Collagen 1 translation inhibitors and methods of use thereof

Abstract

Provided are novel collagen 1 translational inhibitors, compositions comprising the same, methods of making the same, and uses thereof for treating fibrosis (including pulmonary fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, skin fibrosis), IPF (idiopathic pulmonary fibrosis), wound-healing, scar fibromatosis, gingival fibromatosis, systemic sclerosis, alcoholic fat hepatitis, and non-alcoholic fat hepatitis (NASH).SOLUTION: A compound of Formula V, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, isotopic variant, reverse amide analog, or any combination thereof is provided. Wherein X1, X2, X4, and X5 are each independently C or N; X3 is N.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to novel collagen 1 translation inhibitors, compositions containing same, methods for making them, and their use for treating fibrosis (including pulmonary fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, skin fibrosis), IPF (idiopathic pulmonary fibrosis), wound healing, cicatricial fibromatosis, gingival fibromatosis, systemic sclerosis, alcoholic steatohepatitis, and non-alcoholic steatohepatitis (NASH). [Background technology]

[0002] The formation of fibrous connective tissue is part of the normal healing process after tissue damage due to injury or inflammation. During this healing process, activated immune cells, including macrophages, stimulate the proliferation and activation of fibroblasts, resulting in the deposition of connective tissue. However, abnormal or excessive production of connective tissue can lead to the accumulation of fibrous material that interferes with the normal function of tissue. Fibrosis can continue even after the original injury has healed, invading healthy surrounding tissue. This abnormal formation of excess connective tissue occurs as a reparative or reactive process and is called fibrosis.

[0003] Many drugs cause activation of the fibrotic process and are released in response to tissue injury, inflammation, and oxidative stress. Regardless of the initiating event, a common feature of all fibrotic diseases (fibrosis) is the transformation of tissue-resident fibroblasts into ECM-producing myofibroblasts that secrete type I collagen. Current programs indirectly target myofibroblast activation and collagen secretion by inhibiting a single profibrotic signal.

[0004] Physiologically, fibrosis is the deposition of connective tissue, obliterating the structure and function of underlying organs and tissues. Fibrosis, defined by the pathological accumulation of extracellular matrix (ECM) proteins, leads to scarring and thickening of affected tissues, disrupting normal organ function. In a variety of conditions, fibrotic tissue formation is characterized by the deposition of abnormally large amounts of collagen. Collagen synthesis is also involved in a variety of other pathological conditions. Clinical conditions and diseases associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, and autoimmune diseases, are distinguished by the excessive production of connective tissue, which leads to the disruption of normal tissue structure and function. These diseases can best be interpreted in terms of perturbations in cellular function, and their primary symptom is excessive collagen synthesis and deposition. The role of collagen in fibrosis has led to efforts to develop drugs that inhibit collagen accumulation.

[0005] Excessive collagen accumulation is a major pathological feature in various clinical conditions characterized by tissue fibrosis. These clinical conditions include localized processes such as pulmonary fibrosis and liver cirrhosis, as well as systemic processes such as progressive systemic sclerosis. Collagen deposition is a hallmark of various forms of skin fibrosis, including scleroderma, localized or systemic sclerosis, keloids, hypertrophic scars, familial cutaneous collagenoma, and collagenous connective tissue nevi. Recent advances in understanding the normal biochemistry of collagen have made it possible to define specific levels of collagen biosynthesis and degradation at which pharmacological intervention may lead to a reduction in collagen deposition in tissues. Such compounds may provide novel approaches to reducing collagen excess accumulation in disease.

[0006] Liver fibrosis, also referred to herein as hepatic fibrosis, can be caused by various types of chronic liver injury, especially when an inflammatory component is involved. Self-limiting acute liver injury (e.g., acute viral hepatitis A), even in its severe form, does not necessarily distort the scaffold architecture and therefore typically does not cause fibrosis despite the loss of hepatocytes. However, factors such as chronic alcoholism, malnutrition, hemochromatosis, and exposure to poisons, toxins, or drugs can lead to chronic liver injury and liver fibrosis due to exposure to hepatotoxic chemicals. Liver fibrosis can also be caused by liver scarring caused by other forms of injury associated with surgery or mechanical biliary obstruction.

[0007] Although fibrosis itself is not necessarily symptomatic, it can lead to the development of cirrhosis, and scarring can lead to portal hypertension, which distorts blood flow through the liver, destroying normal liver structure and causing liver dysfunction.The degree of each of these pathologies determines the clinical symptoms of liver fibrosis.For example, in congenital hepatic fibrosis, the branches of the portal vein are affected, while the parenchyma is barely affected.As a result, portal hypertension occurs with the preservation of hepatocellular function.

[0008] treatment

[0009] Attempts to develop antifibrotic agents for the treatment of various diseases have been reported. However, treatment of established fibrosis that forms after chronic or repeated injury over months to years remains a challenge.

[0010] Treatments aimed at reversing fibrosis are usually too toxic for long-term use (e.g., corticosteroids, penicillamine) or have no proven efficacy (e.g., colchicine).

[0011] Many patients do not respond to available treatments for fibrosis, and long-term treatment is limited by toxicity and side effects.Therefore, there is still a need to develop therapies that aim to reduce fibrosis.The development of safe and effective treatments for established liver cirrhosis and portal hypertension, and for reducing fibrosis, is highly beneficial.

[0012] Attempts to treat idiopathic pulmonary fibrosis (IPF) with combination anti-inflammatory drugs (prednisone, azathioprine, and N-acetyl-L-cysteine ​​(NAC)) have failed to improve prognosis and instead increased mortality. In 2014, two drugs—pirfenidone, a drug with poorly understood mechanisms, and nintedanib, a tyrosine kinase inhibitor—were approved for the treatment of IPF, primarily based on their ability to inhibit the decline in forced vital capacity (FVC) and slow the pace of disease progression. However, it is currently unknown whether these drugs improve symptoms such as dyspnea and cough, or whether their beneficial effects on functional decline translate into increased survival.

[0013] The compounds of the present invention target activated fibroblasts and collagen overproduction and can therefore be used to treat fibrosis, including primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, autoimmune diseases, pulmonary fibrosis, and idiopathic pulmonary fibrosis (IPF), as well as localized processes, such as pulmonary fibrosis and cirrhosis, or systemic processes, such as progressive systemic sclerosis. In addition to scleroderma, the compounds of the present invention may also be useful in various forms of dermal fibrosis, including localized or systemic sclerosis, keloids, hypertrophic scars, familial cutaneous collagenomas, and collagenous connective tissue nevi. The compounds of the present invention may also be useful in the treatment of pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF), as well as liver fibrosis resulting from liver scarring caused by other forms of injury associated with surgery or mechanical biliary obstruction. Such fibrosis can lead to portal hypertension, or cirrhosis, which distorts blood flow through the liver due to scarring, as well as other liver fibrotic disorders, including nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), and alcoholic fatty liver disease (AFLD), which can also be treated with the compounds of the invention. Summary of the Invention [Means for solving the problem]

[0014] The present invention provides compounds represented by the structures of Formulas I-VIII, defined herein below, and the structures listed in Table 1, or pharmaceutically acceptable salts, optical isomers, tautomers, hydrates, N-oxides, reverse amide analogs, prodrugs, isotopic variants (e.g., deuterated analogs), PROTACs, pharmaceuticals, or any combination thereof. In various embodiments, the compounds of the invention are collagen I translation inhibitors.

[0015] The present invention further provides pharmaceutical compositions comprising a compound represented by the structures of Formulas I-VIII, as defined herein below, and the structures listed in Table 1, or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof, and a pharmaceutically acceptable carrier.

[0016] The present invention further provides methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting fibrosis in a subject, comprising administering to a subject suffering from fibrosis a compound represented by the structures of Formulas I-VIII, as defined herein below, and the structures listed in Table 1, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit fibrosis in the subject. In some embodiments, the fibrosis is systemic fibrosis. In some embodiments, the systemic fibrosis is systemic sclerosis, multiple fibrosclerosis (IgG4-associated fibrosis), nephrogenic systemic fibrosis, scleroderma graft-versus-host, or any combination thereof. In some embodiments, the fibrosis is organ-specific fibrosis. In some embodiments, the organ-specific fibrosis is pulmonary fibrosis, cardiac fibrosis, renal fibrosis, pulmonary fibrosis, hepatic portal fibrosis, radiation-induced fibrosis, bladder fibrosis, intestinal fibrosis, peritoneal sclerosis, diffuse fasciitis, wound healing, scarring, or any combination thereof. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, the cardiac fibrosis is hypertension-related myocardial fibrosis, post-myocardial infarction, Chagas disease-induced myocardial fibrosis, or any combination thereof. In some embodiments, the renal fibrosis is diabetic and hypertensive nephropathy, urinary tract obstruction-induced renal fibrosis, inflammatory / autoimmune-induced renal fibrosis, aristolochic acid nephropathy, polycystic kidney disease, or any combination thereof. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis, silica-induced pneumoconiosis (silicosis), asbestos-induced pulmonary fibrosis (asbestosis), chemotherapy-induced pulmonary fibrosis, or any combination thereof. In some embodiments, the hepatoportal fibrosis is alcoholic liver fibrosis, nonalcoholic liver fibrosis, hepatitis C-induced liver fibrosis, primary biliary cirrhosis, parasite-induced liver fibrosis (schistosomiasis), or any combination thereof. In some embodiments, the diffuse fasciitis is localized scleroderma, keloid, Dupuytren's disease, Peyronie's disease, myelofibrosis, oral submucous fibrosis, or any combination thereof. In some embodiments, the fibrosis is primary fibrosis or secondary fibrosis.In some embodiments, the fibrosis is the result of systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, autoimmune disease, tissue injury, inflammation, oxidative stress, or any combination thereof. In some embodiments, the fibrosis is liver fibrosis, pulmonary fibrosis, or skin fibrosis. In some embodiments, the subject has liver cirrhosis. In some embodiments, the skin fibrosis is scleroderma. In some embodiments, the skin fibrosis is the result of localized or systemic scleroderma, keloids, hypertrophic scars, familial cutaneous collagenoma, collagen-type connective tissue nevi, or any combination thereof. In some embodiments, the liver fibrosis is the result of liver scarring or chronic liver damage. In some embodiments, the chronic liver damage results from alcoholism, malnutrition, hemochromatosis, or exposure to poisons, toxins, or drugs.

[0017] The present invention further provides methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting pulmonary fibrosis in a subject, comprising administering to a subject suffering from pulmonary fibrosis a compound represented by the structures of Formulas I-VIII as defined herein below and the structures listed in Table 1 under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit pulmonary fibrosis in the subject. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

[0018] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting idiopathic pulmonary fibrosis (IPF) in a subject, comprising the step of administering to a subject suffering from idiopathic pulmonary fibrosis (IPF) a compound represented by the structures of Formulas I-VIII as defined herein below and the structures listed in Table 1 under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit idiopathic pulmonary fibrosis (IPF) in the subject.

[0019] The present invention further provides methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting liver fibrosis in a subject, comprising administering to a subject suffering from liver fibrosis a compound represented by the structures of Formulas I-VIII as defined herein below and the structures listed in Table 1 under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit liver fibrosis in the subject. In some embodiments, the liver fibrosis is portal hypertension, cirrhosis, congenital hepatic fibrosis, or any combination thereof.

[0020] The present invention further provides methods for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting cirrhosis in a subject, comprising administering to a subject suffering from cirrhosis a compound represented by the structures of Formulas I-VIII as defined herein below and the structures listed in Table 1 under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit cirrhosis in the subject. In some embodiments, the cirrhosis is the result of hepatitis or alcoholism.

[0021] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholic steatohepatitis (ASH) in a subject, comprising administering to a subject afflicted with alcoholic steatohepatitis (ASH) a compound represented by the structures of Formulas I-VIII as defined herein below and the structures listed in Table 1 under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit alcoholic steatohepatitis (ASH) in the subject.

[0022] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting non-alcoholic steatohepatitis (NASH) in a subject, comprising administering to a subject afflicted with alcoholic steatohepatitis (ASH) a compound represented by the structures of Formulas I-VIII as defined herein below and the structures listed in Table 1 under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit non-alcoholic steatohepatitis (NASH) in the subject.

[0023] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholic fatty liver disease (AFLD) in a subject, comprising the step of administering to a subject afflicted with alcoholic fatty liver disease (AFLD) a compound represented by the structures of Formulas I-VIII as defined herein below and the structures listed in Table 1 under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit alcoholic fatty liver disease (AFLD) in the subject.

[0024] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting non-alcoholic fatty liver disease (NAFLD) in a subject, comprising administering to a subject suffering from non-alcoholic fatty liver disease (NAFLD) a compound represented by the structures of Formulas I-VIII as defined herein below and the structures listed in Table 1 under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit non-alcoholic fatty liver disease (NAFLD) in the subject.

[0025] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting an autoimmune disease or disorder in a subject, comprising the step of administering to a subject suffering from an autoimmune disease or disorder a compound represented by the structures of Formulas I-VIII as defined herein below and the structures listed in Table 1 under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit an autoimmune disease or disorder in the subject.

[0026] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting an autoimmune disease or disorder in a subject, comprising the step of administering to a subject suffering from an autoimmune disease or disorder a compound represented by the structures of Formulas I-VIII as defined herein below and the structures listed in Table 1 under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit an autoimmune disease or disorder in the subject. [Brief explanation of the drawings]

[0027] This patent or application contains at least one color drawing. Copies of this patent or patent application publication with color drawing(s) will be provided by the Patent and Trademark Office upon request and payment of the necessary fee.

[0028] [Figure 1] Figure 1 shows how protein synthesis monitoring (PSM) specifically monitors collagen 1 synthesis. The assay system includes WI-38 cells, a human lung fibroblast cell line that is activated to produce higher levels of collagen. Two tRNAs (di-tRNAs) encoding one specific glycine codon and one specific proline codon were transfected with control RNAi or RNAi targeting collagen 1. The FRET signal specifically monitors collagen 1 translation, as the FRET signal in collagen 1-targeting siRNA-treated cells is inhibited by 90%. Gray represents cell nuclei stained with DAPI. White represents the FRET signal from the tRNA pair decoding the glycine-proline di-codon. [Figure 2] Figure 2 shows hits that selectively modulate collagen translation. In the upper panel, the Y-axis shows the normalized values ​​of metabolic labeling in control cells. Only compounds that showed minimal effects on overall protein synthesis (±20% of the control) and on collagen 1 protein accumulation in WI38 cells, as measured by di-tRNA collagen FRET and collagen 1-specific immunofluorescence, were selected as compounds that selectively modulate collagen synthesis. In the lower panel, the Y-axis shows the collagen-specific di-tRNA FRET score (PSM score), and the X-axis shows the normalized immunofluorescence value (relative to the control). Compounds showing high PSM scores are highlighted by dot size. [Figure 3] FIG. 3 shows that collagen translation modulator compound 327 is tissue selective. [Figure 4] Figure 4 shows that compound 327 acts at the translational level. Figure 4A: WI-38 human lung fibroblasts, cultured with compound for 96 hours. White: collagen type I; gray: DAPI. Immunofluorescence. Figure 4B: WI-38 human lung fibroblasts, cultured with compound for 24 hours. FISH analysis. White: Col-I mRNA; gray: DAPI. [Figure 5A] Figures 5A and 5B show the efficacy and toxicity of Compounds 367, 365, 339, and 366. Figure 5A plots the pEC50 for efficacy against the pEC50 for toxicity. The dashed lines represent the 10-fold or 100-fold window between efficacy and toxicity. [Figure 5B] Figure 5B is a representative image of compound 365. Images were taken with an Operetta apparatus (Perkin Elmer) using a 20x objective. White: collagen type I; grey: DAPI. DETAILED DESCRIPTION OF THE INVENTION

[0029] In various embodiments, the present invention provides a compound represented by Formula I below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0030] [ka]

[0031] During the ceremony, The A and B rings may each independently be a single or fused aromatic or heteroaromatic ring system (e.g., A ring: phenyl, thiophene, imidazole, pyrazole, pyrimidine, 2-, 3-, or 4-pyridine, benzimidazole, indole, benzothiazole, benzoxazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine, pyridazine, pyrazine; B ring: phenyl, pyrimidine, 2-, 3-, or 4-pyridine, pyridazine, pyrazine, thiophene, thiazole, pyrrole, imidazole, indazole), a single or fused C3-C 10 Cycloalkyl (e.g., A ring: pyrrolidin-2-one; B ring: bicyclo[1.1.1]pentyl, cyclobutyl, cyclohexyl, cyclopentyl), or single or fused C3-C 10 heterocycles (e.g., morpholine, piperidine, piperazine, tetrahydro-2H-pyran, azetidine, pyrrolidin-2-one); R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2OH), R8-SH, -R8-OR 10 (e.g. CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3, CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R11 ) (e.g., CH2-NH-CH3, CH2-NH-C(O)CH3, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R (e.g. NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO2R, SO2N(R 10 )(R 11 ), NHSO2(R 10 ) (e.g., NHSO2CH3), CH(CF3)(NH-R 10 ), C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain, substituted or unsubstituted alkenyl, C1-C5 straight, branched or cyclic haloalkyl (e.g., CHF2), C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy) (optionally, at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., azetidine, pyridine), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; or R2 and R1 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic (e.g., benzene) or heterocyclic ring (e.g., 1,4-dioxane, 2,3-dihydro-1,4-dioxine, dioxole, dioxolpyridine); R3 and R4 are independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, N(R 10 )(R 11 ) (e.g., morpholine, piperazine), 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 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)2O-CH3), C(O)N(R 10 )(R 11 ) (e.g., C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH3)2, C(O)-piperazine), SO2R, SO2N(R 10 )(R 11 ), CH(CF3)(NH-R 10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear, branched, or cyclic haloalkyl (e.g., CHF2), C1-C5 linear, branched, or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone ) piperidin-4-oxy) (optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted single, spirocyclic, fused or bridged C3-C 10Heterocycles (e.g., piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)etheone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; or R3 and R4 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole) ring; R5 is H, R 20 , F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 , R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, 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 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R 10 )(R 11 ), SO2R, SO2N(R 10 )(R 11 ), CH(CF3)(NH-R 10 ), C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain, substituted or unsubstituted alkenyl, C1-C5 straight, branched or cyclic haloalkyl (e.g., CHF2), C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy) (optionally, at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., azetidine, pyridine), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; Q1 is NH, S, or O; G=X is C=O, C=S, S=O, or SO2; R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 ) (e.g., NH(CH3)), N(R 10 )(R 11 ), R 20 , C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R 10(e.g., CH2-OH, CH2CH2-OH), C(O)-R 10 (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)2, C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10 (e.g., C(O)-CH2CH2-OH), C(O) substituted or unsubstituted C3-C8 heterocycle (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight or branched chain C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight or branched chain alkoxy, -R8-OR 10 (e.g., CH2-CH2-O-CH3), C1-C5 straight or branched chain haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted heteroaryl (e.g., pyridine (2-, 3-, or 4-pyridine)); or two geminal R substituents join together to form a 3- to 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole) ring; R8 is [CH2]p, where p is 1 to 10 (e.g., 2); R9 is [CH]q, [C]q, where q is 2 to 10; R 10 and R 11are, independently of one another, H, OH, substituted or unsubstituted C1-C5 linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), substituted or unsubstituted C3-C8 heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro-2H-pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl, or S(O)2-alkyl; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R 20 is represented by the following structure:

[0032] [ka]

[0033] Substituents include F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are, independently of each other, integers from 1 to 3 (e.g., 1 or 2); m and k are each independently an integer of 0 to 3 (for example, 0).

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

[0035] [ka]

[0036] During the ceremony, The A ring may be a single or fused aromatic or heteroaromatic ring system (e.g., phenyl, thiophene, imidazole, pyrazole, pyrimidine, 2-, 3-, or 4-pyridine, benzimidazole, indole, benzothiazole, benzoxazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine, pyridazine, pyrazine), a single or fused C3-C 10 Cycloalkyl (e.g., pyrrolidin-2-one) or single or fused C3-C 10 heterocycles (e.g., morpholine, piperidine, piperazine, tetrahydro-2H-pyran, azetidine, pyrrolidin-2-one); R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2OH), R8-SH, -R8-OR 10 (e.g. CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3, CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11) (e.g., CH2-NH-CH3, CH2-NH-C(O)CH3, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R (e.g. NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO2R, SO2N(R 10 )(R 11 ), NHSO2(R 10 ) (e.g., NHSO2CH3), CH(CF3)(NH-R 10 ), C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain, substituted or unsubstituted alkenyl, C1-C5 straight, branched or cyclic haloalkyl (e.g., CHF2), C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy) (optionally, at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., azetidine, pyridine), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; or R2 and R1 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic (e.g., benzene) or heterocyclic ring (e.g., 1,4-dioxane, 2,3-dihydro-1,4-dioxine, dioxole, dioxolpyridine); R3 and R4 are independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, N(R 10 )(R 11 ) (e.g., morpholine, piperazine), 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 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)2O-CH3), C(O)N(R 10 )(R 11 ) (e.g., C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH3)2, C(O)-piperazine), SO2R, SO2N(R 10 )(R 11 ), CH(CF3)(NH-R 10), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear, branched, or cyclic haloalkyl (e.g., CHF2), C1-C5 linear, branched, or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone ) piperidin-4-oxy) (optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted single, spirocyclic, fused or bridged C3-C 10Heterocycles (e.g., piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)etheone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; or R3 and R4 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole) ring; X3, X4, and X5 are, independently of one another, C or N; R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 ) (e.g., NH(CH3)), N(R 10 )(R 11 ), R 20 , C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R 10(e.g., CH2-OH, CH2CH2-OH), C(O)-R 10 (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)2, C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10 (e.g., C(O)-CH2CH2-OH), C(O) substituted or unsubstituted C3-C8 heterocycle (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight or branched chain C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight or branched chain alkoxy, -R8-OR 10 (e.g., CH2-CH2-O-CH3), C1-C5 straight or branched chain haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted heteroaryl (e.g., pyridine (2-, 3-, or 4-pyridine)); or two geminal R substituents join together to form a 3- to 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole) ring; R8 is [CH2]p, where p is 1 to 10 (e.g., 2); R9 is [CH]q, [C]q, where q is 2 to 10; R 10 and R 11are, independently of one another, H, OH, substituted or unsubstituted C1-C5 linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), substituted or unsubstituted C3-C8 heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro-2H-pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl, or S(O)2-alkyl; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R 20 is represented by the following structure:

[0037] [ka]

[0038] Substituents include F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are, independently of each other, integers from 1 to 3 (e.g., 1 or 2); m and k are each independently an integer of 0 to 3 (for example, 0).

[0039] In various embodiments, the present invention provides a compound represented by Formula III below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0040] [ka]

[0041] During the ceremony, R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2OH), R8-SH, -R8-OR 10 (e.g. CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3, CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH-CH3, CH2-NH-C(O)CH3, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R (e.g. NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10, C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO2R, SO2N(R 10 )(R 11 ), NHSO2(R 10 ) (e.g., NHSO2CH3), CH(CF3)(NH-R 10 ), C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain, substituted or unsubstituted alkenyl, C1-C5 straight, branched or cyclic haloalkyl (e.g., CHF2), C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy) (optionally, at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., azetidine, pyridine), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; or R2 and R1 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic (e.g., benzene) or heterocyclic ring (e.g., 1,4-dioxane, 2,3-dihydro-1,4-dioxine, dioxole, dioxolpyridine); R3 and R4 are independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, N(R 10 )(R 11 ) (e.g., morpholine, piperazine), 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 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)2O-CH3), C(O)N(R 10 )(R 11 ) (e.g., C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH3)2, C(O)-piperazine), SO2R, SO2N(R 10 )(R 11 ), CH(CF3)(NH-R 10 ), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear, branched, or cyclic haloalkyl (e.g., CHF2), C1-C5 linear, branched, or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone ) piperidin-4-oxy) (optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted single, spirocyclic, fused or bridged C3-C 10Heterocycles (e.g., piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)etheone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; or R3 and R4 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole) ring; X1, X2, X3, X4, and X5 are, independently of one another, C or N; R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 ) (e.g., NH(CH3)), N(R 10 )(R 11 ), R 20 , C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R 10(e.g., CH2-OH, CH2CH2-OH), C(O)-R 10 (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)2, C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10 (e.g., C(O)-CH2CH2-OH), C(O) substituted or unsubstituted C3-C8 heterocycle (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight or branched chain C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight or branched chain alkoxy, -R8-OR 10 (e.g., CH2-CH2-O-CH3), C1-C5 straight or branched chain haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted heteroaryl (e.g., pyridine (2-, 3-, or 4-pyridine)); or two geminal R substituents join together to form a 3- to 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole) ring; R8 is [CH2]p, where p is 1 to 10 (e.g., 2); R9 is [CH]q, [C]q, where q is 2 to 10; R 10 and R 11are, independently of one another, H, OH, substituted or unsubstituted C1-C5 linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), substituted or unsubstituted C3-C8 heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro-2H-pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl, or S(O)2-alkyl; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R 20 is represented by the following structure:

[0042] [ka]

[0043] Substituents include F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are, independently of each other, integers from 1 to 3 (e.g., 1 or 2); m and k are each independently an integer of 0 to 3 (for example, 0).

[0044] In various embodiments, the present invention provides a compound represented by Formula IV below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0045] [ka]

[0046] During the ceremony, R1 is H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2OH), R8-SH, -R8-OR 10 (e.g. CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3, CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH-CH3, CH2-NH-C(O)CH3, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R (e.g. NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10, C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO2R, SO2N(R 10 )(R 11 ), NHSO2(R 10 ) (e.g., NHSO2CH3), CH(CF3)(NH-R 10 ), C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain, substituted or unsubstituted alkenyl, C1-C5 straight, branched or cyclic haloalkyl (e.g., CHF2), C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy) (optionally, at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., azetidine, pyridine), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; R3 is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, N(R 10 )(R 11 ) (e.g., morpholine, piperazine), 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 ), COOH, -C(O)Ph, C(O)OR10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)2O-CH3), C(O)N(R 10 )(R 11 ) (e.g., C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH3)2, C(O)-piperazine), SO2R, SO2N(R 10 )(R 11 ), CH(CF3)(NH-R 10 ), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear, branched, or cyclic haloalkyl (e.g., CHF2), C1-C5 linear, branched, or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone ) piperidin-4-oxy) (optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted single, spirocyclic, fused or bridged C3-C 10Heterocycles (e.g., piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)etheone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; or R3 and R4 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole) ring; X1, X2, X3, X4, and X5 are, independently of one another, C or N; R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 ) (e.g., NH(CH3)), N(R 10 )(R 11 ), R 20 , C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R 10(e.g., CH2-OH, CH2CH2-OH), C(O)-R 10 (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)2, C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10 (e.g., C(O)-CH2CH2-OH), C(O) substituted or unsubstituted C3-C8 heterocycle (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight or branched chain C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight or branched chain alkoxy, -R8-OR 10 (e.g., CH2-CH2-O-CH3), C1-C5 straight or branched chain haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted heteroaryl (e.g., pyridine (2-, 3-, or 4-pyridine)); or two geminal R substituents join together to form a 3- to 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole) ring; R8 is [CH2]p, where p is 1 to 10 (e.g., 2); R9 is [CH]q, [C]q, where q is 2 to 10; R 10 and R 11are, independently of one another, H, OH, substituted or unsubstituted C1-C5 linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), substituted or unsubstituted C3-C8 heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro-2H-pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl, or S(O)2-alkyl; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R 20 is represented by the following structure:

[0047] [ka]

[0048] Substituents include F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are, independently of each other, integers from 1 to 3 (e.g., 1 or 2); m and k are each independently an integer of 0 to 3 (for example, 0).

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

[0050] [ka]

[0051] During the ceremony, R1 is H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2OH), R8-SH, -R8-OR 10 (e.g. CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3, CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH-CH3, CH2-NH-C(O)CH3, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R (e.g. NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10, C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO2R, SO2N(R 10 )(R 11 ), NHSO2(R 10 ) (e.g., NHSO2CH3), CH(CF3)(NH-R 10 ), C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain, substituted or unsubstituted alkenyl, C1-C5 straight, branched or cyclic haloalkyl (e.g., CHF2), C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy) (optionally, at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., azetidine, pyridine), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; R3 is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, N(R 10 )(R 11 ) (e.g., morpholine, piperazine), 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 ), COOH, -C(O)Ph, C(O)OR10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)2O-CH3), C(O)N(R 10 )(R 11 ) (e.g., C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH3)2, C(O)-piperazine), SO2R, SO2N(R 10 )(R 11 ), CH(CF3)(NH-R 10 ), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear, branched, or cyclic haloalkyl (e.g., CHF2), C1-C5 linear, branched, or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone ) piperidin-4-oxy) (optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted single, spirocyclic, fused or bridged C3-C 10Heterocycles (e.g., piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)etheone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; X1, X2, X3, X4, and X5 are, independently of one another, C or N; R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 ) (e.g., NH(CH3)), N(R 10 )(R 11 ), R 20 , C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R 10 (e.g., CH2-OH, CH2CH2-OH), C(O)-R 10(e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)2, C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10 (e.g., C(O)-CH2CH2-OH), C(O) substituted or unsubstituted C3-C8 heterocycle (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight or branched chain C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight or branched chain alkoxy, -R8-OR 10 (e.g., CH2-CH2-O-CH3), C1-C5 straight or branched chain haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted heteroaryl (e.g., pyridine (2-, 3-, or 4-pyridine)); or two geminal R substituents join together to form a 3- to 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole) ring; R8 is [CH2]p, where p is 1 to 10 (e.g., 2); R9 is [CH]q, [C]q, where q is 2 to 10; R 10 and R 11are, independently of one another, H, OH, substituted or unsubstituted C1-C5 linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), substituted or unsubstituted C3-C8 heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro-2H-pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl, or S(O)2-alkyl; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R 20 is represented by the following structure:

[0052] [ka]

[0053] Substituents include F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are, independently of each other, integers from 1 to 3 (e.g., 1 or 2); m and k are each independently an integer of 0 to 3 (for example, 0).

[0054] In various embodiments, the present invention provides a compound represented by Formula VI below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0055] [ka]

[0056] During the ceremony, R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2OH), R8-SH, -R8-OR 10 (e.g. CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3, CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH-CH3, CH2-NH-C(O)CH3, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R (e.g. NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10, C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO2R, SO2N(R 10 )(R 11 ), NHSO2(R 10 ) (e.g., NHSO2CH3), CH(CF3)(NH-R 10 ), C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain, substituted or unsubstituted alkenyl, C1-C5 straight, branched or cyclic haloalkyl (e.g., CHF2), C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy) (optionally, at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., azetidine, pyridine), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; or R2 and R1 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic (e.g., benzene) or heterocyclic ring (e.g., 1,4-dioxane, 2,3-dihydro-1,4-dioxine, dioxole, dioxolpyridine); R4 is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, N(R 10 )(R 11 ) (e.g., morpholine, piperazine), R8-N(R 10 )(R 11 ), R9-R8-N(R10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R 10 , NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)2O-CH3), C(O)N(R 10 )(R 11 ) (e.g., C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH3)2, C(O)-piperazine), SO2R, SO2N(R 10 )(R 11 ), CH(CF3)(NH-R 10 ), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear, branched, or cyclic haloalkyl (e.g., CHF2), C1-C5 linear, branched, or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone ) piperidin-4-oxy) (optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted single, spirocyclic, fused or bridged C3-C 10Heterocycles (e.g., piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)etheone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; X1, X2, X3, X4, and X5 are, independently of one another, C or N; X6 is O, CH2, CHR (e.g., CH(OH), CH(NH2), CH(NH(CH3))), C(R 10 )(R 11 ) (e.g., C(H)CH2CH2-OH, C(H)CH2-OH, 1-methylazetidine), NH, NR (e.g., N-CH3, N-SO2-CH3, NR 20 , N-CH2CH2-OCH3,) or NC(O)-R 10(e.g., NC(O)O-tBu, NC(O)-CH2CH2-OCH3, NC(O)-CH3, NC(O)-CH2-N(CH3)2, NC(O)-CH2-CH2-N(CH3)2, NC(O)-CH2-OH, NC(O)-CH2CH2-OH, NC(O)-NH-CH3, NC(O)-1-methyl-2-pyrrolidine, NC(O)-1-methyl-3-pyrrolidine, NC(O)-1-methyl-3-piperidine, NC(O)-1-methyl-4-piperidine); R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 ) (e.g., NH(CH3)), N(R 10 )(R 11 ), R 20 , C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R 10 (e.g., CH2-OH, CH2CH2-OH), C(O)-R 10 (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)2, C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10 (e.g., C(O)-CH2CH2-OH), C(O) substituted or unsubstituted C3-C8 heterocycle (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight or branched chain C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight or branched chain alkoxy, -R8-OR 10(e.g., CH2-CH2-O-CH3), C1-C5 straight or branched chain haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted heteroaryl (e.g., pyridine (2-, 3-, or 4-pyridine)); or two geminal R substituents join together to form a 3- to 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole) ring; R8 is [CH2]p, where p is 1 to 10 (e.g., 2); R9 is [CH]q, [C]q, where q is 2 to 10; R 10 and R 11 are, independently of one another, H, OH, substituted or unsubstituted C1-C5 linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), substituted or unsubstituted C3-C8 heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro-2H-pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl, or S(O)2-alkyl; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R 20 is represented by the following structure:

[0057] [ka]

[0058] Substituents include F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are, independently of each other, integers from 1 to 3 (e.g., 1 or 2); m and k are each independently an integer of 0 to 2 (for example, 0).

[0059] In various embodiments, the present invention provides a compound represented by Formula VII below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0060] [ka]

[0061] During the ceremony, The A ring may be a single or fused aromatic or heteroaromatic ring system (e.g., phenyl, thiophene, imidazole, pyrazole, pyrimidine, 2-, 3-, or 4-pyridine, benzimidazole, indole, benzothiazole, benzoxazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine, pyridazine, pyrazine), a single or fused C3-C 10 Cycloalkyl (e.g., pyrrolidin-2-one) or single or fused C3-C 10 heterocycles (e.g., morpholine, piperidine, piperazine, tetrahydro-2H-pyran, azetidine, pyrrolidin-2-one); R1 and R2 are each independently H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2OH), R8-SH, -R8-OR 10 (e.g. CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3, CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH-CH3, CH2-NH-C(O)CH3, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R (e.g. NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO2R, SO2N(R10 )(R 11 ), NHSO2(R 10 ) (e.g., NHSO2CH3), CH(CF3)(NH-R 10 ), C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain, substituted or unsubstituted alkenyl, C1-C5 straight, branched or cyclic haloalkyl (e.g., CHF2), C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy) (optionally, at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., azetidine, pyridine), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; or R2 and R1 join together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic (e.g., benzene) or heterocyclic ring (e.g., 1,4-dioxane, 2,3-dihydro-1,4-dioxine, dioxole, dioxolpyridine); R4 is H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, N(R 10 )(R 11 ) (e.g., morpholine, piperazine), 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), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)2O-CH3), C(O)N(R 10 )(R 11 ) (e.g., C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH3)2, C(O)-piperazine), SO2R, SO2N(R 10 )(R 11 ), CH(CF3)(NH-R 10 ), C1-C5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched, substituted or unsubstituted alkenyl, C1-C5 linear, branched, or cyclic haloalkyl (e.g., CHF2), C1-C5 linear, branched, or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone ) piperidin-4-oxy) (optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted single, spirocyclic, fused or bridged C3-C 10Heterocycles (e.g., piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)etheone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; X3, X4, and X5 are, independently of one another, C or N; X6 is O, CH2, CHR (e.g., CH(OH), CH(NH2), CH(NH(CH3))), C(R 10 )(R 11 ) (e.g., C(H)CH2CH2-OH, C(H)CH2-OH, 1-methylazetidine), NH, NR (e.g., N-CH3, N-SO2-CH3, NR 20 , N-CH2CH2-OCH3,) or NC(O)-R 10(e.g., NC(O)O-tBu, NC(O)-CH2CH2-OCH3, NC(O)-CH3, NC(O)-CH2-N(CH3)2, NC(O)-CH2-CH2-N(CH3)2, NC(O)-CH2-OH, NC(O)-CH2CH2-OH, NC(O)-NH-CH3, NC(O)-1-methyl-2-pyrrolidine, NC(O)-1-methyl-3-pyrrolidine, NC(O)-1-methyl-3-piperidine, NC(O)-1-methyl-4-piperidine); R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 ) (e.g., NH(CH3)), N(R 10 )(R 11 ), R 20 , C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R 10 (e.g., CH2-OH, CH2CH2-OH), C(O)-R 10 (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)2, C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10 (e.g., C(O)-CH2CH2-OH), C(O) substituted or unsubstituted C3-C8 heterocycle (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight or branched chain C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight or branched chain alkoxy, -R8-OR 10(e.g., CH2-CH2-O-CH3), C1-C5 straight or branched chain haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted heteroaryl (e.g., pyridine (2-, 3-, or 4-pyridine)); or two geminal R substituents join together to form a 3- to 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole) ring; R8 is [CH2]p, where p is 1 to 10 (e.g., 2); R9 is [CH]q, [C]q, where q is 2 to 10; R 10 and R 11 are, independently of one another, H, OH, substituted or unsubstituted C1-C5 linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), substituted or unsubstituted C3-C8 heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro-2H-pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl, or S(O)2-alkyl; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R 20 is represented by the following structure:

[0062] [ka]

[0063] Substituents include F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are, independently of each other, integers from 1 to 3 (e.g., 1 or 2); m and k are each independently an integer of 0 to 2 (for example, 0).

[0064] In various embodiments, the present invention provides a compound represented by Formula VIII below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, pharmaceutical, or any combination thereof:

[0065] [ka]

[0066] During the ceremony, R1 is H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2OH), R8-SH, -R8-OR 10 (e.g. CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3, CH2-O-CH3), -O-R8-OR 10(e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH-CH3, CH2-NH-C(O)CH3, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R (e.g. NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO2R, SO2N(R 10 )(R 11 ), NHSO2(R 10 ) (e.g., NHSO2CH3), CH(CF3)(NH-R 10), C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain, substituted or unsubstituted alkenyl, C1-C5 straight, branched or cyclic haloalkyl (e.g., CHF2), C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy) (optionally, at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., azetidine, pyridine), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; X1, X2, X3, X4, and X5 are, independently of one another, C or N; X6 is O, CH2, CHR (e.g., CH(OH), CH(NH2), CH(NH(CH3))), C(R 10 )(R 11 ) (e.g., C(H)CH2CH2-OH, C(H)CH2-OH, 1-methylazetidine), NH, NR (e.g., N-CH3, N-SO2-CH3, NR 20 , N-CH2CH2-OCH3,) or NC(O)-R 10 (e.g., NC(O)O-tBu, NC(O)-CH2CH2-OCH3, NC(O)-CH3, NC(O)-CH2-N(CH3)2, NC(O)-CH2-CH2-N(CH3)2, NC(O)-CH2-OH, NC(O)-CH2CH2-OH, NC(O)-NH-CH3, NC(O)-1-methyl-2-pyrrolidine, NC(O)-1-methyl-3-pyrrolidine, NC(O)-1-methyl-3-piperidine, NC(O)-1-methyl-4-piperidine); R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 ) (e.g., NH(CH3)), N(R 10 )(R 11 ), R 20, C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R 10 (e.g., CH2-OH, CH2CH2-OH), C(O)-R 10 (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)2, C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10 (e.g., C(O)-CH2CH2-OH), C(O) substituted or unsubstituted C3-C8 heterocycle (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight or branched chain C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight or branched chain alkoxy, -R8-OR 10 (e.g., CH2-CH2-O-CH3), C1-C5 straight or branched chain haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted heteroaryl (e.g., pyridine (2-, 3-, or 4-pyridine)); or two geminal R substituents join together to form a 3- to 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole) ring; R8 is [CH2]p, where p is 1 to 10 (e.g., 2); R9 is [CH]q, [C]q, where q is 2 to 10; R 10 and R11 are, independently of one another, H, OH, substituted or unsubstituted C1-C5 linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), substituted or unsubstituted C3-C8 heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro-2H-pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl, or S(O)2-alkyl; Or, R 10 and R 11 are bonded to each other to form a substituted or unsubstituted C3-C8 heterocycle (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R 20 is represented by the following structure:

[0067] [ka]

[0068] Substituents include F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are, independently of each other, integers from 1 to 3 (e.g., 1 or 2); m and k are each independently an integer of 0 to 3 (for example, 0).

[0069] In some embodiments, at least one of R1 and R3 in the compound of Formulas IV is not H. In some embodiments, both R1 and R3 in the compound of Formulas IV are not H.

[0070] In some embodiments, R1 in the compound of Formula I-VIII is Cl. In some embodiments, R1 in the compound of Formula I-VIII is in the ortho position.

[0071] In some embodiments, R3 is a substituted or unsubstituted single, spirocyclic, fused or bridged C3-C 10 In some embodiments, R3 is morpholine, 3-methylmorpholine, 3-hydroxypiperidine, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, or 6-methyl-2,6-diazaspiro[3.3]heptane; each represents a separate embodiment of the present invention. In some embodiments, R3 is N(R 10 )(R 11 In some embodiments, R1 is Cl and R3 is N(R 10 )(R 11 ). In some embodiments, N(R 10 )(R 11 ) is a substituted or unsubstituted C3-C8 heterocycle. In some embodiments, N(R 10 )(R 11 ) is a substituted or unsubstituted 6-membered heterocycle. In some embodiments, N(R 10 )(R 11) is morpholine, alkyl-substituted morpholine, pyrrolidine, pyrrolidinone, piperazine, alkyl-substituted piperazine (e.g., 1-(2-methoxyethyl)piperazine), amido-substituted piperazine (e.g., N-methylpiperazine-1-carboxamide), sulfonyl-substituted piperazine (e.g., 1- or 4-(methylsulfonyl)piperazine), octahydropyrrolo[1,2-α]pyrazine, hydroxy-substituted piperidine, sulfonyl-substituted piperidine (e.g., 1- or 4-(methylsulfonyl)piperidine), 2-methoxy-1-(piperazin-1-yl)ethenone, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, 6-methyl-2,6-diazaspiro[3.3]heptane; each represents a separate embodiment of the present invention.

[0072] In some embodiments, when R3 is a heterocycle, R1 is not H. In some embodiments, when R3 is a heterocycle, R1 is Cl.

[0073] In some embodiments, at least one of X3, X4, and X5 of Formulas II-VIII is N. In some embodiments, at least two of X3, X4, and X5 are N.

[0074] In some embodiments, A of Formula I, II, and / or VII 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 pyrimidine. In other embodiments, A is pyridazine. In other embodiments, A is pyrazine. In other embodiments, A is pyrazole. In other embodiments, A is naphthyl. In other embodiments, A is benzothiazolyl. In other embodiments, A is benzimidazolyl. In other embodiments, A is quinolinyl. In other embodiments, A is isoquinolinyl. In other embodiments, A is indolyl. In other embodiments, A is benzoxazole. In other embodiments, A is imidazopyridine. In other embodiments, A is pyrazolopyridine. In other embodiments, A is pyrrolopyridine. In another embodiment, A is tetrahydronaphthyl. In another embodiment, A is indenyl. In another embodiment, A is benzofuran-2(3H)-one. In another embodiment, A is benzo[d][1,3]dioxole. In another embodiment, A is tetrahydrothiophene 1,1-dioxide. In another embodiment, A is thiazole. In another embodiment, A is piperidine. In another embodiment, A is tetrahydro-2H-pyran. In another embodiment, A is pyrrolidin-2-one. In another embodiment, A is morpholine. In another embodiment, A is piperazine. In another embodiment, A is azetidine. In another embodiment, A is 1-methylpiperidine. In another embodiment, A is imidazole. In another embodiment, A is 1-methylimidazole. In another embodiment, A is thiophene. In another embodiment, A is isoquinoline. In another embodiment, A is 1,3-dihydroisobenzofuran. In another embodiment, A is benzofuran. In another embodiment, A is a single or fused C3-C 10In another embodiment, A is a cycloalkyl ring. In another embodiment, A is bicyclo[1.1.1]pentyl. In another embodiment, A is cyclobutyl. In another embodiment, A is cyclohexyl.

[0075] In some embodiments, B of Formula I is a phenyl ring. In other embodiments, B is pyridinyl. In other embodiments, B is 2-pyridinyl. In other embodiments, B is 3-pyridinyl. In other embodiments, B is 4-pyridinyl. In other embodiments, B is pyrimidine. In other embodiments, B is pyridazine. In other embodiments, B is pyrazine. In other embodiments, B is piperidine. In other embodiments, B is tetrahydro-2H-pyran. In other embodiments, B is azetidine. In other embodiments, B is thiazole. In other embodiments, B is imidazole. In other embodiments, B is indazole. In other embodiments, B is pyrrole. 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 another embodiment, B is tetrahydronaphthyl. In another embodiment, B is quinolinyl. In another embodiment, B is isoquinolinyl. In another embodiment, B is indenyl. In another embodiment, B is naphthalene. In another embodiment, B is tetrahydrothiophene 1,1-dioxide. In another embodiment, B is benzimidazole. In another embodiment, B is piperidine. In another embodiment, B is 1-methylpiperidine. In another embodiment, B is 1-methylimidazole. In another embodiment, B is thiophene. In another embodiment, B is isoquinoline. In another embodiment, B is indole. In another embodiment, B is 1,3-dihydroisobenzofuran. In another embodiment, B is benzofuran. In another embodiment, B is morpholine. In another embodiment, B is piperazine. In another embodiment, B is pyrrolidin-2-one. In another embodiment, B is a single or fused C3-C 10In another embodiment, B is a cycloalkyl ring. In another embodiment, B is bicyclo[1.1.1]pentyl. In another embodiment, B is cyclobutyl. In another embodiment, B is cyclohexyl.

[0076] In some embodiments, X 1 in compounds of Formulas III-VIII is N. In other embodiments, X 1 is C.

[0077] In some embodiments, X2 in compounds of Formula III-VIII is N. In other embodiments, X2 is C.

[0078] In some embodiments, X3 in compounds of Formulas II-VIII is N. In other embodiments, X3 is C.

[0079] In some embodiments, X4 in compounds of Formulas II-VIII is N. In other embodiments, X4 is C.

[0080] In some embodiments, X5 in compounds of Formulas II-VIII is N. In other embodiments, X5 is C.

[0081] In some embodiments, X6 in compounds of Formulas VI-VIII is O. In other embodiments, X6 is CHR. In other embodiments, X6 is CH(OH). In other embodiments, X6 is CH2. In other embodiments, X6 is CHR. In other embodiments, X6 is CH(NH2). In other embodiments, X6 is CH(NH(CH3)). In other embodiments, X6 is C(H)CH2-OH. In other embodiments, X6 is 1-methylazetidine. In other embodiments, X6 is NR 20 In other embodiments, X6 is C(R 10 )(R 11). In another embodiment, X6 is 1-methylpyrrolidin-2-one. In another embodiment, X6 is oxetane. In another embodiment, X6 is C(H)CH2CH2-OH. In another embodiment, X6 is C(H)CH2-OH. In another embodiment, X6 is 1-methylazetidine. In another embodiment, X6 is NH. In another embodiment, X6 is NR. In another embodiment, X6 is N-CH3. In another embodiment, X6 is N-SO2-CH3. In another embodiment, X6 is NR 20 In another embodiment, X6 is N-CH2CH2-OCH3. In another embodiment, X6 is NC(O)O-tBu. In another embodiment, X6 is NC(O)-CH2CH2-OCH3. In another embodiment, X6 is N-CH2CH2-OCH3. In another embodiment, X6 is NC(O)-R 10 In another embodiment, X6 is NC(O)-CH3. In another embodiment, X6 is a C1-C5 substituted or unsubstituted NC(O)-NH-alkyl. In another embodiment, X6 is NC(O)-NH-CH3. In another embodiment, X6 is NC(O)-CH2-N(CH3)2. In another embodiment, X6 is NC(O)-CH2-CH2-N(CH3)2. In another embodiment, X6 is NC(O)-CH2-OH. In another embodiment, X6 is NC(O)-CH2CH2-OH. In another embodiment, X6 is NC(O)-NH-CH3. In another embodiment, X6 is NC(O)-1-methyl-2-pyrrolidine. In another embodiment, X6 is NC(O)-1-methyl-3-pyrrolidine. In another embodiment, X6 is NC(O)-1-methyl-3-piperidine. In other embodiments, X6 is NC(O)-1-methyl-4-piperidine.In other embodiments, X6 is NC(O)-1-methyl-3-piperidine.

[0082] It is understood that when any of X1-X5 is N, then any of R1-R4 cannot be linked.

[0083] In some embodiments, R1 of Formulas I-VIII is H. In some embodiments, R1 is not H. In some embodiments, R1 is Cl. In some embodiments, R1 is F. In some embodiments, R1 is R8-OH. In some embodiments, R1 is CH2OH. In some embodiments, R1 is -R8-OR 10 In some embodiments, R1 is CH2-O-CH2-CH2-O-CH3. In some embodiments, R1 is CH2-O-CH3. In some embodiments, R1 is -O-R8-OR 10 In some embodiments, R1 is O-CH2-CH2-O-CH3. In some embodiments, R1 is CN. In some embodiments, R1 is R8-N(R 10 )(R 11). In some embodiments, R1 is CH2-NH-CH3. In some embodiments, R1 is CH2-NH-C(O)CH3. In some embodiments, R1 is CH2-N(CH3)2. In some embodiments, R1 is alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 is C1-C5 linear, branched, or cyclic haloalkyl, C1-C5 linear, branched, or cyclic alkoxy. In some embodiments, R1 is methoxy. In some embodiments, R1 is a substituted or unsubstituted C3-C8 heterocycle. In some embodiments, R1 is azetidine. In some embodiments, R1 is CF3. In some embodiments, R1 is CHF2. In some embodiments, R1 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In other embodiments, R1 is methyl. In other embodiments, R1 is ethyl. In another embodiment, R1 is isopropyl. In another embodiment, R1 is t-Bu. In another embodiment, R1 is isobutyl. In another embodiment, R1 is pentyl. In another embodiment, R1 is propyl. In another embodiment, R1 is benzyl. In another embodiment, R1 is in the ortho position. In another embodiment, R1 is ortho-methyl.

[0084] In some embodiments, R2 of Formulas I-III, VI, and / or VII is H. In some embodiments, R2 is Cl. In some embodiments, R2 is F. In some embodiments, R2 is R8-OH. In some embodiments, R2 is CH2OH. In some embodiments, R2 is -R8-OR 10 In some embodiments, R2 is CH2-O-CH2-CH2-O-CH3. In some embodiments, R2 is CH2-O-CH3. In some embodiments, R2 is -O-R8-OR 10In some embodiments, R2 is O-CH2-CH2-O-CH3. In some embodiments, R2 is CN. In some embodiments, R2 is R8-N(R 10 )(R 11 ). In some embodiments, R2 is CH2-NH-CH3. In some embodiments, R2 is CH2-NH-C(O)CH3. In some embodiments, R2 is CH2-N(CH3)2. In some embodiments, R2 is C1-C5 straight or branched chain, substituted or unsubstituted alkyl. In other embodiments, R2 is methyl. In other embodiments, R2 is ethyl. In other embodiments, R2 is isopropyl. In other embodiments, R2 is t-Bu. In other embodiments, R2 is isobutyl. In other embodiments, R2 is pentyl. In other embodiments, R2 is propyl. In other embodiments, R2 is benzyl. In other embodiments, R2 is in the ortho position. In other embodiments, R2 is orthomethyl. In other embodiments, R2 is C1-C5 straight, 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 substituted or unsubstituted aryl. In other embodiments, R2 is phenyl. In other embodiments, substituents include C1-C5 straight or branched chain alkyl (e.g., methyl), aryl, phenyl, heteroaryl (e.g., imidazole), and / or C3-C8 cycloalkyl; each represents a separate embodiment of the present invention.

[0085] In some embodiments, R1 and R2 of Formulas I-III, VI, and / or VII are bonded together to form a pyrrole ring. In some embodiments, R1 and R2 are bonded together to form a 1,4-dioxane ring. In some embodiments, R1 and R2 are bonded together to form a 2,3-dihydro-1,4-dioxin ring. In some embodiments, R1 and R2 are bonded together to form a benzene ring. In some embodiments, R1 and R2 are bonded together to form a pyridine ring. In some embodiments, R1 and R2 are bonded together to form a furanone ring (e.g., furan-2(3H)-one).

[0086] In some embodiments, R3 of Formulas I-V is H. In other embodiments, R3 is F. In other embodiments, R3 is Cl. In other embodiments, R3 is BR. In other embodiments, R3 is I. In other embodiments, R3 is N(R 10 )(R 11 In another embodiment, R3 is morpholine. In another embodiment, R3 is piperazine. In another embodiment, R3 is C(O)-R 10 In another embodiment, R3 is C(O)NHR. In another embodiment, R3 is C(O)NH(CH3)2O-CH3. In another embodiment, R3 is C(O)N(R 10 )(R 11). In another embodiment, R3 is C(O)-piperidine. In another embodiment, R3 is C(O)-pyrrolidine. In another embodiment, R3 is C(O)N(CH3)2. In another embodiment, R3 is SO2R. In another embodiment, R3 is C1-C5 linear or branched, substituted or unsubstituted alkyl. In another embodiment, R3 is methyl. In another embodiment, R3 is ethyl. In another embodiment, R3 is C1-C5 linear, branched, or cyclic haloalkyl. In another embodiment, R3 is CHF2. In another embodiment, R3 is C1-C5 linear, branched, or cyclic alkoxy. In another embodiment, R3 is methoxy. In another embodiment, R3 is 1-(methylsulfonyl)piperidin-4-oxy. In another embodiment, R3 is 1-(methyl)piperidin-4-oxy. In another embodiment, R3 is 1-(ethanone)piperidin-4-oxy. In another embodiment, R3 is substituted or unsubstituted C3-C8 cycloalkyl. In another embodiment, R3 is substituted or unsubstituted single, spirocyclic, fused, or bridged C3-C8 cycloalkyl. 10In another embodiment, R3 is a heterocycle. In another embodiment, R3 is piperazine. In another embodiment, R3 is 1-(2-methoxyethyl)piperazine. In another embodiment, R3 is 1- or 4-(methylsulfonyl)piperidine. In another embodiment, R3 is 2-methoxy-1-(piperazin-1-yl)ethenone. In another embodiment, R3 is morpholine. In another embodiment, R3 is 3-methylmorpholine. In another embodiment, R3 is 3-hydroxypiperidine. In another embodiment, R3 is pyrrolidine. In another embodiment, R3 is pyrrolidinone. In another embodiment, R3 is octahydropyrrolo[1,2-α]pyrazine. In another embodiment, R3 is 6-methyl-2,6-diazaspiro[3.3]heptane. In another embodiment, R3 is tetrahydro-2H-thiopyran 1,1-dioxide. In another embodiment, R3 is 1- or 4-methylpiperazine. In another embodiment, R3 is 1- or 4-(methylsulfonyl)piperazine. In another embodiment, R3 is 1-(piperazin-1-yl)ethanone. In another embodiment, R3 is 2-(dimethylamino)-1-(piperazin-1-yl)ethanone. In another embodiment, R3 is 2-(dimethylamino)-1-(piperazin-1-yl)propanone. In another embodiment, R3 is 2-hydroxy-1-(piperazin-1-yl)ethenon. In another embodiment, R3 is N-methylpiperazine-1-carboxamide. In another embodiment, R3 is piperidin-4-ol. In another embodiment, R3 is piperidin-3-ol. In another embodiment, R3 is tetrahydro-2H-pyran. In another embodiment, R3 is 2-oxa-7-azaspiro[3.5]nonane. In another embodiment, R3 is 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone. In another embodiment, R3 is 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone. In another embodiment, R3 is 2,8-diazaspiro[4.5]decan-1-one. In another embodiment, R3 is 2-methyl-2,8-diazaspiro[4.5]decan-1-one.In another embodiment, R3 is 2-oxa-7-azaspiro[3.5]nonane. In another embodiment, R3 is tetrahydro-2H-thiopyran 1,1-dioxide. In another embodiment, R3 is pyrrolidine. In another embodiment, R3 is (1-methylpiperidin-3-yl)(piperazin-1-yl)methanone. In other embodiments, R3 is further selected from the group consisting of F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R. 10 )(R 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, and (benzyloxy)phenyl.

[0087] In some embodiments, R4 of Formulas I-III and / or VI-VII is H. In other embodiments, R4 is C1-C5 straight or branched, substituted or unsubstituted alkyl. In other embodiments, R4 is methyl. In other embodiments, R4 is ethyl.

[0088] In some embodiments, R3 and R4 of Formulas I-III are bonded to each other to form a 5- or 6-membered, substituted or unsubstituted aliphatic ring. In some embodiments, R3 and R4 are bonded to each other to form a cyclopentene. In some embodiments, R3 and R4 are bonded to each other to form an aromatic carbocycle. In some embodiments, R3 and R4 are bonded to each other to form a benzene. In some embodiments, R3 and R4 are bonded to each other to form an aromatic heterocycle. In some embodiments, R3 and R4 are bonded to each other to form a thiophene. In some embodiments, R3 and R4 are bonded to each other to form a furan. In some embodiments, R3 and R4 are bonded to each other to form a pyrrole. In some embodiments, R3 and R4 are bonded to each other to form a pyrazole ring (a [1,3]dioxole ring). In some embodiments, R3 and R4 are bonded to each other to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R3 and R4 are bonded to each other to form a cyclopentene ring. In some embodiments, R3 and R4 are joined together to form an imidazole ring.

[0089] In some embodiments, R5 of formula I is H. In some embodiments, R5 is R 20 In some embodiments, R5 is a C1-C5 straight or branched chain, substituted or unsubstituted alkyl. In some embodiments, R5 is methyl. In some embodiments, R5 is ethyl. In some embodiments, R5 is C(O)-R 10 In some embodiments, R5 is SO2R.

[0090] In some embodiments, R of Formulas I-VIII is H. In other embodiments, R is OH. In other embodiments, R is NH. In other embodiments, R is NH(R 10 In another embodiment, R is NH(CH). In another embodiment, R is R 20In another embodiment, R is a C1-C5 straight or branched chain, substituted or unsubstituted alkyl. In another embodiment, R is a substituted alkyl. In another embodiment, R is methyl. In another embodiment, R is ethyl. In another embodiment, R is CH2CH2OCH3. In another embodiment, R is CH2CH2OH. In another embodiment, R is R8-R 10 In another embodiment, R is CH2-OH. In another embodiment, R is CH2CH2-OH. In another embodiment, R is C(O)-R 10 In another embodiment, R is C(O)-methylpyrrolidine. In another embodiment, R is C(O)-methylpiperidine. In another embodiment, R is C(O)-CH. In another embodiment, R is C1-C5 substituted or unsubstituted C(O)-alkyl. In another embodiment, R is C(O)-CHCH-OCH. In another embodiment, R is C(O)-CH. In another embodiment, R is C(O)-R-R. 10 In another embodiment, R is C(O)-CHCH-OH. In another embodiment, R is a C(O)-substituted or unsubstituted C-C heterocycle. In another embodiment, R is C(O)-methylpyrrolidine. In another embodiment, R is C(O)-methylpiperidine. In another embodiment, R is a C-C substituted or unsubstituted SO-alkyl. In another embodiment, R is SO-CH. In another embodiment, R is -R-OR. 10In another embodiment, R is CH2-CH2-O-CH3. In another embodiment, R is C(O)-CH2-N(CH3)2. In another embodiment, R is C(O)-CH2-CH2-N(CH3)2. In another embodiment, R is C(O)-CH2-OH. In another embodiment, R is C1-C5 substituted or unsubstituted C(O)-NH-alkyl. In another embodiment, R is C(O)-NH-CH3. In another embodiment, R is C1-C5 straight or branched C(O)-O-alkyl. In another embodiment, R is C(O)-O-tBu. In other embodiments, R is further selected from the group consisting of F, Cl, Br, I, OH, SH, CF, CN, NO, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH, C(O)-CH-O-CH), SO2-alkyl (e.g., SO2-CH), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R), N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, and (benzyloxy)phenyl; each represents a separate embodiment of the present invention. In some embodiments, two geminal R substituents are joined together to form a 3-6 membered, substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole) ring.

[0091] In some embodiments, R8 of Formulas I-VIII is CH2. In other embodiments, R8 is CH2CH2. In other embodiments, R8 is CH2CH2CH2.

[0092] In some embodiments, p in Formulas I-VIII is 1. In other embodiments, p is 2. In other embodiments, p is 3.

[0093] In some embodiments, R9 of Formulas I-VIII is C≡C.

[0094] In some embodiments, q in Formulae I-VIII is 2.

[0095] In some embodiments, R of Formulas I-VIII 10 is a substituted or unsubstituted C1-C5 straight or branched alkyl. In other embodiments, R 10 is H. In other embodiments, R 10 is CH3. In other embodiments, R 10 is CH2CH3. In other embodiments, R 10 is CH2CH2CH3. In other embodiments, R 10 is CH2-CH2-O-CH3. In other embodiments, R 10 is OH. In other embodiments, R 10 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R 10 is 1-(methylsulfonyl)piperidine. In another embodiment, R 10 is 1-(methylsulfonyl)piperazine. In another embodiment, R 10 is tetrahydro-2H-pyran. In another embodiment, R 10 is morpholine. In other embodiments, R 10 is thiomorpholine 1,1-dioxide. In other embodiments, R 10 is methyl-pyrrolidine. In another embodiment, R 10 is methyl-piperidine.

[0096] In some embodiments, R of Formulas I-VIII 11 is a C1-C5 straight or branched alkyl. In other embodiments, R 11 is H. In other embodiments, R 11is CH3.

[0097] In some embodiments, R of Formulas I-VIII 10 and R 11 are joined together to form a substituted or unsubstituted C3-C8 heterocycle. 10 and R 11 are linked together to form a morpholine ring. 10 and R 11 are joined together to form an unsubstituted piperazine ring. 10 and R 11 are joined together to form a substituted piperazine ring. In another embodiment, R 10 and R 11 are joined together to form an unsubstituted piperidine ring. 10 and R 11 are joined together to form an unsubstituted pyrrolidine ring. 10 and R 11 are joined together to form a substituted piperidine ring. 10 and R 11 are linked together to form a 1-methylpyrrolidin-2-one ring. 10 and R 11 are linked together to form an oxetane ring. 10 and R 11 are linked together to form an azetidine ring. 10 and R 11are linked together to form 1-methylazetidine. In some embodiments, the substituents include F, Cl, Br, I, OH, SH, CF, CN, NO, substituted or unsubstituted C-C linear or branched alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C-C linear or branched C(O)-alkyl (e.g., C(O)-CH, C(O)-CH-O-CH), SO-alkyl (e.g., SO-CH), C(O)-NH-alkyl, C-C linear or branched alkyl-OH (e.g., C(CH)CH-OH, CHCH-OH), C-C heterocycle (e.g., piperidine), substituted or unsubstituted C-C linear or branched alkoxy, N(R), N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; each represents a separate embodiment of the present invention.

[0098] In some embodiments, n in Formulas I-IV and / or VI-VII is 1. In other embodiments, n is 2.

[0099] In some embodiments, m in Formulas I-III and / or VI-VII is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0100] In some embodiments, k in Formulas I-III and / or VI-VII is 0. In other embodiments, k is 1. In other embodiments, k is 2.

[0101] In some embodiments, l in Formulas I-IV is 1. In other embodiments, l is 2. In other embodiments, l is 3.

[0102] In some embodiments, Q1 of formula I is S. In other embodiments, Q1 is O. In other embodiments, Q1 is NH.

[0103] In some embodiments, G=X of formula I is C=O. In other embodiments, G=X is C=S. In other embodiments, G=X is S=O. In other embodiments, G=X is SO.

[0104] In various embodiments, the present invention relates to compounds of the present invention, pharmaceutical compositions comprising same, and / or methods of use thereof, as set forth in Table 1 below.

[0105] [Table 1-1]

[0106] [Table 1-2]

[0107] [Table 1-3]

[0108] [Table 1-4]

[0109] [Table 1-5]

[0110] [Table 1-6]

[0111] [Table 1-7]

[0112] [Table 1-8]

[0113] Table 1-9

[0114] Table 1-10

[0115] Table 1-11

[0116] Table 1-12

[0117] Table 1-13

[0118] Table 1-14

[0119] Table 1-15

[0120] Table 1-16

[0121] Table 1-17

[0122] Table 1-18

[0123] Table 1-19

[0124] Table 1-20

[0125] Table 1-21

[0126] Table 1-22

[0127] Table 1-23

[0128] Table 1-24

[0129] Table 1-25

[0130] Table 1-26

[0131] Table 1-27

[0132] Table 1-28

[0133] Table 1-29

[0134] [Table 1-30]

[0135] [Table 1-31]

[0136] [Table 1-32]

[0137] [Table 1-33]

[0138] [Table 1-34]

[0139] [Table 1-35]

[0140] [Table 1-36]

[0141] It is well understood that in the structures presented in this invention, when a carbon atom has fewer than four bonds, an H atom is present to complete the carbon valence. It is well understood that in the structures presented in this invention, when a nitrogen atom has fewer than three bonds, an H atom is present to complete the nitrogen valence.

[0142] In some embodiments, the present invention relates to the compounds listed above, pharmaceutical compositions comprising same, and / or methods of use thereof, wherein the compounds of the present invention include pharmaceutically acceptable salts, optical isomers, tautomers, hydrates, N-oxides, reverse amide analogs, prodrugs, isotopic variants (e.g., deuterated analogs), PROTACs, pharmaceuticals, or any combination thereof. In some embodiments, the compounds of the present invention are collagen I translation inhibitors. In some embodiments, the compounds of the present invention are collagen I, II, III, IV, or V translation inhibitors; each represents a separate embodiment of the present invention. In some embodiments, the compounds of the present invention are selective for collagen I, II, III, IV, or V; each represents a separate embodiment of the present invention. In some embodiments, the compounds of the present invention are selective for collagen I. In some embodiments, the compounds of the present invention are selective for collagen IA. In some embodiments, the compounds of the present invention are selective for collagen IA1.

[0143] In various embodiments, the A ring of formula I, II, and / or VII is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, isoquinoline, pyrazolyl, pyrrolyl, furanyl, thiophen-yl, isoquinolinyl, indolyl, 1H-indole, isoindolyl, naphthyl, anthracenyl, benzimidazolyl, indazolyl, 2H-indazole, triazolyl, 4,5,6,7 -tetrahydro-2H-indole, 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, phytazolinyl, quinolinyl, isoquinolinyl, 2,3-dihydroindenyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepin, benzo[d][1,3]dioxole, acrylonitrile, benzo[b][1,4]dioxepine, benzo[d][1,3]dioxole, benzo[b][1,3]dioxole, benzo[b][1,4]dioxepine, benzo[d ... Lysinyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzofuran-2(3H)-one, benzothiophenyl, benzoxadiazole, benzo[c][1,2,5]oxadiazolyl, benzo[c]thiophenyl, benzodioxolyl, benzodioxolyl[d][1,3]dioxole, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiaziolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo [1,2-a]pyridine, 7-oxo-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, imidazopyridine, imidazo[1,2-a]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-imidazo[4,5-c]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazolopyridine, 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]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, pyrrolopyridine, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, or thieno[3,2-c]pyridine; each represents a separate embodiment of the present invention. Alternatively, the A ring of formula I, II, and / or VII is a C3-C8 cycloalkyl (e.g., cyclohexyl, cyclopentyl, bicyclo[1.1.1]pentyl, or cyclobutyl) or a C3-C8 heterocycle (e.g., but not limited to, tetrahydropyran, piperidine, 1-methylpiperidine, tetrahydrothiophene 1,1-dioxide, pyrrolidin-2-one, piperazine, 1-(piperidin-1-yl)ethanone, or morpholine); each represents a separate embodiment of the present invention. In some embodiments, A is phenyl. In some embodiments, A is a C3-C8 heterocycle. In some embodiments, A is tetrahydro-2H-pyran. In other embodiments, A is azetidine. In other embodiments, A is piperidine.

[0144] In various embodiments, the B ring of formula I is selected from the group consisting of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, isoquinoline, pyrazolyl, pyrrolyl, furanyl, thiophen-yl, isoquinolinyl, indolyl, 1H-indole, isoindolyl, naphthyl, anthracenyl, benzimidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, tetrahydronaphthyl, 3,4-dihydro-2H -benzo[b][1,4]dioxepine, benzofuran-2(3H)-one, benzo[d][1,3]dioxole, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indole, 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, phytazolinyl, quinolinyl, isoquinolinyl, Acridinyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzothiophenyl, benzoxadiazole, benzo[c][1,2,5]oxadiazolyl, benzo[c]thiophenyl, benzodioxolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiaziolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazolo[4,5-d]pyridine imidine, [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-c]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, pyrido[2,3-b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, 1,2,3,4-tetrahydroquinoxaline, 1-(pyridin-1(2H)-yl)ethanone, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, In some embodiments, B is eno[3,2-c]pyridine, a C3-C8 cycloalkyl, or a C3-C8 heterocycle (for example, but not limited to, tetrahydropyran, piperidine, 1-methylpiperidine, tetrahydrothiophene 1,1-dioxide, 1-(piperidin-1-yl)ethanone, bicyclo[1.1.1]pentyl, cyclobutyl, cyclohexyl, or morpholine); each represents a separate embodiment of the present invention. In some embodiments, B is a C3-C8 heterocycle. In some embodiments, B is piperidine. In some embodiments, B is piperazine. In some embodiments, B is pyrrolidin-2-one. In some embodiments, B is tetrahydro-2H-pyran. In some embodiments, B is azetidine. In some embodiments, B is pyrimidine. In some embodiments, B is phenyl. In some embodiments, B is pyridinyl. In some embodiments, B is 2-pyridinyl. In some embodiments, B is thiophenyl.

[0145] In various embodiments, the compounds of Formulas I-VIII are R 15 In various embodiments, the compounds of Formulas I-III, VI, and / or VII are substituted by R2. In various embodiments, the compounds of Formulas I-V are substituted by R3. In various embodiments, the compounds of Formulas I-III, and / or VI-VII are substituted by R4. The single substituent can be in the ortho, meta, or para position.

[0146] In various embodiments, R1 of Formulas I-VIII and / or R2 of Formulas I-III are, independently of each other, H.

[0147] In various embodiments, R1 of Formulas I-VIII and R2 of Formulas I-III, VI, and / or VII are, independently of each other, H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2OH), R8-SH, -R8-OR 10 (e.g. CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3, CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R 11 ) (e.g., CH2-NH-CH3, CH2-NH-C(O)CH3, CH2-N(CH3)2), R9-R8-N(R 10 )(R 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R (e.g. NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHC(O)CH3), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO2R, SO2N(R 10 )(R 11 ), NHSO2(R 10 ) (e.g., NHSO2CH3), CH(CF3)(NH-R 10), C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain, substituted or unsubstituted alkenyl, C1-C5 straight, branched, or cyclic haloalkyl (e.g., CHF2), C1-C5 straight, branched, or cyclic alkoxy (e.g., methoxy) (optionally, at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., azetidine, pyridine), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; each represents a separate embodiment of the present invention. In some embodiments, R1 and / or R2 are selected from the group consisting of F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C-C cycloalkyl, halophenyl, and (benzyloxy)phenyl; each represents a separate embodiment of the present invention.

[0148] In some embodiments, R1 and R2 are bonded to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring. In some embodiments, R1 and R2 are bonded to each other to form a 5- or 6-membered heterocyclic ring. In some embodiments, R1 and R2 are bonded to each other to form a pyrrole ring. In some embodiments, R1 and R2 are bonded to each other to form a [1,3]dioxole ring. In some embodiments, R1 and R2 are bonded to each other to form a 1,4-dioxane ring. In some embodiments, R1 and R2 are bonded to each other to form a 2,3-dihydro-1,4-dioxin ring. In some embodiments, R1 and R2 are bonded to each other to form a furan-2(3H)-one ring. In some embodiments, R1 and R2 are bonded to each other to form a benzene ring. In some embodiments, R1 and R2 are bonded to each other to form a pyridine ring. In some embodiments, R1 and R2 are bonded to each other to form a morpholine ring. In some embodiments, R1 and R2 are bonded to each other to form a piperazine ring. In some embodiments, R1 and R2 are bonded to each other to form an imidazole. In some embodiments, R1 and R2 are bonded to each other to form a pyrrole ring. In some embodiments, R1 and R2 are bonded to each other to form a cyclohexene ring. In some embodiments, R1 and R2 are bonded to each other to form a pyrazine ring.

[0149] In various embodiments, R3 of Formulas I-V and R4 of Formulas I-III and VII-IX are each independently selected from H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 , R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, N(R 10 )(R 11 ) (e.g., morpholine, piperazine), 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 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)NH(CH3)2O-CH3, C(O)N(R 10 )(R 11 ), C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH3)2, C(O)-piperazine, SO2R, SO2N(R 10 )(R 11 ), CH(CF3)(NH-R 10 ), C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain, substituted or unsubstituted alkenyl, C1-C5 straight, branched or cyclic haloalkyl, CHF2, C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone)piperidine-4-yl, 1-(methylsulfonyl)piperidine-4-yl, 1-(methyl)piperidine-4-yl, 1-(ethanone)piperidine-4-yl, 1-(methyl ... lysine-4-oxy) (optionally replacing at least one methylene group (CH2) in the alkoxy with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted single, spirocyclic, fused or bridged C3-C 10Heterocycles (e.g., piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)etheone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H- pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; each represents a separate embodiment of the present invention. In some embodiments, R3 and / or R4 are selected from the group consisting of F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11), aryl, phenyl, heteroaryl, C-C cycloalkyl, halophenyl, and (benzyloxy)phenyl; each represents a separate embodiment of the present invention.

[0150] In some embodiments, R3 and R4 are bonded to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring. In some embodiments, R3 and R4 are bonded to each other to form a 5- or 6-membered carbocyclic ring. In some embodiments, R3 and R4 are bonded to each other to form a 5- or 6-membered heterocyclic ring. In some embodiments, R3 and R4 are bonded to each other to form a [1,3]dioxole ring. In some embodiments, R3 and R4 are bonded to each other to form a dihydrofuran-2(3H)-one ring. In some embodiments, R3 and R4 are bonded to each other to form a furan-2(3H)-one ring. In some embodiments, R3 and R4 are bonded to each other to form a benzene ring. In some embodiments, R3 and R4 are bonded to each other to form an imidazole. In some embodiments, R3 and R4 are bonded to each other to form a pyridine ring. In some embodiments, R3 and R4 are bonded to each other to form a thiophene ring. In some embodiments, R3 and R4 are bonded to each other to form a furan ring. In some embodiments, R3 and R4 are bonded to each other to form a pyrrole ring. In some embodiments, R3 and R4 are bonded to each other to form a pyrazole ring. In some embodiments, R3 and R4 are bonded to each other to form a cyclohexene ring. In some embodiments, R3 and R4 are bonded to each other to form a cyclopentene ring. In some embodiments, R4 and R3 are bonded to each other to form a dioxepine ring.

[0151] In some embodiments, R5 of formula I is H, R 20 , F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10, R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, 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 ), COOH, -C(O)Ph, C(O)OR 10 , R8-C(O)-R 10 , C(O)H, C(O)-R 10 , C1-C5 straight or branched chain C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)N(R 10 )(R 11 ), SO2R, SO2N(R 10 )(R 11 ), CH(CF3)(NH-R 10), C1-C5 straight or branched chain, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched chain, substituted or unsubstituted alkenyl, C1-C5 straight, branched, or cyclic haloalkyl (e.g., CHF2), C1-C5 straight, branched, or cyclic alkoxy (e.g., methoxy) (optionally, at least one methylene group (CH2) in the alkoxy is replaced with an oxygen atom), C1-C5 straight or branched chain thioalkoxy, C1-C5 straight or branched chain haloalkoxy, C1-C5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl; each represents a separate embodiment of the present invention. In some embodiments, R5 is F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C-C cycloalkyl, halophenyl, and (benzyloxy)phenyl; each represents a separate embodiment of the present invention.

[0152] In various embodiments, n in the compounds of Formulae I-IV and / or VI-VII is 1. In some embodiments, n is 0 or 1. In some embodiments, n is 1-3. In some embodiments, n is 1-4. In some embodiments, n is 0-2. In some embodiments, n is 0-3. In some embodiments, n is 0-4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0153] In various embodiments, m of compounds of Formulae I-III and / or VI-VII is 0. In some embodiments, m is 0 or 1. In some embodiments, m is 1-3. In some embodiments, m is 1-4. In some embodiments, m is 0-2. In some embodiments, m is 0-3. In some embodiments, m is 0-4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0154] In various embodiments, l in compounds of Formulas I-IV is 0. In some embodiments, l is 0 or 1. In some embodiments, l is 1-3. In some embodiments, l is 1-4. In some embodiments, l is 1 or 2. In some embodiments, l is 0-3. In some embodiments, l is 0-4. In some embodiments, l is 1. In some embodiments, l is 2. In some embodiments, l is 3. In some embodiments, l is 4.

[0155] In various embodiments, k in compounds of Formulae I-III and / or VI-VII is 0. In some embodiments, k is 0 or 1. In some embodiments, k is 1-3. In some embodiments, k is 1-4. In some embodiments, k is 0-2. In some embodiments, k is 0-3. In some embodiments, k is 0-4. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4.

[0156] In the case of heterocycles, it is understood that n, m, l, and / or k are limited to the number of positions available for substitution, i.e., the number of CH or NH groups minus 1. Thus, when ring A and / or ring B is, for example, furanyl, thiophenyl, or pyrrolyl, n, m, l, and k are 0 to 2; when ring A and / or ring B is, for example, oxazolyl, imidazolyl, or thiazolyl, n, m, l, and k are either 0 or 1; and when ring A and / or ring B is, for example, oxadiazolyl or thiadiazolyl, n, m, l, and k are 0.

[0157] In various embodiments, R8 in the compounds of Formulas I-VIII is CH2. In some embodiments, R8 is CH2CH2. In some embodiments, R8 is CH2CH2CH2. In some embodiments, R8 is CH2CH2CH2CH2. In some embodiments, R8 is CH2CH2CH2CH2.

[0158] In various embodiments, p in compounds of Formulas I-VIII is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 1-3. In some embodiments, p is 1-5. In some embodiments, p is 1-10.

[0159] In some embodiments, R9 in a compound of Formulas I-VIII 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.

[0160] In some embodiments, q in compounds of Formulas I-VIII is 2. In some embodiments, q is 4. In some embodiments, q is 6. In some embodiments, q is 8. In some embodiments, q is 2-6.

[0161] In various embodiments, R of the compounds of Formulas I-VIII 10 is H. In some embodiments, R 10 is a substituted or unsubstituted C1-C5 straight or branched chain alkyl. In some embodiments, R 10 is methyl. In some embodiments, R 10 is ethyl. In some embodiments, R 10 is propyl. In some embodiments, R 10 is isopropyl. In some embodiments, R 10 is butyl. In some embodiments, R 10 is isobutyl. In some embodiments, R 10 is t-butyl. In some embodiments, R 10 is cyclopropyl. In some embodiments, R 10 is pentyl. In some embodiments, R 10 is isopentyl. In some embodiments, R 10 is neopentyl. In some embodiments, R 10 is benzyl. In some embodiments, R 10 is CH2-CH2-O-CH3. In some embodiments, R 10 is a substituted or unsubstituted C-C heterocycle. In some embodiments, R 10is 1-(methylsulfonyl)piperidine. In some embodiments, R 10 is 1-(methylsulfonyl)piperazine. In some embodiments, R 10 is tetrahydro-2H-pyran. In some embodiments, R 10 is morpholine. In some embodiments, R 10 is thiomorpholine 1,1-dioxide. In some embodiments, R 10 is methyl-pyrrolidine. In some embodiments, R 10 is methyl-piperidine. In some embodiments, R 10 is C(O)-alkyl. In some embodiments, R 10 is S(O)-alkyl. In other embodiments, R 10 may further include F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C-C cycloalkyl, halophenyl, and (benzyloxy)phenyl; each represents a separate embodiment of the present invention.

[0162] In various embodiments, R of the compounds of Formulas I-VIII 11 is H. In some embodiments, R 11 is a C1-C5 straight or branched chain alkyl. In some embodiments, R 11 is methyl. In some embodiments, R 11is ethyl. In some embodiments, R 11 is propyl. In some embodiments, R 11 is isopropyl. In some embodiments, R 11 is butyl. In some embodiments, R 11 is isobutyl. In some embodiments, R 11 is t-butyl. In some embodiments, R 11 is cyclopropyl. In some embodiments, R 11 is pentyl. In some embodiments, R 11 is isopentyl. In some embodiments, R 11 is neopentyl. In some embodiments, R 11 is benzyl. In some embodiments, R 11 is CH2-CH2-O-CH3. In some embodiments, R 11 is a substituted or unsubstituted C-C heterocycle. In some embodiments, R 11 is 1-(methylsulfonyl)piperidine. In some embodiments, R 11 is 1-(methylsulfonyl)piperazine. In some embodiments, R 11 is tetrahydro-2H-pyran. In some embodiments, R 11 is morpholine. In some embodiments, R 11 is thiomorpholine 1,1-dioxide. In some embodiments, R 11 is methyl-pyrrolidine. In some embodiments, R 11 is methyl-piperidine. In some embodiments, R 11 is C(O)-alkyl. In some embodiments, R 11 is S(O)-alkyl. In other embodiments, R 11may further include F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C-C cycloalkyl, halophenyl, and (benzyloxy)phenyl; each represents a separate embodiment of the present invention.

[0163] In some embodiments, R of Formulas I-VIII 10 and R 11 are joined together to form a substituted or unsubstituted C3-C8 heterocycle. 10 and R 11 are linked together to form a morpholine ring. 10 and R 11 are linked together to form a piperazine ring. 10 and R 11 are joined together to form a substituted piperazine ring. In another embodiment, R 10 and R 11 are linked together to form a piperidine ring. 10 and R 11 are joined together to form an unsubstituted pyrrolidine ring. 10 and R 11 are linked together to form a 1-methylpyrrolidin-2-one ring. 10 and R 11 are linked together to form an oxetane. In another embodiment, R 10and R 11 are linked together to form an azetidine. In another embodiment, R 10 and R 11 are linked together to form 1-methylazetidine. In another embodiment, R 10 and / or R 11 may further include F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C-C cycloalkyl, halophenyl, and (benzyloxy)phenyl; each represents a separate embodiment of the present invention.

[0164] In some embodiments, R in Formulas I-VIII is H. In other embodiments, R is OH. In other embodiments, R is F. In other embodiments, R is Cl. In other embodiments, R is Br. In other embodiments, R is I. In other embodiments, R is CN. In other embodiments, R is CF. In other embodiments, R is NO. In other embodiments, R is NH. In other embodiments, R is NH(R 10 In another embodiment, R is NH(CH). In another embodiment, R is N(R 10 )(R 11 In other embodiments, R is R 20In another embodiment, R is a C1-C5 straight or branched chain, substituted or unsubstituted alkyl. In another embodiment, R is methyl. In another embodiment, R is ethyl. In another embodiment, R is substituted alkyl. In another embodiment, R is CH2CH2OH. In another embodiment, R is CH2CH2OCH3. In another embodiment, R is R8-R 10 In another embodiment, R is CH2-OH. In another embodiment, R is CH2CH2-OH. In another embodiment, R is C(O)-R 10 In another embodiment, R is C(O)-methylpyrrolidine. In another embodiment, R is C(O)-methylpiperidine. In another embodiment, R is C(O)-CH. In another embodiment, R is -R-OR. 10 In another embodiment, R is CH2-CH2-O-CH3. In another embodiment, R is a C1-C5 substituted or unsubstituted C(O)-alkyl. In another embodiment, R is C(O)-CH2CH2-OCH3. In another embodiment, R is C(O)-CH3. In another embodiment, R is C(O)-CH2-N(CH3)2. In another embodiment, R is C(O)-CH2-CH2-N(CH3)2. In another embodiment, R is C(O)-CH2-OH. In another embodiment, R is C(O)-R8-R 10In another embodiment, R is C(O)-CHCH-OH. In another embodiment, R is a C(O)-substituted or unsubstituted C3-C8 heterocycle. In another embodiment, R is C(O)-methylpyrrolidine. In another embodiment, R is C(O)-methylpiperidine. In another embodiment, R is SO2-alkyl. In another embodiment, R is SO2-CH3. In another embodiment, R is C1-C5 substituted or unsubstituted C(O)-NH-alkyl. In another embodiment, R is C(O)-NH-CH3. In another embodiment, R is C1-C5 straight or branched chain C(O)-O-alkyl. In another embodiment, R is C(O)-O-tBu. In another embodiment, R is C1-C5 straight or branched chain alkoxy. In another embodiment, R is -R8-OR 10In another embodiment, R is CH2-CH2-O-CH3. In another embodiment, R is a C1-C5 straight or branched chain haloalkyl. In another embodiment, R is CF3. In another embodiment, R is CF2CH3. In another embodiment, R is CH2CF3. In another embodiment, R is CF2CH2CH3. In another embodiment, R is CH2CH2CF3. In another embodiment, R is CF2CH(CH3)2. In another embodiment, R is CF(CH3)-CH(CH3)2. In another embodiment, R is R8-aryl. In another embodiment, R is CH2-Ph. In another embodiment, R is substituted or unsubstituted aryl. In another embodiment, R is phenyl. In another embodiment, R is substituted or unsubstituted heteroaryl. In another embodiment, R is pyridine. In another embodiment, R is 2, 3, or 4-pyridine. In other embodiments, R3 is further selected from the group consisting of F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight or branched chain alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight or branched chain C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight or branched chain alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), substituted or unsubstituted C1-C5 straight or branched chain alkoxy, N(R)2, N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, and (benzyloxy)phenyl; each represents a separate embodiment of the present invention. In some embodiments, two geminal R substituents are joined together to form a 3-6 membered, substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole) ring.

[0165] In some embodiments, X1 in the compound of Formula III-VIII is N. In other embodiments, X1 is C.

[0166] In some embodiments, X2 in compounds of Formula III-VIII is N. In other embodiments, X2 is C.

[0167] In some embodiments, X3 in compounds of Formula II-VIII is N. In other embodiments, X3 is C.

[0168] In some embodiments, X4 in the compound of Formula II-VIII is C. In other embodiments, X4 is N.

[0169] In some embodiments, X5 in the compound of Formula II-VIII is C. In other embodiments, X5 is N.

[0170] It is understood that H atoms are added as necessary to complete the valence of an unsubstituted carbon atom of X1-X5 of any one of formulas II-VIII.

[0171] In some embodiments, X6 in the compound of Formula VI-VIII is O. In other embodiments, X6 is CH2. In other embodiments, X6 is CHR. In other embodiments, X6 is CH(OH). In other embodiments, X6 is CH(NH2). In other embodiments, X6 is CH(NH(CH3)). In other embodiments, X6 is C(R 10 )(R 11 ). In another embodiment, X6 is C(H)CH2CH2-OH. In another embodiment, X6 is C(H)CH2-OH. In another embodiment, X6 is 1-methylpyrrolidin-2-one. In another embodiment, X6 is oxetane. In another embodiment, X6 is NH. In another embodiment, X6 is NR. In another embodiment, X6 is N-CH3. In another embodiment, X6 is N-SO2-CH3. In another embodiment, X6 is NR20 In another embodiment, X6 is NC(O)O-tBu. In another embodiment, X6 is NC(O)-CH2CH2-OCH3. In another embodiment, X6 is N-CH2CH2-OCH3. In another embodiment, X6 is NC(O)-CH3. In another embodiment, X6 is a C1-C5 substituted or unsubstituted NC(O)-NH-alkyl. In another embodiment, X6 is NC(O)-NH-CH3. In another embodiment, X6 is NC(O)-CH2-N(CH3)2. In another embodiment, X6 is NC(O)-CH2-CH2-N(CH3)2. In another embodiment, X6 is NC(O)-CH2CH2-OH. In another embodiment, X6 is NC(O)-CH2-OH. In another embodiment, X6 is NC(O)-R 10 In another embodiment, X6 is 1-methylazetidine. In another embodiment, X6 is NC(O)-1-methyl-2-pyrrolidine. In another embodiment, X6 is NC(O)-1-methyl-3-pyrrolidine. In another embodiment, X6 is NC(O)-1-methyl-3-piperidine. In another embodiment, X6 is NC(O)-1-methyl-4-piperidine. In another embodiment, X6 is NR 20 is.

[0172] In some embodiments, at least one of X 1 -X 2 is N.

[0173] In some embodiments, at least one of X3-X5 is N. In some embodiments, at least two of X3-X5 are N.

[0174] In some examples, Q1 of formula I is S. In other examples, Q1 is O. In other embodiments, Q1 is NH.

[0175] In some embodiments, G=X of Formula I is C=O. In other embodiments, G=X is C=S. In other embodiments, G=X is S=O. In other embodiments, G=X is SO.

[0176] As used herein, "monocyclic or fused ring aromatic or heteroaromatic ring system" includes, but is not limited to, phenyl, naphthyl, pyridinyl, (2-, 3-, and 4-pyridinyl), quinolinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, pyrazolyl, pyrrolyl, furanyl, thiophen-yl, quinolinyl, isoquinolinyl, 2,3-dihydroindenyl, indenyl, and tetrahydronaphthyl. , 3,4-dihydro-2H-benzo[b][1,4]dioxepine, benzodioxolyl, benzo[d][1,3]dioxole, tetrahydronaphthyl, indolyl, 1H-indole, isoindolyl, anthracenyl, benzimidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl benzo[c][1,2,5]oxadiazolyl, benzo[c]thiophenyl, benzodioxolyl, thiazole, benzo[c]thiophenyl, benzodioxolyl, benzo[c]thiazole ... Diazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiaziolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2-d]pyrimidin-4(3H)-one, 4-oxo-4H-thieno[3,2-d][1,3]thiazine, imidazo[1,2-a]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-imidazo[4,5-c]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrido[2,3-b]pyrazine, pyrido[2,3-b]pyrazine-3 (4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thieno[3,2-c]pyridine, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole, etc.

[0177] As used herein, the term "alkyl," unless otherwise specified, can be a straight or branched chain alkyl group containing up to about 30 carbons. In various embodiments, alkyl includes C1-C5 carbons. In some embodiments, alkyl includes C1-C6 carbons. In some embodiments, alkyl includes C1-C8 carbons. In some embodiments, alkyl includes C1-C 10 In some embodiments, alkyl is C-C 12 In some embodiments, alkyl is C-C 20In some embodiments, the branched alkyl is an alkyl substituted with an alkyl side chain of 1 to 5 carbons. In various embodiments, the alkyl group can be unsubstituted. In some embodiments, the alkyl group can be substituted with halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, COH, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C1-C5 straight or branched chain haloalkoxy, CF3, phenyl, halophenyl, (benzyloxy)phenyl, -CH2CN, NH2, NH-alkyl, N(alkyl)2, -OC(O)CF3, -OCH2Ph, -NHCO-alkyl, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH2, or any combination thereof.

[0178] An alkyl group can be the sole substituent or part of a larger substituent such as alkoxy, alkoxyalkyl, haloalkyl, arylalkyl, alkylamino, dialkylamino, alkylamide, alkylurea, etc. Preferred alkyl groups are methyl, ethyl, and propyl, thus halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, halopropyl, dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl, arylethyl, arylpropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylamide, acetamide, propylamide, halomethylamide, haloethylamide, halopropylamide, methyl-urea, ethyl-urea, propyl-urea, 2,3,4-CH2-C6H4-Cl, C(OH)(CH3)(Ph), and the like.

[0179] As used herein, the term "aryl" refers to any aromatic ring directly attached to another group and which may be either substituted or unsubstituted. An aryl group may be the sole substituent or may be a component part of a larger substituent such as arylalkyl, arylamino, or arylamido. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, xylyl, furanyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiophen-yl, pyrrolyl, indolyl, phenylmethyl, phenylethyl, phenylamino, phenylamido, 3-methyl-4H-1,2,4-triazolyl, and 5-methyl-1,2,4-oxadiazolyl. Substituents include, but are not limited to, F, Cl, Br, I, C1-C5 straight or branched chain alkyl, C1-C5 straight or branched chain haloalkyl, C1-C5 straight or branched chain alkoxy, C1-C5 straight or branched chain haloalkoxy, CF3, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, -CH2CN, NH2, NH-alkyl, N(alkyl)2, hydroxyl, -OC(O)CF3, -OCH2Ph, -NHCO-alkyl, COOH, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH2, or combinations thereof.

[0180] As used herein, the term "alkoxy" refers to an ether group substituted with an alkyl group, as defined above. Alkoxy refers to both straight-chain and branched-chain alkoxy groups. Non-limiting examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and tert-butoxy.

[0181] As used herein, the term "aminoalkyl" refers to an amine group substituted with an alkyl group, as defined above. Aminoalkyl refers to a mono-, di-, or tri-alkylamine. Non-limiting examples of aminoalkyl groups include -N(Me)2, -NHMe, and -NH3.

[0182] A "haloalkyl" group, in some embodiments, 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, i.e., an alkyl group having at least one fluorine atom. Non-limiting examples of haloalkyl groups include CF, CFCF, CFCH, CHCF, CFCHCH, CHCHCF, CFCH(CH), and CF(CH)-CH(CH).

[0183] A "halophenyl" group, in some embodiments, refers to a phenyl substituent that is substituted with one or more halogen atoms, such as F, Cl, Br, or I. In one embodiment, the halophenyl is 4-chlorophenyl.

[0184] An "alkoxyalkyl" group refers, in some embodiments, to an alkyl group as defined above that is substituted with an alkoxy group as defined above, for example, methoxy, ethoxy, propoxy, i-propoxy, t-butoxy, etc. Non-limiting examples of alkoxyalkyl groups include -CH2-O-CH3, -CH2-O-CH(CH3), -CH2-OC(CH3), -CH2-CH2-O-CH3, -CH2-CH2-O-CH(CH3), -CH2-CH2-OC(CH3).

[0185] A "cycloalkyl" or "carbocyclic" group, in various embodiments, refers to a ring structure that includes carbon atoms as ring atoms, and may be saturated or unsaturated, substituted or unsubstituted, monocyclic or fused. In some embodiments, a cycloalkyl is a 3- to 10-membered ring. In some embodiments, a cycloalkyl is a 3- to 12-membered ring. In some embodiments, a cycloalkyl is a 6-membered ring. In some embodiments, a cycloalkyl is a 5- to 7-membered ring. In some embodiments, a cycloalkyl is a 3- to 8-membered ring. In some embodiments, a cycloalkyl group can be unsubstituted or substituted with halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, COH, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C-C straight or branched chain haloalkoxy, CF, phenyl, halophenyl, (benzyloxy)phenyl, —CHCN, NH, NH-alkyl, N(alkyl), —OC(O)CF, —OCHPh, —NHCO-alkyl, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH, or any combination thereof. In some embodiments, a cycloalkyl ring can be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3- to 8-membered ring. In some embodiments, the cycloalkyl ring is a saturated ring. In some embodiments, the cycloalkyl ring is an unsaturated ring. Non-limiting examples of cycloalkyl groups include cyclohexyl, cyclohexenyl, cyclopropyl, cyclopropenyl, cyclopentyl, cyclopentenyl, cyclobutyl, cyclobutenyl, cyclooctyl, cyclooctadienyl (COD), cyclooctaene (COE), and the like.

[0186] A "heterocycle" or "heterocyclic" group, in various embodiments, refers to a ring structure that, in addition to carbon atoms, includes sulfur, oxygen, nitrogen, or any combination thereof as part of the ring. A "heteroaromatic ring," in various embodiments, refers to an aromatic ring structure that, in addition to carbon atoms, includes sulfur, oxygen, nitrogen, or any combination thereof as part of the ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3- to 10-membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3- to 12-membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 6-membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 5- to 7-membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3- to 8-membered ring. In some embodiments, a heterocyclic group or heteroaromatic ring can be unsubstituted or substituted with halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, COH, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C-C straight or branched chain haloalkoxy, CF, phenyl, halophenyl, (benzyloxy)phenyl, —CHCN, NH, NH-alkyl, N(alkyl), —OC(O)CF, —OCHPh, —NHCO-alkyl, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH, or any combination thereof. In some embodiments, a heterocyclic or heteroaromatic ring can be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3- to 8-membered ring. In some embodiments, a heterocyclic ring is a saturated ring. In some embodiments, a heterocyclic ring is an unsaturated ring.Non-limiting examples of heterocyclic or heteroaromatic ring systems include pyridine, piperidine, morpholine, piperazine, thiophene, pyrrole, benzodioxole, benzofuran-2(3H)-one, benzo[d][1,3]dioxole, indole, oxazole, isoxazole, imidazole and 1-methylimidazole, furan, triazole, pyrimidine, pyrazine, oxacyclobutane (1 or 2-oxacyclobutane), naphthalene, tetrahydrothiophene 1,1-dioxide, thiazole, benzimidazole, piperidine, 1-methylpiperidine, isoquinoline, 1,3-dihydroisobenzofuran, benzofuran, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole, or indole.

[0187] 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, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, polymorph, crystal, or any combination thereof. In some embodiments, the present invention provides an isomer of a compound of the present invention. In some embodiments, the present invention provides a metabolite of a compound of the present invention. In some embodiments, the present invention provides a pharmaceutically acceptable salt of a compound of the present invention. In some embodiments, the present invention provides a pharmaceutical product of a compound of the present invention. In some embodiments, the present invention provides a tautomer of a compound of the present invention. In some embodiments, the present invention provides a hydrate of a compound of the present invention. In some embodiments, the present invention provides an N-oxide of a compound of the present invention. In some embodiments, the present invention provides a reverse amide analog of a compound of the present invention. In some embodiments, the present invention provides a prodrug of a compound of the present invention. In some embodiments, the present invention provides an isotopic variant of a compound of the present invention (e.g., but not limited to, a deuterated analog). In some embodiments, the present invention provides a PROTAC (proteolysis-induced chimera) of a compound of the present invention. In some embodiments, the present invention provides a polymorph of a compound of the present invention. In some embodiments, the present invention provides crystals of the compounds of the present invention. In some embodiments, the present invention provides compositions comprising a compound of the present invention described herein, or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), PROTAC, polymorph, crystal, or any combination thereof of a compound of the present invention.

[0188] In various embodiments, the term "isomer" includes, but is not limited to, a stereoisomer or analog thereof, an optical isomer or analog thereof, a structural isomer or analog thereof, a conformational isomer or analog thereof, etc. In some embodiments, an isomer is an optical isomer. In some embodiments, an isomer is a stereoisomer.

[0189] In various embodiments, the present invention encompasses the use of various optical isomers of the compounds of the present invention. It will be understood by those skilled in the art that the compounds of the present invention may contain at least one chiral center. Accordingly, the compounds used in the methods of the present invention may exist in and be isolated in optically active or racemic forms. Thus, the compounds of the present invention may exist as optically active isomers (enantiomers or diastereomers, including but not limited to, (R), (S), (R)(R), (R)(S), (S)(R), (R)(R)(R), (R)(R)(S), (R)(S)(R), (S)(R)(S), (S)(R)(S), or (S)(S)(S) isomers), either as racemic mixtures or as enantiomerically enriched mixtures. Some compounds may also exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically active, polymorphic, or stereoisomeric form, or combination thereof, which forms have properties useful in the treatment of the various diseases (conditions) described herein.

[0190] It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases.

[0191] The compounds of the present invention can also exist in the form of racemic mixtures containing substantially equal amounts of stereoisomers. In some embodiments, the compounds of the present invention can be prepared or otherwise isolated using known procedures to obtain stereoisomers that are substantially free of their corresponding stereoisomers (i.e., substantially pure). By substantially pure, it is intended that the stereoisomers are at least about 95% pure, more preferably at least about 98% pure, and most preferably at least about 99% pure.

[0192] The compounds of the present invention can also be in the form of hydrates, which means that the compounds further contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0193] As used herein, when a chemical functional group (eg, alkyl or aryl) is said to be "substituted," it is defined that one or more substitutions are possible.

[0194] The compounds of the present invention may exist in one or more of the possible tautomeric forms, and depending on the conditions, it is possible to separate some or all of the tautomers into separate entities. It is understood that all possible tautomers, including all additional enol and keto tautomers and / or isomers, are encompassed by the present invention. For example, but not limited to, the following tautomers are included:

[0195] [ka]

[0196] The present invention includes "pharmaceutically acceptable salts" of the compounds of the present invention prepared by reacting the compounds with an acid or base. Certain compounds, particularly those containing acidic or basic groups, may be in the form of a salt, preferably a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, even if it is not biologically or otherwise undesirable. Salts may be prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. Other salts are known to those skilled in the art and can be readily adapted for use in accordance with the present invention.

[0197] Suitable pharmaceutically acceptable salts of the amine of the compound of the present invention can be prepared from inorganic or organic acids.In various embodiments, examples of inorganic salts of amine include hydrogen sulfate, borate, bromide, chloride, hemisulfate, hydrobromide, hydrochloride, 2-hydroxyethylsulfonate (hydroxyethanesulfonate), iodate, iodide, isothionate, nitrate, persulfate, phosphate, sulfate, sulfamate, sulfanilate, sulfonic acid (alkylsulfonate, arylsulfonate, halogen-substituted alkylsulfonate, halogen-substituted arylsulfonate), sulfonate and thiocyanate.

[0198] In various embodiments, examples of organic salts of amines can be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, including acetate, arginine, aspartate, ascorbate, adipate, anthranilate, algenate, alkanecarboxylate, substituted alkanecarboxylate, alginate, benzenesulfonate, benzoate, bisulfate, butyrate, bicarbonate, bitartrate, citrate, camphorate, camphorsulfonate, cyclohexylsulfam ... Clopentanepropionate, calcium edetate, camsylate, carbonate, clavulanate, cinnamate, dicarboxylate, digluconate, dodecylsulfonate, dihydrochloride, decanoate, enanthate, ethanesulfonate, edetate, edisylate, estolate, esylate, fumarate, formate, fluoride, galacturonate, gluconate, glutamate, glycolate, glucolate, glucoheptanoate, glycerophosphate, gluceptate, glycolylarsanilate, glutarate, glutamate, heptanoate, heptanoate Xanthate, Hydroxymaleate, Hydroxycarboxylic Acid, Hexylresorcylate, Hydroxybenzoate, Hydroxynaphthoate, Hydrofluoride, Lactate, Lactobionate, Laurate, Malate, Maleate, Methylenebis(beta-oxynaphthoate), Malonate, Mandelate, Mesylate, Methanesulfonate, Methyl Bromide, Methyl Nitrate, Methanesulfonate, Monopotassium Maleate, Mucate, Monocarboxylate, Naphthalenesulfonate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Napsylate, N -Methylglucamine, oxalate, octanoate, oleate, pamoate, phenylacetate, picrate, phenylbenzoate, pivalate, propionate, phthalate, phenylacetate, pectinate, phenylpropionate, palmitate, pantothenate, polygalacturonate, pyruvate, quinate, salicylate, succinate, stearate, sulfanilate, diacetate, tartrate, theophylline acetate, p-toluenesulfonate (tosylate), trifluoroacetate, terephthalate, tannate, teoclate,Trihaloacetates, triethiodides, tricarboxylates, undecanoates, and valerates.

[0199] In various embodiments, examples of inorganic salts of carboxylic acids or hydroxyls can be selected from alkali metals including ammonium, lithium, sodium, potassium, cesium; alkaline earth metals including calcium, magnesium, aluminum; zinc, barium, choline, quaternary ammonium.

[0200] In some embodiments, examples of organic salts of carboxylic acids or hydroxyls can be selected from arginine, organic amines (including aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathine, t-butylamine, betamin (N-benzylphenethylamine), dicyclohexylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, hydrabamine, imidazole, lysine, methylamine, meglamine, N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, nicotinamide, organic amines, ornithine, pyridine, picoline, piperazine, procaine, tris(hydroxymethyl)methylamine, triethylamine, triethanolamine, trimethylamine, tromethamine), and urea.

[0201] In various embodiments, salts can be made by conventional means, for example, by reacting the product in its free base or free acid form with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed under vacuum or by lyophilization, or by exchanging an ion of an existing salt with another ion or with a suitable ion exchange resin.

[0202] Pharmaceutical Composition

[0203] Another aspect of the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to an aspect of the present invention. The pharmaceutical composition of the present invention may contain one or more of the compounds of the present invention described above. Generally, the pharmaceutical composition of the present invention may comprise a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to any suitable adjuvant, carrier, excipient, or stabilizer, and may be in the form of a solid or liquid, such as a tablet, capsule, powder, solution, suspension, or emulsion.

[0204] Typically, the compositions of the present invention may contain about 0.01 to 99 percent, preferably about 20 to 75 percent, of the active compound, along with adjuvants, carriers, and / or excipients. While individual needs may vary, determining the optimal range of effective amounts of each component is within the skill of those in the art. A typical dosage is about 0.01 to 100 mg / kg body weight. A preferred dosage is about 0.1 to 100 mg / kg body weight. A most preferred dosage is about 1 to 100 mg / kg body weight. Furthermore, therapeutic regimens for administering the compounds of the present invention can be readily determined by those skilled in the art. That is, administration frequency and dosage can be established by routine optimization, preferably while minimizing side effects.

[0205] Solid form dosage forms can be, for example, capsules, such as ordinary gelatin types, containing a compound of the invention and a carrier such as a lubricant or inert filler (e.g., lactose, sucrose, or cornstarch). In some embodiments, the compounds are tableted in combination with a conventional tablet base such as lactose, sucrose, or cornstarch, a binder such as acacia, cornstarch, or gelatin, a disintegrating agent such as cornstarch, potato starch, or alginic acid, and a lubricant such as stearic acid or magnesium stearate.

[0206] Tablets, capsules, and the like may also contain binders such as tragacanth gum, acacia, corn starch, or gelatin, excipients such as dicalcium phosphate, disintegrating agents such as corn starch, potato starch, or alginic acid, lubricants such as magnesium stearate, and sweeteners such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0207] Various other materials can be used as coatings or to modify the physical form of the dosage unit. For example, tablets can be coated with shellac, sugar, or both. A syrup can contain, in addition to the active ingredient, sucrose as a sweetening agent, methylparaben or propylparaben as preservatives, a dye, and a flavoring such as cherry or orange flavor.

[0208] For oral therapeutic administration, these active compounds can be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage of the compound in these compositions may, of course, be varied and may conveniently be about 2-60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions according to the present invention are prepared so that an oral dosage unit contains about 1-800 mg of active compound.

[0209] The active compounds of the present invention may be administered orally, for example, with an inert diluent or an assimilable edible carrier, enclosed in a hard or soft capsule, compressed into tablets, or incorporated directly into the food of the animal.

[0210] Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the pharmaceutical form must be sterile and fluid enough to be easily injected with a syringe. It must also be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), a suitable mixture thereof, or a vegetable oil.

[0211] The compounds or pharmaceutical compositions of the present invention may also be administered in injectable dosages as a solution or suspension in a physiologically acceptable diluent with a pharmaceutical adjuvant, carrier, or excipient. Such adjuvants, carriers, and / or excipients include, but are not limited to, sterile liquids such as water and oils, with or without the addition of surfactants or other pharmaceutically and physiologically acceptable ingredients. Exemplary oils are those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose or related sugar solutions, and glycols, such as propylene glycol and polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.

[0212] These active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Exemplary oils are those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose or related sugar solutions, and glycols, such as propylene glycol and polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0213] For use as an aerosol, the compounds of the invention in solution or suspension can be packaged in a pressurized aerosol container with a suitable propellant, e.g., a conventional adjuvant and a hydrocarbon propellant such as propane, butane, or isobutane. The materials of the invention can also be administered in a non-pressurized form, such as in a nebulizer or atomizer.

[0214] In various embodiments, the compounds of the present invention are administered in combination with a pulmonary fibrosis treatment drug. In some embodiments, the pulmonary fibrosis treatment drug is selected from pirfenidone and nintedanib. Other examples of drugs useful for treating pulmonary fibrosis, including IPF, that can be administered in combination with the compounds of the present invention include, but are not limited to, pioglitazone, tralokinumab, lebrikizumab, FG-3019, simtuzumab, STX-100, BMS-986020, rituximab, carbon monoxide, azithromycin, and cotrimoxazole. In various embodiments, the compounds of the present invention are administered in combination with a NASH treatment drug.

[0215] When administering the compounds of the present invention, the compounds of the present invention may be administered systemically or directly to the specific site where cancer cells or precancerous cells are present.Therefore, administration can be achieved by any method that is effective for delivering the compounds or pharmaceutical compositions of the present invention to cancer cells or precancerous cells.Exemplary administration modes of the compounds or compositions of the present invention include, but are not limited to, oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, intracavity, intravesical, intraocular, intraarterial, intralesional, or administration or application to mucous membranes such as the nose, throat, and bronchi.

[0216] biological activity

[0217] In various embodiments, the present invention provides compounds and compositions, including any of the embodiments described herein, for use in any of the methods of the present invention. In various embodiments, the use of the compounds of the present invention or compositions comprising same will have utility in inhibiting, suppressing, enhancing, or stimulating a desired response in a subject, as will be understood by those skilled in the art. In some embodiments, the compositions of the present invention may further comprise additional active ingredients having activities useful in the particular application for which the compounds of the present invention are administered.

[0218] The present invention relates to the treatment, inhibition, and amelioration of fibrosis, including pulmonary and hepatic fibrosis. More specifically, embodiments of the present invention provide compositions and methods useful for the treatment and inhibition of fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), or hepatic fibrosis associated with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), employing the use of a compound according to the present invention, or a pharmaceutically acceptable salt thereof.

[0219] In another embodiment, the human subject suffers from pulmonary fibrosis. In another embodiment, the human subject suffers from idiopathic pulmonary fibrosis (IPF). In another embodiment, the human subject suffers from non-alcoholic fatty liver disease (NAFLD). In another embodiment, the human subject suffers from non-alcoholic steatohepatitis (NASH).

[0220] In various conditions, the formation of fibrous tissue is characterized by the deposition of abnormally large amounts of collagen. Collagen synthesis is also involved in a variety of other pathological conditions. Clinical conditions and diseases associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, and autoimmune diseases, are distinguished by the excessive production of connective tissue, which leads to the disruption of normal tissue structure and function. These diseases can best be interpreted in terms of perturbations in cellular function, and their primary symptom is excessive collagen synthesis and deposition. The role of collagen in fibrosis has led to attempts to develop drugs that inhibit collagen accumulation.

[0221] Excessive collagen accumulation is a major pathological feature in various clinical conditions characterized by tissue fibrosis. These clinical conditions include localized processes such as pulmonary fibrosis and liver cirrhosis, as well as systemic processes such as progressive systemic sclerosis. Collagen deposition is a hallmark of various forms of skin fibrosis, including scleroderma, localized or systemic sclerosis, keloids, hypertrophic scars, familial cutaneous collagenoma, and collagenous connective tissue nevi. Recent advances in understanding the normal biochemistry of collagen have made it possible to define specific levels of collagen biosynthesis and degradation at which pharmacological intervention may lead to a reduction in collagen deposition in tissues. Such compounds may provide novel approaches to reducing collagen excess accumulation in disease.

[0222] Thus, in various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting fibrosis in a subject, comprising administering a compound of the present invention to a subject suffering from fibrosis under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit fibrosis in the subject. In some embodiments, the fibrosis is systemic. In some embodiments, the fibrosis is organ-specific. In some embodiments, the fibrosis is the result of wound healing. In some embodiments, the fibrosis is the result of scarring. In some embodiments, the fibrosis is primary fibrosis or secondary fibrosis. In some embodiments, the fibrosis is the result of systemic sclerosis, progressive systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, autoimmune disease, or any combination thereof; each represents a separate embodiment of the present invention. In another embodiment, the human subject is suffering from pulmonary fibrosis. In another embodiment, the human subject is suffering from idiopathic pulmonary fibrosis (IPF). In some embodiments, the fibrosis is pulmonary fibrosis. In some embodiments, the subject has cirrhosis. In some embodiments, the fibrosis is liver fibrosis, pulmonary fibrosis, or dermal fibrosis. In some embodiments, the dermal fibrosis is scleroderma. In some embodiments, the dermal fibrosis is the result of localized or systemic scleroderma, keloids, hypertrophic scars, familial cutaneous collagenoma, collagen-type connective tissue nevi, or any combination thereof; each represents a separate embodiment of the present invention. In some embodiments, the fibrosis is the result of tissue injury, inflammation, oxidative stress, or any combination thereof; each represents a separate embodiment of the present invention. In some embodiments, the fibrosis is gingival fibromatosis. In some embodiments, the compounds of the present invention are collagen I translation inhibitors. In some embodiments, the compounds of the present invention are selective for collagen I. In some embodiments, the compounds of the present invention are selective for collagen IA. In some embodiments, the compounds of the present invention are selective for collagen IA1.In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0223] Human fibrosis represents a major global health problem due to the large number of patients affected, incomplete knowledge of the pathogenesis of the fibrotic process, significant heterogeneity in etiology and clinical manifestations, the lack of appropriate and well-validated biomarkers, and, most importantly, the current lack of effective disease-modifying therapeutics. Fibrosis encompasses a wide range of clinical manifestations, including systemic fibroses such as systemic sclerosis (SSc), scleroderma graft-versus-host disease, and nephrogenic systemic fibrosis, as well as various organ-specific diseases such as radiation-induced fibrosis, cardiac fibrosis, pulmonary fibrosis, liver fibrosis, and kidney fibrosis. Although the causative mechanisms of these diseases are highly diverse and, in some cases, remain unclear, they share a common feature: the uncontrolled, progressive accumulation of fibrotic tissue in affected organs, leading to their dysfunction and eventual failure. Despite the significant heterogeneity in the pathogenetic mechanisms involved in the development of fibrosis and its clinical manifestations, numerous studies have identified activated myofibroblasts as a common cellular element ultimately responsible for the replacement of normal tissue with nonfunctional fibrotic tissue.

[0224] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting systemic fibrosis in a subject, comprising administering a compound of the present invention to a subject suffering from systemic fibrosis under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit systemic fibrosis in the subject. In some embodiments, the systemic fibrosis is systemic sclerosis. In some embodiments, the systemic fibrosis is multiple fibrosclerosis (IgG4-related fibrosis). In some embodiments, the systemic fibrosis is nephrogenic systemic fibrosis. In some embodiments, the systemic fibrosis is graft-versus-host scleroderma.

[0225] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting organ-specific fibrosis in a subject, comprising administering a compound of the present invention to a subject suffering from organ-specific fibrosis under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit organ-specific fibrosis in the subject.

[0226] In some embodiments, the organ-specific fibrosis is pulmonary fibrosis. In some embodiments, the organ-specific fibrosis is idiopathic pulmonary fibrosis (IPF).

[0227] In some embodiments, the organ-specific fibrosis is cardiac fibrosis. In some embodiments, the cardiac fibrosis is hypertension-associated cardiac fibrosis. In some embodiments, the cardiac fibrosis is a post-myocardial infarction condition. In some embodiments, the cardiac fibrosis is Chagas disease-induced myocardial fibrosis.

[0228] In some embodiments, the organ-specific fibrosis is renal fibrosis. In some embodiments, the renal fibrosis is diabetic and hypertensive nephropathy. In some embodiments, the renal fibrosis is urinary tract obstruction-induced renal fibrosis. In some embodiments, the renal fibrosis is inflammatory / autoimmune-induced renal fibrosis. In some embodiments, the renal fibrosis is aristolochic acid nephropathy. In some embodiments, the renal fibrosis is polycystic kidney disease.

[0229] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting myocardial fibrosis in a subject, comprising administering a compound of the present invention to a subject afflicted with myocardial fibrosis under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit myocardial fibrosis in the subject. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0230] In some embodiments, the organ-specific fibrosis is pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is silica-induced pneumoconiosis (silicosis). In some embodiments, the pulmonary fibrosis is asbestos-induced pulmonary fibrosis (asbestosis). In some embodiments, the pulmonary fibrosis is chemotherapy-induced pulmonary fibrosis.

[0231] In some embodiments, the organ-specific fibrosis is hepatic portal fibrosis. In some embodiments, the hepatic portal fibrosis is alcoholic liver fibrosis or non-alcoholic liver fibrosis. In some embodiments, the hepatic portal fibrosis is hepatitis C-induced liver fibrosis. In some embodiments, the hepatic portal fibrosis is primary biliary cirrhosis. In some embodiments, the hepatic portal fibrosis is parasite-induced liver fibrosis (schistosomiasis).

[0232] In some embodiments, the organ-specific fibrosis is radiation-induced fibrosis (various organs). In some embodiments, the organ-specific fibrosis is bladder fibrosis. In some embodiments, the organ-specific fibrosis is intestinal fibrosis. In some embodiments, the organ-specific fibrosis is peritoneal sclerosis.

[0233] In some embodiments, the organ-specific fibrosis is diffuse fasciitis. In some embodiments, the diffuse fasciitis is localized scleroderma, keloid. In some embodiments, the diffuse fasciitis is Dupuytren's disease. In some embodiments, the diffuse fasciitis is Peyronie's disease. In some embodiments, the diffuse fasciitis is myelofibrosis. In some embodiments, the diffuse fasciitis is oral submucous fibrosis.

[0234] In some embodiments, the organ-specific fibrosis is a result of wound healing. In some embodiments, the organ-specific fibrosis is a result of scarring.

[0235] Liver fibrosis, also referred to herein as hepatic fibrosis, can be caused by various types of chronic liver injury, especially when an inflammatory component is involved. Self-limiting acute liver injury (e.g., acute viral hepatitis A), even in its severe form, does not necessarily distort the scaffold architecture and therefore typically does not cause fibrosis despite the loss of hepatocytes. However, factors such as chronic alcoholism, malnutrition, hemochromatosis, and exposure to poisons, toxins, or drugs can lead to chronic liver injury and liver fibrosis due to exposure to hepatotoxic chemicals. Liver fibrosis can also be caused by liver scarring caused by other forms of injury associated with surgery or mechanical biliary obstruction.

[0236] Thus, in various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting liver fibrosis in a subject, comprising administering a compound of the present invention to a subject suffering from liver fibrosis under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit liver fibrosis in the subject. In some embodiments, the liver fibrosis is the result of liver scarring. In some embodiments, the liver fibrosis is the result of chronic liver injury. In some embodiments, the chronic liver injury is due to chronic alcoholism, malnutrition, hemochromatosis, or exposure to a poison, toxin, or drug; each represents a separate embodiment of the present invention. In some embodiments, the subject has cirrhosis. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0237] Although fibrosis itself is not necessarily symptomatic, it can lead to the development of cirrhosis, and scarring can lead to portal hypertension, which distorts blood flow through the liver, destroying normal liver structure and causing liver dysfunction.The degree of each of these pathologies determines the clinical symptoms of liver fibrosis.For example, in congenital hepatic fibrosis, the branches of the portal vein are affected, while the parenchyma is barely affected.As a result, portal hypertension occurs with the preservation of hepatocellular function.

[0238] Thus, in various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting liver fibrosis in a subject, comprising administering a compound of the present invention to a subject suffering from liver fibrosis under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit liver fibrosis in the subject. In some embodiments, the liver fibrosis is portal hypertension, cirrhosis, congenital hepatic fibrosis, or any combination thereof; each represents a separate embodiment of the present invention. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0239] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting portal hypertension in a subject, comprising administering a compound of the present invention to a subject suffering from portal hypertension under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit portal hypertension in the subject. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0240] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting cirrhosis in a subject, comprising administering a compound of the present invention to a subject suffering from cirrhosis under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit cirrhosis in the subject. In some embodiments, the cirrhosis is the result of hepatitis. In some embodiments, the cirrhosis is the result of alcoholism. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0241] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholism in a subject, comprising administering a compound of the present invention to a subject suffering from alcoholism under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit alcoholism in the subject. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0242] Nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) share similar pathogenesis and histopathology but differ in etiology and epidemiology. NASH and ASH are advanced stages of nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is characterized by excessive hepatic fat accumulation (steatosis), the absence of other clear causes of chronic liver disease (e.g., viral, autoimmune, or genetic), and an alcohol intake of 20-30 g / day or less. In contrast, AFLD is defined by the presence of steatosis and an alcohol intake of more than 20-30 g / day.

[0243] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting non-alcoholic steatohepatitis (NASH) in a subject, comprising administering a compound of the present invention to a subject suffering from non-alcoholic steatohepatitis (NASH) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit non-alcoholic steatohepatitis (NASH) in the subject. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0244] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholic steatohepatitis (ASH) in a subject, comprising administering a compound of the present invention to a subject suffering from alcoholic steatohepatitis (ASH) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit alcoholic steatohepatitis (ASH) in the subject. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0245] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting non-alcoholic fatty liver disease (NAFLD) in a subject, comprising administering a compound of the present invention to a subject suffering from non-alcoholic fatty liver disease (NAFLD) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit non-alcoholic fatty liver disease (NAFLD) in the subject. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0246] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholic fatty liver disease (AFLD) in a subject, comprising administering a compound of the present invention to a subject suffering from alcoholic fatty liver disease (AFLD) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit alcoholic fatty liver disease (AFLD) in the subject. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0247] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting pulmonary fibrosis in a subject, comprising administering a compound of the present invention to a subject suffering from pulmonary fibrosis under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit pulmonary fibrosis in the subject. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0248] Idiopathic pulmonary fibrosis (IPF) is an age-related, refractory lung disease that has historically had limited treatment options. The 2014 approval of two drugs, pirfenidone and nintedanib, by the U.S. Food and Drug Administration (FDA) signaled a new era in IPF treatment. Both drugs demonstrated efficacy in phase III clinical trials by slowing the rate of IPF progression. However, neither drug appears to be able to completely halt disease progression. Advances in understanding the pathobiology of IPF have led to an unprecedented expansion of the number of potential therapeutic targets. Drugs targeting some of these are under investigation in various stages of clinical development.

[0249] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting idiopathic pulmonary fibrosis (IPF) in a subject, comprising administering a compound of the present invention to a subject suffering from idiopathic pulmonary fibrosis (IPF) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit idiopathic pulmonary fibrosis (IPF) in the subject. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention. In some embodiments, the compound of the present invention is administered in combination with an agent treating IPF. In some embodiments, the compound is administered in combination with pirfenidone, nintedanib, or a combination thereof; each represents a separate embodiment of the present invention.

[0250] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting dermal fibrosis in a subject, comprising administering a compound according to the present invention to a subject suffering from dermal fibrosis under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit dermal fibrosis in the subject. In some embodiments, the dermal fibrosis is scleroderma. In some embodiments, the dermal fibrosis is the result of localized or generalized scleroderma, keloids, hypertrophic scars, familial cutaneous collagenoma, collagen-type connective tissue nevi, or any combination thereof; each represents a separate embodiment of the present invention. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0251] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting scleroderma in a subject, comprising administering a compound according to the present invention to a subject suffering from scleroderma under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit scleroderma in the subject. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0252] In various embodiments, the present invention relates to methods for inhibiting collagen I (ColI) overproduction in a subject, the method comprising administering a compound of the present invention to a subject suffering from collagen I (ColI) overproduction under conditions effective to inhibit collagen I (ColI) overproduction in the subject. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is a collagen I translation inhibitor, a collagen II translation inhibitor, a collagen III translation inhibitor, a collagen IV translation inhibitor, or a collagen V translation inhibitor; each compound represents a separate embodiment of the present invention. In some embodiments, the compound of the present invention is selective for collagen I. In some embodiments, the compound of the present invention is selective for collagen IA. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0253] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting an autoimmune disease or disorder in a subject, comprising administering a compound according to the present invention to a subject suffering from an autoimmune disease or disorder under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the autoimmune disease or disorder in the subject. In some embodiments, the compound of the present invention is a collagen I translation inhibitor. In some embodiments, the compound of the present invention is any of the compounds listed in Table 1; each compound represents a separate embodiment of the present invention.

[0254] As used herein, subject or patient refers to any mammalian patient or subject, including, but not limited to, humans or other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice, and other rodents. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the methods of the invention described herein may be useful for treating either males or females.

[0255] The following examples are presented in order to more fully illustrate the preferred embodiments of the invention, but they should in no way be construed as limiting the broad scope of the invention.

[0256] Example

[0257] overview

[0258] All compounds were profiled for cellular potency in inhibiting collagen 1 (COL1) protein translation using a phenotypic screening platform.

[0259] Example 1: Synthetic Details of Compounds of the Invention (Schemes 1-48)

[0260] General method

[0261] All reagents were commercial grade and were used as received without further purification unless otherwise stated. Reagent-grade solvents were used in all cases unless otherwise stated. Thin-layer chromatography was performed using precoated silica gel F-254 plates (0.25 mm thick). 1 H-NMR and 19 F-NMR spectra were recorded on a Bruker Avance 400 MHz or Avance III 400 MHz spectrometer. Chemical shifts are expressed in ppm using residual solvent as the internal standard. Splitting patterns are designated as s (singlet), d (doublet), dd (doublet of doublets), t (triplet), dt (doublet of triplets), q (quartet), m (multiplet), and br s (broad singlet).

[0262] Abbreviation AcOH: acetic acid amphos: bis(di-tert-butyl(4-dimethylaminophenyl))phosphine Boc: tert-butyloxycarbonyl BuLi: n-butyllithium t-BuLi: tert-butyllithium CDI: 1,1´-carbonyldiimidazole DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene dppb: 1,4-bis(diphenylphosphino)butane dppf: 1,1'-bis(diphenylphosphino)ferrocene DCM: dichloromethane DCE: 1,2-dichloroethane DEAD: Diethyl azodicarboxylate DIAD: Diisopropyl azodicarboxylate DIBAL-H: Diisobutylaluminum hydride DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMA: Dimethylacetamide DMAP: 4-(dimethylamino)pyridine DME: 1,2-dimethoxyethane DMSO: dimethylsulfonamide EDC.HCl: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride HATU: [0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate] HPLC: High Performance Liquid Chromatography MsCl: methanesulfonyl chloride NBS: N-bromosuccinimide NMP: N-methyl-2-pyrrolidone rt: room temperature SEM: 2-(trimethylsilyl)ethoxymethyl T3P: Propylphosphonic anhydride TBAF: Tetrabutylammonium fluoride TBDMS: tert-butyldimethylsilyl TBDPS: tert-butyldiphenylsilyl TCFH: N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate THF: tetrahydrofuran TMS-OTf: Trimethylsilyl trifluoromethanesulfonate

[0263] General Methods for Synthesizing Compounds of the Invention

[0264] RHS Qualification

[0265] A two-step synthetic sequence to RHS-modified analogs of compound 300 (see Table 1 for structures) is shown in Scheme 1. Scheme 1. Synthesis of 4-aryl modified analogues 5

[0266] [ka]

[0267] The first step of the synthesis involved an amide coupling reaction of 4-bromothiazol-2-amine 1 and 4-methoxybenzoic acid 2 in the presence of propylphosphonic anhydride (T3P) at elevated temperature to give intermediate 3. In the second and final step, intermediate 3 was used in Suzuki coupling reactions under microwave conditions at 120 °C. Various different arylboronic acids or pinacol esters 4 were used in the synthesis of the final compounds (4-aryl modified analogs 5) using sodium carbonate as the base and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) as catalyst in a mixture of dioxane and water.

[0268] Following a synthetic sequence similar to that shown in Scheme 1, the synthesis of 4-aryl modified analogs of 6-methylnicotinamide shown in Scheme 2 was carried out. Scheme 2. Synthesis of 4-aryl modified analogues of 6-methylnicotinamide 8

[0269] [ka]

[0270] 4-Bromothiazol-2-amine 1 was coupled in the presence of 6-methylnicotinic acid 6, propylphosphonic anhydride (T3P), and triethylamine to give the amide intermediate 7. Suzuki coupling of intermediate 7 with various boronic acids or pinacol esters 4 to introduce the RHS aryl moiety could then be carried out to give the desired final compound (6-methylnicotinamide 8). A general synthetic scheme for RHS-modified analogs of 2-methoxypyrimidine-5-carboxamide is shown in Scheme 3. Scheme 3. Synthesis of RHS-modified analogues of 2-methoxypyrimidine-5-carboxamide 11

[0271] [ka]

[0272] 4-Bromothiazol-2-amine 1 was coupled with 2-methoxypyrimidine-5-carboxylic acid 9 in the presence of propylphosphonic anhydride (T3P) and triethylamine to give the amide intermediate 10. The RHS aryl group was introduced by performing Suzuki coupling of intermediate 10 with several boronic acids or pinacol esters 4 to give the desired final compounds (2-methoxypyrimidine-5-carboxamides 11).

[0273] A general synthetic scheme to RHS-modified analogs of compound 327 (see Table 1 for structures) is shown in Scheme 4. Scheme 4. Synthesis of 4-aryl modified analogues of 4-morpholinobenzamide 14

[0274] [ka]

[0275] Coupling of 4-bromothiazol-2-amine 1 with 4-morpholinobenzoic acid 12 in the presence of propylphosphonic anhydride (T3P) and triethylamine gave the amide intermediate 13. The RHS aryl moiety was introduced by Suzuki coupling of intermediate 13 with various boronic acids or pinacol esters 4 to give the desired target compounds (4-morpholinobenzamides 14).

[0276] An alternative synthetic route was used to prepare the RHS 2-pyridyl analog 19 compound (compound 370) shown in Scheme 5. Scheme 5.2 - Synthesis of pyridyl analogue 19 (compound 370)

[0277] [ka]

[0278] Commercially available 2-acylpyridine 15 was brominated at the α-position of the keto function using N-bromosuccinimide in the presence of TMS triflate in acetonitrile to give the α-bromoketone intermediate 16. Intermediate 16 was then heated at reflux with thiourea 17 in ethanol to give the intermediate aminothiazole 18. The final amide coupling step was achieved by reacting aminotriazole 18 and 4-morpholinobenzoic acid 12 in the presence of propylphosphonic anhydride (T3P) and triethylamine to give the final compound (2-pyridyl analog 19).

[0279] LHS qualification

[0280] A synthetic route to the LHS amide analogs of compound 300 and compound 304 is shown in Scheme 6. Scheme 6. Synthesis of amide analogues 25a and 25b

[0281] [ka]

[0282] Suzuki reaction of N-Boc-4-bromothiazol-2-amine 20 with boronic acid 21a or 21b in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and sodium carbonate in dioxane and water afforded intermediate 22a or 22b. Removal of the N-Boc protecting group was achieved by treating 22a or 22b with a 4 M solution of HCl in dioxane to afford aminothiazole 23a or 23b. The key aminothiazole intermediate (aminothiazole 23a) or 23b) was converted to the target amide (amide analog 25a or 25b) using carboxylic acid 24 and the T3P protocol.

[0283] Urea-based analogues were synthesized as detailed in Scheme 7. Scheme 7. Synthesis of urea analogue 30

[0284] [ka]

[0285] The aminothiazole intermediate (aminothiazole 26) was converted to the activated carbamate intermediate (carbamate intermediate 28) by treatment with phenylchloroformate (26) in pyridine at room temperature. Carbamate intermediate 28 was then reacted with 4-(piperidin-4-yl)morpholine 29 in the presence of triethylamine and pyridine to give the desired urea analog 30.

[0286] Piperazine sulfonamide analogs were accessed via the synthetic route shown in Scheme 8. Scheme 8. Synthesis of piperazine sulfonamide analogue 34

[0287] [ka]

[0288] The starting aminothiazole 26 was coupled with 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid 31 using the previously described T3P protocol to give the intermediate amide 32. N-Boc deprotection of these N-Boc-protected piperazine amide intermediates (intermediate amide 32) with a 4 M solution of HCl in dioxane gave the amine intermediate 33 as the free base after basic aqueous workup. Sulfonylation of the piperazine intermediate (amine intermediate 33) with methanesulfonyl chloride in DCM in the presence of triethylamine gave the desired piperazine sulfonamide (piperazine sulfonamide analog 34).

[0289] The synthesis of two commercially unavailable morpholinocarboxylic acids is summarized in Scheme 9. Scheme 9. Synthesis of two commercially unavailable morpholinocarboxylic acids

[0290] [ka]

[0291] Aromatic substitution of commercially available chloropyrazine and pyridazine esters 35 and 39 with morpholine 36 using microwave at 100 °C provided access to the morpholino ester intermediates 37 and 40, respectively. Refluxing of these intermediates 37 and 40 in 6 M aqueous hydrochloric acid gave the morpholino carboxylic acids 38 and 41, respectively, as their hydrochloride salts.

[0292] Scaffold modification

[0293] The synthesis of oxazole analog 45 is shown in Scheme 10. Scheme 10. Synthesis of oxazole analogue 45 (compound 368)

[0294] [ka]

[0295] Commercially available 2-chlorophenyl-bromoketone 42 was heated in DMF with urea 43 in a microwave at 130 °C to give the cyclized aminooxazole 44. Amide coupling of the aminooxazole intermediate 43 and 4-morpholinobenzoic acid 12 in the final step using the propylphosphonic anhydride (T3P) protocol gave the desired target (oxazole analog 45) (compound 368).

[0296] The general synthesis of combinatorial analogs combining a morpholino heteroaryl LHS moiety with an RHS aryl / heteroaryl group is shown in Scheme 11 (see Table 1 for structures). Scheme 11. General synthesis of combination analogs 51 to 55

[0297] [ka]

[0298] Suzuki coupling of N-Boc 4-bromothiazol-2-amine 20 and various boronic acids or pinacol esters 4 using [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and sodium carbonate in dioxane and water at 100 °C enabled the synthesis of N-Boc aminothiazole intermediates 46.

[0299] Removal of the N-Boc protecting group was achieved by treating the N-Boc aminothiazole intermediate 46 with a 4 M HCl solution in dioxane, followed by a basic aqueous workup to give the aminothiazole intermediate 47 as the free radical. The aminothiazole intermediate 47 was converted to the desired amides (analogs 51 to 55) using one of two amide coupling protocols. For free-base morpholino carboxylic acids of types 48, 49, and 50, the T3P protocol was used to prepare the target amide analogs (analogs 51, 52, and 53). The hydrochloride salts of 38 and 41 were successfully converted to the final target amides 54 and 55, respectively, using the TCFH coupling reagent in the presence of 1-methylimidazole.

[0300] A three-step synthesis of compound 60 (compound 376) is outlined in Scheme 12. Scheme 12. Synthesis of Compound 60 (Compound 376)

[0301] [ka]

[0302] In the first step, amide coupling of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid 31 with 4-(2-chlorophenyl)thiazol-2-amine 56 was carried out using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and DMAP in DMF at 100 °C to deliver intermediate 57 in high yield. This amide coupling protocol facilitated scale-up and was an alternative approach to the T3P protocol described in Scheme 8. Removal of the N-Boc protecting group was achieved by treating intermediate 57 with a 4 M solution of HCl in dioxane to give aminothiazole intermediate 58. In the final step, amide coupling of aminothiazole intermediate 58 with 3-methoxypropanoic acid 59 using HATU coupling conditions gave the final compound 60 (compound 376).

[0303] A single-step synthesis of compound 62 (compound 377) from intermediate 58 is outlined in Scheme 13. Scheme 13. Synthesis of Compound 62 (Compound 377)

[0304] [ka]

[0305] The piperazine intermediate (58) was N-alkylated with 2-bromoethyl methyl ether 61 in the presence of potassium carbonate and potassium iodide in DMF at 80 °C to readily synthesize the final compound 62 (compound 377).

[0306] The single-step synthesis of compounds 64 and 66 (compounds 378 and 379) is shown in Scheme 14. Scheme 14. Synthesis of Compounds 64 and 66 (Compounds 378 and 379)

[0307] [ka]

[0308] Suzuki coupling of bromothiazole intermediate (intermediate 13) and (2-(2-methoxyethoxy)phenyl)boronic acid 63, typically by combining tetrakis(triphenylphosphine)palladium(0) and cesium carbonate in dioxane and water at 100 °C, enabled the synthesis of compound 64 (compound 378).

[0309] 2-[(2-methoxyethoxy)methyl]phenylboronic acid 65 was subjected to a conventional thermal Suzuki coupling protocol to give the final compound 66 (compound 379).

[0310] The single-step synthesis of compounds (amide N-methyl substituted analogs 69) and 70 (compounds 399 and 400) (see Table 1 for structures) is shown in Scheme 15. Scheme 15. Synthesis of Amide N-Methyl-Substituted Analogues 69 and 70

[0311] [ka]

[0312] The intermediate amides 67 and 68 were N-alkylated with sodium hydride in DMF as a base at 0 °C, followed by the addition of iodomethane at room temperature to give the final compounds (amide N-methyl-substituted analogs 69) and 70 (compounds 399 and 400).

[0313] The general synthesis of bisamide analogs combining various amine LHS moieties with RHS aryl / heteroaryl groups is shown in Scheme 16 (see Table 1 for structures). Scheme 16. General synthesis of bisamide 79

[0314] [ka]

[0315] The first step of the synthesis involved the amide coupling reaction of 4-(2-chlorophenyl)thiazol-2-amine 56 and 4-(methoxycarbonyl)benzoic acid 75 in the presence of HATU and DIPEA in DMF to give intermediate 76. In the second step of the synthesis, the methyl ester intermediate 76 was hydrolyzed using lithium hydroxide to give the carboxylic acid intermediate 77. The final step of the synthesis was an amide coupling reaction using the same reaction conditions as in the first step. Various amines 78 were used to finally give the bisamide compound 79.

[0316] Using a synthetic sequence similar to that described above, the compound outlined in Scheme 17 (Compound 430) was synthesized. Scheme 17. Synthesis of (1r,3r)-N-(4-(2-chlorophenyl)thiazol-2-yl)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)cyclobutane-1-carboxamide 84 (compound 430)

[0317] [ka]

[0318] HATU-mediated amide coupling reaction of 4-(2-chlorophenyl)thiazol-2-amine 56 and 3-(methoxycarbonyl)cyclobutane-1-carboxylic acid 80 gave amide 81. The methyl ester intermediate (81) was hydrolyzed with lithium hydroxide in aqueous THF to give carboxylic acid intermediate 82. In the final step, HATU-mediated amide coupling of the carboxylic acid (carboxylic acid intermediate 82) with amine 83 gave the final compound (compound 430).

[0319] The piperazine sulfonamide analogue compound 91 (compound 403) was accessed via the synthetic route shown in Scheme 18. Scheme 18. Synthesis of piperazine sulfonamide analogue compound 91 (compound 403)

[0320] [ka]

[0321] The first step of the synthetic sequence involves the Buchwald CN coupling reaction of 5-bromopicolinate 85 and tert-butylpiperazine-1-carboxylate 86 to generate the methyl ester intermediate 87. Hydrolysis of the intermediate methyl ester with lithium hydroxide in aqueous THF at room temperature gave the carboxylic acid intermediate 88. Intermediate 88 then underwent a two-step amide coupling reaction to generate the amide intermediate 89. First, an acylimidazole-activated intermediate of carboxylic acid 88 was generated using CDI in DMF at 50 °C. The acylimidazole-activated intermediate was then reacted with 4-(2-chlorophenyl)thiazol-2-amine 56 in the presence of sodium hydride at 0 °C to generate the amide. Removal of the N-Boc protecting group was achieved by treating intermediate 89 with a 4 M solution of HCl in dioxane to give the key piperazine intermediate (piperazine intermediate 90) as the hydrochloride salt. The piperazine key intermediate (piperazine intermediate 90) was sulfonylated with methanesulfonyl chloride in the presence of triethylamine in DMF to give the desired piperazine sulfonamide (piperazine sulfonamide analogue compound 91) (compound 403).

[0322] An alternative synthesis for preparing the piperazine key intermediate (piperazine intermediate 90) is shown in Scheme 19. Scheme 19. Alternative synthesis of the piperazine key intermediate amine (piperazine intermediate 90)

[0323] [ka]

[0324] The amide intermediate 92 was generated by reacting 4-(2-chlorophenyl)thiazol-2-amine 56 and 5-fluoropicolinic acid (91) in the presence of propylphosphonic anhydride (T3P) and triethylamine in ethyl acetate at elevated temperature. In this synthetic route, intermediate 89 was generated by nucleophilic aromatic substitution with tert-butylpiperazine-1-carboxylate (86) using DIPEA as the base in NMP at 110 °C. Removal of the N-Boc protecting group under acidic conditions, as described in Scheme 19, afforded the same piperazine intermediate 90 as its hydrochloride salt.

[0325] A synthetic sequence similar to that described above in Scheme 18 was used to synthesize the 2-substituted 2,7-diazaspiro[3.5]nonane intermediate 96 outlined in Scheme 20. Scheme 20. Synthesis of 2-substituted 2,7-diazaspiro[3.5]nonane key intermediate (96)

[0326] [ka]

[0327] In the first step of the synthetic sequence, the methyl ester intermediate 93 was generated by a Buchwald CN coupling reaction of methyl 5-bromopicolinate 85 and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylic acid (92). Hydrolysis of the intermediate methyl ester with lithium hydroxide in aqueous THF at room temperature gave the carboxylic acid intermediate (carboxylic acid 94). The amide intermediate 95 was generated by a two-step amide coupling reaction of intermediate 93. First, an acylimidazole-activated intermediate of carboxylic acid 94 was generated using CDI in DMF at 50 °C. The acylimidazole-activated intermediate was then reacted with 4-(2-chlorophenyl)thiazol-2-amine 56 in the presence of sodium hydride at 0 °C to generate the amide. Removal of the N-Boc protecting group was achieved by treating intermediate 95 with a 4 M solution of HCl in dioxane to give the intermediate substituted 2,7-diazaspiro[3.5]nonane (96) as the hydrochloride salt.

[0328] Using a synthetic sequence similar to that described above in Scheme 19, the synthesis of 2-substituted 2,6-diazaspiro[3.3]heptane intermediate 99 was accomplished as shown in Scheme 21. Scheme 21. Synthesis of 2-substituted 2,6-diazaspiro[3.3]heptane key intermediate (heptane intermediate 99)

[0329] [ka]

[0330] In this synthetic route, intermediate 98 was generated by aromatic nucleophilic substitution with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate 97 using DIPEA as a base in NMP at 110 °C. Removal of the N-Boc protecting group was achieved by treating intermediate 98 with trifluoroacetic acid in DCM at room temperature. The substituted 2,6-diazaspiro[3.3]heptane key intermediate (heptane intermediate 99) was generated as the trifluoroacetate salt.

[0331] The synthesis of O-linked piperidine intermediate 105 is shown in Scheme 22. Scheme 22. Synthesis of O-linked piperidine intermediate 105

[0332] [ka]

[0333] The first step of the synthesis involved the Mitsunobu reaction of methyl 5-hydroxypicolinate 100 and N-substituted piperidin-4-ol 101 in the presence of triphenylphosphine, followed by DEAD or DIAD in THF at room temperature to give the methyl ester intermediate 102. Hydrolysis of the methyl ester intermediate 102 with lithium hydroxide in aqueous THF at room temperature gave the carboxylic acid 103. The carboxylic acid intermediate (carboxylic acid 103) was amide-coupled with 4-(2-chlorophenyl)thiazol-2-amine 56 using HATU and DIPEA in DMF at room temperature to give the amide intermediate 104. Removal of the N-Boc protecting group of intermediate 104a was achieved using a 4 M solution of HCl in dioxane to give piperidine 105 as the hydrochloride salt.

[0334] The synthesis of the commercially unavailable boronic ester 109 is outlined in Scheme 23. Scheme 23. Synthesis of (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl acetate (boronic ester 109)

[0335] [ka]

[0336] (3-Bromopyridin-2-yl)methanol 106 was protected as acetate 107 using acetic anhydride in the presence of triethylamine and DMAP in DCM at room temperature. The acetate intermediate (acetate 107) was reacted with bis(pinacolato)diboron 108 in the presence of potassium acetate in dioxane at elevated temperature using [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) as catalyst to give the heteroaryl boronate reagent (boronate 109).

[0337] A general synthetic scheme for RHS-modified analogs of compound 471 (compound 114) (see Table 1 for structures) is shown in Scheme 24. Scheme 24. Synthesis of RHS-modified analogues of compound 114

[0338] [ka]

[0339] Amide intermediate 110 was synthesized by reacting commercially available 4-bromothiazol-2-amine 1 and 5-fluoropicolinic acid (91) in ethyl acetate in the presence of T3P at 70 °C. Subsequent aromatic nucleophilic substitution of amide intermediate 110 and tert-butylpiperazine-1-carboxylic acid ester (86) in NMP and DIPEA at 90 °C yielded intermediate 111. Removal of the N-Boc protecting group was achieved by treating intermediate 111 with a 4 M solution of HCl in dioxane to afford piperazine 112 as the hydrochloride salt. Acetylation of piperazine 112 with acetic anhydride and triethylamine in DMF at room temperature afforded N-acetylpiperazine intermediate 113. The final step in the synthesis of intermediate 113 was a Suzuki coupling to deliver the RHS-modified analog (compound 114). Various arylboronic acid or pinacol esters 4 were used in a mixture of dioxane and water at elevated temperature using tetrakis(triphenylphosphine)palladium(0) as catalyst in the presence of potassium carbonate.

[0340] The synthesis of amide imidazole analog 118 (compound 404) is shown in Scheme 25. Scheme 25. Synthesis of imidazole analog 118 (compound 404)

[0341] [ka]

[0342] Cyclization by condensation of 2-bromo-1-(2-chlorophenyl)ethan-1-one (42) with N-carbamidoylacetamide 115 using microwave heating at 90 °C gave the acetamidoimidazole 116 intermediate. Removal of the N-acetyl protecting group was achieved by treating acetamidoimidazole 116 with concentrated sulfuric acid in aqueous ethanol using microwave heating at 100 °C. The resulting aminoimidazole intermediate 117 was then coupled with carboxylic acid 49 in the final step using a similar protocol as described in Scheme 22 to give the amide imidazole analog 118 (compound 404).

[0343] A three-step synthesis of commercially unavailable 4-substituted-2-aminethiazole 122 is outlined in Scheme 26. Scheme 26. Synthesis of 4-(tetrahydro-2H-pyran-4-yl)thiazol-2-amine (122)

[0344] [ka]

[0345] The synthesis began with the Suzuki coupling reaction of tert-butyl (4-bromothiazol-2-yl)carbamate 20 with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 119 in aqueous dioxane at 80 °C using palladium(0) tetrakis and potassium carbonate as catalysts to give intermediate 120. In the second step, the double bond of intermediate 120 was reduced by hydrogenation to give tetrahydro-2H-pyran-4-yl intermediate 121 using Pearlman's catalyst in methanol at room temperature. Removal of the N-Boc protecting group was achieved by treating intermediate 121 with trifluoroacetic acid in DCM at room temperature to give 4-(tetrahydro-2H-pyran-4-yl)thiazol-2-amine (122).

[0346] The two-step synthesis of another commercially unavailable 4-substituted-2-aminethiazole 125 is outlined in Scheme 27. Scheme 27. Synthesis of 1-(2-aminothiazol-4-yl)pyrrolidin-2-one (125)

[0347] [ka]

[0348] The synthesis of 1-(2-aminothiazol-4-yl)pyrrolidin-2-one (125) began with the Buchwald CN coupling reaction of tert-butyl (4-bromothiazol-2-yl)carbamate 20 and pyrrolidin-2-one 123 to give the N-Boc protected intermediate 124. In the final step, the N-Boc protecting group was removed by treating intermediate 124 with trifluoroacetic acid in DCM at room temperature to give 1-(2-aminothiazol-4-yl)pyrrolidin-2-one (125).

[0349] As summarized in Scheme 28, the Hantzsch thiazole cyclization reaction was used to synthesize the commercially unavailable 4-substituted-2-amine thiazole 127. Scheme 28. Synthesis of 4-(2-(methoxymethyl)phenyl)thiazol-2-amine (127)

[0350] [ka]

[0351] Commercially available 2-bromo-1-(2-(methoxymethyl)phenyl)ethan-1-one 126 was heated at reflux in ethanol with thiourea 17 to give 2-aminothiazole (127).

[0352] The two-step synthesis of three commercially unavailable 4-morpholino-2-substituted-benzoic acids 130a, 130b and 130c is summarized in Scheme 29 below. Scheme 29. Synthesis of 4-morpholino-2-substituted-benzoic acid 130

[0353] [ka]

[0354] In the first step, the nucleophilic aromatic substitution reaction of commercially available 4-fluorobenzaldehyde 128 and morpholine 36 was carried out in the presence of potassium carbonate in DMF at 120 °C to give the 2-substituted-4-morpholinobenzaldehyde intermediate 129. Finally, the aldehyde moiety of intermediate 129 was oxidized to the carboxylic acid (130) via Pinnick oxidation.

[0355] A two-step synthesis of the commercially unavailable 2-methoxy-4-morpholinobenzoic acid 130d is outlined in Scheme 30. Scheme 30. Synthesis of 2-methoxy-4-morpholinobenzoic acid 130d

[0356] [ka]

[0357] In the first step, Buchwald C-N coupling reaction of methyl 4-bromo-2-methoxybenzoate 131 and morpholine 36 gave the methyl ester intermediate 132. The methyl ester was then hydrolyzed with lithium hydroxide in aqueous THF at room temperature to give 2-methoxy-4-morpholinobenzoic acid 130d, a non-commercially available reagent.

[0358] The synthesis of three commercially unavailable carboxylic acids 138a, 138b and 138c is summarized in Scheme 31. Scheme 31. Synthesis of commercially unavailable carboxylic acid 138

[0359] [ka]

[0360] In the first step, Suzuki coupling reaction of commercially available allyl bromide methyl ester 133 and boronate ester 134 (X = O or S) was carried out using tetrakis(triphenylphosphine)palladium(0) as catalyst in the presence of a mixture of potassium carbonate, dioxane, and water to give intermediate 135. In the second step, the double bond of 135 was reduced by hydrogenation using white oxide (Adams catalyst) in methanol to give methyl ester intermediate 136. For intermediate 136 where X is sulfur, the tetrahydro-2H-thiopyran moiety was oxidized to tetrahydro-2H-thiopyran 1,1-dioxide using Oxone as the oxidant in a mixture of methanol, acetone, and water at room temperature to generate methyl ester intermediate 137. In the final step of the synthesis, the methyl ester moiety of intermediate 136 or 137 was hydrolyzed using lithium hydroxide in aqueous THF to deliver the carboxylic acid intermediate (carboxylic acid 138). The overall synthetic sequence involved four steps for carboxylic acids 138a and 138b, but only three steps for carboxylic acid 138c.

[0361] The two-step synthesis of several other non-commercially available 5-(aminoalkyl)picolinic acids (141) is summarized in Scheme 32. Scheme 32. Synthesis of commercially unavailable 5-(aminoalkyl)picolinic acids (141)

[0362] [ka]

[0363] The synthetic sequence in Scheme 32 was similar to the first two steps described in Scheme 19. The first step involved a Buchwald C—N coupling reaction between methyl 5-bromopicolinate 85 and a variety of different amines 139 to generate the methyl ester intermediate 140. Hydrolysis of the intermediate methyl ester with lithium hydroxide in aqueous THF at room temperature afforded the carboxylic acid 141 intermediate.

[0364] The seven-step synthesis of compound 150 (compound 454) is summarized in Scheme 33. Scheme 33. Synthesis of Compound 150 (Compound 454)

[0365] [ka]

[0366] Carboxylic acid 144 was prepared in three steps from commercially available tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylic acid 87. Removal of the N-Boc protecting group of the starting material (tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylic acid 87) with a 4 M solution of HCl in dioxane gave piperazine intermediate 142. Sulfonylation of piperazine intermediate 142 by reaction with methanesulfonyl chloride in DCM in the presence of triethylamine gave sulfonamide intermediate 143. Subsequent hydrolysis of the methyl ester of intermediate 143 with lithium hydroxide in aqueous THF at room temperature gave carboxylic acid 144.

[0367] Amide coupling of the carboxylic acid intermediate (144) with 4-(2-bromophenyl)thiazol-2-amine 145 in four steps using HATU and DIPEA in DMF at room temperature gave amide intermediate 146. Palladium-catalyzed cross-coupling of the 2-bromophenyl moiety of intermediate 146 with commercially available potassium vinyltrifluoroborate 147 in the presence of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and cesium carbonate in aqueous dioxane at elevated temperature gave intermediate 148. Oxidative cleavage of the 2-vinylphenyl intermediate 148 facilitated the synthesis of the aldehyde intermediate 149. Oxidative cleavage was carried out using potassium osmate(VI) dihydrate and sodium periodate in the presence of 2,6-lutidine in a mixture of ethyl acetate and water at ambient temperature. In the final step, the aldehyde group of intermediate 149 was reduced using sodium borohydride in methanol at room temperature to give the final primary alcohol compound 150.

[0368] The synthesis of the commercially unavailable 3-(4-(methylsulfonyl)piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid 157 is outlined in Scheme 34. Scheme 34. Synthesis of commercially unavailable 3-(4-(methylsulfonyl)piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid 157

[0369] [ka]

[0370] Commercially available benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate 151 was oxidatively cleaved using conditions similar to those determined in Scheme 33 to give the bis-aldehyde intermediate 152. Reductive amination of bis-aldehyde intermediate 152 with methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride 153 in the presence of sodium cyanoborohydride and acetic acid in methanol afforded the N-Cbz-protected piperazine intermediate 154. Removal of the N-Cbz-protecting group by palladium-catalyzed hydrogenation in ethyl acetate at ambient temperature produced piperazine intermediate 155 as the free base. Sulfonylation of piperazine intermediate 155 by reaction with methanesulfonyl chloride in DCM in the presence of triethylamine afforded sulfonamide intermediate 156. In the final step, the methyl ester of intermediate 156 was hydrolyzed with lithium hydroxide in aqueous THF at room temperature to give the desired carboxylic acid 157.

[0371] The synthesis of the commercially unavailable 3-morpholinobicyclo[1.1.1]pentane-1-carboxylic acid 160 and (1R,3R)-3-morpholinocyclobutane-1-carboxylic acid 163 is summarized in Scheme 35. Scheme 35. Synthesis of commercially unavailable carboxylic acids 160 and 163

[0372] [ka]

[0373] The starting material (methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride 153) and the amino moiety of 161 were subjected to an N-dialkylation cyclization step using 1-bromo-2-(2-bromoethoxy)ethane 158 to generate the morpholine ring in intermediates 159 and 162, respectively. The N-dialkylation cyclization reaction was carried out in potassium carbonate-based acetonitrile at 90 °C. In the final step, the methyl esters of intermediates 159 and 162 were hydrolyzed with lithium hydroxide in aqueous THF at room temperature to give the desired carboxylic acids 160 and 163, respectively.

[0374] The four-step synthesis of compound 168 (compound 455) is summarized in Scheme 36. Scheme 36. Synthesis of Compound 168 (Compound 455)

[0375] [ka]

[0376] Carboxylic acid 166 was synthesized in two steps from commercially available ethyl 3-hydroxypropanoate 164. The first step involved protection of the primary alcohol of the starting material (ethyl 3-hydroxypropanoate 164) with a tert-butyldiphenylsilyl (TBDPS) protecting group using TBDPSCl in the presence of imidazole in DCM at room temperature to give the ethyl ester intermediate 165. In the second step, the ethyl ester of intermediate 156 was hydrolyzed with lithium hydroxide in aqueous THF at room temperature to give the carboxylic acid intermediate (carboxylic acid 166). The carboxylic acid intermediate (carboxylic acid 166) underwent amide coupling with piperazine amide intermediate 90 using HATU and DIPEA in DMF at room temperature to give piperazine amide intermediate 167. In the final step, the O-TBDPS protecting group of intermediate 167 was removed using TBAF in aqueous THF at elevated temperature to give the final compound 168 (compound 455).

[0377] The synthesis of compound 171 (compound 460) is summarized in Scheme 37. Scheme 37. Synthesis of Compound 171 (Compound 460)

[0378] [ka]

[0379] The first step of the synthesis involved the amide coupling reaction of 4-bromothiazol-2-amine 1 and 5-(4-(methylsulfonyl)piperazin-1-yl)picolinic acid (144) in the presence of propylphosphonic anhydride (T3P) in ethyl acetate at 70 °C to give the amide intermediate 169. The final step involved the palladium-catalyzed Suzuki coupling reaction of 4-bromothiazolamide intermediate 169 and 2-[(dimethylamino)methyl]phenylboronic acid 170 to give the final compound 171 (compound 460). The Suzuki coupling reaction was carried out using tetrakis(triphenylphosphine)palladium(0) as the catalyst and potassium carbonate as the base in aqueous dioxane at 110 °C.

[0380] The synthesis of compound 176 (compound 468) is summarized in Scheme 38. Scheme 38. Synthesis of Compound 176 (Compound 468)

[0381] [ka]

[0382] Carboxylic acid 172 was synthesized using the chemistry described in Scheme 32 (172 is an example of carboxylic acid 141 in Scheme 32). In the first step of the synthesis, an amide coupling reaction between 4-bromothiazol-2-amine 1 and 5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)picolinic acid (172) was carried out in ethyl acetate in the presence of propylphosphonic anhydride (T3P) at 70 °C to generate amide intermediate 173. In step 2, a palladium-catalyzed Suzuki coupling reaction of 4-bromothiazolamide intermediate 173 and 2-(methoxymethyl)phenylboronic acid 174 gave O-TBDMS-protected intermediate 175. In the final step, removal of the O-TBDMS protecting group of intermediate 175 was achieved by treatment with TBAF in THF at room temperature to give final compound 176 (compound 468).

[0383] The two-step synthesis of the three final compounds 179, 182 and 185 (see Table 1 for structures) is shown in Scheme 39. Scheme 39. Synthesis of final compounds 179, 182 and 185

[0384] [ka]

[0385] In the first step of the synthesis, the corresponding acids 177, 180, and 183 of 4-(2-chlorophenyl)thiazol-2-amine 56 were subjected to amide coupling reaction in the presence of propylphosphonic anhydride (T3P) at 70 °C to generate the amide intermediates 178, 181, and 184, respectively. In the final step, the aryl / heteroaryl bromide moieties of amide intermediates 178, 181, and 184 were subjected to palladium-catalyzed Buchwald CN coupling reaction with various secondary amines 139 to give the final compounds 179, 182, and 185, respectively.

[0386] The synthesis of compound 186 is outlined in Scheme 40. Scheme 40. Synthesis of Compound 186

[0387] [ka]

[0388] The aryl nucleophilic substitution (SNAr) reaction of N-(4-(2-chlorophenyl)thiazol-2-yl)-5-fluoropicolinamide (92) with various secondary cyclic amines gave the final compound 186. The reaction was carried out in DMF with DIPEA as the base at elevated temperature.

[0389] The synthesis of final compounds 188a and 189 is outlined in Scheme 41. Scheme 41. Synthesis of Compounds 188a and 189 (Compounds 437 and 451)

[0390] [ka]

[0391] In the first step of the synthesis, a palladium-catalyzed direct amidation reaction was carried out using 5-bromo-N-(4-(2-chlorophenyl)thiazol-2-yl)picolinamide (amide intermediate 181), carbon monoxide (for CO insertion), and either 1-methylpiperazine 187 or tert-butylpiperazine-1-carboxylic acid (86) as the secondary amine to give final compound 188a or intermediate 188b, respectively. Removal of the N-Boc protecting group was achieved by treating intermediate 188b with a 4 M solution of HCl in dioxane to give the final piperazine compound 189.

[0392] The related syntheses of compounds 193 and 196 (compounds 463 and 462) are summarized in Scheme 42. Scheme 42. Synthesis of Compounds 193 and 196 (Compounds 463 and 462)

[0393] [ka]

[0394] In the first step of the synthesis, 4-(2-chlorophenyl)thiazol-2-amine 56, carboxylic acids 190, and 194 underwent an amide coupling reaction in the presence of propylphosphonic anhydride (T3P) at 70 °C to give amide intermediates 191 and 195, respectively. In the final step, the heteroaryl bromide moiety of amide intermediates 191 and 195 and 1-acetylpiperazine 192 underwent a palladium-catalyzed Buchwald C-N coupling reaction to give final compounds 193 and 196, respectively.

[0395] The synthesis of compounds 200, 201 and 204 (compounds 435, 434 and 421) is summarized in Scheme 43. Scheme 43. Synthesis of Compounds 200, 201, and 204 (Compounds 435, 434, and 421)

[0396] [ka]

[0397] The first step of the synthesis was the amide coupling reaction of 4-(2-chlorophenyl)thiazol-2-amine 56 with carboxylic acids 197 and 202 in the presence of HATU and triethylamine at room temperature to generate amide intermediates 198 and 203, respectively. The final step was the reductive alkylation of the ketone functionality of intermediates 198 or 203 with 1-(methylsulfonyl)piperazine 199 and morpholine 36, respectively. The reaction was carried out in methanol using sodium cyanoborohydride and acetic acid to give the final compounds 200, 201, and 204.

[0398] The synthesis of amide compounds 206, 208, 210 and 212 is summarized in Scheme 44. Scheme 44. Synthesis of amide compounds 206, 208, 210, and 212

[0399] [ka]

[0400] Starting from carboxylic acids 205, 207 (different R3 substituents), 209, and 211, the final amide compounds (amide compounds 206, 208, 210, and 212) were synthesized via thiazolamine 26 and amide formation, respectively. Generally, the reaction was carried out at room temperature using HATU and DIPEA in DMF. Alternative reaction conditions may be employed for carboxylic acid 207, including a two-step protocol for preparing final amide compound 208. Carboxylic acid 207 was first activated with CDI in DMF at 50 °C, and then in the second step, treated with the thiazolamine intermediate (thiazolamine 26) and deprotonated using sodium hydride as a strong base in DMF.

[0401] The synthesis of amide compound 216 is summarized in Scheme 45. Scheme 45. Synthesis of amide compound 216

[0402] [ka]

[0403] Amide compound 216 was synthesized by the reaction of the NH of the piperazine group of 213 with acid anhydride 214a or various acid chlorides 214b. The reaction was carried out in DCM in the presence of triethylamine as a base at room temperature. Alternatively, amide formation can be carried out using carboxylic acid 215 in the presence of HATU and DIPEA in DMF at room temperature.

[0404] The synthesis of sulfonamide compound 217 is summarized in Scheme 46. Scheme 46. Synthesis of sulfonamide compound 217

[0405] [ka]

[0406] Sulfonamide compound 217 was synthesized by sulfonation of the NH of the piperazine group of 213 with methanesulfonyl chloride using triethylamine in DCM at room temperature.

[0407] The synthesis of N-alkyl compound 219 is summarized in Scheme 47. Scheme 47. Synthesis of N-Alkyl Compound 219

[0408] [ka]

[0409] The N-alkyl compounds 219 were synthesized by reductive alkylation of the NH of the piperazine group of 213 with various aldehydes 218. The reaction was carried out in methanol with sodium cyanoborohydride at room temperature.

[0410] The synthesis of N-alkyl compound 221 is summarized in Scheme 48. Scheme 48. Synthesis of N-Alkyl Compound 221

[0411] [ka]

[0412] The N-alkylated compounds 221 were synthesized by direct alkylation of the NH of the piperazine group of 213 with various alkyl halides 220. The reaction was carried out at elevated temperature using DIPEA as a base in DMF.

[0413] Detailed synthesis of intermediates for compounds of the present invention

[0414] Synthesis of N-(4-bromothiazol-2-yl)-4-methoxybenzamide

[0415] [ka]

[0416] To a solution of 4-bromothiazol-2-amine (1 g, 5.59 mmol) and 4-methoxybenzoic acid (1.28 g, 8.38 mmol) in anhydrous DCM (10 mL) was added triethylamine (4.7 mL, 33.5 mmol), followed by a solution of T3P (50% in ethyl acetate, 10 mL, 33.5 mmol). The reaction mixture was heated at 40° C. for 18 h. After cooling to room temperature, the mixture was partitioned between DCM (30 mL) and water (30 mL). The layers were separated, and the organic phase was washed with brine (50 mL). The organic layer was dried (MgSO), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-25% ethyl acetate in cyclohexane) to give N-(4-bromothiazol-2-yl)-4-methoxybenzamide as a pale yellow solid.

[0417] Yield 1.32g (75%). 1H NMR(400MHz,DMSO)δ12.82(brs,1H),8.12(d,J=9.0Hz,2H),7.39(s,1H),7.21(d,J=9.0Hz,2H),3.94(s,3H).

[0418] Synthesis of N-(4-bromothiazol-2-yl)-6-methylnicotinamide

[0419] [ka]

[0420] To a solution of 4-bromothiazol-2-amine (1 g, 5.59 mmol) and 6-methylnicotinic acid (1.15 g, 8.38 mmol) in anhydrous DCM (10 mL) was added triethylamine (4.7 mL, 33.5 mmol), followed by a solution of T3P (50% in ethyl acetate, 10 mL, 33.5 mmol). The reaction mixture was heated at 45° C. for 18 h. After cooling to room temperature, the mixture was partitioned between DCM (30 mL) and water (30 mL). The layers were separated, and the organic phase was washed with brine (50 mL). The organic layer was dried (MgSO), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% ethyl acetate in cyclohexane) to give N-(4-bromothiazol-2-yl)-6-methylnicotinamide as a pale yellow solid.

[0421] Yield 898mg (54%). 1 H NMR(400MHz,DMSO)δ13.09(s,1H),9.11(d,J=2.0Hz,1H),8.32(dd,J=2.0,8.0Hz,1H),7.46(d,J=8.0Hz,1H),7.41(s,1H),2.58(s,3H).

[0422] Synthesis of tert-butyl (4-(2,4-dichlorophenyl)thiazol-2-yl)carbamate

[0423] [ka]

[0424] To a mixture of tert-butyl 4-bromothiazol-2-ylcarbamate (1.5 g, 5.37 mmol) and (2,4-dichlorophenyl)boronic acid (2.05 g, 10.75 mmol) was added a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (439 mg, 0.537 mmol) in 1,4-dioxane (25 mL) and an aqueous solution of sodium carbonate (1.71 mg, 16.12 mmol) in water (1 mL). The reaction mixture was heated at 85 °C for 18 h. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL) and filtered through a plug of Celite. The filtrate was collected, washed with brine (50 mL), dried (MgSO), filtered, and evaporated. The residue was purified by silica gel (4-(2,4-dichlorophenyl)thiazol-2-yl) column chromatography to give the tert-butyl carbamate as an off-white foam.

[0425] Yield 1.46g (79%). 1 H NMR(400MHz,DMSO)δ11.63(brs,1H),7.87(d,J=8.5Hz,1H),7.71(d,J=2.1Hz,1H),7.64(s,1H),7.53(dd,J=2.2,8.5Hz,1H),1.51(s,9H).

[0426] Synthesis of 4-(2,4-dichlorophenyl)thiazol-2-amine

[0427] [ka]

[0428] To a solution of tert-butyl(4-(2,4-dichlorophenyl)thiazol-2-yl)carbamate (1.46 g, 4.23 mmol) in 1,4-dioxane was added a 4 M solution of HCl in 1,4-dioxane (4 mL, 16 mmol) in 1,4-dioxane (8 mL). The reaction mixture was stirred at room temperature for 18 h and then heated at 50 °C for 3 days. After cooling to room temperature, the mixture was partitioned between ethyl acetate (15 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (2 × 15 mL), and the combined organic extracts were dried (MgSO), filtered, and concentrated to give 4-(2,4-dichlorophenyl)thiazol-2-amine as a pale yellow solid.

[0429] Yield 1g (96%). 1 H NMR(400MHz,DMSO)δ7.89(d,J=8.6Hz,1H),7.66(s,1H),7.48(d,J=8.6Hz,1H),7.11(m,3H).

[0430] Synthesis of 1-(2-bromophenyl)azetidine

[0431] [ka]

[0432] To a degassed mixture of 1-bromo-2-iodobenzene (0.14 mL, 1.06 mmol), azetidine (0.086 mL, 1.27 mmol), and sodium tert-butoxide (357 mg, 3.71 mmol) in THF (4 mL) was added tris(dibenzylideneacetone)dipalladium(0) (97 mg, 0.106 mmol) and rac-BINAP (330 mg, 0.53 mmol). The reaction mixture was stirred at 50 °C for 18 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL), filtered through Celite, and the filtrate was evaporated. The orange residue was purified by column chromatography on silica gel (0–10% ethyl acetate in cyclohexane) to give 1-(2-bromophenyl)azetidine as a colorless oily solid.

[0433] Yield 168mg (75%).1 H NMR(400MHz,CDCl3)δ7.40(dd,J=1.5,8.0Hz,1H),7.17(dd,J=6.9,8.4Hz,1H),6.66(dt,J=1 .5,6.9Hz,1H),6.54(dd,J=1.5,8.4Hz,1H),4.06(dd,J=7.3,7.3Hz,4H),2.30-2.22(m,2H).

[0434] Synthesis of tert-butyl (4-(2-chlorophenyl)thiazol-2-yl)carbamate

[0435] [ka]

[0436] To a degassed (nitrogen) mixture of tert-butyl 4-bromothiazol-2-ylcarbamate (1 g, 3.58 mmol) and (2-chlorophenyl)boronic acid (1.12 g, 7.16 mmol), 1,4-dioxane (15 mL) was added, followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (293 mg, 0.358 mmol), and a solution of sodium carbonate (1.139 g, 10.7 mmol) in water (1 mL). The reaction mixture was sparged with nitrogen for 5 minutes and heated at 90 °C for 18 hours. After cooling to room temperature, the solvent was evaporated, and the residue was purified by column chromatography on silica gel (0-25% ethyl acetate in cyclohexane) to give tert-butyl (4-(2-chlorophenyl)thiazol-2-yl)carbamate as a yellow solid.

[0437] Yield 1.2g (quantitative). 1 H NMR(400MHz,DMSO)δ11.60(s,1H),7.83(dd,J=1.9,7.7Hz,1H),7.57(s,1H),7.55(dd,J =1.5,7.8Hz,1H),7.42(dd,J=1.5,7.8Hz,1H),7.38(dd,J=1.9,7.7Hz,1H),1.44(s,9H).

[0438] Synthesis of 4-(2-chlorophenyl)thiazol-2-amine

[0439] [ka]

[0440] tert-Butyl (4-(2-chlorophenyl)thiazol-2-yl)carbamate (1.1 g, 3.58 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (5.4 mL, 19.3 mmol), and the reaction mixture was stirred at room temperature for 18 h. The mixture was partitioned between ethyl acetate (15 mL) and water (20 mL). The layers were separated, the aqueous layer was extracted with ethyl acetate (2 × 15 mL), and the combined organic extracts were dried (MgSO), filtered, and concentrated to give 4-(2-chlorophenyl)thiazol-2-amine as a yellow solid.

[0441] Yield 646mg (86%). 1 H NMR(400MHz,DMSO)δ7.85(dd,J=1.8,7.8Hz,1H),7.50(dd,J=1.2,7.9Hz,1H),7.4 1(dd,J=1.2,7.9Hz,1H),7.36(dd,J=1.8,7.8Hz,1H),7.07(brs,2H),7.05(s,1H).

[0442] Synthesis of tert-butyl 4-(4-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)phenyl)-piperazine-1-carboxylate (Method 1)

[0443] [ka]

[0444] 4-(4-(tert-butoxycarbonyl))piperazine-1-carboxylic acid compound 4-(4-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)phenyl)piperazine-1-carboxylic acid ester was prepared from 4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl))benzoic acid in a similar procedure to the synthesis of N-[4-(tert-butoxycarbonyl)thiazol-2-yl]-6-methyl-pyridine-3-carboxamide, except that it was purified by silica gel (0-100% ethyl acetate in cyclohexane) column chromatography and isolated as a pale yellow solid.

[0445] Yield 320mg (68%). 1 H NMR(400MHz,DMSO)δ12.46(brs,1H),8.07(d,J=9.0Hz,2H),7.92(dd,J=1.5,8.0Hz,1H),7.63(s,1H),7.58(dd,J=1.5,8.0Hz,1H), 7.45(dd,J=1.5,7.6Hz,1H),7.41(dd,J=1.5,7.6Hz,1H),7.04(d,J=9.0Hz,2H),3.51-3.44(m,4H),3.39-3.35(m,4H),1.44(s,9H).

[0446] Synthesis of N-(4-bromothiazol-2-yl)-2-methoxypyrimidine-5-carboxamide

[0447] [ka]

[0448] To a solution of 4-bromothiazol-2-amine (726 mg, 4.06 mmol) and 2-methoxypyrimidine-5-carboxylic acid (750 mg, 4.87 mmol) in anhydrous DCM (4 mL) was added triethylamine (3.4 mL, 24.3 mmol), followed by a solution of T3P (50% in ethyl acetate, 7.2 mL, 24.3 mmol). The reaction mixture was heated at 45° C. for 18 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried (MgSO), filtered, and evaporated. The residue was purified by column chromatography on silica gel (0–25% ethyl acetate in cyclohexane) to give N-(4-bromothiazol-2-yl)-2-methoxypyrimidine-5-carboxamide as a pale yellow solid.

[0449] Yield: 978mg (76%). 1 H NMR(400MHz,DMSO)δ13.13(s,1H),9.21(s,2H),7.42(s,1H),4.03(s,3H).

[0450] Synthesis of N-(4-bromothiazol-2-yl)-4-morpholinobenzamide

[0451] [ka]

[0452] To a solution of 4-bromothiazol-2-amine (1 g, 5.59 mmol) and 4-morpholinobenzoic acid (1.74 g, 8.38 mmol) in anhydrous DCM (10 mL) was added triethylamine (4.7 mL, 33.5 mmol), followed by T3P solution (50% in ethyl acetate, 10 mL, 33.5 mmol). The reaction mixture was heated at 45 °C for 18 h. After cooling to room temperature, the mixture was partitioned between DCM (30 mL) and water (30 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic extracts were dried (MgSO), filtered, and evaporated. The residue was purified by column chromatography on silica gel (0-25% ethyl acetate in cyclohexane) to give N-(4-bromothiazol-2-yl)-4-morpholinobenzamide as a pale yellow solid.

[0453] Yield 1.19g (58%). 1 H NMR(400MHz,DMSO)δ12.65(s,1H),8.06(d,J=9.1Hz,2H),7.36(s,1H),7.08(d,J=9.1Hz,2H),3.81-3.77(m,4H),3.35-3.30(m,4H).

[0454] Synthesis of phenyl(4-(2-chlorophenyl)thiazol-2-yl)carbamate

[0455] [ka]

[0456] To a solution of 4-(2-chlorophenyl)thiazol-2-amine (150 mg, 0.712 mmol) in pyridine (3 mL) was added phenyl chloroformate (0.11 mL, 0.854 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate (20 mL) and brine (20 mL). The layers were separated, and the aqueous layer was further extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried (MgSO), filtered, and evaporated. The residue was purified by column chromatography on silica gel (0-25% ethyl acetate in cyclohexane) to give phenyl (4-(2-chlorophenyl)thiazol-2-yl)carbamate as an off-white solid.

[0457] Yield 262mg (quantitative). 1 H NMR(400MHz,DMSO)δ12.49(s,1H),7.87(dd,J=1.6,7.8Hz,1H),7.67(s,1H),7.58(dd,J=1. 6,7.8Hz,1H),7.49(d,J=7.6Hz,2H),7.40(d,J=7.6Hz,2H),7.35(s,1H),7.33-7.28(m,2H).

[0458] Synthesis of 4-(pyridin-2-yl)thiazol-2-amine

[0459] [ka]

[0460] To a solution of 2-bromo-1-(pyridin-2-yl)ethan-1-one (300 mg, 1.50 mmol) in ethanol (5 mL) was added thiourea (171 mg, 2.25 mmol). The reaction was stirred at reflux for 4 h and cooled to room temperature. The solvent was evaporated and the residue was partitioned between DCM (20 mL) and a saturated solution of NaHCO3 (20 mL). The layers were separated and the aqueous layer was further extracted with DCM (2 x 20 mL). The organic layers were combined, dried (MgSO4), and filtered. The solvent was evaporated to give 4-(pyridin-2-yl)thiazol-2-amine as a brown solid. This material was used directly without purification.

[0461] Yield 229mg (86%). 1 H NMR(400MHz,DMSO)δ8.58(dt,J=1.3,4.7Hz,1H),7.89-7.83(m,2H),7.32-7.28(m,2H),7.15(brs,2H).

[0462] Synthesis of 4-(2-chlorophenyl)oxazol-2-amine

[0463] [ka]

[0464] To a solution of 2-bromo-1-(2-chlorophenyl)ethan-1-one (530 mg, 2.27 mmol) in anhydrous DMF (3 mL) was added urea (1.36 g, 22.70 mmol). The reaction mixture was heated in a microwave oven at 130 °C for 30 minutes and cooled to room temperature. The solvent was evaporated, and the residue was dissolved in DCM (30 mL) and washed with water (30 mL). The layers were separated using a phase separator, and the DCM was evaporated to give a residue that was purified by column chromatography on silica gel (0-50% ethyl acetate in cyclohexane) to give 4-(2-chlorophenyl)oxazol-2-amine as an off-white solid.

[0465] Yield 230mg (52%). 1 H NMR(400MHz,CDCl3)δ7.98(dd,J=1.5,7.9Hz,1H),7.88(s,1H),7.41(dd,J=1.5,7 .9Hz,1H),7.31(dt,J=1.5,7.6Hz,1H),7.20(dt,J=1.5,7.6Hz,1H),4.72(s,2H).

[0466] Synthesis of methyl 5-morpholinopyrazine-2-carboxylate

[0467] [ka]

[0468] To a solution of methyl 5-chloropyrazine-2-carboxylate (250 mg, 1.45 mmol) in 1,4-dioxane was added triethylamine (0.5 mL, 3.62 mmol) and morpholine (0.15 mL, 1.74 mmol). The reaction was heated in a microwave at 100 °C for 30 minutes and cooled to room temperature. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL), and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2 × 20 mL), and the organic layers were combined. The combined organic layers were dried (MgSO), filtered, and the solvent removed by evaporation to give methyl 5-morpholinopyrazine-2-carboxylate as an off-white solid.

[0469] Yield 305mg (94%). 1 HNMR(400MHz,CDCl3)δ8.81(d,J=1.3Hz,1H),8.13(d,J=1.3Hz,1H),3.96(s,3H),3.85-3.81(m,4H),3.75-3.71(m,4H).

[0470] Synthesis of 5-chloropyrazine-2-carboxylic acid hydrochloride

[0471] [ka]

[0472] A solution of methyl 5-morpholinopyrazine-2-carboxylate (305 mg, 1.37 mmol) in 6 M hydrochloric acid (10 mL) was heated under reflux for 3 h and cooled to room temperature. Evaporation of the solvent gave an off-white solid, which was azeotroped with acetonitrile (3 × 50 mL) to give 5-chloropyrazine-2-carboxylic acid hydrochloride as an off-white powder.

[0473] Yield 350mg (quantitative). 1 H NMR (400 MHz, DMSO) δ 8.67 (d, J = 1.3 Hz, 1H), 8.37 (d, J = 1.3 Hz, 1H), 3.72 (s, 8H). The acid and HCl protons were obscured by the water peaks.

[0474] Synthesis of ethyl 6-morpholinopyridazine-3-carboxylate

[0475] [ka]

[0476] To a solution of ethyl 6-chloropyridazine-3-carboxylate (250 mg, 1.34 mmol) in 1,4-dioxane (2 mL) was added morpholine (0.14 mL, 1.61 mmol) and triethylamine (0.47 mL, 1.61 mmol). The reaction was heated in a microwave at 100 °C for 30 minutes and cooled to room temperature. The reaction was partitioned between ethyl acetate (20 mL) and water (20 mL), and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2 × 20 mL), and the combined organic layers were dried (MgSO) and filtered. The solvent was removed by evaporation to give ethyl 6-morpholinopyridazine-3-carboxylate as an off-white solid.

[0477] Yield 292mg (91%). 1 H NMR (400MHz, CDCl3) δ7.92(d,J=9.5Hz,1H),6.86(d,J=9.5Hz,1H),4.47(q,J=7.1Hz,2H),3.86-3.84(m,4H),3.79-3.75(m,4H),1.44(t,J=7.1Hz,3H).

[0478] Synthesis of 6-morpholinopyridazine-3-carboxylic acid hydrochloride

[0479] [ka]

[0480] A solution of ethyl 6-morpholinopyridazine-3-carboxylate (292 mg, 1.31 mmol) in 6 M hydrochloric acid (10 mL) was heated under reflux for 3 h and cooled to room temperature. The solvent was evaporated to give an off-white solid, which was azeotroped from acetonitrile (3 × 30 mL) to give 6-morpholinopyridazine-3-carboxylic acid hydrochloride as an off-white powder.

[0481] Yield 318mg (quantitative). 1 H NMR (400 MHz, DMSO) δ 7.92 (d, J = 9.7 Hz, 1H), 7.40 (d, J = 9.7 Hz, 1H), 3.78-3.70 (m, 8H). The acid and HCl protons were obscured by the water peaks.

[0482] Synthesis of tert-butyl (4-(2-methylpyridin-3-yl)thiazol-2-yl)carbamate

[0483] [ka]

[0484] To a degassed solution of tert-butyl(4-bromothiazol-2-yl)carbamate (1.50 g, 5.37 mmol) in 1,4-1,4-dioxane (20 mL) and water (5 mL) at room temperature was added sodium carbonate (2.28 g, 21.49 mmol), 2-methylpyridine-3-boronic acid (1.10 g, 8.06 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (439 mg, 0.537 mmol). The reaction was heated at 100° C. for 24 hours and then cooled to room temperature. Ethyl acetate (40 mL) was added and the layers were separated. The organic layer was dried (MgSO), filtered, and evaporated to give a residue which was purified by column chromatography on silica gel (0-80% ethyl acetate in cyclohexane) to give tert-butyl (4-(2-methylpyridin-3-yl)thiazol-2-yl)carbamate as an orange solid.

[0485] Yield 682mg (43%).1 H NMR(400MHz,DMSO)δ11.62(s,1H),8.48(dd,J=1.6,4.7Hz,1H),7.96(dd,J=1.6, 7.6Hz,1H),7.40(s,1H),7.34(dd,J=4.7,7.6Hz,1H),2.66(s,3H),1.56(s,9H).

[0486] Synthesis of 4-(2-methylpyridin-3-yl)thiazol-2-amine

[0487] [ka]

[0488] To a solution of tert-butyl (4-(2-methylpyridin-3-yl)thiazol-2-yl)carbamate (682 mg, 2.34 mmol) in DCM (10 mL) was added 4 M hydrogen chloride in 1,4-dioxane (7 mL). The reaction was stirred at room temperature for 24 h and then at 40° C. for 3 h. The reaction was cooled to room temperature and ethyl acetate (50 mL) was added. The mixture was neutralized with saturated sodium bicarbonate and the layers separated. The aqueous layer was further extracted with ethyl acetate (50 mL) and the organic layers were combined, dried (MgSO4) and filtered. The filtrate was concentrated by evaporation to give 4-(2-methylpyridin-3-yl)thiazol-2-amine as an orange solid.

[0489] Yield 474mg (quantitative). 1 H NMR(400MHz,DMSO)δ8.39(dd,J=1.8,4.9Hz,1H),7.91(dd,J=1.8,7.9Hz,1H),7.26(dd,J=4.9,7.9Hz,1H),7.08(s,2H),6.78(s,1H),2.63(s,3H).

[0490] Synthesis of tert-butyl 4-(4-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)phenyl)piperazine-1-carboxylate (Method 2)

[0491] [ka]

[0492] To a solution of 4-(2-chlorophenyl)thiazol-2-amine (1.00 g, 4.75 mmol) in DMF (20 mL), 4-(2.18 g, 7.12 mmol)DMAP (0.58 g, 4.75 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1.09 g, 5.70 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1% to 40% ethyl acetate in petroleum ether to give tert-butyl 4-(4-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)phenyl)piperazine-1-carboxylate as an off-white solid.

[0493] Yield 1.70g (72%). 1 H NMR(300MHz,CDCl3)δ10.08(s,1H),7.85(d,J=8.9Hz,2H),7.80(dd,J=1.9,7.6,Hz,1H),7.49-7.40(m,2 H),7.37-7.20(m,2H),6.90(d,J=8.9Hz,2H),3.61(t,J=5.3Hz,4H),3.35(t,J=5.3Hz,4H),1.51(s,9H). 1H NMR(400MHz,DMSO)δ12.47(s,1H),8.04(d,J=8.9Hz,2H),7.91(dd,J=1.9,7.7Hz,1H),7.63(s,1H),7.57(dd,J=1.5,7.8Hz1H),7.45(td, m / z:[ESI + ]499,501(M+H) + .

[0494] Synthesis of methyl 4-(3,6-dihydro-2H-thiopyran-4-yl)benzoate

[0495] [ka]

[0496] To a mixture of methyl 4-bromobenzoate (2.00 g, 9.30 mmol), potassium carbonate (2.57 g, 18.60 mmol), and 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.15 g, 13.93 mmol) and water (4 mL) in 1,4-dioxane (20 mL) was added tetrakis(triphenylphosphine)palladium(0) (3.22 g, 2.79 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 85 °C for 3 hours. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-16% ethyl acetate in petroleum ether to give methyl 4-(3,6-dihydro-2H-thiopyran-4-yl)benzoate as an off-white solid.

[0497] Yield 1.00g (46%). 1H NMR(400MHz,CDCl3)δ8.01(d,J=8.4Hz,2H),7.42(d,J=8.4Hz,2H),6.33-6.30(m,1 H),3.94(s,3H),3.43-3.34(m,2H),2.96-2.88(m,2H),2.78-2.70(m,2H).No MS signal.

[0498] Synthesis of methyl 4-(tetrahydro-2H-thiopyran-4-yl)benzoate

[0499] [ka]

[0500] To a stirred solution of methyl 4-(3,6-dihydro-2H-thiopyran-4-yl)benzoate (0.40 g, 1.71 mmol) in methanol (8 mL) was added platinum(IV) oxide (0.80 g, 3.52 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere (1.5 atm). The resulting mixture was filtered, and the filter cake was washed with methanol (3 × 2 mL). The combined washes and filtrate were concentrated under reduced pressure. The residue was purified using reverse-phase flash chromatography using the following conditions: Column: WelFlash™ C18-I, 20-40 μm, 330 g, Eluent A: water (+10 mmol / L NH4HCO3), Eluent B: acetonitrile, Gradient: 38%-58% B (25 min), Flow rate: 90 mL / min, Detector: UV 220 / 254 nm. Fractions containing the desired product were combined and concentrated under reduced pressure to give methyl 4-(tetrahydro-2H-thiopyran-4-yl)benzoate as an off-white solid.

[0501] Yield 0.18g (45%). 1 H NMR(400MHz,DMSO)δ7.90(d,J=8.4Hz,2H),7.38(d,J=8.4Hz,2H),3.84(s,3H),2. 86-2.73(m,2H),2.69-2.61(m,3H),2.07-2.01(m,2H),1.80-1.65(m,2H).No MS signal.

[0502] Synthesis of methyl 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoate

[0503] [ka]

[0504] To a stirred solution of methyl 4-(tetrahydro-2H-thiopyran-4-yl)benzoate (0.18 g, 0.76 mmol) in methanol (16 mL) was added water (3 mL), potassium peroxymonosulfate (Oxone®) (0.48 g, 1.56 mmol), and acetone (4 mL) at 0° C. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether to give methyl 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoate as an off-white solid.

[0505] Yield 160mg (78%). 1 H NMR(400MHz,DMSO)δ7.92(d,J=8.4Hz,2H),7.43(d,J=8.4Hz,2H),3.84(s,3H),3. 44-3.27(m,2H),3.18-3.08(m,2H),3.08-2.98(m,1H),2.16-2.04(m,4H).No MS signal.

[0506] Synthesis of 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid

[0507] [ka]

[0508] To a stirred solution of methyl 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoate (160 mg, 0.596 mmol) in water (2 mL) and THF (2 mL) was added lithium hydroxide monohydrate (100 mg, 2.383 mmol) at room temperature. The resulting mixture was stirred overnight at room temperature. 2M aqueous HCl was added and the mixture was concentrated under reduced pressure to adjust the pH of the solution to 5. The residue was purified using reverse-phase flash chromatography under the following conditions: Column: WelFlash™ C18-I, 20-40 μm, 330 g, Eluent A: water (+10 mmol / L HCOOH), Eluent B: acetonitrile, Gradient: 5%-20% B (25 min), Flow rate: 80 mL / min, Detector: UV 220 / 254 nm. The desired fractions were collected and concentrated under reduced pressure to give 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid as an off-white solid.

[0509] Yield 142mg (94%). 1 H NMR(400MHz,DMSO)δ12.85(brs,1H),7.90(d,J=8.4Hz,2H),7.40(d,J=8.4Hz,2H),3 .38-3.28(m,2H),3.19-3.08(m,2H),3.08-2.96(m,1H),2.16-2.05(m,4H).m / z:[ESI - ]253(MH) - .

[0510] Synthesis of methyl 5-(3,6-dihydro-2H-thiopyran-4-yl)picolinate

[0511] [ka]

[0512] Methyl 5-(3,6-dihydro-2H-thiopyran-4-yl)picolinate was prepared from methyl 5-bromopicolinate (2.40 g, 11.11 mmol) and 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.50 g, 11.06 mmol) by a procedure similar to the synthesis of methyl 4-(3,6-dihydro-2H-thiopyran-4-yl)benzoate and isolated as a yellow solid.

[0513] Yield 1.71g (66%). 1 H NMR(400MHz,DMSO)δ8.77(d,J=2.0Hz,1H),8.02(d,J=8.0Hz,1H),7.98(dd,J=2.0,8.0Hz,1H),6.5 8-6.48(m,1H),3.88(s,3H),3.33-3.38(m,2H),2.87(t,J=5.6Hz,2H),2.71-2.65(m,2H).m / z:[ESI + ]236(M+H) + .

[0514] Synthesis of methyl 5-(tetrahydro-2H-thiopyran-4-yl)picolinate

[0515] [ka]

[0516] The compound 5-(tetrahydro-2H-thiopyran-4-yl)picolinate was prepared from 5-(1.71 g, 7.27 mmol) picolinate in a procedure similar to the synthesis of methyl 4-(3,6-dihydro-2H-thiopyran-4-yl)benzoate and isolated as an off-white solid.

[0517] Yield 0.83g (48%). 1H NMR(400MHz,DMSO)δ8.61(d,J=2.0Hz,1H),8.00(d,J=8.0Hz,1H),7.86(dd,J=2.0,8.0Hz,1H),3. 87(s,3H),2.86-2.72(m,3H),2.72-2.63(m,2H),2.12-2.01(m,2H),1.86-1.70(m,2H).m / z:[ESI + ]238(M+H) + .

[0518] 5-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)picolinic acid methyl ester

[0519] [ka]

[0520] Methyl 5-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)picolinate was prepared from methyl 5-picolinate (0.80 g, 3.37 mmol) and potassium peroxymonosulfate (Oxone®) (4.31 g, 14.04 mmol) by a procedure similar to the synthesis of methyl 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoate and isolated as an off-white solid.

[0521] Yield 0.65g (72%). 1 H NMR(400MHz,DMSO)δ8.66(d,J=2.0Hz,1H),8.03(d,J=8.0Hz,1H),7.96(dd,J=2.0,8.0H m / z:[ESI + ]270(M+H) + .

[0522] Synthesis of 5-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)picolinic acid

[0523] [ka]

[0524] The compound 5-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)picolinic acid was prepared from methyl 5-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)picolinate (0.50 g, 1.86 mmol) and lithium hydroxide monohydrate (0.30 g, 7.15 mmol) in a similar manner to the synthesis of 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid and isolated as an off-white solid.

[0525] Yield 0.30g (63%). 1 H NMR(400MHz,DMSO)δ13.10(brs,1H),8.62(d,J=2.0Hz,1H),8.00(d,J=8.0Hz,1H),7.89( dd,J=2.0,8.0Hz,1H),3.40-3.28(m,2H),3.19-2.99(m,3H),2.21-2.09(m,4H).m / z:[ESI + ]256(M+H) + .

[0526] Synthesis of methyl 5-(3,6-dihydro-2H-pyran-4-yl)picolinate

[0527] [ka]

[0528] The compound 5-(3,6-dihydro-2H-thiopyran-4-yl)picolinate, prepared from methyl 5-bromopicolinate (216 mg, 1.00 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (210 mg, 1.00 mmol) in a manner similar to the synthesis of methyl 4-(3,6-dihydro-2H-pyran-4-yl)benzoate, was isolated as an off-white solid.

[0529] Yield 120 mg (55%). m / z: [ESI +]220(M+H) + .

[0530] Synthesis of methyl 5-(tetrahydro-2H-pyran-4-yl)picolinate

[0531] [ka]

[0532] Compound 5-(tetrahydro-2H-pyran-4-yl)picolinate was prepared from 5-(100 mg, 0.456 mmol) picolinate following a procedure similar to the synthesis of methyl 4-(3,6-dihydro-2H-pyran-4-yl)benzoate and isolated as an off-white solid.

[0533] Yield 50mg (50%). 1 H NMR(400MHz,DMSO)δ8.65(d,J=2.4Hz,1H),8.01(d,J=8.0Hz,1H),7.89(dd,J=2.4,8.0Hz,1H),3. 03-3.94(m,2H),3.87(s,3H),3.51-3.41(m,2H),3.02-2.90(m,1H),1.77-1.68(m,4H).m / z:[ESI + ]222(M+H) + .

[0534] Synthesis of 5-(tetrahydro-2H-pyran-4-yl)picolinic acid

[0535] [ka]

[0536] The compound 5-(tetrahydro-2H-pyran-4-yl)picolinic acid was prepared from methyl 5-(tetrahydro-2H-pyran-4-yl)picolinate (50 mg, 0.226 mmol) and lithium hydroxide monohydrate (38 mg, 0.906 mmol) in a similar manner to the synthesis of 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid and isolated as an off-white solid.

[0537] Yield 39mg (83%). 1 H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.82 (dd, J = 2.0, 8.0 Hz, 1H), 4.21-4.09 (m, 2H), 3.58 (dt, J = 3.2, 11.6 Hz, 2H), 3.03-2.87 (m, 1H), 1.97-1.76 (m, 4H). No carboxylic acid OH protons were observed. m / z: [ESI + ]208(M+H) + .

[0538] Synthesis of benzyl bis(2-oxoethyl)carbamate

[0539] [ka]

[0540] To a stirred mixture of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (3.80 g, 18.70 mmol), sodium periodate (16.00 g, 74.80 mmol), and 2,6-lutidine (4.01 g, 37.42 mmol) in ethyl acetate (40 mL) and water (40 mL) was added potassium osmate(VI) dihydrate (0.34 g, 0.92 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-9% methanol in DCM to give benzyl bis(2-oxoethyl)carbamate as a dark brown semisolid.

[0541] Yield 3.30g (75%). 1 H NMR (400 MHz, DMSO) δ 7.44-7.25 (m, 5H), 5.09 (s, 2H), 3.35 (s, 4H). Aldehyde CH protons not observed. No MS signal.

[0542] Synthesis of benzyl 4-(3-(methoxycarbonyl)bicyclo[1.1.1]pentan-1-yl)piperazine-1-carboxylate

[0543] [ka]

[0544] To a stirred mixture of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (0.80 g, 4.50 mmol) and benzyl bis(2-oxoethyl)carbamate (1.17 g, 4.97 mmol) in methanol (10 mL) was added acetic acid (0.95 g, 15.82 mmol) and sodium cyanoborohydride (0.99 g, 15.75 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: Column: WelFlash™ C18-I, 20-40 μm, 330 g, Eluent A: water (+10 mmol / L NH4HCO3), Eluent B: acetonitrile, Gradient: 40%-60% B (20 min), Flow rate: 60 mL / min, Detector: UV 220 / 254 nm. The desired fractions were collected and concentrated under reduced pressure to give benzyl 4-(3-(methoxycarbonyl)bicyclo[1.1.1]pentan-1-yl)piperazine-1-carboxylate as an off-white solid.

[0545] Yield 0.58g (37%). 1 H NMR(400MHz,DMSO)δ7.42-7.28(m,5H),5.08(s,2H),3.61(s,3H),3.45-3.35(m,4H),2.40-2.27(m,4H),1.96(s,6H).m / z:[ESI + ]345(M+H) + .

[0546] Synthesis of methyl 3-(piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

[0547] [ka]

[0548] A mixture of benzyl 4-(3-(methoxycarbonyl)bicyclo[1.1.1]pentan-1-yl)piperazine-1-carboxylate (0.58 g, 1.68 mmol) and 10% by weight palladium on charcoal (0.18 g) in ethyl acetate (10 mL) was stirred under a hydrogen atmosphere (1.5 atm) at room temperature for 16 hours. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 50 mL). The combined washings and filtrate were concentrated under reduced pressure to give methyl 3-(piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxylate as a yellow oil.

[0549] Yield 0.27g (76%). 1 H NMR (400 MHz, DMSO) δ 3.60 (s, 3H), 2.65 (t, J = 4.8 Hz, 4H), 2.26 (t, J = 4.8 Hz, 4H), 1.93 (s, 6H). No aliphatic NH was observed. m / z: [ESI + ]211(M+H) + .

[0550] Synthesis of methyl 3-(4-(methylsulfonyl)piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

[0551] [ka]

[0552] To a stirred solution of methyl 3-(piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxylate (0.27 g, 1.28 mmol) and triethylamine (0.39 g, 3.85 mmol) in DCM (5 mL) was added methanesulfonyl chloride (0.22 g, 1.92 mmol) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified using reverse-phase flash chromatography using the following conditions: Column: WelFlash™ C18-I, 20-40 μm, 120 g, Eluent A: water (+10 mmol / L NH4CO3), Eluent B: acetonitrile, Gradient: 40%-60% B (20 min), Flow rate: 60 mL / min, Detector: UV 220 / 254 nm. The desired fractions were collected and concentrated under reduced pressure to give methyl 3-(4-(methylsulfonyl)piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxylate as a pale yellow solid.

[0553] Yield 0.26g (70%). 1 H NMR(400MHz,DMSO)δ3.61(s,3H),3.10(t,J=4.8Hz,4H),2.87(s,3H),2.46(t,J=4.8Hz,4H),1.97(s,6H).m / z:[ESI + ]289(M+H) + .

[0554] Synthesis of 3-(4-(methylsulfonyl)piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

[0555] [ka]

[0556] The compound 3-(4-(methylsulfonyl)piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid was prepared from methyl 3-(4-(methylsulfonyl)piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxylate (260 mg, 0.902 mmol) and lithium hydroxide monohydrate (151 mg, 3.598 mmol) in a similar procedure to the synthesis of 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid and isolated as an off-white semisolid.

[0557] Yield 210 mg (85%). m / z: [ESI + ]275(M+H) + .

[0558] Synthesis of methyl 3-morpholinobicyclo[1.1.1]pentane-1-carboxylate

[0559] [ka]

[0560] To a stirred mixture of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (0.50 g, 2.81 mmol) and potassium carbonate (1.95 g, 14.11 mmol) in acetonitrile (10 mL) was added 1-bromo-2-(2-bromoethoxy)ethane (1.96 g, 8.45 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The resulting mixture was cooled to room temperature, filtered, and the filter cake was washed with DCM (3 × 20 mL). The combined washings and filtrate were concentrated under reduced pressure. The residue was purified using silica gel column chromatography, eluting with 0-9% methanol in DCM, to give methyl 3-morpholinobicyclo[1.1.1]pentane-1-carboxylate as a yellow oil.

[0561] Yield 0.37g (62%). 1H NMR(400MHz,DMSO)δ3.61(s,3H),3.59-3.54(m,4H),2.38-2.29(m,4H),1.96(s,6H).m / z:[ESI + ]212(M+H) + .

[0562] Synthesis of 3-morpholinobicyclo[1.1.1]pentane-1-carboxylic acid

[0563] [ka]

[0564] The compound 3-morpholinobicyclo[1.1.1]pentane-1-carboxylic acid was prepared from methyl 3-morpholinobicyclo[1.1.1]pentane-1-carboxylate (0.37 g, 1.75 mmol) and lithium hydroxide monohydrate (0.22 g, 5.24 mmol) in a similar manner to the synthesis of 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid above, and isolated as an off-white solid.

[0565] Yield: 0.30 g (87%). 1H NMR (400 MHz, DMSO) δ 3.59-3.53 (m, 4H), 2.36-2.27 (m, 4H), 1.79 (s, 6H). No carboxylic acid protons were observed. m / z: [ESI + ]198(M+H) + .

[0566] Synthesis of methyl (1r,3r)-3-morpholinocyclobutane-1-carboxylate

[0567] [ka]

[0568] Following a procedure similar to the synthesis of methyl 3-morpholinobicyclo[1.1.1]pentane-1-carboxylate, the compound methyl (1r,3r)-3-morpholinocyclobutane-1-carboxylate was prepared from methyl (1r,3r)-3-aminocyclobutane-1-carboxylate hydrochloride (0.50 g, 3.02 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (2.10 g, 9.05 mmol) and isolated as an off-white solid.

[0569] Yield 0.60g (99%). 1 H NMR(400MHz,DMSO)δ3.99(dd,J=3.2,12.4Hz,2H),3.90(q,J=8.4Hz,1H),3.74-3.61(m,2H),3.65(s,3H), 3.40-3.30(m,2H),3.18-3.09(m,1H),2.98-2.85(m,2H),2.70-2.56(m,2H),2.46-2.36(m,2H).m / z:[ESI + ]200(M+H) + .

[0570] Synthesis of (1r,3r)-3-morpholinocyclobutane-1-carboxylic acid

[0571] [ka]

[0572] The compound (1r,3r)-3-morpholinocyclobutane-1-carboxylic acid was prepared from methyl (1r,3r)-3-morpholinocyclobutane-1-carboxylate (0.60 g, 3.01 mmol) and lithium hydroxide monohydrate (0.38 g, 9.06 mmol) by a procedure similar to the synthesis of 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid and isolated as a pale yellow semisolid.

[0573] Yield 0.4g (72%). 1H NMR(400MHz,DMSO)δ12.51(brs,1H),3.99-3.74(m,5H),3.27(d,J=12.4Hz,2H),3. 08-2.96(m,1H),2.94-2.81(m,2H),2.79-2.64(m,2H),2.41-2.28(m,2H).m / z:[ESI + ]186(M+H) + .

[0574] Synthesis of methyl 5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)picolinate

[0575] [ka]

[0576] To a stirred mixture of methyl 5-bromopicolinate (0.63 g, 2.92 mmol) and 2-methyl-2,8-diazaspiro[4.5]decan-1-one hydrochloride (0.50 g, 2.44 mmol) in DMF (12 mL) was added 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.28 g, 0.48 mmol), palladium(II) acetate (55 mg, 0.245 mmol), and cesium carbonate (2.39 g, 7.34 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100 °C overnight. The resulting mixture was cooled to room temperature, filtered, and the filter cake was washed with DMF (3 × 2 mL). The combined washings and filtrate were concentrated under reduced pressure. The residue was purified using reverse-phase flash chromatography as follows: Column: WelFlash™ C18-I, 20-40 μm, 330 g, Eluent A: water (+10 mmol / L NH4HCO3), Eluent B: acetonitrile, Gradient: 25%-45% B (25 min), Flow rate: 80 mL / min, Detector: UV 220 / 254 nm. The desired fractions were collected and concentrated under reduced pressure to give methyl 5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)picolinate as an off-white solid.

[0577] Yield 440mg (59%). 1 H NMR(400MHz,DMSO)δ8.39(d,J=2.8Hz,1H),7.87(d,J=8.8Hz,1H),7.36(dd,J=2.8,8.8Hz,1H),3.91(dt,J=4.0,13.6Hz,2H),3.8 1(s,3H),3.35-3.25(m,5H),3.13-3.01(m,2H),1.99(t,J=6.8Hz,2H),1.78-1.70(m,2H),1.45(dd,J=4.0,13.6Hz,2H).m / z:[ESI + ]304(M+H) + .

[0578] Synthesis of 5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)picolinic acid

[0579] [ka]

[0580] The compound 5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)picolinic acid was prepared from methyl 5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)picolinate (0.44 g, 1.45 mmol) and lithium hydroxide monohydrate (0.18 g, 4.29 mmol) using a procedure similar to the synthesis of 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid and isolated as an off-white solid.

[0581] Yield 0.3g (71%). 1H NMR (400 MHz, DMSO) δ 8.28 (d, J = 2.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 2.8, 8.8 Hz, 1H), 3.79 (d, J = 12.8 Hz, 2H), 3.31 (t, J = 6.8 Hz, 2H), 2.98 (t, J = 12.4 Hz, 2H), 2.74 (s, 3H), 1.97 (t, J = 6.8 Hz, 2H), 1.74 (dt, J = 4.0, 12.8 Hz, 2H), 1.42 (d, J = 13.2 Hz, 2H). No carboxylic acid protons were observed. m / z: [ESI + ]290(M+H) + .

[0582] Synthesis of methyl 5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)picolinate

[0583] [ka]

[0584] The compound 5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)picolinate was prepared from methyl 5-bromopicolinate (1.80 g, 8.33 mmol) and 2-oxa-7-azaspiro(1.20 g, 9.43 mmol)nonan-3.5 by a procedure similar to the synthesis of 5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)picolinate and isolated as an off-white solid.

[0585] Yield 1.40g (64%). 1 H NMR(400MHz,CDCl3)δ8.35(d,J=2.8Hz,1H),7.99(d,J=8.8Hz,1H),7.16(dd,J=2.8,8 .8Hz,1H),4.50(s,4H),3.96(s,3H),3.37-3.27(m,4H),2.05-1.97(m,4H).m / z:[ESI + ]263(M+H) + .

[0586] Synthesis of 5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)picolinic acid

[0587] [ka]

[0588] The compound 5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)picolinic acid was prepared from methyl 5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)picolinate (1.40 g, 5.34 mmol) and lithium hydroxide monohydrate (0.67 g, 15.97 mmol) by a procedure similar to the synthesis of 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid and isolated as an off-white solid.

[0589] Yield 1.20g (91%). 1 H NMR (400 MHz, DMSO) δ 8.29 (d, J = 2.8 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 2.8, 8.8 Hz, 1H), 4.34 (s, 4H), 3.27 (t, J = 5.6 Hz, 4H), 1.86 (t, J = 5.6 Hz, 4H). No carboxylic acid protons were observed. m / z: [ESI + ]249(M+H) + .

[0590] Synthesis of methyl 2-methoxy-4-morpholinobenzoate

[0591] [ka]

[0592] The compound methyl 2-methoxy-4-morpholinobenzoate was prepared from methyl 4-bromo-2-methoxybenzoate (500 mg, 2.04 mmol) and morpholine (267 mg, 3.07 mmol) using a procedure similar to the synthesis of methyl picolinate (2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl) described above, and isolated as an off-white solid.

[0593] Yield 300mg (59%).1 H NMR(400MHz,DMSO)δ7.63(d,J=8.8Hz,1H),6.54(dd,J=2.4,8.8Hz,1H),6.51(d,J=2 .4Hz,1H),3.80(s,3H),3.76-3.71(m,4H),3.70(s,3H),3.30-3.25(m,4H).m / z:[ESI + ]252(M+H) + .

[0594] Synthesis of 2-methoxy-4-morpholinobenzoic acid

[0595] [ka]

[0596] The compound 2-methoxy-4-morpholinobenzoic acid was prepared from methyl 2-methoxy-4-morpholinobenzoate (300 mg, 1.19 mmol) and lithium hydroxide monohydrate (200 mg, 4.77 mmol) using a procedure similar to the synthesis of 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid and isolated as an off-white solid.

[0597] Yield 250mg (88%). 1 H NMR(400MHz,DMSO)δ11.81(brs,1H),7.64(d,J=8.8Hz,1H),6.57-6.47(m,2H),3.81(s,3H),3.73(t,J=4.8Hz,4H),3.26(t,J=4.8Hz,4H).m / z:[ESI + ]238(M+H) + .

[0598] Synthesis of methyl 5-((1-methylpiperidin-4-yl)oxy)picolinate

[0599] [ka]

[0600] To a solution of methyl 5-hydroxypicolinate (1.53 g, 9.99 mmol) in THF (50 mL) was added 1-methylpiperidin-4-ol (2.30 g, 19.97 mmol), triphenylphosphine (3.93 g, 14.98 mmol), and DIAD (3.03 g, 14.98 mmol) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using reverse-phase flash chromatography using the following conditions: Column: WelFlash™ C18-I, 20-40 μm, 330 g; Eluent A: water (+10 mmol / L NH4HCO3); Eluent B: acetonitrile; Gradient: 35%-55% B (25 min); Flow rate: 80 mL / min; Detector: UV 220 / 254 nm. The desired fractions were collected and concentrated under reduced pressure to give methyl 5-((1-methylpiperidin-4-yl)oxy)picolinate as an off-white solid.

[0601] Yield 1.31g (52%). 1 H NMR(400MHz,DMSO)δ8.37(d,J=2.8Hz,1H),8.01(d,J=8.8Hz,1H),7.56(dd,J=2.8,8.8Hz,1H),4.59(tt,J=4.0, m / z:[ESI + ]251(M+H) + .

[0602] Synthesis of 5-((1-methylpiperidin-4-yl)oxy)picolinic acid

[0603] [ka]

[0604] The compound 5-((1-methylpiperidin-4-yl)oxy)picolinic acid was prepared from methyl 5-((1-methylpiperidin-4-yl)oxy)picolinate (1.31 g, 5.23 mmol) and lithium hydroxide monohydrate (0.88 g, 20.97 mmol) by a procedure similar to the synthesis of 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid and isolated as an off-white solid.

[0605] Yield 1.15g (93%). 1 H NMR (400 MHz, DMSO) δ 8.37 (d, J = 2.8 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.58 (dd, J = 2.8, 8.8 Hz, 1H), 4.80-4.66 (m, 1H), 4.19-4.04 (m, 2H), 3.07-2.93 (m, 2H), 2.51 (s, 3H), 2.17-2.03 (m, 2H), 1.94-1.77 (m, 2H). No carboxylic acid protons were observed. m / z: [ESI + ]237(M+H) + .

[0606] Synthesis of 2-chloro-4-morpholinobenzaldehyde

[0607] [ka]

[0608] To a stirred solution of 2-chloro-4-fluorobenzaldehyde (5.00 g, 31.53 mmol) in DMF (100 mL) was added morpholine (5.51 g, 63.25 mmol) and potassium carbonate (8.75 g, 63.31 mmol) at room temperature. The resulting mixture was stirred at 120 °C for 16 hours under a nitrogen atmosphere. The resulting mixture was cooled to room temperature and diluted with water (300 mL). The resulting mixture was extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether to give 2-chloro-4-morpholinobenzaldehyde as an off-white solid.

[0609] Yield 4.72g (66%). 1 H NMR(400MHz,DMSO)δ10.08(s,1H),7.70(d,J=9.6Hz,1H),7.05-6.96(m,2H),3.75-3.67(m,4H),3.42-3.36(m,4H).m / z:[ESI + ]226,228(M+H) + .

[0610] Synthesis of 2-chloro-4-morpholinobenzoic acid

[0611] [ka]

[0612] To a stirred mixture of 2-chloro-4-morpholinobenzaldehyde (1.00 g, 4.43 mmol) and 2-methylbut-2-ene (8.00 mL) in tert-butanol (40 mL) was added dropwise a solution of sodium dihydrogen phosphate dihydrate (0.86 g, 5.51 mmol) in water (10 mL) and a solution of sodium chlorite (0.60 g, 6.65 mmol) in water (5 mL) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and acidified to pH 5 with 1 M aqueous HCl. The resulting mixture was extracted with ethyl acetate (5 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-chloro-4-morpholinobenzoic acid as an off-white solid.

[0613] Yield 0.85g (79%). 1 H NMR(400MHz,DMSO)δ12.75(brs,1H),7.78(d,J=8.8Hz,1H),6.98(d,J=2.4Hz,1 H),6.93(dd,J=2.4,8.8Hz,1H),3.74-3.68(m,4H),3.29-3.25(m,4H).m / z:[ESI + ]242,244(M+H) + .

[0614] Synthesis of 2-methyl-4-morpholinobenzaldehyde

[0615] [ka]

[0616] The compound 2-methyl-4-morpholinobenzaldehyde was prepared from 4-fluoro-2-methylbenzaldehyde (1.00 g, 7.24 mmol) and morpholine (1.30 g, 14.92 mmol) in a similar procedure to the synthesis of 2-chloro-4-morpholinobenzaldehyde and isolated as an off-white solid.

[0617] Yield 1.22g (82%). 1H NMR(400MHz,DMSO)δ9.94(s,1H),7.65(d,J=8.8Hz,1H),6.89(dd,J=2.4,8.8Hz,1H) ,6.81(d,J=2.4Hz,1H),3.79-3.68(m,4H),3.34-3.30(m,4H),2.55(s,3H).m / z:[ESI + ]206(M+H) + .

[0618] Synthesis of 2-methyl-4-morpholinobenzoic acid

[0619] [ka]

[0620] The compound 2-methyl-4-morpholinobenzoic acid was prepared from 2-methyl-4-morpholinobenzaldehyde (1.21 g, 5.89 mmol) in a procedure similar to the synthesis of 2-chloro-4-morpholinobenzoic acid and was isolated as an off-white solid.

[0621] Yield: 882mg (68%). 1 H NMR(400MHz,DMSO)δ12.26(brs,1H),7.77(d,J=9.6Hz,1H),6.81-6.77(m,2H),3.76-3.68(m,4H),3.27-3.18(m,4H),2.51(s,3H).m / z:[ESI + ]222(M+H) + .

[0622] Synthesis of 4-morpholino-2-(trifluoromethyl)benzaldehyde

[0623] [ka]

[0624] The compound 4-morpholino-2-(trifluoromethyl)benzaldehyde was prepared from 4-fluoro-2-(trifluoromethyl)benzaldehyde (1.00 g, 5.21 mmol) and morpholine (0.90 g, 10.33 mmol) using a procedure similar to the synthesis of 2-chloro-4-morpholinobenzaldehyde and isolated as an off-white solid.

[0625] Yield: 916mg (68%). 1 H NMR(400MHz,DMSO)δ9.99(q,J=2.0Hz,1H),7.95(d,J=8.8Hz,1H),7.40-7.16(m,2H ),3.84-3.69(m,4H),3.48-3.40(m,4H).19FNMR(376MHz,DMSO)δ-55.81.m / z:[ESI + ]260(M+H) + .

[0626] Synthesis of 4-morpholino-2-(trifluoromethyl)benzoic acid

[0627] [ka]

[0628] The compound 4-morpholino-2-(trifluoromethyl)benzoic acid was prepared from 4-morpholino-2-(trifluoromethyl)benzaldehyde (0.92 g, 3.55 mmol) in a similar procedure to the synthesis of 2-chloro-4-morpholinobenzoic acid and isolated as a yellow solid.

[0629] Yield 585mg(60%).m / z:[ESI + ]276(M+H) + .

[0630] Synthesis of methyl (1r,3r)-3-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)cyclobutane-1-carboxylate

[0631] [ka]

[0632] To a stirred solution of 3-(methoxycarbonyl)cyclobutane-1-carboxylic acid (1.00 g, 6.32 mmol), 4-(2-chlorophenyl)thiazol-2-amine (1.47 g, 6.98 mmol), and DIPEA (1.63 g, 12.61 mmol) in DMF (20 mL) was added HATU (3.61 g, 9.49 mmol) in portions at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at room temperature under a nitrogen atmosphere for 16 h. The solution was diluted with water (60 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0 to 30% ethyl acetate in petroleum ether, to give methyl (1r,3r)-3-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)cyclobutane-1-carboxylate (A) (presumed) and methyl (1s,3s)-3-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)cyclobutane-1-carboxylate (B) (presumed) as off-white solids.

[0633] A: Yield 0.81g (37%). 1 H NMR(400MHz,DMSO)δ12.23(brs,1H),7.83(dd,J=2.0,7.6Hz,1H),7.61(s,1H),7.55(dd,J=1.6,7.6Hz, 1H),7.46-7.33(m,2H),3.65(s,3H),3.48-3.36(m,1H),3.25-3.15(m,1H),2.55-2.38(m,4H).m / z:[ESI + ]351(M+H) + . B: Yield 1.00g (45%). 1H NMR(400MHz,DMSO)δ12.27(brs,1H),7.83(dd,J=2.0,7.6Hz,1H),7.60(s,1H),7.54(dd,J=1.6,7.6Hz, 1H),7.45-7.33(m,2H),3.62(s,3H),3.38-3.26(m,1H),3.23-3.13(m,1H),2.48-2.34(m,4H).m / z:[ESI + ]351(M+H) + .

[0634] Synthesis of (1r,3r)-3-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)cyclobutane-1-carboxylic acid

[0635] [ka]

[0636] The compound (1r,3r)-3-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)cyclobutane-1-carboxylic acid was isolated as an off-white solid from methyl (1r,3r)-3-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)cyclobutane-1-carboxylate (810 mg, 2.309 mmol) and lithium hydroxide monohydrate (388 mg, 9.247 mmol) following a procedure similar to the synthesis of 2-chloro-4-morpholinobenzoic acid.

[0637] Yield 700mg (90%). 1 H NMR(400MHz,DMSO)δ12.21(brs,2H),7.83(dd,J=2.0,7.6Hz,1H),7.61(s,1H),7.55(dd,J=1.6,7 m / z:[ESI + ]337,339(M+H) + .

[0638] Synthesis of methyl 4-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)benzoate

[0639] [ka]

[0640] The compound methyl 4-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)benzoate was prepared from 4-(methoxycarbonyl)benzoic acid (3.00 g, 16.65 mmol) and 4-(2-chlorophenyl)thiazol-2-amine (2.46 g, 11.68 mmol) following a procedure similar to the synthesis of (1r,3r)-3-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)cyclobutane-1-carboxylic acid ester and was isolated as an off-white solid.

[0641] Yield 2.50g (57%). 1 H NMR(400MHz,DMSO)δ13.03(brs,1H),8.24(d,J=8.4Hz,2H),8.11(d,J=8.4Hz,2H),7.91(dd,J=2. 0,7.6Hz,1H),7.72(s,1H),7.58(dd,J=1.6,7.6Hz,1H),7.51-7.39(m,2H),3.91(s,3H).m / z:[ESI + ]373,375(M+H) + .

[0642] Synthesis of 4-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)benzoic acid

[0643] [ka]

[0644] The compound 4-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)benzoic acid was prepared from methyl 4-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)benzoate (500 mg, 1.34 mmol) and lithium hydroxide monohydrate (225 mg, 5.36 mmol) in a similar procedure to the synthesis of 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid and isolated as a red solid.

[0645] Yield 400mg (83%). 1 H NMR(400MHz,DMSO)δ13.30(brs,1H),13.09(brs,1H),8.22(d,J=8.4Hz,2H),8.09(d,J=8.4Hz,2 H),7.91(dd,J=1.6,7.6Hz,1H),7.71(s,1H),7.58(d,J=7.6Hz,1H),7.50-7.36(m,2H).m / z:[ESI + ]359,361(M+H) + .

[0646] Synthesis of tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate

[0647] [ka]

[0648] The compound tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate was prepared from methyl 5-bromopicolinate (10.00 g, 46.29 mmol) and tert-butyl piperazine-1-carboxylate (12.93 g, 69.42 mmol) in a similar manner to the synthesis of 5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)picolinate and isolated as a yellow solid.

[0649] Yield 7.20g (48%). 1H NMR(400MHz,CDCl3)δ8.33(d,J=2.8Hz,1H),8.00(d,J=8.8Hz,1H),7.15(dd,J=2.8,8 m / z:[ESI + ]322(M+H) + .

[0650] Synthesis of methyl 5-(piperazin-1-yl)picolinate hydrochloride

[0651] [ka]

[0652] tert-Butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (25.00 g, 77.79 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (250 mL). The resulting solution was stirred at room temperature under a nitrogen atmosphere for 6 hours. The precipitated solid was collected by filtration. The filter cake was washed with diethyl ether (6 × 80 mL) and dried under vacuum to give methyl 5-(piperazin-1-yl)picolinate hydrochloride as a yellow solid.

[0653] Yield: 19.60g (98%). 1 H NMR(400MHz,DMSO)δ9.93(brs,2H,NH2+),8.44(d,J=2.8Hz,1H),8.05(d,J=8.8Hz,1H),7.70 (dd,J=2.8,8.8Hz,1H),3.88(s,3H),3.76(t,J=5.6Hz,4H),3.20(t,J=5.6Hz,4H).m / z:[ESI + ]222(M+H) + .

[0654] Synthesis of methyl 5-(4-(methylsulfonyl)piperazin-1-yl)picolinate

[0655] [ka]

[0656] Following a procedure similar to the synthesis of methyl 3-(4-(methylsulfonyl)piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxylate, the compound methyl 5-(4-(methylsulfonyl)piperazin-1-yl)picolinate was prepared from methyl 5-(piperazin-1-yl)picolinate hydrochloride (8.00 g, 31.04 mmol) and methanesulfonyl chloride (5.33 g, 46.53 mmol) and isolated as an off-white solid.

[0657] Yield 3.73g (40%). 1 H NMR(400MHz,DMSO)δ8.42(d,J=2.8Hz,1H),7.91(d,J=8.8Hz,1H),7.41(dd,J=2.8,8 .8Hz,1H),3.82(s,3H),3.55-3.47(m,4H),3.28-3.22(m,4H),2.93(s,3H).m / z:[ESI + ]300(M+H) + .

[0658] Synthesis of 5-(4-(methylsulfonyl)piperazin-1-yl)picolinic acid

[0659] [ka]

[0660] The compound 5-(4-(methylsulfonyl)piperazin-1-yl)picolinic acid was prepared from methyl 5-(4-(methylsulfonyl)piperazin-1-yl)picolinate (1.80 g, 6.01 mmol) and lithium hydroxide monohydrate (1.01 g, 24.07 mmol) in a similar procedure to the synthesis of 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid and isolated as an off-white solid.

[0661] Yield 1.58g (92%). 1H NMR (400 MHz, DMSO) δ 8.40 (d, J = 2.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 2.8, 8.8 Hz, 1H), 3.51 (t, J = 4.8 Hz, 4H), 3.26 (t, J = 4.8 Hz, 4H), 2.93 (s, 3H). No carboxylic acid protons were observed. m / z: [ESI + ]286(M+H) + .

[0662] Synthesis of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid

[0663] [ka]

[0664] The compound 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid was prepared from tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (5.00 g, 15.56 mmol) and lithium hydroxide monohydrate (2.61 g, 62.20 mmol) in a procedure similar to the synthesis of 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid and isolated as an off-white solid.

[0665] Yield 3.07g (64%). 1 H NMR(400MHz,DMSO)δ12.51(brs,1H),8.36(d,J=2.8Hz,1H),7.87(d,J=8.8Hz,1H),7.3 6(dd,J=2.8,8.8Hz,1H),3.51-3.43(m,4H),3.39-3.32(m,4H),1.42(s,9H).m / z:[ESI + ]308(M+H) + .

[0666] Synthesis of tert-butyl 4-(6-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate (Method 1)

[0667] [ka]

[0668] To a stirred solution of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid (1.00 g, 3.25 mmol) in DMF (5 mL) was added CDI (0.79 g, 4.87 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50°C for 2 hours under a nitrogen atmosphere to form solution A. Concurrently, to a stirred solution of 4-(2-chlorophenyl)thiazol-2-amine (0.75 g, 3.56 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 0.38 g, 9.50 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 minutes to form solution B. Solution B was then added dropwise to Solution A at room temperature under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 16 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using reverse-phase flash chromatography with the following conditions: Column: WelFlash™ C18-I, 20-40 μm, 330 g, Eluent A: water (+10 mmol / L NH4HCO3), Eluent B: acetonitrile, Gradient: 50%-70% B, 25 min, Flow rate: 80 mL / min, Detector: UV 220 / 254 nm. The desired fractions were collected and concentrated under reduced pressure to give tert-butyl 4-(6-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate as a yellow solid.

[0669] Yield 1.39g (85%). 1H NMR(400MHz,DMSO)δ11.65(brs,1H),8.42(d,J=2.8Hz,1H),8.02(d,J=8.8Hz,1H),7.93(dd,J=2.0,7.6Hz,1H),7.71(s,1H),7.57( m / z:[ESI + ]500,502(M+H) + .

[0670] Synthesis of N-(4-(2-chlorophenyl)thiazol-2-yl)-5-(piperazin-1-yl)picolinamide hydrochloride

[0671] [ka]

[0672] The compound N-(4-(2-chlorophenyl)thiazol-2-yl)-5-(piperazin-1-yl)picolinamide hydrochloride was prepared from tert-butyl 4-(6-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate (20.00 g, 40.00 mmol) in a procedure similar to the synthesis of methyl 5-(piperazin-1-yl)picolinate hydrochloride and isolated as a yellow solid.

[0673] Yield: 16.00g (92%). 1 H NMR(400MHz,DMSO)δ11.83(brs,1H),9.58(brs,2H,NH.HCl),8.48(d,J=2.8Hz,1H),8.09(d,J=8.8Hz,1H),7.92(dd,J=2.0,7.6Hz,1H),7 .73(s,1H),7.61(dd,J=2.8,8.8Hz,1H),7.58(dd,J=1.6,7.6Hz,1H),7.49-7.36(m,2H),3.78-3.63(m,4H),3.30-3.17(m,4H).m / z:[ESI +]400,402(M+H) + .

[0674] Synthesis of N-(4-(2-chlorophenyl)thiazol-2-yl)-5-fluoropicolinamide

[0675] [ka]

[0676] To a stirred mixture of 5-fluoropicolinic acid (1.00 g, 7.09 mmol) and triethylamine (2.15 g, 21.25 mmol) in ethyl acetate (20 mL) was added 4-(2-chlorophenyl)thiazol-2-amine (1.94 g, 9.21 mmol) and T3P (50% wt. in ethyl acetate, 13.52 g, 21.25 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 70° C. under a nitrogen atmosphere. The resulting mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with ethyl acetate (5×5 mL) to give N-(4-(2-chlorophenyl)thiazol-2-yl)-5-fluoropicolinamide as an off-white solid.

[0677] Yield 1.50g (63%). 1 H NMR(400MHz,CDCl3)δ11.08(brs,1H),8.53(d,J=2.8Hz,1H),8.38(dd,J=4.4,8.8Hz,1H),7.93(dd,J=1.6,7.6Hz,1H),7.72-7.61( m,1H),7.59(s,1H),7.50(dd,J=1.6,8.0Hz,1H),7.40-7.35(m,1H),7.32-7.27(m,1H).19FNMR(376MHz,CDCl3)δ119.38.m / z:[ESI + ]334,336(M+H) + .

[0678] Synthesis of tert-butyl 4-(6-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate (Method 2)

[0679] [ka]

[0680] The compound tert-butyl 4-(6-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate was prepared from N-(4-(2-chlorophenyl)thiazol-2-yl)-5-fluoropicolinamide (22.00 g, 65.91 mmol) and tert-butyl piperazine-1-carboxylate (18.42 g, 98.89 mmol) in a similar procedure to the synthesis of 2-chloro-4-morpholinobenzaldehyde and isolated as a dark yellow solid.

[0681] Yield: 32.00g (97%). 1 H NMR(400MHz,CDCl3)δ11.11(brs,1H),8.27(d,J=2.8Hz,1H),8.17(d,J=8.8Hz,1H),7.93(dd,J=1.6,7.6Hz,1H),7.53(s,1H),7.50 (dd,J=1.6,8.0Hz,1H),7.40-7.35(m,1H),7.32-7.25(m,2H),3.65(t,J=5.2Hz,4H),3.41(t,J=5.2Hz,4H),1.52(s,9H).m / z:[ESI + ]500,502(M+H) + .

[0682] Synthesis of tert-butyl 6-(6-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid

[0683] [ka]

[0684] The compound tert-butyl 6-(6-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid was prepared from N-(4-(2-chlorophenyl)thiazol-2-yl)-5-fluoropicolinamide (1.00 g, 3.00 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylic acid (0.71 g, 3.58 mmol) using a procedure similar to the synthesis of 2-chloro-4-morpholinobenzaldehyde and isolated as an orange liquid.

[0685] Yield 1.30g (85%). 1 H NMR(400MHz,CDCl3)δ11.02(brs,1H),8.09(d,J=8.4Hz,1H),7.91(dd,J=1.6,7.6Hz,1H),7.77(d,J=2.8Hz,1H),7.50(s,1H),7.47(dd, m / z:[ESI + ]512,514(M+H) + .

[0686] Synthesis of N-(4-(2-chlorophenyl)thiazol-2-yl)-5-(2,6-diazaspiro[3.3]heptan-2-yl)picolinamide 2,2,2-trifluoroacetate salt

[0687] [ka]

[0688] A mixture of tert-butyl 6-(6-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.30 g, 2.54 mmol) and 2,2,2-trifluoroacetic acid (13 mL) in DCM (13 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give N-(2,6-diazaspiro[3.3]heptan-2-yl)-5-(4-(2-chlorophenyl)thiazol-2-yl)picolinamide 2,2-trifluoroacetate as a yellow liquid.

[0689] Yield 1.30g (97%). 1 H NMR (400 MHz, DMSO) δ 11.57 (brs, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.95-7.88 (m, 2H), 7.70 (s, 1H), 7.56 (dd, J = 1.6, 8.0 Hz, 1H), 7.49-7.35 (m, 2H), 7.01 (dd, J = 2.8, 8.8 Hz, 1H), 4.24-4.19 (m, 8H). No aliphatic NH protons were observed. m / z: [ESI + ]412,414(M+H) + .

[0690] Synthesis of tert-butyl 7-(6-(methoxycarbonyl)pyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0691] [ka]

[0692] The compound tert-butyl 7-(6-(methoxycarbonyl)pyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate was prepared from methyl 5-bromopicolinate (1.60 g, 7.41 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.40 g, 6.19 mmol) in a similar manner to the synthesis of 5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)picolinate and isolated as a yellow solid.

[0693] Yield 2.20g (98%). 1 H NMR(400MHz,CDCl3)δ8.35(d,J=2.8Hz,1H),7.99(d,J=8.8Hz,1H),7.16(dd,J=2.8,8.8Hz, m / z:[ESI + ]362(M+H) + .

[0694] Synthesis of 5-(2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-7-yl)picolinic acid

[0695] [ka]

[0696] The compound 5-(2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-7-yl)picolinic acid was prepared from tert-butyl 7-(6-(methoxycarbonyl)pyridin-3.5-3-yl)-2,7-diazaspiro (2.00 g, 5.53 mmol)nonane-2-carboxylate and lithium hydroxide monohydrate (928 mg, 22.12 mmol) in a similar manner to the synthesis of 4-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)benzoic acid and isolated as an off-white solid.

[0697] Yield 1.56g (81%).1 H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 2.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.24 (dd, J = 2.8, 8.8 Hz, 1H), 3.71 (s,...

Claims

1. A compound represented by Formula I below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, isotopic variant, reverse amide analog, or any combination thereof. 【Chemistry 1】 During the ceremony, The A ring is a single aromatic or heteroaromatic ring system selected from phenyl, pyrazole, pyrimidine, 2-, 3- or 4-pyridine, pyridazine or pyrazine, or a single saturated C ３ -C １０ It is a heterocyclic ring; The B ring may be pyridazine, pyrazine, thiophene, thiazole, imidazole, or indazole, a single or fused C ４ -C １０ Cycloalkyl or single or fused saturated C ３ -C １０ It is a heterocyclic ring; R １ are F, Cl, Br, I, OH, SH, and R ８ -OH, R ８ -SH, -R ８ -O-R １０ , -O-R ８ -O-R １０ , C.F. ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , N.H. ２ , NHR, N(R) ２ , R ８ -N(R １０ ) (R １１ ), NHC(O)-R １０ , COOH, C(O)OR １０ , C(O)-R １０ , —C(O)NH ２ , C(O)N(R １０ ) (R １１ ), SO ２ R, SO ２ N (R １０ ) (R １１ ), NHSO ２ (R １０ ), CH(CF ３ ) (NH-R １０ ), C １ -C ５ linear or branched alkyl of C ２ -C ５ straight-chain, branched-chain or cyclic haloalkyl of C １ -C ５ linear, branched or cyclic alkoxy of C １ -C ５ a straight or branched chain thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle or substituted or unsubstituted aryl; R ２ are H, F, Cl, Br, I, OH, SH, and CF ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , N.H. ２ , C １ -C ５ straight or branched chain unsubstituted alkyl of C １ -C ５ straight-chain, branched-chain or cyclic haloalkyl of C １ -C ５ is a straight chain, branched chain or cyclic alkoxy; R ３ are F, Cl, Br, I, OH, SH, and CF ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , N.H. ２ , N(R １０ ) (R １１ ), C(O)-R １０ , —C(O)NH ２ , C(O)N(R １０ ) (R １１ ), SO ２ R, SO ２ N (R １０ ) (R １１ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl of C １ -C ５ straight-chain, branched-chain or cyclic haloalkyl of C １ -C ５ a straight chain, branched chain or cyclic alkoxy (optionally with at least one methylene group (CH ２ ) substituted with an oxygen atom), substituted or unsubstituted C ３ -C ８ Cycloalkyl or substituted or unsubstituted single, spirocyclic, fused or bridged C ３ -C １０ It is a heterocyclic ring; R ４ is H, F, Cl, Br, I, OH, SH, -R ８ -O-R １０ , C.F. ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , N.H. ２ , N(R １０ ) (R １１ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl of C １ -C ５ straight-chain, branched-chain or cyclic haloalkyl of C １ -C ５ linear, branched or cyclic alkoxy of C １ -C ５ a straight or branched chain thioalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl or substituted or unsubstituted single, spirocyclic, fused or bridged C ３ -C １０ It is a heterocyclic ring; R ５ is H, C １ -C ５ or a straight or branched chain, substituted or unsubstituted alkyl of １ -C ５ is a straight-chain, branched-chain or cyclic haloalkyl; Q １ is S; G=X is C=O; R is H, OH, or C １ -C ５ is a substituted or unsubstituted alkyl of the formula: R ８ is [CH ２ ]p, where p is 1 to 3; R １０ and R １１ are each independently H, OH, substituted or unsubstituted C １ -C ５ linear or branched alkyl of C １ -C ５ linear or branched alkoxy, substituted or unsubstituted C ３ -C ８ Heterocycle, C(O)-alkyl, or S(O) ２ - alkyl; Or, R １０ and R １１ are bonded to each other to form a substituted or unsubstituted C ３ -C ８ Forming a heterocyclic ring; The substituents are F, Cl, Br, I, OH, SH, and CF ３ , C.N., N.O. ２ , C １ -C ５ linear or branched alkyl, methoxyethyl, C １ -C ５ straight or branched chain C(O)-alkyl, C(O)-CH ２ -O-CH ３ , S.O. ２ -alkyl, C(O)-NH-alkyl, C １ -C ５ linear or branched alkyl-OH, C(CH ３ ) ２ CH ２ -OH, CH ２ CH ２ -OH, C ３ -C ８ Heterocycle, substituted or unsubstituted C １ -C ５ straight or branched chain alkoxy, N(R) ２ , N(R １０ ) (R １１ ), aryl, phenyl, heteroaryl, C ３ -C ８ cycloalkyl, or any combination thereof; n and l are, independently of each other, integers from 1 to 3; m and k are, independently of each other, integers from 0 to 3; In addition, the compound is not N-[4-(2-chlorophenyl)-2-thiazolyl]-6-methyl-3-pyridinecarboxamide or N-[4-(2-chlorophenyl)-2-thiazolyl]-4-(4-morpholinyl)-2-pyridinecarboxamide.

2. 2. The compound of claim 1 , The A ring is a single saturated C selected from morpholine, piperidine, piperazine, tetrahydro-2H-pyran, azetidine, or pyrrolidin-2-one. ３ -C １０ It is a heterocyclic ring; The B ring is a single or fused C ring selected from bicyclo[1.1.1]pentyl, cyclobutyl, cyclohexyl, or cyclopentyl. ４ -C １０ cycloalkyl or a single or fused saturated C selected from morpholine, piperidine, piperazine, tetrahydro-2H-pyran, azetidine, or pyrrolidin-2-one; ３ -C １０ It is a heterocyclic ring; R １ is CH ２ OH, CH ２ -CH ２ -O-CH ３ , C.H. ２ -O-CH ２ -CH ２ -O-CH ３ , C.H. ２ -O-CH ３ , O-CH ２ -CH ２ -O-CH ３ , C.H. ２ -NH-CH ３ , C.H. ２ -NH-C(O)CH ３ , C.H. ２ -N(CH ３ ) ２ , NHCO-Ph, NHCO-CH ３ , C(O)NH-Ph, NHSO ２ CH ３ , methyl, ethyl, CHF ２ , methoxy, cyclopropyl, azetidine, pyridine, or phenyl; R ２ is methyl, ethyl, CHF ２ , or methoxy; R ３ is morpholine, piperazine, C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH ３ ) ２ , C(O)-piperazine, methyl, ethyl, CHF ２ , methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone)piperidin-4-oxy, cyclopropyl, piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethenone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)ethenone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2,8-diazaspiro[4.5]decan-1-one, or 2-oxa-7-azaspiro[3.5]nonane; R ４ is CH ２ -CH ２ -O-CH ３ , C.H. ２ -O-CH ２ -CH ２ -O-CH ３ , O-CH ２ -CH ２ -O-CH ３ , morpholine, piperazine, methyl, ethyl, CHF ２ , methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone)piperidin-4-oxy, cyclopropyl, piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)ethenone, N-methylpiperazine-1-carboxamide amide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, diazaspiro[4.5]decan-1-one, or 2-oxa-7-azaspiro[3.5]nonane; R ５ is methyl, ethyl, or CHF ２ is; R is methyl, ethyl, CH ２ CH ２ OH or CH ２ CH ２ OCH ３ is; p is 2; R １０ and R １１ are each independently methyl, ethyl, CH ２ -CH ２ -O-CH ３ , O-CH ３ , 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro-2H-pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, or methyl-piperidine; Or, R １０ and R １１ are joined together to form morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, or 1-methylazetidine; n and l are, independently of each other, 1 or 2; m and k are, independently of each other, 0; The isotopic variant is a deuterated analog; or any combination thereof.

3. 3. A compound according to claim 1 or 2, Compounds represented by the structures set out in the table below. Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8

4. A compound represented by Formula V below: or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, isotopic variant, reverse amide analog, or any combination thereof. 【Chemistry 2】 During the ceremony, R １ are F, Cl, Br, I, OH, SH, and R ８ -OH, R ８ -SH, -R ８ -O-R １０ , -O-R ８ -O-R １０ , C.F. ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , N.H. ２ , NHR, N(R) ２ , R ８ -N(R １０ ) (R １１ ), R ９ -R ８ -N(R １０ ) (R １１ ), NHC(O)-R, NHC(O)-R １０ , COOH, C(O)OR １０ , C(O)-R １０ , —C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), SO ２ R, SO ２ N (R １０ ) (R １１ ), NHSO ２ (R １０ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl of C １ -C ５ straight-chain, branched-chain or cyclic haloalkyl of C １ -C ５ linear, branched or cyclic alkoxy of C １ -C ５ a straight or branched chain thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle or substituted or unsubstituted aryl; R ３ are F, Cl, Br, I, OH, SH, and CF ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , N.H. ２ , N(R １０ ) (R １１ ), C(O)-R １０ , —C(O)NH ２ , C(O)N(R １０ ) (R １１ ), SO ２ R, SO ２ N (R １１ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl of C １ -C ５ straight-chain, branched-chain or cyclic haloalkyl of C １ -C ５ linear, branched or cyclic alkoxy (optionally with at least one methylene group (CH ２ ) substituted with an oxygen atom), substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted, single, spirocyclic, fused or bridged C ３ -C １０ heterocycle or substituted or unsubstituted aryl; X ３ is N; X ４ and X ５ are, independently of each other, C or N; R is H, OH, C １ -C ５ is a straight or branched chain, substituted or unsubstituted alkyl; R ８ is [CH ２ ]p, where p is 1 to 10; R １０ and R １１ are each independently H, OH, substituted or unsubstituted C １ -C ５ linear or branched alkyl of C １ -C ５ or a substituted or unsubstituted C ３ -C ８ It is a heterocyclic ring; Or, R １０ and R １１ are bonded to each other to form a substituted or unsubstituted C ３ -C ８ Forming a heterocyclic ring; The substituents are F, Cl, Br, I, OH, SH, and CF ３ , C.N., N.O. ２ , substituted or unsubstituted C １ -C ５ linear or branched alkyl, methoxyethyl, substituted or unsubstituted C １ -C ５ straight or branched chain C(O)-alkyl, C(O)-CH ２ -O-CH ３ , S.O. ２ -alkyl, C(O)-NH-alkyl, C １ -C ５ linear or branched alkyl-OH, C(CH ３ ) ２ CH ２ -OH, CH ２ CH ２ -OH, C ３ -C ８ Heterocycle, substituted or unsubstituted C １ -C ５ straight or branched chain alkoxy, N(R) ２ , N(R １０ ) (R １１ ), aryl, phenyl, heteroaryl, C ３ -C ８ cycloalkyl, or any combination thereof.

5. 10. A compound according to claim 1 or 4, R １ is Cl, -R ８ -O-R １０ , or C.H. ２ -O-CH ３ is; R ３ is N(R １０ ) (R １１ ), or substituted or unsubstituted, single, spirocyclic, fused or bridged C ３ -C １０ It is a heterocyclic ring; R is H or OH; R １０ is a substituted or unsubstituted C ３ -C １０ heterocycle, or methylpiperidine; Or, R １０ and R １１ are bonded to each other to form a substituted or unsubstituted C ３ -C ８ Compounds that form a heterocycle, or 1-methylazetidine.

6. 5. The compound of claim 4, R １ is CH ２ OH, CH ２ -CH ２ -O-CH ３ , C.H. ２ -O-CH ２ -CH ２ -O-CH ３ , C.H. ２ -O-CH ３ , O-CH ２ -CH ２ -O-CH ３ , C.H. ２ -NH-CH ３ , C.H. ２ -NH-C(O)CH ３ , C.H. ２ -N(CH ３ ) ２ , NHCO-Ph, NHCO-CH ３ , C(O)NH-Ph, NHSO ２ CH ３ , methyl, ethyl, CHF ２ , methoxy, cyclopropyl, azetidine, pyridine, or phenyl; R ３ are morpholine, piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)etheone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methyl morpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenonone, 2,8-diazaspiro[4.5]decan-1-one, or 2-oxa-7-azaspiro[3.5]nonane; R is methyl, ethyl, CH ２ CH ２ OH or CH ２ CH ２ OCH ３ is; p is 2; R １０ and R １１ are each independently methyl, ethyl, CH ２ -CH ２ -O-CH ３ , O-CH ３ , 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro-2H-pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, or methyl-piperidine; Or, R １０ and R １１ are joined together to form morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, or 1-methylazetidine; The isotopic variant is a deuterated analog; or any combination thereof.

7. The compound according to any one of claims 4 to 6, Compounds represented by the structures set out in the table below. Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12

8. A compound represented by Formula VI below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, isotopic variant, reverse amide analog, or any combination thereof: 【Transformation 3】 During the ceremony, R １ are F, Cl, Br, I, OH, SH, and R ８ -OH, R ８ -SH, -R ８ -O-R １０ , -O-R ８ -O-R １０ , C.F. ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , N.H. ２ , NHR, N(R) ２ , R ８ -N(R １０ ) (R １１ ), NHC(O)-R, NHC(O)-R １０ , COOH, C(O)OR １０ , C(O)-R １０ , —C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), SO ２ R, SO ２ N (R １０ ) (R １１ ), NHSO ２ (R １０ ), C １ -C ５ linear or branched alkyl of C １ -C ５ straight-chain, branched-chain or cyclic haloalkyl of C １ -C ５ linear, branched or cyclic alkoxy of C １ -C ５ a straight or branched chain thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle or substituted or unsubstituted aryl; R ２ are H, F, Cl, Br, I, OH, SH, and CF ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , N.H. ２ , C １ -C ５ linear or branched, substituted or unsubstituted alkyl of C １ -C ５ or a straight, branched or cyclic haloalkyl of １ -C ５ is a straight chain, branched chain or cyclic alkoxy; Or, R ２ and R １ are joined together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; R ４ is H, F, Cl, Br, I, OH, SH, -R ８ -O-R １０ , C.F. ３ , CDs ３ , OCD ３ , C.N., N.O. ２ , N.H. ２ , N(R １０ ) (R １１ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl of C １ -C ５ straight-chain, branched-chain or cyclic haloalkyl of C １ -C ５ linear, branched or cyclic alkoxy of C １ -C ５ a straight or branched chain thioalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl or substituted or unsubstituted single, spirocyclic, fused or bridged C ３ -C １０ It is a heterocyclic ring; X ３ is N; X １ , X ２ , X ４ , and X ５ are, independently of each other, C or N; X ６ is O, CH ２ , CHR, C(R １０ ) (R １１ ), NH, N—R, or N—C(O)—R １０ is; R is H, OH, NH ２ , NH(R １０ ), N(R １０ ) (R １１ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl, CH ２ CH ２ OH or C １ -C ５ Substituted or unsubstituted SO ２ - alkyl; R ８ is [CH ２ ]p, where p is 1 to 10; R １０ and R １１ are each independently H, substituted or unsubstituted C １ -C ５ linear or branched alkyl of C １ -C ５ linear or branched alkoxy, substituted or unsubstituted C ３ -C ８ Heterocycle, C(O)-alkyl, or S(O) ２ - alkyl; Or, R １０ and R １１ are bonded to each other to form a substituted or unsubstituted C ３ -C ８ Forming a heterocyclic ring; The substituents are F, Cl, Br, I, OH, SH, and CF ３ , C.N., N.O. ２ , C １ -C ５ linear or branched alkyl, methoxyethyl, C １ -C ５ straight or branched chain C(O)-alkyl, C(O)-CH ３ , C(O)—CH ２ -O-CH ３ , S.O. ２ -alkyl, C(O)-NH-alkyl, C １ -C ５ linear or branched alkyl-OH, C(CH ３ ) ２ CH ２ -OH, CH ２ CH ２ -OH, C ３ -C ８ Heterocycle, C １ -C ５ linear or branched alkoxy, N(R １０ ) (R １１ ), aryl, phenyl, heteroaryl, C ３ -C ８ cycloalkyl, or any combination thereof; n and l are, independently of each other, integers from 1 to 3; m and k are each independently an integer of 0 to 2;

9. 9. The compound of claim 8, R １ is Cl, -R ８ -O-R １０ , or C.H. ２ -O-CH ３ and / or X ６ is CHR, CH(OH), C(R １０ ) (R １１ ), 1-methylazetidine, N—R, N—SO ２ -CH ３ , N—C(O)—R １０ , N-C(O)-CH ３ , N-C(O)-NH-CH ３ or N—C(O)-1-methyl-3-piperidine.

10. 9. The compound of claim 8, R １ is CH ２ OH, CH ２ -CH ２ -O-CH ３ , C.H. ２ -O-CH ２ -CH ２ -O-CH ３ , C.H. ２ -O-CH ３ , O-CH ２ -CH ２ -O-CH ３ , C.H. ２ -NH-CH ３ , C.H. ２ -NH-C(O)CH ３ , C.H. ２ -N(CH ３ ) ２ , NHCO-Ph, NHCO-CH ３ , C(O)NH-Ph, NHSO ２ CH ３ , methyl, ethyl, CHF ２ , methoxy, cyclopropyl, azetidine, pyridine, or phenyl; Or, R ２ and R １ are combined together to form benzene, 1,4-dioxane, 2,3-dihydro-1,4-dioxine, dioxole, or dioxolepyridine; R ４ is CH ２ -CH ２ -O-CH ３ , C.H. ２ -O-CH ２ -CH ２ -O-CH ３ , O-CH ２ -CH ２ -O-CH ３ , morpholine, piperazine, methyl, ethyl, CHF ２ , methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone)piperidin-4-oxy, cyclopropyl, piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)ethenone, N-methylpiperazine-1-carboxamide amide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, diazaspiro[4.5]decan-1-one, or 2-oxa-7-azaspiro[3.5]nonane; X ６ is CH(OH), CH(NH ２ ), CH(NH(CH ３ )), C(H)CH ２ CH ２ -OH, C(H)CH ２ -OH, 1-methylazetidine, N-CH ３ , N-SO ２ -CH ３ , N-R ２０ , N-CH ２ CH ２ -OCH ３ , N-C(O)O-tBu, N-C(O)-CH ２ CH ２ -OCH ３ , N-C(O)-CH ３ , N-C(O)-CH ２ -N(CH ３ ) ２ , N-C(O)-CH ２ -CH ２ -N(CH ３ ) ２、 N—C(O)—CH ２ -OH, N-C(O)-CH ２ CH ２ -OH, N-C(O)-NH-CH ３ , N—C(O)-1-methyl-2-pyrrolidine, N—C(O)-1-methyl-3-pyrrolidine, N—C(O)-1-methyl-3-piperidine, or N—C(O)-1-methyl-4-piperidine; R is NH(CH ３ ), methyl, ethyl, CH ２ CH ２ OH, CH ２ CH ２ OCH ３ , C(O)-methylpyrrolidine, C(O)-methylpiperidine, or C(O)-CH ３ is; p is 2; R １０ and R １１ are each independently methyl, ethyl, CH ２ -CH ２ -O-CH ３ , O-CH ３ , 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro-2H-pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, or methyl-piperidine; Or, R １０ and R １１ are joined together to form morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, or 1-methylazetidine; n and l are, independently of each other, 1 or 2; m and k are, independently of each other, 0; The isotopic variant is a deuterated analog; or any combination thereof.

11. 9. The compound of claim 8, Compounds represented by the structures set out in the table below. Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8

12. 9. The compound of claim 8, A compound represented by the following formula VIII: 【Chemistry 4】

13. 9. A compound according to claim 4 or 8, X ３ , X ４ , and X ５ wherein at least two of are N.

14. 13. A compound according to claim 8 or 12, X ６ CHR, CH(OH), C(R １０ ) (R １１ ), 1-methylazetidine, N—R, N—SO ２ -CH ３ , N—C(O)—R １０ , N-C(O)-CH ３ , N-C(O)-NH-CH ３ or N—C(O)-1-methyl-3-piperidine.

15. 13. A compound according to claim 8 or 12, The compound wherein R is H or OH.

16. A compound according to any one of claims 8 or 12 to 15, R １０ is substituted or unsubstituted C ３ -C ８ a heterocycle or a methyl-piperidine, or R １０ and R １１ are bonded to each other to form a substituted or unsubstituted C ３ -C ８ Compounds that form a heterocycle or 1-methylazetidine.

17. A compound selected from the table below. Table 4-1 Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 4-9 Table 4-10 Table 4-11 Table 4-12 Table 4-13 Table 4-14 Table 4-15 Table 4-16

18. A compound according to any one of claims 1 to 17; and a pharmaceutically acceptable carrier.

19. 20. Use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting fibrosis in a subject.

20. 20. The use according to claim 19, The fibrosis is systemic fibrosis. The fibrosis is organ-specific fibrosis. The fibrosis is primary fibrosis or secondary fibrosis. The fibrosis is the result of systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, autoimmune disease, tissue injury, inflammation, oxidative stress, or any combination thereof; The fibrosis is liver fibrosis, pulmonary fibrosis, or skin fibrosis. the subject has cirrhosis. or any combination thereof, use.

21. 21. The use according to claim 20, The systemic fibrosis is systemic sclerosis, multiple fibrosclerosis (IgG4-associated fibrosis), nephrogenic systemic fibrosis, scleroderma graft-versus-host, or any combination thereof; The organ-specific fibrosis is pulmonary fibrosis, cardiac fibrosis, renal fibrosis, pulmonary fibrosis, hepatic portal fibrosis, radiation-induced fibrosis, bladder fibrosis, intestinal fibrosis, peritoneal sclerosis, diffuse fasciitis, wound healing, scarring, or any combination thereof; The skin fibrosis is scleroderma. The skin fibrosis is the result of localized or generalized scleroderma, keloids, hypertrophic scars, familial cutaneous collagenoma, collagenous connective tissue nevus, or any combination thereof; The liver fibrosis is the result of liver scarring or chronic liver damage; or any combination thereof, use.

22. 22. The use according to claim 21, The pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). The cardiac fibrosis is hypertension-related myocardial fibrosis, post-myocardial infarction, Chagas disease-induced myocardial fibrosis, or any combination thereof; The renal fibrosis is diabetic and hypertensive nephropathy, urinary tract obstruction-induced renal fibrosis, inflammatory / autoimmune-induced renal fibrosis, aristolochic acid nephropathy, polycystic kidney disease, or any combination thereof; The pulmonary fibrosis is idiopathic pulmonary fibrosis, silica-induced pneumoconiosis (silicosis), asbestos-induced pulmonary fibrosis (asbestosis), chemotherapy-induced pulmonary fibrosis, or any combination thereof; The hepatic portal fibrosis is alcoholic liver fibrosis, non-alcoholic liver fibrosis, hepatitis C-induced liver fibrosis, primary biliary cirrhosis, parasite-induced liver fibrosis (schistosomiasis), or any combination thereof; The diffuse fasciitis is localized scleroderma, keloid, Dupuytren's disease, Peyronie's disease, myelofibrosis, oral submucous fibrosis, or any combination thereof; The chronic liver damage is due to alcoholism, malnutrition, hemochromatosis, or exposure to poisons, toxins, or drugs. or any combination thereof, use.

23. 20. Use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting pulmonary fibrosis in a subject.

24. 24. The use according to claim 23, The pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

25. 20. Use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting idiopathic pulmonary fibrosis (IPF) in a subject.

26. 20. Use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting liver fibrosis in a subject.

27. 27. The use according to claim 26, The use, wherein the liver fibrosis is portal hypertension, cirrhosis, congenital hepatic fibrosis, or any combination thereof.

28. 20. Use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting cirrhosis in a subject.

29. 29. The use according to claim 28, The use, wherein the cirrhosis is the result of hepatitis or alcoholism.

30. 20. Use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholic steatohepatitis (ASH) in a subject.

31. 20. Use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting non-alcoholic steatohepatitis (NASH) in a subject.

32. 20. Use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholic fatty liver disease (AFLD) in a subject.

33. 20. Use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting non-alcoholic fatty liver disease (NAFLD) in a subject.

34. 20. Use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting an autoimmune disease or disorder in a subject.

35. Use of a compound represented by the structure set forth in the table below for the manufacture of a medicament for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, cirrhosis, alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), alcoholic fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD), or an autoimmune disease in a subject. Table 5-1 Table 5-2 Table 5-3 Table 5-4

36. 36. The use according to claim 35, The fibrosis is systemic fibrosis. The fibrosis is organ-specific fibrosis. The fibrosis is primary fibrosis or secondary fibrosis. The fibrosis is the result of systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, autoimmune disease, tissue injury, inflammation, oxidative stress, or any combination thereof; the subject has cirrhosis. The fibrosis is liver fibrosis, pulmonary fibrosis, or skin fibrosis. The pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). The liver fibrosis is portal hypertension, cirrhosis, congenital hepatic fibrosis, or any combination thereof; the cirrhosis is the result of hepatitis or alcoholism; or any combination thereof, use.

37. 37. The use according to claim 36, The systemic fibrosis is systemic sclerosis, multiple fibrosclerosis (IgG4-associated fibrosis), nephrogenic systemic fibrosis, scleroderma graft-versus-host, or any combination thereof; The organ-specific fibrosis is pulmonary fibrosis, cardiac fibrosis, renal fibrosis, pulmonary fibrosis, hepatic portal fibrosis, radiation-induced fibrosis, bladder fibrosis, intestinal fibrosis, peritoneal sclerosis, diffuse fasciitis, wound healing, scarring, or any combination thereof; The skin fibrosis is scleroderma. The skin fibrosis is the result of localized or generalized scleroderma, keloids, hypertrophic scars, familial cutaneous collagenoma, collagenous connective tissue nevus, or any combination thereof; The liver fibrosis is the result of liver scarring or chronic liver damage; or any combination thereof, use.

38. 38. The use according to claim 37, The pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). The cardiac fibrosis is hypertension-related myocardial fibrosis, post-myocardial infarction, Chagas disease-induced myocardial fibrosis, or any combination thereof; The renal fibrosis is diabetic and hypertensive nephropathy, urinary tract obstruction-induced renal fibrosis, inflammatory / autoimmune-induced renal fibrosis, aristolochic acid nephropathy, polycystic kidney disease, or any combination thereof; The pulmonary fibrosis is idiopathic pulmonary fibrosis, silica-induced pneumoconiosis (silicosis), asbestos-induced pulmonary fibrosis (asbestosis), chemotherapy-induced pulmonary fibrosis, or any combination thereof; The hepatic portal fibrosis is alcoholic liver fibrosis, non-alcoholic liver fibrosis, hepatitis C-induced liver fibrosis, primary biliary cirrhosis, parasite-induced liver fibrosis (schistosomiasis), or any combination thereof; The diffuse fasciitis is localized scleroderma, keloid, Dupuytren's disease, Peyronie's disease, myelofibrosis, oral submucous fibrosis, or any combination thereof; The chronic liver damage is due to alcoholism, malnutrition, hemochromatosis, or exposure to poisons, toxins, or drugs. or any combination thereof, use.

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