cancer, central nervous system cancer, hepatocellular carcinoma, blood cancer, colon cancer, or any combination thereof. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0371] Glucose-independent acetate metabolism has been shown to promote melanoma cell survival and tumor growth. Glucose-deprived melanoma cells are highly dependent on acetate to maintain ATP levels, cell viability, and proliferation. Conversely, depletion of ACSS1 or ACSS2 reduces melanoma growth in mice. Overall, the data implicate acetate metabolism as a causal factor in melanoma.

[0372] Thus, in various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of, or preventing melanoma, comprising administering a compound of the present invention to an individual suffering from melanoma under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent the development of 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 a BRAF mutant melanoma. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0373] Acetyl-CoA synthetase, which catalyzes the conversion of acetate to acetyl-CoA, has been implicated in the growth of hepatocellular carcinoma, glioblastoma, breast cancer, and prostate cancer.

[0374] Hepatocellular carcinoma (HCC) is a fatal 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 Organization for Research and Treatment of Cancer, 2012). Despite many available treatment strategies, the survival rate of HCC patients is very low. Given its rising prevalence, there is an urgent need for more targeted and effective treatment strategies for HCC.

[0375] In various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing hepatocellular carcinoma (HCC), comprising administering a compound of the present invention to an individual suffering from hepatocellular carcinoma (HCC) under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of developing, or prevent hepatocellular carcinoma (HCC). In some embodiments, hepatocellular carcinoma (HCC) is early-stage hepatocellular carcinoma (HCC). In some embodiments, hepatocellular carcinoma (HCC) is advanced hepatocellular carcinoma (HCC). In some embodiments, hepatocellular carcinoma (HCC) is invasive hepatocellular carcinoma (HCC). In some embodiments, hepatocellular carcinoma (HCC) is metastatic hepatocellular carcinoma (HCC). In some embodiments, hepatocellular carcinoma (HCC) is drug-resistant hepatocellular carcinoma (HCC). In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0376] ACSS2-mediated acetate metabolism contributes to lipid synthesis and aggressive growth in glioblastoma and breast cancer.

[0377] Nuclear ACSS2 has been shown to activate HIF-2α through acetylation and thus accelerate the growth and metastasis of HIF2α-driven cancers, such as certain renal cell carcinomas and glioblastomas (Chen, R. et al. Coordinated regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells. PLoS One, 12(12):1-31, 2017).

[0378] Therefore, and in various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing a glioblastoma, comprising administering a compound of the present invention to an individual suffering from a glioblastoma under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of developing, or prevent the 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 infiltrating 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 is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0379] Therefore, and in various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of, or preventing renal cell carcinoma, comprising administering a compound of the present invention to an individual suffering from renal cell carcinoma under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent 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 compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0380] In various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of, or preventing breast cancer, comprising administering a compound of the present invention to an individual suffering from breast cancer under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent the 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 is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0381] In various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of, or preventing prostate cancer, comprising administering a compound of the present invention to an individual suffering from prostate cancer under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent said 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 is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0382] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of, or preventing liver cancer, comprising administering a compound of the present invention to an individual suffering from liver cancer under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent said 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 is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0383] Nucleating ACSS2 has also been shown to promote lysosomal biogenesis, autophagy, and brain tumorigenesis by affecting histone H3 acetylation (Li, X et al.: Nuclear translocation of ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy, Molecular Cell 66, 1-14, 2017).

[0384] In various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of, or preventing brain cancer, comprising administering a compound of the present invention to an individual suffering from brain cancer under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent said brain cancer. In some embodiments, the brain cancer is early-stage brain cancer. In some embodiments, the brain cancer is advanced brain cancer. In some embodiments, the brain cancer is invasive brain cancer. In some embodiments, the brain cancer is metastatic brain cancer. In some embodiments, the brain cancer is drug-resistant brain cancer. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0385] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of, or preventing pancreatic cancer, comprising administering a compound of the present invention to an individual suffering from pancreatic cancer under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent said 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 is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0386] In various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing Lewis lung cancer (LLC) comprising administering a compound of the present invention to an individual suffering from Lewis lung cancer (LLC) under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of developing, or prevent Lewis lung cancer (LLC). In some embodiments, Lewis lung cancer (LLC) is early-stage Lewis lung cancer (LLC). In some embodiments, Lewis lung cancer (LLC) is advanced Lewis lung cancer (LLC). In some embodiments, Lewis lung cancer (LLC) is invasive Lewis lung cancer (LLC). In some embodiments, Lewis lung cancer (LLC) is metastatic Lewis lung cancer (LLC). In some embodiments, Lewis lung cancer (LLC) is drug-resistant Lewis lung cancer (LLC). In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0387] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing colon cancer, comprising administering a compound of the present invention to an individual suffering from colon cancer under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing, or prevent 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 compound is a "programmed cell death receptor 1" (PD-1) modulator. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0388] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of breast cancer, reducing the risk of developing breast cancer, or preventing breast cancer, comprising administering a compound of the present invention to an individual suffering from breast cancer under conditions effective to treat, inhibit, reduce the severity of breast cancer, reduce the risk of developing breast cancer, or prevent 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 is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0389] In various embodiments, the present invention relates to a method for inhibiting, reducing or preventing tumor growth in an individual, comprising administering a compound according to the present invention to an individual suffering from a proliferative disorder (e.g., cancer) under conditions that effectively inhibit, reduce or prevent the growth of the tumor in the individual. In some embodiments, tumor growth is enhanced by increasing acetate absorption by cancer cells. In some embodiments, the increase in acetate metabolism is mediated by ACSS2. In some embodiments, the cancer cells are under hypoxic stress. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, tumor growth is inhibited by inhibiting the metabolism of acetate mediated by ACSS2 into lipid synthesis (e.g., fatty acids) induced by acetyl-CoA. In some embodiments, tumor growth is inhibited by inhibiting the metabolism of acetate mediated by ACSS2 into histone acetylation and function induced by acetyl-CoA. In some embodiments, synthesis is inhibited under hypoxia (hypoxic stress). In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0390] In various embodiments, the present invention relates to a method for inhibiting, reducing or preventing lipid synthesis and / or regulating histone acetylation and function in a cell, comprising contacting a compound of the present invention with a cell under conditions that effectively inhibit, reduce or prevent lipid synthesis and / or regulate histone acetylation and function in the cell. In various embodiments, the method is performed in vitro. In various embodiments, the method is performed in vivo. In various embodiments, lipid synthesis is induced by acetate metabolism to acetyl-CoA mediated by ACSS2. In various embodiments, histone acetylation and function are induced by acetate metabolism to acetyl-CoA mediated by ACSS2. In various embodiments, the cell is a cancer cell. In various embodiments, the lipid is a fatty acid. In various embodiments, acetate metabolism of acetyl-CoA is performed under hypoxia (i.e., hypoxic stress). In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0391] In various embodiments, the present invention relates to a method of inhibiting, reducing or preventing fatty acid accumulation in the liver, comprising administering a compound of the present invention to an individual in need thereof under conditions that effectively inhibit, reduce or prevent fatty acid accumulation in the liver of the individual. In various embodiments, fatty acid accumulation is induced by acetate metabolism mediated by ACSS2 to acetyl-CoA. In various embodiments, the individual suffers from fatty liver disease. In various embodiments, acetate metabolism of acetyl-CoA in the liver is carried out under hypoxia (i.e., hypoxic stress). In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0392] In various embodiments, the present invention relates to a method for binding an ACSS2 inhibitor compound to an ACSS2 enzyme, comprising the steps of 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 is performed in vitro. In other embodiments, the method is performed in vivo. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0393] In various embodiments, the present invention relates to a method for inhibiting, reducing, or preventing the synthesis of acetyl-CoA from acetate in a cell, comprising contacting a compound according to the present invention with the cell under conditions effective to inhibit, reduce, or prevent the synthesis of acetyl-CoA from acetate in the cell. In some embodiments, the cell is a cancer cell. In some embodiments, the method is performed in vitro. In other embodiments, the method is performed in vivo. In some embodiments, the synthesis is mediated by ACSS2. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the cell is under hypoxic stress. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0394] In various embodiments, the present invention relates to a method of inhibiting, reducing, or preventing acetate metabolism in cancer cells, comprising contacting a compound according to the present invention with the cancer cells under conditions effective to inhibit, reduce, or prevent acetate metabolism in the cells. In some embodiments, acetate metabolism is mediated by ACSS2. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the cancer cells are under hypoxic stress. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0395] In various embodiments, the present invention provides a method for treating, inhibiting, reducing the severity of, reducing the risk of, or preventing metastatic cancer, comprising the steps of administering to the individual a compound of the present invention and / or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, polymorph, or crystal, or any combination thereof. In some embodiments, the compound is an ACSS2 inhibitor. 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 cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer.

[0396] In various embodiments, the present invention provides a method for improving the survival rate of an individual suffering from metastatic cancer, comprising the steps of administering to the individual a compound of the present invention and / or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, polymorph or crystal, or any combination thereof. In some embodiments, the compound is an ACSS2 inhibitor. 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 cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer.

[0397] In various embodiments, the present invention provides a method for treating, inhibiting, reducing the severity of, reducing the risk of, or preventing advanced cancer, comprising the steps of administering to the individual a compound of the invention and / or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, polymorph, or crystal, or any combination thereof. In some embodiments, the compound is an ACSS2 inhibitor. 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 cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer.

[0398] In various embodiments, the present invention provides a method for improving the survival rate of an individual suffering from advanced cancer, comprising the following steps: administering to the individual a compound of the present invention and / or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, polymorph or crystal, or any combination thereof. In some embodiments, the compound is an ACSS2 inhibitor. 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 cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer.

[0399] The compounds of the present invention are suitable for treating cancer, metastatic cancer, advanced cancer, drug-resistant cancer and various forms of cancer, reducing its severity, reducing its risk or preventing cancer, metastatic cancer, advanced cancer, drug-resistant cancer and various forms of cancer. In a preferred embodiment, cancer is hepatocellular carcinoma, melanoma (e.g., BRAF mutant melanoma), glioblastoma, breast cancer, prostate cancer, liver cancer, brain cancer, pancreatic cancer, Lewis lung cancer (LLC), colon cancer, renal cell carcinoma and / or breast cancer, each representing a separate embodiment according to the present invention. Based on its mode of action, it is believed that when the compound or composition of the present invention is administered to a patient, other forms of cancer will be equally treatable or preventable. The preferred compounds of the present invention have selective destructiveness to cancer cells, causing ablation of cancer cells, but preferably do not cause ablation of normal cells. Significantly, damage to normal cells is minimized because cancer cells are susceptible to destruction at much lower concentrations of the compounds of the present invention.

[0400] In various embodiments, other types of cancer that can be treated with an ACSS2 inhibitor according to 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 tumor, pineal tumor, hypothalamic glioma, carcinoid tumor, carcinoma, cervical cancer, colon cancer, central nervous system (CNS) cancer, endometrial cancer, esophageal cancer, extrahepatic bile duct cancer, Ewing's family of tumors, and cholangiocarcinoma. tumors, Pnet), extracranial germ cell tumors, eye cancer, intraocular melanoma, gallbladder cancer, gastric cancer, germ cell tumors, extragonadal gestational trophoblastic tumors, head and neck cancer, hypopharyngeal cancer, islet cell cancer, 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 disease, 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 cancer, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low-grade malignant potential tumor, pancreatic cancer, exocrine pancreatic cancer, islet cell carcinoma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma, pituitary cancer, plasma cell neoplasm, prostate cancer, rhabdomyosarcoma, rectal cancer, kidney cancer, renal cell carcinoma, salivary gland cancer, Sézary syndrome In some embodiments, the cancer is invasive. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is advanced. In some embodiments, the cancer is drug-resistant.

[0401] In various embodiments, " metastatic cancer " refers to the cancer that spreads (metastasizes) to another area of ​​the body from its original position.Almost all cancers have the potential for spread.Whether metastasis occurs depends on the complex interaction of many tumor cell factors, including the type of cancer, the maturity (differentiation) degree of tumor cells, the existing position and existence time of cancer, and other factors not fully understood.Metastasis spreads in three ways-by local expansion from the tumor to surrounding tissues, by blood flow to distant sites or by lymphatic system to adjacent or distant lymph nodes.Every kind of cancer can have a typical diffusion pathway.Tumor is referred to as the primary site (for example, breast cancer that spreads to the brain is referred to as metastatic breast cancer of the brain).

[0402] In various embodiments, "drug-resistant cancer" refers to cancer cells that are resistant to chemotherapy. Cancer cells can acquire resistance to chemotherapy through a variety of mechanisms, including mutation or overexpression of drug targets, drug inactivation, or elimination of drugs from cells. Tumors that relapse after an initial response to chemotherapy may be resistant to multiple drugs (which is multidrug resistant). In conventional drug resistance views, one or a few cells in a tumor population acquire genetic changes that confer drug resistance. Therefore, the causes of drug resistance are, among other things: a) some cells that are not killed by chemotherapy mutate (change) and become resistant to the drug. Once they multiply, there may be more resistant cells than cells that are sensitive to chemotherapy; b) gene amplification. Cancer cells can produce hundreds of copies of a particular gene. This gene triggers overproduction of a protein that renders anticancer drugs ineffective; c) Cancer cells can use a molecule called P-glycoprotein to pump drugs out of the cell as quickly as they enter; d) Cancer cells may stop absorbing drugs because the proteins that deliver drugs to the cell wall stop working; e) Cancer cells can learn how to repair DNA breaks caused by some anticancer drugs; f) Cancer cells can develop mechanisms that render drugs ineffective. A major contributor to multidrug resistance is overexpression of P-glycoprotein (P-gp). This protein is a clinically important transporter that belongs to the ATP-binding cassette family of cell membrane transporters. It can pump substrates, including anticancer drugs, out of tumor cells through an ATP-dependent mechanism; g) Cells and tumors with activating RAS mutations are relatively resistant to most anticancer agents. Therefore, resistance to anticancer drugs used in chemotherapy is a major cause of treatment failure in malignant conditions, allowing tumors to become drug-resistant. Drug resistance is a major cause of failure in cancer chemotherapy.

[0403] In various embodiments, "drug-resistant cancer" refers to a drug-resistant cancer as described above. In some embodiments, "drug-resistant cancer" refers to cancer cells that are resistant to any therapy, such as chemotherapy, radiation therapy, or biological therapy.

[0404] In various embodiments, the present invention is directed to treating, inhibiting, reducing the severity of, reducing the risk of, or preventing cancer in an individual wherein the individual has previously been treated with chemotherapy, radiation therapy, or biotherapy.

[0405] In various embodiments, "chemotherapy" refers to chemical treatments for cancer, such as drugs that directly kill cancer cells. These drugs are called "anti-cancer" drugs or "antineoplastic agents." Today's therapies use over 100 drugs to treat cancer. They are used to treat specific cancers. When a cure is not possible, chemotherapy can be used to control the growth of tumors; shrink tumors before surgery or radiation therapy; relieve symptoms (such as pain); and destroy any microscopic cancer cells that may be present after a known tumor has been removed surgically (called adjuvant therapy). Adjuvant therapy is given to prevent possible recurrence of the cancer.

[0406] In various embodiments, "radiation therapy" (also referred to herein as "radiotherapy") refers to high-energy x-rays and similar rays (e.g., electrons) used to treat diseases. Many cancer patients use radiation therapy as part of their treatment. This can be done using x-rays from outside the body as external radiation therapy or from inside the body as internal radiation therapy. Radiation therapy works by destroying cancer cells in the treatment area. Although normal cells may also be damaged by radiation therapy, they can usually repair themselves. Radiation therapy treatment can cure some cancers and can also reduce the chance of cancer recurrence after surgery. It can be used to reduce cancer symptoms.

[0407] In various embodiments, "biological therapy" refers to substances that occur naturally in the body to destroy cancer cells. There are several types of treatment, including monoclonal antibodies, cancer growth inhibitors, vaccines, and gene therapy. Biological therapy is also called immunotherapy.

[0408] When the compounds or pharmaceutical compositions of the present invention are administered to treat, inhibit, reduce the severity of, reduce the risk of, or prevent a cancerous condition, the pharmaceutical composition may also contain or be administered in conjunction with other therapeutic agents or treatment regimens currently known or hereafter developed for the treatment of various types of cancer. Examples of other therapeutic agents or treatment regimens include, but are not limited to, radiation therapy, immunotherapy, chemotherapy, surgical intervention, and combinations thereof.

[0409] It is this metabolic plasticity—the ability to exploit and survive on a variety of nutrient sources—that confers resistance to many cancer metabolic drugs currently used as monotherapy. Interestingly, ACSS2 is highly expressed in many cancer tissues, and its upregulation due to hypoxia and low nutrient availability suggests that it is an important enzyme for responding to typical stresses in the tumor microenvironment and, therefore, a potential Achilles' heel. Furthermore, high-stress areas of tumors have been shown to select for apoptosis resistance and promote aggressive behavior, treatment resistance, and recurrence. In this way, combining ACSS2 inhibitors with therapies specifically targeting oxygenated areas of the tumor (such as radiation therapy) may be an effective treatment.

[0410] Therefore, and in various embodiments, the compounds according to the present invention are administered in combination with anticancer therapies. Examples of such therapies include, but are not limited to, chemotherapy, immunotherapy, radiation therapy, biological therapy, surgical intervention, and combinations thereof. In some embodiments, the compounds according to the present invention are administered in combination with therapies specifically targeting oxygenated areas of the tumor. In some embodiments, the compounds according to the present invention are administered in combination with radiation therapy.

[0411] In various embodiments, the compounds described herein are administered in combination with anti-cancer agents, either by administering the compounds alone or in combination with other agents.

[0412] In various embodiments, the compositions of the present invention for cancer treatment can be used together with existing chemotherapy drugs or prepared as a mixture with them. Such chemotherapy drugs include, for example, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant-derived alkaloids, topoisomerase inhibitors, hormone therapy drugs, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapy drugs, and other anticancer agents. In addition, it can be used together with leukopenia (neutrophil) drugs, thrombocytopenia drugs, antiemetic drugs, and cancer pain drugs used for patient QOL restoration as cancer treatment adjuvants or prepared as a mixture with them.

[0413] In various embodiments, the present invention relates to a method of destroying cancer cells, comprising: providing a compound of the present invention and contacting the cancer cells with the compound under conditions effective to destroy the contacted cancer cells. According to various embodiments of destroying cancer cells, the cells to be destroyed can be located in vivo or in vitro (i.e., in culture).

[0414] 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 lymphoma, glioblastoma, renal cell carcinoma, Merkel cell skin cancer (Merkel cell carcinoma), and combinations thereof. 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 lymphoma, glioblastoma, Merkel cell skin cancer (Merkel cell carcinoma), esophageal cancer, gastroesophageal junction cancer, liver cancer (hepatocellular carcinoma), lung cancer (small cell) (SCLC), gastric cancer, upper urinary tract cancer (urothelial carcinoma), glioblastoma multiforme, multiple myeloma, anal cancer (squamous cell), cervical cancer, endometrial cancer. carcinoma, nasopharyngeal carcinoma, 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, pancreatic cancer, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, or any combination thereof.

[0415] Another aspect of the present invention relates to a method of treating or preventing a cancerous condition comprising providing a compound of the present invention and subsequently administering to the patient an effective amount of the compound in a manner effective to treat or prevent the cancerous condition.

[0416] According to one embodiment, the patient to be treated is characterized by the presence of a precancerous condition, and administration of the compound is effective to prevent the precancerous condition from progressing to a cancerous condition. This can be done by destroying the cancer cells before or simultaneously with their progression to a cancerous state.

[0417] According to other embodiments, the patient to be treated is characterized by the presence of a cancerous condition, and administration of the compound is effective to cause the cancerous condition to regress or to arrest its growth, i.e., to completely stop its growth or reduce its growth rate. This preferably occurs by destroying the cancer cells, regardless of their location within the patient's body. That is, whether the cancer cells are located at the site of a primary tumor or whether the cancer cells have metastasized and given rise to a secondary tumor within the patient's body.

[0418] The ACSS2 gene has recently been implicated in human alcoholism and ethanol consumption. Thus, in various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of, or preventing alcoholism in a human subject, comprising administering a compound of the present invention to a subject suffering from alcoholism under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent alcoholism in the subject. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0419] Nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) have similar pathogenesis and histopathology, but different etiologies and epidemiology. NASH and ASH are advanced forms of nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is characterized by excessive fat accumulation in the liver (steatosis), the absence of any other obvious cause of chronic liver disease (viral, autoimmune, genetic, etc.), and alcohol consumption ≤20-30g / day. In contrast, AFLD is defined by the presence of steatosis and alcohol consumption >20-30g / day.

[0420] It has been demonstrated that the synthesis of metabolically available acetyl-CoA from acetate is crucial for the increased acetylation of proinflammatory genes and the consequent enhancement of the inflammatory response in macrophages exposed to ethanol. This mechanism represents a potential therapeutic target in acute alcoholic hepatitis.

[0421] Thus, in various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing alcoholic steatohepatitis (ASH) in an individual, comprising administering a compound of the present invention to an individual suffering from alcoholic steatohepatitis (ASH) under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of developing, or prevent alcoholic steatohepatitis (ASH) in the individual. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0422] Therefore, in various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, or preventing non-alcoholic fatty liver disease (NAFLD) in an individual, comprising administering a compound of the present invention to an individual suffering from non-alcoholic fatty liver disease (NAFLD) under conditions that effectively treat, inhibit, reduce the severity of, or prevent non-alcoholic fatty liver disease (NAFLD) in the individual. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0423] In various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing non-alcoholic steatohepatitis (NASH) in an individual, comprising administering a compound of the present invention to an individual suffering from non-alcoholic steatohepatitis (NASH) under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of developing, or prevent non-alcoholic steatohepatitis (NASH) in the individual. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0424] ACSS2-mediated acetyl-CoA synthesis from acetate has also been shown to be essential for human cytomegalovirus infection. It has been shown that glucose carbons can be converted to acetate and used to produce cytosolic acetyl-CoA for lipid synthesis by acetyl-CoA synthetase short-chain family member 2 (ACSS2), which is important for HCMV-induced lipogenesis and viral growth. Therefore, ACSS2 inhibitors are expected to be useful as antiviral therapies and for treating HCMV infection.

[0425] Thus, in various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of, or preventing a viral infection in a subject, comprising administering a compound of the present invention to a subject suffering from a viral infection under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent the viral infection in the subject. In some embodiments, the viral infection is HCMV. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0426] It was found that in a diet-induced obesity model, mice lacking ACSS2 exhibited weight loss and hepatic steatosis (Z. Huang et al., ACSS2 promotes systemic fat storage and utilization by selectively regulating genes involved in lipid metabolism PNAS 115, (40), E9499-E9506, 2018).

[0427] Thus, in various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of, or preventing a metabolic disorder in a subject, comprising administering a compound of the present invention to a subject suffering from a metabolic disorder under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent the metabolic disorder in the subject. In some embodiments, the metabolic disorder is obesity. In other embodiments, the metabolic disorder is weight gain. In other embodiments, the metabolic disorder is hepatic steatosis. In other embodiments, the metabolic disorder is fatty liver disease. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0428] In various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of obesity, reducing the risk of developing obesity, or preventing obesity in an individual, comprising administering a compound of the present invention to an individual suffering from obesity under conditions effective to treat, inhibit, reduce the severity of obesity, reduce the risk of developing obesity, or prevent obesity in the individual. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0429] In various embodiments, the present invention relates to a method of treating, inhibiting weight gain, reducing the severity of weight gain, reducing the risk of weight gain, or preventing weight gain in an individual, comprising administering to an individual suffering from weight gain a compound of the present invention under conditions effective to treat, inhibit weight gain, reduce the severity of weight gain, reduce the risk of weight gain, or prevent weight gain in the individual. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0430] In various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of, or preventing hepatic steatosis in an individual, comprising administering a compound of the present invention to an individual suffering from hepatic steatosis under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent hepatic steatosis in the individual. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0431] In various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of, or preventing fatty liver disease in an individual, comprising administering a compound of the present invention to an individual suffering from fatty liver disease under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent fatty liver disease in the individual. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0432] It is also shown that ACSS2 enters the nucleus under certain conditions (hypoxia, high fat, etc.), and affects the acetylation and crotonylation of histones by providing acetyl-CoA and crotonyl-CoA, and thus regulates gene expression. For example, ACSS2 reduces the reduction of nuclear acetyl-CoA and histone acetylation levels in display neurons, affecting the expression of many neuronal genes. It was found in the hippocampus that this redIt of ACSS2 has an impact on memory and neuronal plasticity (Mews P et al., "Nature (Nature)", Vol. 546, 381, 2017). This epigenetic modification is related to neuropsychiatric diseases, such as anxiety, PTSD, depression, etc. (Graff, J et al. Histone acetylation: molecular mnemonics of chromatin. "Natural Review Neuroscience (Nat Rev. Neurosci.)" 14, 97-111 (2013)). Therefore, the inhibitor of ACSS2 can find useful applications under these conditions.

[0433] Thus, in various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of, or preventing a neuropsychiatric disease or condition in an individual, comprising administering a compound of the present invention to an individual suffering from a neuropsychiatric disease or condition under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent the neuropsychiatric disease or condition in the individual. In some embodiments, the neuropsychiatric disease or condition is selected from anxiety, depression, schizophrenia, autism, and / or post-traumatic stress disorder; each represents a separate embodiment according to the present invention. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0434] In various embodiments, the present invention relates to a method of treating, suppressing, reducing the severity of, reducing the risk of, or preventing anxiety in an individual, comprising administering a compound of the present invention to an individual suffering from an anxiety disorder under conditions effective to treat, suppress, reduce the severity of, reduce the risk of, or prevent anxiety in the individual. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0435] In various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of depression, reducing the risk of developing depression, or preventing depression in an individual, comprising administering a compound of the present invention to an individual suffering from depression under conditions effective to treat, inhibit, reduce the severity of depression, reduce the risk of developing depression, or prevent depression in the individual. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0436] In various embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of, or preventing a post-traumatic stress disorder in a subject, comprising administering to a subject suffering from post-traumatic stress disorder a compound of the present invention under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent a post-traumatic stress disorder in the subject. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0437] In some embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of, or preventing an inflammatory condition in a subject, comprising administering a compound of the present invention to a subject suffering from an inflammatory condition under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent an inflammatory condition in the subject. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0438] In some embodiments, the present invention relates to a method of treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing an autoimmune disease or condition in an individual, comprising administering a compound of the present invention to an individual suffering from an autoimmune disease or condition under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of, or prevent an autoimmune disease or condition in the individual. In some embodiments, the compound is an ACSS2 inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0439] As used herein, "subject" or "patient" refers to any mammalian patient, including but not limited to humans and other primates, dogs, cats, horses, cattle, sheep, pigs, rats, mice, and other rodents. In various embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, however, the methods described herein can be applied to treat males or females.

[0440] When the compounds of this invention are administered, they can be administered systemically, or alternatively, they can be administered directly to the specific site where cancer cells or precancerous cells are present. Therefore, administration can be achieved in any manner that effectively compounds or pharmaceutical compositions are delivered to cancer cells or precancerous cells. Exemplary modes of administration include, but are not limited to, oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, by intranasal administration, by intracavitary or intravesical administration, intraocular, intraarterial, intraarterial, intralesional, or by being applied to mucous membranes, such as the mucous membranes of the nose, throat, and bronchus to administer compounds or compositions.

[0441] The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. However, they should in no way be construed as limiting the broad scope of the invention.

[0442] Example

[0443] Example 1

[0444] Synthesis details of the compounds of the present invention ( Figure 1-3 )

[0445] Experimental steps:

[0446] General synthesis of compound 3

[0447]

[0448] A solution of compound 1 (1.00 equivalent) and compound 2 (1.0 equivalent) in AcOH (0.5 to 10 mL) was stirred at 90° C. under N 2 for 3 to 10 hours. The mixture was concentrated in vacuo. The residue was purified by trituration (in ethyl acetate or EtOH) to afford compound 3.

[0449] General preparation of compound 5

[0450]

[0451] To a solution of compound 3 (1.00 eq) in DCM (5 to 10 mL) was added EtN (2.00 eq). After stirring at 25°C for 30 minutes, compound 4 (1.00 eq) was added, and the mixture was then stirred under N at 25°C for 2.5 hours. It was concentrated in vacuo to give crude compound 5, which was used as is in the next step.

[0452] General preparation of final compounds 100-277

[0453] Method 1

[0454]

[0455] To a solution of compound 5 (1.50 equiv) in MeCN (10 mL) and HOBT (2.00 equiv) was added compound 7 (1.00 equiv) and DIEA (3.00 equiv). The mixture was stirred at 70 ° C for 2 hours. It was concentrated in vacuo. The residue was purified by preparative HPLC to give the final compound 100-277.

[0456] Method 2

[0457]

[0458] To a solution of compound 3 (1.00 equiv) in DCM (1 to 10 mL) was added EtN (2.00 equiv). After stirring at 20°C for 0.5 h, compound 6 (1.00 equiv) was added thereto after the mixture was stirred at 20°C for 10 h. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC to give compound 100-277.

[0459] Analyze the data

[0460] 3-Methyl-5-oxo-N,1-diphenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0461] Compound ID: 182

[0462]

[0463] LCMS: m / z 294.2 [M+H] + ;

[0464] 1HNMR (400MHz, DMSO-d6) δ13.39 (s, 1H), 10.68 (s, 1H), 7.75 (d, J = 8.4Hz, 2H), 7.62 (dd, J = 7. 6,1.2Hz,2H),7.52(t,J=8.0Hz,2H),7.34-7.29(m,3H),7.03(t,J=8.0Hz,1H),2.57(s,3H).

[0465] N-(3-Acetylphenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0466] Compound ID: 183 Batch 2

[0467]

[0468] LCMS: m / z 336.2 [M+H] + ;

[0469] 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),8.24(s,1H),7.84(d,J=8.0Hz,1H),7.74(d,J=7.6Hz,2H),7.64(d ,J=8.0Hz,1H),7.55(t,J=8.0Hz,2H),7.48(t,J=8.0Hz,1H),7.38-7.31(m,1H),2.60(s,3H),2.58(s,3H)

[0470] N-(3-ethylphenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0471] Compound ID: 184

[0472]

[0473] LCMS: m / z 322.2 [M+H] + ;

[0474] 1H NMR(400MHz, DMSO-d6)δ10.65(s,1H),7.71(dd,J=1.0,8.4Hz,2H),7.57-7.50(m,2H),7.47(s,1H),7.44(d,J=8.0Hz,1H) ,7.37-7.29(m,1H),7.22(t,J=7.6Hz,1H),6.89(d,J=7.6Hz,1H),2.62-2.57(m,2H),2.56(s,3H),1.18(t,J=7.6Hz,3H).

[0475] 1 H NMR(400MHz,CHLOROFORM-d)δ8.02(s,1H),7.95(d,J=8.0Hz,1H),7.86(br s, 1H), 7.69 (d, J = 7.6Hz, 1H), 7.43 (t, J = 8.0Hz, 1H), 2.61 (s, 3H), 2.22 (s, 3H).

[0476] 3-Methyl-N-(naphthalen-1-yl)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0477] Compound ID: 185

[0478]

[0479] LCMS: m / z 344.2 [M+H] + ;

[0480] 1 H NMR (400MHz, MeOH) δ8.28-8.30 (d, J=8.0Hz, 2H), 7.86-7.88 (d, J=8.0Hz, 1H), 7.72-7.74 (d, J= 8.0Hz,2H),7.63-7.65(d,J=8.0Hz,1H),7.45-7.57(m,5H),7.36(t,J=8.0Hz,1H),3.31(s,1H).

[0481] N-Benzyl-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0482] Compound ID: 186

[0483]

[0484] LCMS: m / z 308.0 [M+H] + ;

[0485] 1 H NMR (400MHz, DMSO-d6) δ8.8 (s, 1H), 7.68-7.71 (m, 2H), 7.49 (t, J = 8.8, 2H), 7.23-7.32 (m, 6H), 4.54 (s, 2H), 2.54-2.56 (m, 3H).

[0486] 1-Isopropyl-3-methyl-5-oxo-N-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0487] Compound ID: 187

[0488]

[0489] LCMS: m / z 260.1[M+H] + ;

[0490] 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),7.56(d,J=7.6,2H),7.29(t,J=8.0,2H ), 7.00 (t, J = 7.2, 1H), 4.50-4.57 (m, 1H), 2.45 (s, 3H), 1.28 (d, J = 6.8Hz, 6H).

[0491] N-(4-Methoxyphenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0492] Compound ID: 188

[0493]

[0494] LCMS: m / z 324.1[M+H] + ;

[0495] 1 H NMR (400MHz, DMSO-d6) δ13.24 (s, 1H), 10.52 (s, 1H), 7.72 (d, J = 7.6Hz, 2H), 7.55 -7.50(m,4H),7.35-7.32(m,1H),6.90(d,J=7.2Hz,2H),3.73(s,3H),2.55(s,3H)

[0496] N-(4-Fluorophenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0497] Compound ID: 189

[0498]

[0499] LCMS: m / z 312.0 [M+H] + ;

[0500] 1 H NMR (400MHz, DMSO-d6) δ = 13.18 (s, 1H), 10.68 (s, 1H), 7.73-7.72 (m, 2H), 7.71-7 .64(m,2H),7.64-7.52(m,2H),7.40-7.30(m,1H),7.18-7.15(m,2H),2.55(s,3H)

[0501] 1,5-Dimethyl-3-oxo-N,2-diphenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

[0502] Compound ID: 190

[0503]

[0504] LCMS: m / z 308.3 [M+H] + ;

[0505] 1 HNMR (400MHz, DMSO-d6) δ=10.60(s,1H),7.59(d,J=8.0Hz,2H),7.48(t,J=7.6Hz,2H),7.38(t,J=7.6H z, 1H), 7.29 (d, J = 7.6Hz, 2H), 7.23 (t, J = 7.6Hz, 2H), 6.98 (t, J = 7.2Hz, 1H), 3.27 (s, 3H), 2.72 (s, 3H).

[0506] 3-Methyl-5-oxo-1-phenyl-N-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0507] Compound ID: 191

[0508]

[0509] LCMS: m / z 295.2 [M+H] + ;

[0510] 1H NMR (400MHz, DMSO-d6) δ = 11.32 (s, 1H), 8.83 (s, 1H), 8.13-8.09 (m, 2H), 8.01 (d, J=8.0Hz, 2H), 7.35 (t, J=8.0Hz, 3H), 7.07 (t, J=7.6Hz, 1H), 2.34 (s, 3H).

[0511] 5-Hydroxy-3-methyl-N-phenyl-1-(pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0512] Compound ID: 192

[0513]

[0514] LCMS: m / z 295.0 [M+H] + ;

[0515] 1 H NMR (400MHz, DMSO-d6) δ = 10.53 (s, 1H), 8.49 (d, J = 8.0Hz, 1H), 8.40 (d, J = 8.0Hz, 1H), 8.02 (d ,J=8.0Hz,1H),7.61(d,J=8.0Hz,2H),7.29-7.35(m,3H),7.03(d,J=8.0Hz,1H),2.52(s,3H).

[0516] 3-Methyl-5-oxo-N-phenyl-1-(pyridin-4-yl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0517] Compound ID: 193

[0518]

[0519] LCMS: m / z 295.2 [M+H] + ;

[0520] 1 H NMR (400MHz, DMSO-d6) δ = 10.51 (s, 1H), 8.65-8.41 (m, 4H), 7.57 (d, J = 7.6Hz, 2H), 7.25 (t, J = 7.2Hz, 2H), 6.93 (t, J = 7.2Hz, 1H), 2.32 (s, 3H).

[0521] 1-Benzyl-5-hydroxy-3-methyl-N-phenyl-1H-pyrazole-4-carboxamide

[0522] Compound ID: 194

[0523]

[0524] LCMS: m / z 308.1[M+H] + ;

[0525] 1 H NMR (400MHz, DMSO-d6) δ10.80 (s, 1H), 7.59 (d, J = 7.6Hz, 2H), 7.37 (t, J = 7.6Hz, 2H), 7.30 (t, J=8.0Hz, 3H), 7.23 (d, J=7.2Hz, 2H), 7.01 (t, J=8.0Hz, 1H), 4.98 (s, 2H), 2.41 (s, 3H).

[0526] 3-Methyl-5-oxo-N-phenyl-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0527] Compound ID: 195

[0528]

[0529] LCMS: m / z 295.1[M+H] + ;

[0530] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),9.38(s,1H),8.71(d,J=8.0Hz,1H),8.52(dd,J=1.2,5.2Hz,1H),7 .86(dd,J=5.2,8.4Hz,1H),7.60(d,J=7.6Hz,2H),7.28(t,J=8.0Hz,2H),7.06-6.88(m,1H),2.42(s,3H).

[0531] 1,3-Dimethyl-5-oxo-N-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0532] Compound ID: 196

[0533]

[0534] LCMS: m / z 232.2 [M+H] + ;

[0535] 1H NMR (400MHz, DMSO-d6) δ 10.80 (s, 1H), 7.59 (d, J = 7.6Hz, 2H), 7.28-7.32 (m, 2H), 6.99-7.03 (m, 1H), 3.35 (s, 3H), 2.43 (s, 3H).

[0536] 1-(4-Methoxyphenyl)-3-methyl-5-oxo-N-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0537] Compound ID: 197

[0538]

[0539] LCMS: m / z 324.1[M+H] + ;

[0540] 1 H NMR (400MHz, DMSO-d6) δ 10.76 (s, 1H), 7.59-7.61 (m, 4H), 7.29 (t, J = 8.0Hz, 2H), 7.06-7.07 (m, 2H), 7.00-7.05 (m, 1H), 3.79 (s, 3H), 2.48 (s, 3H).

[0541] 1 H NMR (400MHz, DMSO-d6) δ12.58(s,1H),8.72(d,J=7.2Hz,1H),7.90(dd,J=1.6,8.0Hz,1H),7.46-7.34(m,1H),7.18(t,J=7.2Hz,2H),6.93-6.85(m, 2H),6.79(s,3H),4.29(m,1H),3.88-3.69(m,1H),2.45-2.36(m,1H),2.0 4-1.90(m,2H),1.84-1.69(m,1H),1.68-1.60(m,1H),1.59-1.47(m,1H).

[0542] 5-Hydroxy-3-methyl-1-(naphthalen-2-yl)-N-phenyl-1H-pyrazole-4-carboxamide

[0543] Compound ID: 198

[0544]

[0545] LCMS: m / z 366.0 [M+H] + ;

[0546] 1H NMR (400MHz, DMSO-d6) δ10.73 (s, 1H), 8.24 (s, 1H), 8.07 (d, J = 8.8Hz, 1H), 8.05-7.94 (m, 3H), 7. 64(d,J=7.6Hz,2H),7.63-7.49(m,2H),7.32(t,J=8.0Hz,2H),7.03(t,J=7.2Hz,1H),2.58(s,3H)

[0547] N,3-Dimethyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0548] Compound ID: 199

[0549]

[0550] LCMS: m / z 232.1[M+H] + ;

[0551] 1 H NMR (400MHz, CHLOROFORM-d) δ11.10(s,1H),7.96(s,1H),7.45(m,2H),7.37(m,2H),7.29(m,1H),2.78(s,3H),2.40(s,3H).

[0552] N-Isopropyl-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0553] Compound ID: 200

[0554]

[0555] LCMS: m / z 260.2 [M+H] + ;

[0556] 1 H NMR (400MHz, DMSO-d6) δ12.83(s,1H),8.30(s,1H),7.70(d,J=7.6Hz,2H),7.47(t,J=8.0Hz, 2H),7.27(t,J=7.2Hz,1H),4.00(dt,J=12.8,6.4Hz,1H),2.46(s,3H),1.12(d,J=6.8Hz,6H)

[0557] 3-Methyl-5-oxo-N-phenyl-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0558] Compound ID: 201

[0559]

[0560] LCMS: m / z 362.1[M+H] + ;

[0561] 1 H NMR (400MHz, DMSO-d6) δ10.56(s,1H),8.03(d,J=8.4Hz,2H),7.89(d,J=8.8Hz,2H),7 .62(dd,J=8.8,1.2Hz,2H),7.32(t,J=8.0Hz,2H),7.04(t,J=7.2Hz,1H),2.57(s,3H)

[0562] 1-(1,1-dioxotetrahydrothiophen-3-yl)-3-methyl-5-oxo-N-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0563] Compound ID: 202

[0564]

[0565] LCMS: m / z 336.0 [M+H] + ;

[0566] 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),7.56(d,J=8.0Hz,2H),7.30(t,J=7.6Hz,2H),7.02(t,J=7.6Hz,1H), 5.15-5.04(m,1H),3.58-3.52(m,1H),3.50-3.42(m,1H),3.36-3.20(m,2H),2.49-2.46(m,2H),2.44(s,3H)

[0567] N-(4-Acetylphenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0568] Compound ID: 203

[0569]

[0570] LCMS: m / z 336.2 [M+H] + ;

[0571] 1H NMR (400MHz, DMSO-d6) δ11.33(s,1H),7.95-7.85(m,4H),7.73(d,J=8.4Hz,2H),7.41(t,J=8.0Hz,2H),7.15(t,J=7.6Hz,1H),2.40(s,3H)

[0572] N,3-Dimethyl-5-oxo-N,1-diphenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0573] Compound ID: 204

[0574]

[0575] LCMS: m / z 308.1[M+H] + ;

[0576] 1 H NMR (400MHz, DMSO-d6+D2O) δ7.48(d,J=7.6Hz,2H),7.38(t,J=7.2Hz,2H),7.28(t,J=8.0Hz,2H),7.23-7.10(m,4H),3.31(s,3H),1.98(s,3H)

[0577] N-(4-Hydroxyphenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0578] Compound ID: 205

[0579]

[0580] LCMS: m / z 310.2 [M+H] + ;

[0581] 1 H NMR (400MHz, DMSO-d6) δ13.07(s,1H),10.42(s,1H),9.17(s,1H),7.72(d,J=7.6Hz,2H),7 .52(d,J=7.6Hz,2H),7.41-7.38(m,2H),7.38-7.31(m,1H),6.72-6.69(m,2H),2.53(s,3H)

[0582] 3-(3-Methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamido)benzoate

[0583] Compound ID: 206

[0584]

[0585] LCMS: m / z 352.2 [M+H] + ;

[0586] 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.36(s,1H),7.83(d,J=6.8Hz,2H),7.76(d,J=8.8Hz, 1H), 7.59 (d, J = 7.2Hz, 1H), 7.48-7.42 (m, 3H), 7.25-7.23 (m, 1H), 3.86 (s, 3H), 2.47 (s, 3H).

[0587] N-Benzoyl-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0588] Compound ID: 207

[0589]

[0590] LCMS: m / z 322.1[M+H] + ;

[0591] 1 H NMR (400MHz, DMSO-d6) δ12.42(s,1H),7.97(d,J=7.6Hz,2H),7.74(d,J=7.6Hz,2H),7.6 8-7.62(m,1H),7.61-7.55(m,2H),7.52(t,J=8.0Hz,2H),7.37-7.28(m,1H),2.52(s,3H)

[0592] 3-Methyl-5-oxo-1-phenyl-N-(3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0593] Compound ID: 208

[0594]

[0595] LCMS: m / z 362.0 [M+H] + ;

[0596] 1H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.28(s,1H),7.72(d,J=8.0Hz,2H),7.67(d,J= 8.4Hz,1H),7.57-7.50(m,3H),7.38(d,J=7.6Hz,1H),7.36-7.29(m,1H),2.55(s,3H)

[0597] N-(2,3-dihydro-1H-inden-5-yl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0598] Compound ID: 209

[0599]

[0600] LCMS: m / z 334.1[M+H] + ;

[0601] 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),7.75(d,J=7.6Hz,2H),7.58(s,1H),7.52(t,J=7.6Hz,2H ),7.34-7.26(m,2H),7.14(d,J=8.0Hz,1H),2.87-2.79(m,4H),2.54(s,3H),2.06-1.97(m,2H)

[0602] N-(3-chlorophenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0603] Compound ID: 210

[0604]

[0605] LCMS: m / z 350.2 [M+Na] + ;

[0606] 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),8.05-7.91(m,1H),7.79-7.65(m,2H),7.56-7.47(m,2H),7.36-7.26(m,3H),7.14-7.00(m,1H),2.54(s,3H).

[0607] N-(3-Methoxyphenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0608] Compound ID: 211

[0609]

[0610] LCMS: m / z 324.2 [M+H] + ;

[0611] 1 H NMR (400MHz, DMSO-d6) δ10.71(s,1H),7.75-7.66(m,2H),7.52(t,J=7.6Hz,2H),7.39(t,J=2.4Hz,1H),7.3 6-7.29(m,1H),7.24-7.16(m,1H),7.08-7.04(m,1H),6.61(dd,J=1.6,8.0Hz,1H),3.75(s,3H),2.54(s,3H)

[0612] 3-Methyl-5-oxo-1-phenyl-N-(m-tolyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0613] Compound ID: 212

[0614]

[0615] LCMS: m / z 308.1[M+H] + ;

[0616] 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),7.78(d,J=8.0Hz,2H),7.53-7.44(m,3H),7.40(d,J=8.0Hz, 1H),7.27(t,J=8.0Hz,1H),7.17(t,J=7.6Hz,1H),6.83(d,J=7.6Hz,1H),2.53(s,3H),2.28(s,3H)

[0617] 3-Methyl-5-oxo-1-phenyl-N-(3-(pyrazin-2-yl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0618] Compound ID: 213

[0619]

[0620] LCMS: m / z 336.1[M+H] + ;

[0621] 1 H NMR (400MHz, DMSO-d6) δ11.81(s,1H),8.42(d,J=8.0Hz,1H),7.89(dd,J=1.2,7.6Hz,1H),7.77(d,J=7 .6Hz,2H),7.56-7.45(m,3H),7.27(t,J=7.2Hz,1H),7.19-7.10(m,1H),2.57(s,3H),2.51-2.55(m,3H)

[0622] 3-Methyl-5-oxo-1-phenyl-N-(pyridin-2-yl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0623] Compound ID: 214

[0624]

[0625] LCMS: m / z 295.0 [M+H] + ;

[0626] 1 H NMR (400MHz, DMSO-d6) δ11.64 (s, 1H), 8.27 (d, J = 4.4Hz, 1H), 8.11-8.00 (m, 1H), 7.95-7.7 6(m,3H),7.45(t,J=7.6Hz,2H),7.22(t,J=7.6Hz,1H),7.12(t,J=6.8Hz,1H),2.46(s,3H).

[0627] N-(3-Bromophenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0628] Compound ID: 215

[0629]

[0630] LCMS: m / z 371.9 [M+H] + ;

[0631] 1 H NMR (400MHz, DMSO-d6) δ = 10.84 (s, 1H), 8.14 (s, 1H), 7.74 (d, J = 8.0Hz, 2H), 7 .53(t,J=7.6Hz,2H),7.40(d,J=7.6Hz,1H),7.35-7.19(m,3H),2.54(s,3H).

[0632] 3-Methyl-5-oxo-1-phenyl-N-(pyridin-4-yl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0633] Compound ID: 216

[0634]

[0635] LCMS: m / z 295.0 [M+H] + ;

[0636] 1 H NMR (400MHz, DMSO-d6) δ12.58(s,1H),8.49(d,J=6.8Hz,2H),8.14-7.97(m,4H),7.32(t,J=7.6Hz,2H),7.03(t,J=7.6Hz,1H),2.27(s,3H)

[0637] 13 C NMR (101MHz, DMSO-d6) δ165.63,163.57,154.18,149.06,142.29,141.04,128.79,122.97,118.23,113.47,93.82,15.84

[0638] 3-Methyl-5-oxo-1-phenyl-N-(thiazol-2-yl)-4,5-dihydro-1H-pyrazole-4-

[0639] Formamide

[0640] Compound ID: 217

[0641]

[0642] LCMS: m / z 301.2 [M+H] + ;

[0643] 1 H NMR (400MHz, METHANOL-d4) δ7.65 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.47 (d, J = 3.6 Hz, 1H), 7.43-7.34 (m, 1H), 7.16 (d, J = 3.6 Hz, 1H), 2.63 (s, 3H).

[0644] (2S)-2-(3-Methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamido)propanoic acid

[0645] Compound ID: 218

[0646]

[0647] LCMS: m / z 290.4 [M+H] + ;

[0648] 1 H NMR (400MHz, DMSO-d6) δ12.72(s,1H),8.77(d,J=6.4Hz,1H),7.72(d,J=8.0Hz,2H),7.49 (t,J=8.0Hz,2H),7.28(t,J=8.0Hz,1H),4.41(m,1H),2.47(s,3H),1.34(d,J=7.2Hz,3H).

[0649] N-(1H-Benzo[d]imidazol-5-yl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0650] Compound ID: 219

[0651]

[0652] LCMS: m / z 334.2 [M+H] + ;

[0653] 1 H NMR (400MHz, DMSO-d6) δ = 11.05 (d, J = 9.2Hz, 1H), 9.49 (d, J = 14.8Hz, 1H), 8.51 (d, J = 1.6Hz ,1H),7.86-7.70(m,3H),7.59-7.44(m,3H),7.33(t,J=7.2Hz,1H),2.59(d,J=4.0Hz,3H).

[0654] N-(3-(Dimethylcarbamoyl)phenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide Compound ID: 220

[0655]

[0656] LCMS: m / z 365.3 [M+H] + ;

[0657] 1H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 7.79 (t, J = 1.6Hz, 1H), 7.76-7.69 (m, 2H), 7.56-7.47 (m, 3H) ,7.37(t,J=8.0Hz,1H),7.35-7.29(m,1H),7.04(d,J=7.6Hz,1H),3.08-2.84(m,6H),2.54(s,3H).

[0658] 3-Methyl-1-(1-methylpiperidin-4-yl)-5-oxo-N-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0659] Compound ID: 221

[0660]

[0661] LCMS: m / z 315.2 [M+H] + ;

[0662] 1 H NMR (400MHz, DMSO-d6) δ11.19(s,1H),8.16(s,1H),7.52(d,J=7.6Hz,2H),7.19(t,J=7.6Hz,2H),6.84(t,J=7.6Hz,1H),4.25 -4.15(m,1H),3.34-3.33(m,2H),2.93(t,J=12.0Hz,2H),2.68(s,3H),2.15(s,3H),2.14-2.03(m,2H),1.78(d,J=11.7Hz,2H)

[0663] N-(3-Hydroxyphenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0664] Compound ID: 222

[0665]

[0666] LCMS: m / z 310.2 [M+H] + ;

[0667] 1H NMR (400MHz, DMSO-d6) δ10.76(s,1H),9.28(s,1H),7.86(d,J=7.6Hz,2H),7.44(t,J=7.6Hz,2H),7.25(t,J=2 .0Hz,1H),7.23-7.17(m,1H),7.08-7.02(m,1H),6.92-6.87(m,1H),6.39(dd,J=1.6,7.2Hz,1H),2.45(s,3H).

[0668] N-(3-Isopropylphenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0669] Compound ID: 100

[0670]

[0671] LCMS: m / z 336.1[M+H] + ;

[0672] 1 H NMR (400MHz, DMSO-d6) δ10.68 (s, 1H), 7.74 (d, J = 7.6Hz, 2H), 7.56-7.41 (m, 4H), 7.37-7.29 (m, 1H), 7.23(t,J=7.6Hz,1H),6.92(d,J=8.0Hz,1H),2.95-2.80(m,1H),2.55(s,3H),1.21(d,J=6.8Hz,6H).

[0673] 3-Methyl-5-oxo-1-phenyl-N-(3-(thien-2-yl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0674] Compound ID: 101

[0675]

[0676] LCMS: m / z 376.2 [M+H] + ;

[0677] 1 H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 8.03 (s, 1H), 7.74 (d, J = 7.6Hz, 2H), 7. 58-7.45(m,5H),7.37-7.29(m,3H),7.14(dd,J=4.0,5.2Hz,1H),2.56(s,3H).

[0678] N-(\[1,1'-biphenyl]-3-yl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0679] Compound ID: 102

[0680]

[0681] LCMS: m / z 370.1[M+H] + ;

[0682] 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),7.99(s,1H),7.75(d,J=7.7Hz,2H),7.65(d,J=7.4Hz,2H ),7.56(d,J=8.8Hz,1H),7.54-7.45(m,4H),7.43-7.35(m,2H),7.34-7.28(m,2H),2.55(s,3H)

[0683] N-(3-(Methoxymethyl)phenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0684] Compound ID: 103

[0685]

[0686] LCMS: m / z 338.2 [M+H] + ;

[0687] 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),8.13(s,1H),8.06(s,2H),7.60(s,1H),7.49(d,J=8.0Hz,1H),7.30 (s,2H),7.20(t,J=7.6Hz,1H),7.00(s,1H),6.84(d,J=7.6Hz,1H),4.37(s,2H),3.29(s,3H),2.28(s,3H).

[0688] 3-Methyl-5-oxo-1-phenyl-N-(3-(pyridin-4-yl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0689] Compound ID: 104

[0690]

[0691] LCMS: m / z 371.3 [M+H] + ;

[0692] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),8.71(d,J=5.2Hz,2H),8.16(d,J=13.8Hz,1H),7.8 8-7.78(m,4H),7.77-7.65(m,1H),7.53-7.45(m,4H),7.27(t,J=7.2Hz,1H),2.49(s,3H).

[0693] N-(3-(Aminomethyl)phenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0694] Compound ID: 223

[0695]

[0696] LCMS: m / z 323.2 [M+H] + ;

[0697] 1 H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.35(br s,2H),7.80-7.75(m,2H),7.75-7.69(m,2H),7.52(t,J=8.0Hz,2H),7.41 -7.29(m,2H),7.15(d,J=7.6Hz,1H),4.00(d,J=5.6Hz,2H),2.57(s,3H).

[0698] N-(4-(N,N-dimethylsulfamoyl)phenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0699] Compound ID: 105

[0700]

[0701] LCMS: m / z 401.2 [M+H] + ;

[0702] 1H NMR(400MHz,METHANOL-d4)δ8.16(s,1H),7.87(d,J=8.8Hz,2H),7.77(d,J=7.8Hz,2H),7 .71(d,J=8.8Hz,2H),7.43(t,J=8.0Hz,2H),7.27-7.18(m,1H),2.68(s,6H),2.47(s,3H).

[0703] 3-Methyl-5-oxo-1-phenyl-N-(tetrahydrofuran-3-yl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0704] Compound ID: 106

[0705]

[0706] LCMS: m / z 288.1[M+H] + ;

[0707] 1 H NMR(400MHz,DMSO-d6)δ8.62(br s,1H),7.71(d,J=7.6Hz,2H),7.48(t,J=7.6Hz,2H),7.28(t,J=7.6Hz,1H),4.43(s,1H),3.85-3.77(m, 2H),3.76-3.69(m,1H),3.49(dd,J=3.6,8.8Hz,1H),2.47(s,3H),2.23-2.13(m,1H),1.78-1.68(m,1H)

[0708] N-(3-(1H-imidazol-2-yl)phenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0709] Compound ID: 107

[0710]

[0711] LCMS: m / z 360.1[M+H] + ;

[0712] 1 H NMR(400MHz, METHANOL-d4)δ8.19(s,1H),7.83-7.74(d,J=8.4Hz,3H),7.57-7.49(m,4H),7.43(t,J=7.6Hz,2H),7.22(t,J=7.2Hz,1H),2.47(s,3H)

[0713] N-(3-(Furan-2-yl)phenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0714] Compound ID: 108

[0715]

[0716] LCMS: m / z 360.2 [M+H] + ;

[0717] 1 H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.10-7.96(m,1H),7.86-7.67(m,3H),7.61-7.43(m,3H),7. 41-7.34(m,2H),7.33-7.27(m,1H),6.94(d,J=3.2Hz,1H),6.60(dd,J=1.6,3.2Hz,1H),2.54(s,3H)

[0718] 3-Methyl-5-oxo-1-phenyl-N-(3-(pyrazin-2-yl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0719] Compound ID: 109

[0720]

[0721] LCMS: m / z 372.1[M+H] + ;

[0722] 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),9.24(d,J=1.6Hz,1H),8.74-8.73(m,1H),8.63(d,J=2.4Hz,1H),8.44(t, J=2.0Hz,1H),7.81(d,J=7.6Hz,1H),7.77-7.73(m,3H),7.56-7.47(m,3H),7.34(t,J=7.6Hz,1H),2.58(s,3H).

[0723] 1-(4-(N,N-dimethylsulfamoyl)phenyl)-3-methyl-5-oxo-N-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0724] Compound ID: 110

[0725]

[0726] LCMS: m / z 401.2 [M+H] + ;

[0727] 1 H NMR (400MHz, DMSO-d6) δ = 11.00 (s, 1H), 8.39 (d, J = 8.8Hz, 2H), 7.66 (d, J = 8.8Hz, 2H), 7.59 (d, J=7.6Hz, 2H), 7.23 (t, J=7.6Hz, 2H), 6.89 (t, J=7.2Hz, 1H), 2.58 (s, 6H), 2.27 (s, 3H).

[0728] N-(3-(Hydroxymethyl)phenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0729] Compound ID: 111

[0730]

[0731] LCMS: m / z 324.1[M+H] + ;

[0732] 1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H),7.72(d,J=7.6Hz,2H),7.57-7.54(m,1H),7.52-7.50(m ,3H),7.34-7.25(m,1H),7.25-7.23(m,1H),6.98(d,J=7.6Hz,1H),4.48(s,2H),2.55(s,3H).

[0733] 3-Methyl-5-oxo-1-phenyl-N-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0734]

[0735] Compound ID: 112

[0736] LCMS: m / z 302.2 [M+H] + ;

[0737] 1H NMR (400MHz, DMSO-d6) δ8.47(s,1H),7.75(d,J=8.0Hz,2H),7.44(t,J=7.6Hz,2H),7.23(t,J=7.2Hz,1H),3.96- 3.92(m,1H),3.83-3.80(m,2H),3.41(t,J=10.4Hz,2H),2.43(s,3H),1.80(d,J=10.8Hz,2H),1.45-1.37(m,2H).

[0738] Ethyl 3-(3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamido)benzoate

[0739] Compound ID: 113

[0740]

[0741] LCMS: m / z 366.2 [M+H] + ;

[0742] 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.31(t,J=2.0Hz,1H),7.81-7.76(m,3H),7.62(d,J=7.6Hz,1H) ,7.52-7.43(m,3H),7.29(t,J=7.6Hz,1H),4.33(q,J=7.2Hz,2H),2.52(s,3H),1.38(t,J=7.2Hz,3H).

[0743] N-(3-Butyrylphenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0744] Compound ID: 114

[0745]

[0746] LCMS: m / z 364.1[M+H] + ;

[0747] 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.25(t,J=1.6Hz,1H),7.82(dd,J=1.2,8.0Hz,3H),7.62(d,J=8.0Hz,1H),7.5 1-7.44(m,3H),7.32-7.26(m,1H),2.99(t,J=7.2Hz,2H),2.52(s,3H),1.64(q,J=7.2Hz,2H),0.94(t,J=8.0Hz,3H).

[0748] N-(3-(tert-Butyl)phenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0749] Compound ID: 115

[0750]

[0751] LCMS: m / z 350.3 [M+H] + ;

[0752] 1 H NMR(400MHz,DMSO-d6)δ10.72(s,1H),7.76(d,J=7.6Hz,2H),7.58(s,1H),7.50-7.45(m,3H) ,7.27-7.21(m,1H),7.20(t,J=7.6Hz,1H),7.03(d,J=7.6Hz,1H),2.49(s,3H),1.27(s,9H).

[0753] 3-(3-Methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamido)benzoic acid

[0754] Compound ID: 116

[0755]

[0756] LCMS: m / z 338.2 [M+H] + ;

[0757] 1 H NMR(400MHz,DMSO-d6)δ13.12(s,1H),10.84(s,1H),8.31(s,1H),7.79-7.70(m,3 H),7.64-7.59(m,1H),7.57-7.49(m,2H),7.44(s,1H),7.33(s,1H),2.56(s,3H).

[0758] 3-Methyl-5-oxo-1-phenyl-N-(3-propionylphenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0759] Compound ID: 117

[0760]

[0761] LCMS: m / z 350.2 [M+H] + ;

[0762] 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.21(d,J=1.6Hz,1H),7.80(d,J=7.6Hz,1H),7.74(d,J=7.6Hz,2H),7.60(d,J=8.0Hz,1H),7 .49(t,J=7.6Hz,2H),7.44-7.42(d,J=8.0Hz,1H),7.26(d,J=7.6Hz,1H),3.05(q,J=7.2Hz,2H),2.54(s,3H),1.10(t,J=7.2Hz,3H).

[0763] 3-Methyl-5-oxo-N-(3-pentylphenyl)-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0764] Compound ID: 118

[0765]

[0766] LCMS: m / z 364.3 [M+H] + ;

[0767] 1 H NMR (400MHz, DMSO-d6) δ = 10.66 (s, 1H), 7.74 (d, J = 8.0Hz, 2H), 7.52-7.51 (m, 2H), 7.51-7.49 (m, 2H), 7.45-7.43 (m, 1H), 7. 24-7.15(t,J=6.8Hz,1H),6.88-6.81(J=7.2Hz,1H),2.57-2.52(m,5H),1.62-1.51(m,2H),1.35-1.23(m,4H),0.86(s,3H).

[0768] N-(3-cyclopropylphenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0769] Compound ID: 119

[0770]

[0771] LCMS: m / z 334.2 [M+H] + ;

[0772] 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),7.73(d,J=7.6Hz,2H),7.54-7.49(m,2H),7.36-7.32(m,3H),7.17(t, J=8.0Hz,1H),6.75(d,J=7.6Hz,1H),2.54(s,3H),1.90-1.89(m,1H),0.95-0.92(m,2H),0.66-0.64(m,2H).

[0773] 4-(4-((3-acetylphenyl)carbamoyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid

[0774] Compound ID: 120

[0775]

[0776] LCMS: m / z 380.2 [M+H] + ;

[0777] 1 H NMR (400MHz, METHANOL-d4) δ 8.35 (s, 1H), 8.09-8.01 (m, 4H), 7.83-7.81 (m, 1H), 7.67 (d, J = 4.4Hz, 1H), 7.47-7.44 (m, 1H), 2.62 (s, 3H), 2.53 (s, 3H).

[0778] 3-Methyl-5-oxo-1-phenyl-N-(4-piperidinyl)-4H-pyrazole-4-carboxamide

[0779] Compound ID: 121

[0780]

[0781] LCMS: m / z 301.2 [M+H] + ;

[0782] 1H NMR (400MHz, METHANOL-d4) δ = 8.36 (s, 1H), 7.73 (d, J = 8.0Hz, 2H), 7.40 (t, J = 7.6Hz, 2H), 7.28-7.05 (m, 1H), 4.24-3.98(m,1H),3.40-3.34(m,2H),3.18-3.07(m,2H),2.40(s,3H),2.25-2.06(m,2H),1.87-1.64(m,2H)

[0783] 3-Methyl-5-oxo-N-(3-oxo-1,3-dihydroisobenzofuran-5-yl)-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0784] Compound ID: 122

[0785]

[0786] LCMS: m / z 350.0 [M+H] + ;

[0787] 1 H NMR (400MHz, DMSO-d6) δ = 10.99 (s, 1H), 8.37 (s, 1H), 7.80-7.77 (m, 3H), 7.75- 7.69(m,1H),7.54-7.49(m,2H),7.38-7.31(m,1H),5.36(s,2H),2.54(s,3H).

[0788] 3-(4-((3-acetylphenyl)carbamoyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid Compound ID: 123

[0789]

[0790] LCMS: m / z 380.0 [M+H] + ;

[0791] 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.38(s,1H),8.26(t,J=2.0Hz,1H),8.10-8.04(m,1H ),7.85(d,J=8.0Hz,2H),7.64-7.62(m,2H),7.47(d,J=8.0Hz,1H),2.59(s,3H),2.56(s,3H)

[0792] 3-Methyl-N-(3-(oxazol-2-yl)phenyl)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0793] Compound ID: 124

[0794]

[0795] LCMS: m / z 361.1[M+H] + ;

[0796] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.47(s,1H),8.23(s,1H),7.78(d,J=8.0Hz,2H),7. 62(dd,J=7.6,18.4Hz,2H),7.53-7.44(m,3H),7.39(s,1H),7.32-7.26(m,1H),2.53(s,3H)

[0797] N-(3-ethylphenyl)-3-methyl-5-oxo-1-(pyridin-4-yl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0798] Compound ID: 125

[0799]

[0800] LCMS: m / z 323.1[M+H] + ;

[0801] 1 H NMR(400MHz,METHANOL-d4)δ8.46-8.60(m,4H),7.47(s,1H),7.41(d,J=8.0Hz,1H),7.20(t,J =8.0Hz,1H),6.89(d,J=7.6Hz,1H),2.64(q,J=7.6Hz,2H),2.44(s,3H),1.25(t,J=7.6Hz,3H)

[0802] N-(3-Ethylphenyl)-5-oxo-1,3-diphenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0803] Compound ID: 126

[0804]

[0805] LCMS: m / z 384.2 [M+H] + ;

[0806] 1 H NMR (400MHz, DMSO-d6) δ11.00-10.73(s,1H),7.84(d,J=7.6Hz,4H),7.59-7.46(m,6H),7.44-7.39(m,1H), 7.38-7.33(m,1H),7.25-7.15(m,1H),6.88(d,J=8.0Hz,1H),2.57(d,J=7.6Hz,2H),1.17(t,J=7.6Hz,3H).

[0807] N-(3-ethylphenyl)-3-methyl-5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0808] Compound ID: 127

[0809]

[0810] LCMS: m / z 390.2 [M+H] + ;

[0811] 1 H NMR(400MHz,CHLOROFORM-d)δ7.83(s,2H),7.65(s,2H),7.39-7.29(m,2H),7.22(s,1 H), 6.98 (d, J = 7.2Hz, 1H), 2.62 (d, J = 7.2Hz, 2H), 2.54 (s, 3H), 1.22 (t, J = 7.6Hz, 3H).

[0812] N-(3-Ethylphenyl)-3-isopropyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0813] Compound ID: 128

[0814]

[0815] LCMS: m / z 350.3 [M+H] + ;

[0816] 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),7.67(d,J=8.0Hz,2H),7.53(t,J=8.0Hz,2H),7.47(s,1H),7.42(d,J=8.0Hz,1H),7.34(d,J=8.0H z,1H),7.20(t,J=7.6Hz,1H),6.88(d,J=8.0Hz,1H),3.95-3.91(m,1H),2.59-2.51(m,2H),1.32(d,J=7.2Hz,6H),1.18(t,J=7.6Hz,3H).

[0817] 3-Benzyl-N-(3-ethylphenyl)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0818] Compound ID: 129

[0819]

[0820] LCMS: m / z 398.3 [M+H] + ;

[0821] 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H),7.72(d,J=8.0Hz,2H),7.54(t,J=8.0Hz,2H),7.45-7.43(m,4H),7.43-7. 41(m,3H),7.34-7.32(m,2H),6.88(d,J=7.8Hz,1H),4.36(s,2H),2.59(q,J=7.8Hz,2H),1.17(t,J=7.5Hz,3H).

[0822] N-(3-Ethylphenyl)-5-oxo-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0823] Compound ID: 130

[0824]

[0825] LCMS: m / z 376.2 [M+H] + ;

[0826] 1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),8.02(d,J=8.0Hz,2H),7.49(s,1H),7.42-7.40(m,3H ),7.24-7.13(m,2H),6.81-6.79(d,J=8.0Hz,1H),2.53-2.61(m,2H),1.18(t,J=7.6Hz,3H).

[0827] N-(3-((Dimethylamino)methyl)phenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0828] Compound ID: 131

[0829]

[0830] LCMS: m / z 351.2 [M+H] + ;

[0831] 1 H NMR(400MHz,METHANOL-d4)δ7.80-7.77(m,3H),7.65-7.58(m,1H),7.44-7.36(m,3 H),7.23-7.20(m,1H),7.07(d,J=7.6Hz,1H),4.21(s,2H),2.80(s,6H),2.45(s,3H)

[0832] 3-Methyl-5-oxo-1-phenyl-N-(3-(pyrimidin-5-yl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0833] Compound ID: 132

[0834]

[0835] LCMS: m / z 372.2 [M+H] + ;

[0836] 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.20(s,1H),9.12(s,2H),8.01(s,1H),7.74(d,J=7.6Hz,1H) ,7.74-7.72(m,2H),7.55-7.51(t,J=8.0Hz,2H),7.49-7.47(m,2H),7.47-7.34(m,1H),2.58(s,3H).

[0837] N-(3-Ethylphenyl)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0838] Compound ID: 133

[0839]

[0840] LCMS: m / z 308.0 [M+H] + ;

[0841] 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),8.28(s,1H),7.78(d,J=8.4Hz,2H),7.53-7.47(m,4H),7.32- 7.29(m,1H),7.28-7.23(m,1H),6.90(d,J=7.6Hz,1H),2.57(q,J=7.6Hz,2H),1.19(t,J=7.6Hz,3H)

[0842] 1-(4-Ethoxyphenyl)-N-(3-ethylphenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-4-carboxamide

[0843] Compound ID: 134

[0844]

[0845] LCMS: m / z 285.1 [M-80];

[0846] 1 H NMR (400MHz, DMSO-d6) δ8.51(s,1H),8.43(s,1H),7.33(d,J=8.8Hz,2H),7.30(s,1H),7.24-7.19(m,1H),7.16(t,J=7.6Hz,1H),6.84(d,J= 7.2Hz, 2H), 6.80 (d, J = 7.6Hz, 1H), 3.97 (q, J = 6.8Hz, 2H), 2.56 (q, J = 7.6Hz, 2H), 2.52 (s, 3H), 1.30 (t, J = 6.8Hz, 3H), 1.17 (t, J = 7.6Hz, 3H).

[0847] Ethyl 4-(3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamido)picolinate

[0848] Compound ID: 135

[0849]

[0850] LCMS: m / z 367.0 [M+H] + ;

[0851] 1 H NMR (400MHz, DMSO-d6) δ11.81(s,1H),8.51(d,J=6.0Hz,1H),8.44(s,1H),7.87(d,J=7.6Hz,3H),7. 44(t,J=7.6Hz,2H),7.20(t,J=7.6Hz,1H),4.39(q,J=6.8Hz,2H),2.43(s,3H),1.36(t,J=6.8Hz,3H)

[0852] 3-Ethyl-N-(3-ethylphenyl)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0853] Compound ID: 136

[0854]

[0855] LCMS: m / z 336.2 [M+H] + ;

[0856] 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H),7.72(d,J=8.0Hz,2H),7.53(t,J=7.6Hz,2H),7.48(s,1H),7.43(d,J=7.6Hz,1H),7.38-7.30(m,1H) ,7.21(t,J=7.6Hz,1H),6.89(d,J=7.6Hz,1H),2.97(q,J=7.6Hz,2H),2.59(q,J=7.6Hz,2H),1.28(t,J=7.6Hz,3H),1.18(t,J=7.6Hz,3H).

[0857] N-(3-ethylphenyl)-5-oxo-1-phenyl-3-(pyridin-4-yl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0858] Compound ID: 137

[0859]

[0860] LCMS: m / z 385.3 [M+H] + ;

[0861] 1H NMR (400MHz, DMSO-d6) δ11.79(s,1H),8.81(q,J=6.4Hz,4H),8.21(d,J=7.6Hz,2H),7.49-7.40(m ,4H),7.18(t,J=7.6Hz,2H),6.81(d,J=7.6Hz,1H),2.58(q,J=7.6Hz,2H),1.19(t,J=7.6Hz,3H).

[0862] N-(3-ethylphenyl)-1-(4-methoxyphenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-4-carboxamide

[0863] Compound ID: 138

[0864]

[0865] LCMS: m / z 352.0 [M+H] + ;

[0866] 1 H NMR(400MHz,CHLOROFORM-d)δ7.39(s,1H),7.31(d,J=7.6Hz,3H),7.21(t,J=7.6Hz,1H),6.94(d,J=7.2 Hz, 1H), 6.81 (d, J = 7.2Hz, 2H), 3.74 (s, 3H), 2.62 (q, J = 7.2Hz, 2H), 2.41 (s, 3H), 1.22 (t, J = 7.6Hz, 3H).

[0867] N-(3-(N,N-dimethylsulfamoyl)phenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0868] Compound ID: 139

[0869]

[0870] LCMS: m / z 401.0 [M+H] + ;

[0871] 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.26(t,J=1.6Hz,1H),7.73(d,J=8.0Hz,3H),7.58(t,J=7.6 Hz, 1H), 7.53 (t, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.36-7.29 (m, 1H), 2.63 (s, 6H), 2.55 (s, 3H).

[0872] 3-Methyl-5-oxo-1-phenyl-N-(3-propylphenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0873] Compound ID: 140

[0874]

[0875] LCMS: m / z 336.1[M+H] + ;

[0876] 1 H NMR (400MHz, DMSO-d6) δ10.70(s,1H),7.76(d,J=7.6Hz,2H),7.51(t,J=8.0Hz,2H),7.46(s,1H),7.43(d,J=8.0Hz,1H),7.30(t, J=7.6Hz,1H),7.20(t,J=7.6Hz,1H),6.86(d,J=7.6Hz,1H),2.55(s,2H),2.53(s,3H),1.64-1.54(m,2H),0.90(t,J=7.6Hz,3H).

[0877] N-(3-(1,1-difluoroethyl)phenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0878] Compound ID: 141

[0879]

[0880] LCMS: m / z 358.1[M+H] + ;

[0881] 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),7.95(s,1H),7.76(d,J=7.6Hz,2H),7.62(d,J=8.0Hz,1H),7.51(t,J=7.6 Hz,2H),7.42(t,J=8.0Hz,1H),7.30(t,J=7.6Hz,1H),7.21(d,J=8.0Hz,1H),2.53(s,3H),1.96(t,J=18.8Hz,3H)

[0882] N-(3-ethylphenyl)-1-(4-isopropoxyphenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-4-carboxamide

[0883] Compound ID: 142

[0884]

[0885] LCMS: m / z 380.3 [M+H] + ;

[0886] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),7.69(s,2H),7.45(s,1H),7.41(d,J=8.0Hz,1H),7.17(t,J=7.6Hz,1H),7.01-6.94(m,2H),6.82 (d,J=7.2Hz,1H),4.61(td,J=5.6,11.2Hz,1H),2.62-2.53(q,J=7.6Hz,2H),2.42(s,3H),1.27(d,J=6.0Hz,6H),1.18(t,J=7.6Hz,3H)

[0887] 1-(4-(Cyclopropylmethoxy)phenyl)-N-(3-ethylphenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-4-carboxamide

[0888] Compound ID: 143

[0889]

[0890] LCMS: m / z 392.2 [M+H] + ;

[0891] 1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),7.61(d,J=9.2Hz,2H),7.46(s,1H),7 .42(d,J=8.0Hz,1H),7.20(t,J=8.0Hz,1H),7.03(d,J=9.2Hz,2H),6.86(d,J =7.6Hz,1H),3.85(d,J=6.8Hz,2H),2.58(q,J=7.6Hz,2H),2.48(s,3H),1.2 8-1.21(m,1H),1.18(t,J=7.6Hz,3H),0.63-0.54(m,2H),0.38-0.30(m,2H).

[0892] 1-(4-Acetylaminophenyl)-N-(3-ethylphenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-4-carboxamide

[0893] Compound ID: 144

[0894]

[0895] LCMS: m / z 379.2 [M+H] + ;

[0896] 1 H NMR (400MHz, DMSO-d6) δ10.70(s,1H),10.07(s,1H),7.69(d,J=8.0Hz,2H),7.62(d,J=8.8Hz,2H),7.46(s,1H),7.42(d,J=8. 0Hz,1H),7.20(t,J=8.0Hz,1H),6.87(d,J=7.2Hz,1H),2.58(q,J=8.0Hz,2H),2.51(s,3H),2.06(s,3H),1.17(t,J=7.6Hz,3H)

[0897] 3-Methyl-5-oxo-N-(3-(2-oxopropyl)phenyl)-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0898] Compound ID: 145

[0899]

[0900] LCMS: m / z 350.2 [M+H] + ;

[0901] 1H NMR (400MHz, DMSO-d6) δ10.71(s,1H),7.74(d,J=8.0Hz,2H),7.54-7.49(t,J=7.2Hz,3H),7.47(s,1H),7. 31(t,J=7.6Hz,1H),7.25(t,J=7.6Hz,1H),6.86(d,J=7.6Hz,1H),3.74(s,2H),2.54(s,3H),2.13(s,3H).

[0902] N-(3-cyclopentylphenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0903]

[0904] Compound ID: 146

[0905] LCMS: m / z 362.2 [M+H] + ;

[0906] 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),7.79-7.68(d,J=7.8Hz,2H),7.55-7.51(m,3H),7.40(d,J=8.0Hz,1H),7.33(d,J=7.6Hz,1H),7.21(t,J= 8.0Hz,1H),6.93(d,J=7.6Hz,1H),2.99-2.90(m,1H),2.55(s,3H),2.0 4-1.97(m,2H),1.82-1.71(m,2H),1.691.59(m,2H),1.58-1.48(m,2H).

[0907] N-(3-Isobutylphenyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxamide

[0908] Compound ID: 147

[0909]

[0910] LCMS: m / z 350.1 [M+H] + ;

[0911] 1H NMR (400MHz, DMSO-d6) δ10.70(s,1H),7.76(d,J=8.0Hz,2H),7.51(d,J=7.6Hz,2H),7.49-7.42(m,2H),7.30-7.25(m,1 H),7.22-7.20(m,1H),6.83-6.80(m,1H),2.67(s,3H),2.42(d,J=7.2Hz,2H),1.85-1.81(m,1H),0.87(d,J=6.8Hz,6H)

[0912] N-(3-(1-H-imidazol-2-yl)phenyl)-3-methyl-5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0913] Compound ID: 148

[0914]

[0915] LCMS: m / z 428.2 [M+H] + ;

[0916] 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),8.26(s,1H),8.18(d,J=8.4Hz,2H),8.01(d,J=8.0Hz ,1H),7.81(s,3H),7.80(s,1H),7.67(d,J=7.6Hz,1H),7.56(t,J=8.0Hz,1H),2.48(s,3H).

[0917] N-(3-(1H-imidazol-2-yl)phenyl)-3-methyl-5-oxo-1-(3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0918]

[0919] Compound ID: 149

[0920] LCMS: m / z 428.0 [M+H] + ;

[0921] 1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),8.37(s,1H),8.23(s,1H),8.13(d,J=8.8Hz,1H), 8.07(d,J=8.0Hz,1H),7.82(s,2H),7.74-7.71(m,2H),7.60-7.56(m,2H),2.54(s,3H).

[0922] 3-Methyl-5-oxo-N-(3-(pyrazin-2-yl)phenyl)-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0923] Compound ID: 150

[0924]

[0925] LCMS: m / z 440.0 [M+H] + ;

[0926] 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),9.24(d,J=1.6Hz,1H),8.74(dd,J=1.6,2.4Hz,1H),8.63(d,J=2.4Hz,1H), 8.44(s,1H),8.08(d,J=8.8Hz,2H),7.87(d,J=8.8Hz,2H),7.83-7.71(m,2H),7.47(t,J=7.6Hz,1H),2.55(s,3H).

[0927] 3-Methyl-5-oxo-N-(3-(pyrazin-2-yl)phenyl)-1-(3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0928] Compound ID: 166

[0929]

[0930] LCMS: m / z 440.2 [M+H] + ;

[0931] 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),9.25(d,J=1.6Hz,1H),8.77-8.71(m,1H),8.63(d,J=2.4Hz,1H),8.44(t,J=1.6Hz,1H),8.28(s,1 H), 8.12 (d, J = 9.6Hz, 1H), 7.80 (dd, J = 2.0, 7.6Hz, 2H), 7.74 (t, J = 8.0Hz, 1H), 7.62 (d, J = 7.6Hz, 1H), 7.48 (t, J = 8.0Hz, 1H), 2.55 (s, 3H).

[0932] 4-((3-ethylphenyl)carbamoyl)-3-methyl-1-(4-(methylamino)phenyl)-1H-pyrazol-5-yl dimethylcarbamate

[0933] Compound ID: 224

[0934]

[0935] LCMS: m / z 422.1[M+H] + ;

[0936] 1 H NMR (400MHz, DMSO-d6) δ9.50(s,1H),7.51(s,1H),7.41(d,J=8.0Hz,1H),7.26-7.16(m,3H),6.92(d,J=7.6Hz,1H),6.62(d,J=8.8Hz ,2H),6.04-5.97(m,1H),3.02(s,3H),2.79(s,3H),2.71(d,J=4.8Hz,3H),2.59(q,J=7.6Hz,2H),2.37(s,3H),1.18(t,J=7.6Hz,3H).

[0937] 3-Methyl-5-oxo-1-phenyl-N-(3-(2,2,2-trifluoroacetyl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0938] Compound ID: 152

[0939]

[0940] LCMS: m / z 408.3 [M+H+H2O] + ;

[0941] 1H NMR (400MHz, DMSO-d6) δ10.77(s,1H),7.82(s,1H),7.74-7.71(m,2H),7.55-7.51(m,3H),7.36-7.32(m,3H),2.56(s,3H)

[0942] 19 F NMR(400MHz,DMSO-d6)δ:-82.71(s,3F).

[0943] N-(3-ethylphenyl)-3-methyl-1-(4-nitrophenyl)-5-oxo-4,5-dihydro-1H-pyrazole-4-carboxamide

[0944] Compound ID: 153

[0945]

[0946] LCMS: m / z 367.2 [M+H] + ;

[0947] 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),8.37(d,J=9.2Hz,2H),8.12(d,J=9.6Hz,2H),7.47(s,1H),7.44(d,J=8.0 Hz, 1H), 7.21 (t, J = 8.0Hz, 1H), 6.87 (d, J = 7.6Hz, 1H), 2.58 (q, J = 7.6Hz, 2H), 2.54 (s, 3H), 1.18 (t, J = 7.6Hz, 3H).

[0948] 1-(4-aminophenyl)-N-(3-ethylphenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-4-carboxamide

[0949] Compound ID: 154

[0950]

[0951] LCMS: m / z 337.2 [M+H] + ;

[0952] 1H NMR (400MHz, DMSO-d6) δ10.80(s,1H),7.45(s,1H),7.41(d,J=8.4Hz,1H),7.28(d,J=6.8Hz,2H),7.20(t,J=7.6 Hz,1H),6.86(d,J=7.6Hz,1H),6.69(d,J=8.4Hz,2H),2.57(q,J=7.6Hz,2H),2.47(s,3H),1.17(t,J=7.6Hz,3H)

[0953] 1-(4-(3,3-dimethylureido)phenyl)-N-(3-ethylphenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-4-carboxamide

[0954] Compound ID: 155

[0955]

[0956] LCMS: m / z 408.3 [M+H] + ;

[0957] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.32(s,1H),7.67(s,2H),7.50(d,J=9.2Hz,2H),7.45(s,1H),7.41(d,J=8.4Hz,1 H),7.16(t,J=7.6Hz,1H),6.81(d,J=7.6Hz,1H),2.93(s,6H),2.56(q,J=7.6Hz,2H),2.41(s,3H),1.17(t,J=7.6Hz,3H).

[0958] N-(3-ethylphenyl)-5-oxo-1-phenyl-3-(pyridin-2-yl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0959] Compound ID: 156

[0960]

[0961] LCMS: m / z 385.1[M+H] + ;

[0962] 1H NMR(400MHz,DMSO-d6)δ12.03(s,1H),9.00(s,1H),8.65(d,J=7.6Hz,1H),8 .49(t,J=7.6Hz,1H),8.21(d,J=8.0Hz,2H),7.90(t,J=2.4Hz,1H),7.53(d,J =8.0Hz,1H),7.50-7.46(m,3H),7.30(t,J=7.6Hz,1H),7.25(t,J=7.6Hz,1H ), 6.98 (d, J = 7.6Hz, 1H), 2.66-2.60 (q, J = 7.6Hz, 2H), 1.21 (t, J = 7.6Hz, 3H).

[0963] N-(3-ethylphenyl)-5-oxo-1-phenyl-3-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0964] Compound ID: 157

[0965]

[0966] LCMS: m / z 385.2 [M+H] + ;

[0967] 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),9.68(s,1H),9.11(d,J=8.0Hz,1H),8.81(d,J=5.2Hz,1H),8.20(d,J=7.6Hz,2H),8.04(dd,J=5.6,8. 0Hz,1H),7.49(s,1H),7.47-7.37(m,3H),7.16(td,J=7.6,10.0Hz,2H),6.81(d,J=7.6Hz,1H),2.58(q,J=7.6Hz,2H),1.19(t,J=7.6Hz,3H).

[0968] N-(3-ethylphenyl)-3-methyl-5-oxo-1-(4-propoxyphenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0969] Compound ID: 158

[0970]

[0971] LCMS: m / z 380.1[M+H] + ;

[0972] 1H NMR (400MHz, DMSO-d6) δ13.24 (s, 1H), 10.71 (s, 1H), 7.56 (d, J = 9.2Hz, 2H), 7.47-7.45(m,1H),7.43-7.41(m,1H),7.22-7.20(m,1H),7.07(d,J=8.8Hz, 2H),6.88(d,J=7.6Hz,1H),3.97(t,J=6.4Hz,2H),2.61-2.58(m,2H),2.57( s, 3H), 1.76 (t, J = 6.8Hz, 2H), 1.18 (t, J = 7.6Hz, 3H), 0.99 (t, J = 7.6Hz, 3H).

[0973] 3-(4-((3-(Furan-2-yl)phenyl)carbamoyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid Compound ID: 159

[0974]

[0975] LCMS: m / z 404.0 [M+H] + ;

[0976] 1 H NMR (400MHz, METHANOL-d4) δ8.33 (s, 1H), 7.89-8.10 (m, 3H), 7.66-7.63 (m, 1H), 7.55 (d, J = 1.2Hz, 1H),7.48-7.40(m,2H),7.36-7.34(m,1H),6.78(d,J=3.2Hz,1H),6.52-6.50(m,1H),2.63(s,3H).

[0977] 1-(4-(N,N-dimethylsulfamoyl)phenyl)-N-(3-(furan-2-yl)phenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-4-carboxamide

[0978] Compound ID: 160

[0979]

[0980] LCMS: m / z 467.1[M+H] + ;

[0981] 1H NMR(400MHz, METHANOL-d4)δ8.19-8.05(m,3H),7.88(d,J=8.4Hz,2H),7.57(d,J=1.2Hz,1H),7.50(d,J=7.6Hz,1H), 7.45-7.39(m,1H),7.38-7.31(m,1H),6.80(d,J=3.2Hz,1H),6.54(dd,J=1.6,3.2Hz,1H),2.73(s,6H),2.58(s,3H).

[0982] 3-Methyl-5-oxo-1-phenyl-N-(3-(2,2,2-trifluoroethyl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0983] Compound ID: 161

[0984]

[0985] LCMS: m / z 376.0 [M+H] + ;

[0986] 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),7.78(d,J=7.6Hz,2H),7.67(s,1H),7.60(d,J=8.0Hz,1H),7. 50(t,J=8.0Hz,2H),7.34-7.25(m,2H),7.01(d,J=7.6Hz,1H),3.63(q,J=11.6Hz,2H),2.52(s,3H).

[0987] N-(3-(Furan-2-yl)phenyl)-3-methyl-5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-4-carboxamide

[0988]

[0989] Compound ID: 162

[0990] LCMS: m / z 428.0 [M+H] + ;

[0991] 1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.10(d,J=8.0Hz,2H),8.06(s,1H),7.86(s,2H) ,7.75(s,1H),7.48(s,1H),7.35(s,2H),6.97-6.89(m,1H),6.60(s,1H),2.53(s,3H).

[0992] N-(3-(1H-imidazol-2-yl)phenyl)-1-(4-(N,N-dimethylsulfamoyl)phenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-4-carboxamide

[0993] Compound ID: 173

[0994]

[0995] LCMS: m / z 467.1[M+H] + ;

[0996] 1 H NMR (400MHz, METHANOL-d4) δ8.35(s,1H),7.99(q,J=8.8Hz,4H),7.90-7.86(m,1H),7.69(s,2H),7.66-7.61(m,2H),2.75(s,6H),2.72(s,3H)

[0997] Example 2

[0998] Biological activities of the compounds of the present invention

[0999] ACSS2 cell-free activity assay (cell-free IC 50 )

[1000] The assay is based on a coupled reaction with pyrophosphatase: ACSS2 converts ATP + CoA + acetate => AMP + pyrophosphate + acetyl-CoA (Ac-CoA). Pyrophosphatase converts pyrophosphate, the product of the ACSS2 reaction, into phosphate, which can be detected by measuring absorbance at 620 nm after incubation with Biomol green reagent (Enzo Life Science, BML-AK111).

[1001] Cell-free IC 50 Determination:

[1002] 10 nM human ACSS2 protein (OriGene Technologies, Inc.) was incubated at 37°C with various compound concentrations for 90 minutes in a reaction containing 50 mM Hepes pH 7.5, 10 mM DTT, 90 mM KCl, 0.006% Tween-20, 0.1 mg / ml BSA, 2 mM MgCl2, 10 μM Coenzyme A, 5 mM NaAc, 300 μM ATP, and 0.5 U / ml pyrophosphatase (Sigma). At the end of the reaction, Biomol Green was added for 30 minutes at room temperature, and activity was measured by reading absorbance at 620 nm. IC 50 Values ​​were calculated using nonlinear regression curve fitting with 0% and 100% constraints (CDD Vault, Collaborative Drug Discovery, Inc.).

[1003] result:

[1004] The results are presented in Table 2 below:

[1005] Table 2. ACSS2 cell-free activity assay results (cell-free IC 50 ).

[1006]

[1007]

[1008]

[1009] ACSS2 cell activity assay (cell IC50)

[1010] The cell activity of ACSS2 is based on tracking the 13 The carbon of the C-acetate is incorporated into a fatty acid.

[1011] Cell treatment:

[1012] BT474 / MDA-MB-468 cells grown in DMEM+25mM D-glucose+1mM sodium pyruvate+10% FBS+2mM glutamine were plated at 0.4×10 6 Cells were seeded in 12-well plates at 100 cells / well. Cells were then cultured in a CO2 incubato...

Claims

1. A compound represented by the structure of formula (I): in Ring A and Ring B are each independently a monocyclic or fused aromatic or heteroaromatic ring system, or a monocyclic or fused C3-C 10 Heterocyclic ring; R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, R8-SH, -R8-OR 10 , CD3, OCD3, CN, NO2, -R8CN, N(R)2, R8-N(R 10 )(R 11 )、R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R 10 、NHCO-N(R 10 )(R 11 )、-C(O)Ph、C(O)OR 10 、R8-C(O)-R 10 、C(O)-R 10 、C1-C5 straight chain or branched C(O)-haloalkyl、C(O)N(R 10 )(R 11 )、SO2R、SO2N(R 10 )(R 11 ); unsubstituted C1-C5 straight or branched alkyl, or C1-C5 straight or branched alkyl substituted by F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2; C1-C5 straight, branched or cyclic alkoxy, optionally wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom; C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, unsubstituted C3-C8 cycloalkyl, substituted by F, Cl, C3-C8 cycloalkyl substituted with Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2, unsubstituted C3-C8 heterocycle, C3-C8 heterocycle substituted with F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2, unsubstituted aryl, aryl substituted with F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2, or CH(CF3)(NH-R 10 ); or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring, wherein the substituted aliphatic or aromatic carbocyclic or heterocyclic ring is substituted by F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2; R3 is C2-C5 straight or branched haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycle, wherein the substituted C3-C8 cycloalkyl and the substituted C3-C8 heterocycle are substituted by F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2; R4 is H, F, Cl, Br, I, OH, SH, R8-SH, -R8-OR 10 , CD3, OCD3, CN, NO2, -R8CN, N(R)2, R8-N(R 10 )(R 11 )、R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, -NHCO-R 10 、NHCO-N(R 10 )(R 11 )、-C(O)Ph、C(O)OR 10 、R8-C(O)-R 10 、C(O)-R 10 、C1-C5 straight chain or branched C(O)-haloalkyl、C(O)N(R 10 )(R 11 )、SO2R、SO2N(R 10 )(R 11 ); unsubstituted C1-C5 straight or branched alkyl, or C1-C5 straight or branched alkyl substituted by F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2; C1-C5 straight, branched or cyclic alkoxy; C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, unsubstituted C3-C8 cycloalkyl, substituted by F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2 C3-C8 cycloalkyl substituted with F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2, unsubstituted C3-C8 heterocycle, C3-C8 heterocycle substituted with F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2, unsubstituted aryl, aryl substituted with F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2, or CH(CF3)(NH-R 10 ); or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring, wherein the substituted aliphatic or aromatic carbocyclic or heterocyclic ring is substituted by F, Cl, Br, I, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2; R5 is H; unsubstituted C1-C5 straight chain or branched alkyl, or C1-C5 straight chain or branched alkyl substituted by F, Cl, Br, I, C1-C5 straight chain or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2; R8-aryl, unsubstituted aryl, aryl substituted by F, Cl, Br, I, C1-C5 straight chain or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2, unsubstituted heteroaryl, or heteroaryl substituted by F, Cl, Br, I, C1-C5 straight chain or branched alkyl, OH, alkoxy, N(R)2, CF3, CN or NO2; R6 is H, or a C1-C5 straight or branched chain alkyl group; R8 is [CH2] p Where p is between 1 and 10; R9 is [CH] q or [C] q Where q is between 2 and 10; R 10 and R 11 Each is independently H, C1-C5 straight or branched alkyl, C(O)R or S(O)2R; R is H, C1-C5 straight or branched chain alkyl, C1-C5 straight or branched chain alkoxy, aryl or heteroaryl, or two geminal R substituents are linked together to form a 5-membered or 6-membered heterocyclic ring; m, n and k are each independently an integer between 0 and 4; l is an integer between 1 and 4; Q1 and Q2 are each independently S or O; or a pharmaceutically acceptable salt, optical isomer, tautomer, N-oxide or any combination thereof.

2. The compound according to claim 1, wherein R3 is CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycle.

3. The compound according to claim 1, which is represented by the structure of formula (II): in R1, R2, R3, R4, R5, R6, R8, R 10 , R 11 , R, m, n, l, k, Q1 and Q2 are as defined in claim 1; and X1, X2, X3, X4, X5, X6, X7, X8, X9 and X 10 Each is independently C or N.

4. The compound of claim 1, which is represented by the structure of formula (IV): in R1, R2, R3, R4 and R5 are as defined in claim 1; X3, X4, X7 and X8 are each independently C or N; wherein if X3 is N, then R4 does not exist; and If X8 is N, R2 does not exist.

5. A compound selected from the group consisting of: or a pharmaceutically acceptable salt, optical isomer, tautomer, N-oxide or any combination thereof.

6. A compound represented by the following structure: or a pharmaceutically acceptable salt, optical isomer, tautomer, N-oxide or any combination thereof.

7. The compound according to any one of the preceding claims, wherein the compound is an acyl-CoA synthetase short-chain family member 2 (ACSS2) inhibitor.

8. Use of a compound for the preparation of a medicament for treating, inhibiting, reducing the severity of, reducing the risk of, or preventing cancer in an individual, wherein the cancer is a cancer for which an ACSS2 inhibitor is effective, or The medicament is for treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing alcoholism in a human in an individual, wherein the alcoholism is alcoholism for which an ACSS2 inhibitor is effective, or The medicament is used to treat, inhibit, reduce the severity of, reduce the risk of, or prevent a viral infection in an individual, wherein the viral infection is one for which an ACSS2 inhibitor is effective, or The medicament is used to treat, inhibit, reduce the severity of, reduce the risk of developing, or prevent alcoholic steatohepatitis (ASH) in an individual, wherein the alcoholic steatohepatitis is an alcoholic steatohepatitis for which an ACSS2 inhibitor is effective, or The medicament is used to treat, inhibit, reduce the severity of, reduce the risk of developing, or prevent non-alcoholic fatty liver disease (NAFLD) in an individual, wherein the non-alcoholic fatty liver disease is a non-alcoholic fatty liver disease for which an ACSS2 inhibitor is effective, or The medicament is for treating, inhibiting, reducing the severity of, reducing the risk of, or preventing a metabolic disorder in an individual, wherein the metabolic disorder is a metabolic disorder for which an ACSS2 inhibitor is effective, or The medicament is for treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing a neuropsychiatric disease or disorder in an individual, wherein the neuropsychiatric disease or disorder is a neuropsychiatric disease or disorder for which an ACSS2 inhibitor is effective, or The medicament is for treating, inhibiting, reducing the severity of, reducing the risk of, or preventing an inflammatory disorder in an individual, wherein the inflammatory disorder is an inflammatory disorder for which an ACSS2 inhibitor is effective, or The medicament is for treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing an autoimmune disease or disorder in an individual, wherein the autoimmune disease or disorder is an autoimmune disease or disorder for which an ACSS2 inhibitor is effective, The compound is represented by the following structure:

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1 to 7 in the preparation of a medicament for treating, inhibiting, reducing the severity of, reducing the risk of, or preventing cancer in an individual, wherein the cancer is a cancer for which an ACSS2 inhibitor is effective.

11. The method according to claim 8 or 10, wherein the cancer is selected from the group consisting of melanoma, glioblastoma, breast cancer, prostate cancer, liver cancer, brain cancer, ovarian cancer, lung cancer, colon cancer, pancreatic cancer and renal cell carcinoma, or wherein the cancer is early stage cancer, advanced stage cancer, invasive cancer, metastatic cancer, drug-resistant cancer or any combination thereof, or wherein the individual has been previously treated with chemotherapy, immunotherapy, radiation therapy, biological therapy, surgical intervention, or any combination thereof, or wherein the compound is administered in combination with an anti-cancer therapy, or any combination thereof.

12. The use according to claim 8 or 10, wherein the cancer is selected from stem cell cancer, Lewis lung carcinoma (LLC) and breast cancer.

13. The use according to claim 11, wherein the melanoma is a BRAF mutant melanoma. The use according to claim 11 , wherein the breast cancer is invasive ductal breast carcinoma or triple-negative breast cancer.

15. The use according to claim 11, wherein the anti-cancer therapy is chemotherapy, immunotherapy, radiotherapy, biological therapy, surgical intervention or any combination thereof.

16. Use of a compound according to any one of claims 1 to 7 in the preparation of a medicament for treating, inhibiting, reducing or preventing tumor growth in a subject, wherein the tumor growth is one against which an ACSS2 inhibitor is effective.

17. Use according to claim 16, wherein the tumor growth is enhanced by increased acetate uptake by cancer cells of the cancer.

18. The use according to claim 17, wherein the increased acetate uptake is mediated by ACSS2, and / or wherein the cancer cells are under hypoxic stress, or wherein tumor growth is inhibited due to inhibition of lipid synthesis and / or regulation of histone acetylation and function induced by ACSS2-mediated acetate metabolism to acetyl-CoA.

19. An in vitro method for inhibiting, reducing or preventing lipid synthesis induced by ACSS2-mediated acetate metabolism to acetyl-CoA, or regulating histone acetylation and function induced by ACSS2-mediated acetate metabolism to acetyl-CoA in cells; or Inhibit, reduce or prevent the synthesis of acetyl-CoA from acetate in cells; or inhibiting, reducing or preventing acetate metabolism in cancer cells, optionally wherein the cancer cells are under hypoxic stress, The method comprises contacting the cell with a compound according to any one of claims 1 to 7.

20. The method of claim 19, wherein the cell is a cancer cell.

21. The method of claim 19, wherein the synthesis of acetyl-CoA is ACSS2-mediated synthesis of acetyl-CoA.

22. The method of claim 19, wherein the acetate metabolism is ACSS2-mediated acetate metabolism.

23. An in vitro method for binding an ACSS2 inhibitor compound to an ACSS2 enzyme, comprising the steps of contacting the ACSS2 enzyme with an ACSS2 inhibitor compound according to any one of claims 1 to 7, in an amount effective to bind the ACSS2 inhibitor compound to the ACSS2 enzyme.

24. Use of a compound according to any one of claims 1 to 7 in the preparation of a medicament for treating, inhibiting, reducing the severity of, reducing the risk of developing or preventing human alcoholism in a subject, wherein the human alcoholism is human alcoholism for which an ACSS2 inhibitor is effective, or The medicament is used to treat, inhibit, reduce the severity of, reduce the risk of, or prevent a viral infection in an individual, wherein the viral infection is one for which an ACSS2 inhibitor is effective, or The medicament is used to treat, inhibit, reduce the severity of, reduce the risk of developing, or prevent alcoholic steatohepatitis (ASH) in an individual, wherein the alcoholic steatohepatitis is an alcoholic steatohepatitis for which an ACSS2 inhibitor is effective, or The medicament is used to treat, inhibit, reduce the severity of, reduce the risk of developing, or prevent non-alcoholic fatty liver disease (NAFLD) in an individual, wherein the non-alcoholic fatty liver disease is a non-alcoholic fatty liver disease for which an ACSS2 inhibitor is effective, or The medicament is for treating, inhibiting, reducing the severity of, reducing the risk of, or preventing a metabolic disorder in an individual, wherein the metabolic disorder is a metabolic disorder for which an ACSS2 inhibitor is effective, or The medicament is for treating, inhibiting, reducing the severity of, reducing the risk of developing, or preventing a neuropsychiatric disease or disorder in an individual, wherein the neuropsychiatric disease or disorder is a neuropsychiatric disease or disorder for which an ACSS2 inhibitor is effective, or The medicament is for treating, inhibiting, reducing the severity of, reducing the risk of, or preventing an inflammatory disorder in an individual, wherein the inflammatory disorder is an inflammatory disorder for which an ACSS2 inhibitor is effective, or The medicament is used to treat, inhibit, reduce the severity of, reduce the risk of developing, or prevent an autoimmune disease or disorder in an individual, wherein the immune disease or disorder is an immune disease or disorder for which an ACSS2 inhibitor is effective.

25. The use according to claim 8 or 24, wherein the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis (NASH).

26. The use according to claim 8 or 24, wherein the viral infection is human cytomegalovirus (HCMV) infection.

27. The use according to claim 8 or 24, wherein the metabolic disorder is obesity, weight gain or fatty liver disease.

28. The use according to claim 8 or 24, wherein the metabolic disorder is hepatic steatosis.

29. The use according to claim 8 or 24, wherein the neuropsychiatric disease or disorder is anxiety, depression, schizophrenia, autism or post-traumatic stress disorder.

30. The compound of claim 1, wherein R1 and R2 are each independently CF3, R8-OH, -R8CN, NHR, COOH, C(O)H, or C(O)NHR.

31. The compound of claim 1, wherein R1 and R2 are each independently CF3, R8-OH, -CH2CN, NH2, COOH, C(O)H or -C(O)NH2.

32. The compound of claim 1, wherein R4 is CF3, R8-OH, -CH2CN, NHR, COOH, C(O)H or C(O)NHR.

33. The compound of claim 1, wherein R4 is CF3, R8-OH, -CH2CN, NH2, COOH, C(O)H or -C(O)NH2.

34. The compound of claim 1, wherein R is H, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkoxy, phenyl or heteroaryl, or two geminal R substituents are linked together to form a 5- or 6-membered heterocyclic ring.

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