Collagen 1 translation inhibitors and methods of use thereof

Abstract

The present invention relates to novel collagen 1 translation inhibitors, compositions and preparation methods thereof, and uses thereof for treating: fibrosis, including pulmonary fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis and skin fibrosis; IPF; wound healing; scar formation and gingival fibromatosis; systemic sclerosis; alcoholic steatohepatitis; and non-alcoholic steatohepatitis (NASH).

Description

Technical Field

[0001] The present invention relates to novel collagen 1 translation inhibitors, compositions and preparation methods thereof, and uses thereof for treating fibrosis, including pulmonary fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis and skin fibrosis; IPF; wound healing; scarring and gingival fibromatosis; systemic sclerosis; alcoholic steatohepatitis; and non-alcoholic steatohepatitis (NASH). Background Art

[0002] The formation of fibrous connective tissue is part of the normal healing process following tissue damage caused by injury or inflammation. During this process, activated immune cells, including macrophages, stimulate the proliferation and activation of fibroblasts, which in turn deposit connective tissue. However, abnormal or excessive production of connective tissue can lead to a buildup of fibrous material that interferes with the normal function of the tissue. Fibrotic growths can proliferate and invade healthy surrounding tissue even after the original injury has healed. This abnormal formation of excess connective tissue that occurs during the repair or reaction process is known as fibrosis.

[0003] Many agents trigger the 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 is the conversion 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 fibrosis-inducing signal.

[0004] Physiologically, fibrosis plays a role in the deposition of connective tissue, which can eliminate the structure and function of underlying organs or tissues. Defined by the pathological accumulation of extracellular matrix (ECM) proteins, fibrosis causes scarring and thickening of affected tissues, thereby interfering with normal organ function. Among various conditions, the formation of fibrotic tissue is characterized by the deposition of an abnormally large amount of collagen. The synthesis of collagen also relates to many other pathological conditions. For example, the clinical conditions and illnesses associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, and autoimmune disorders, are characterized by the excessive production of connective tissue, which causes the destruction of normal tissue structure and function. These diseases are best explained based on the disorder of cell function, and their main manifestations are the excessive synthesis and deposition of collagen. The role of collagen in fibrosis has prompted people to try to develop drugs that inhibit its accumulation.

[0005] Excessive accumulation of collagen is the main pathological feature of the various clinical conditions of illness that is characterised in tissue fibrosis. These conditions of illness comprise localised processes (e.g., pulmonary fibrosis and liver cirrhosis) or more generalised processes (e.g., progressive systemic sclerosis). Collagen deposition is the feature of different forms of skin fibrosis, which, in addition to scleroderma, also comprises localised and generalised morphea, keloids, hypertrophic scars, familial skin collagenomas and collagen type connective tissue nevi. The latest progress in the understanding of the normal biochemistry of collagen allows us to define the specific levels of collagen biosynthesis and degradation, and at these levels, pharmacological intervention can cause the collagen deposition in tissue to reduce. Such compounds can potentially provide us with novel means to reduce the excessive collagen accumulation in disease.

[0006] The fibrosis of the liver (also referred to as liver fibrosis in this article) can be caused by various types of chronic liver damage, especially when related to inflammatory components. Even if self-limiting acute liver damage (for example, acute viral hepatitis A) is fulminant, it is not necessarily distorted stent architecture, and therefore does not usually cause fibrosis, although liver cells are lost. However, factors such as chronic alcoholism, malnutrition, hemochromatosis and poison exposure, toxin exposure or drug exposure may cause chronic liver damage and liver fibrosis due to hepatotoxic chemical exposure. Liver scarring caused by surgery or other forms of damage relevant to mechanical biliary obstruction may also cause liver fibrosis.

[0007] Fibrosis itself is not necessarily symptomatic; however, it can lead to the development of portal hypertension, in which scarring distorts blood flow through the liver, or cirrhosis, in which scarring leads to disruption of normal liver architecture and liver dysfunction. The extent of each of these pathologies determines the clinical manifestations of liver fibrosis. For example, congenital hepatic fibrosis affects the branches of the portal vein, largely sparing the parenchyma. The result is portal hypertension without impairing liver cell function.

[0008] treat

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

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

[0011] Many patients do not respond to available treatments for fibrotic conditions, and long-term treatment is limited by toxicity and side effects. Therefore, there remains a need to develop therapeutic modalities aimed at reducing fibrosis. Developing safe and effective treatments for established cirrhosis and portal hypertension, as well as for reducing fibrosis, would be highly beneficial.

[0012] Attempts to treat idiopathic pulmonary fibrosis (IPF) with a combination of anti-inflammatory drugs (prednisone, azathioprine, and N-acetyl-l-cysteine ​​(NAC)) have failed to improve outcomes and have instead increased mortality. In 2014, two drugs—pirfenidone, a drug with an unknown mechanism of action, and nintedanib, a tyrosine kinase inhibitor—were approved for the treatment of IPF, primarily based on their ability to reduce the decline in forced vital capacity (FVC) and slow the rate of disease progression. However, to date, it has been unclear 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 are therefore useful for treating fibrosis, including primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis and autoimmune disorders, pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF), as well as localized processes (e.g., pulmonary fibrosis and liver cirrhosis) or more generalized processes (e.g., progressive systemic sclerosis). The compounds can further be used to treat different forms of skin fibrosis, including localized and generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenomas, and collagenous connective tissue nevi, in addition to scleroderma. The compounds can further be used to treat pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF), as well as liver fibrosis caused by liver scarring due to surgery or other forms of injury associated with mechanical biliary obstruction. This fibrosis can lead to portal hypertension, in which scarring distorts blood flow through the liver, or cirrhosis, as well as other fibrotic liver conditions including nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), and alcoholic fatty liver disease (AFLD), which can similarly be treated by the compounds of the present invention. Summary of the Invention

[0014] The present invention provides a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), pharmaceutical product, or any combination thereof, which is represented by the structure of Formula IX as defined below and the structures listed in Table 1. In various embodiments, the compound is a collagen I translation inhibitor.

[0015] The present invention further provides a pharmaceutical composition comprising: a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., deuterated analog), pharmaceutical product, or any combination thereof, represented by the structure of Formula IX and the structures listed in Table 1 as defined below; and a pharmaceutically acceptable carrier.

[0016] The present invention further provides a method of treating fibrosis in a subject, curbing fibrosis in a subject, reducing the severity of fibrosis in a subject, reducing the risk of a subject developing fibrosis, or inhibiting fibrosis in a subject, the method comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1 as defined below under conditions effective to treat fibrosis in a subject with fibrosis, curbing fibrosis in a subject with fibrosis, reducing the severity of fibrosis in a subject with fibrosis, reducing the risk of a subject developing fibrosis, or inhibiting fibrosis in a subject with fibrosis. In some embodiments, the fibrosis is a systemic fibrotic disease. In some embodiments, the systemic fibrotic disease is systemic sclerosis, multifocal fibrosing sclerosis (IgG4-related fibrosis), nephrogenic systemic fibrosis, scleroderma graft-versus-host disease, or any combination thereof. In some embodiments, the fibrosis is an organ-specific fibrotic disease. In certain embodiments, the organ-specific fibrotic disease is pulmonary fibrosis, cardiac fibrosis, renal fibrosis, pulmonary fibrosis, liver and portal vein fibrosis, radiation-induced fibrosis, bladder fibrosis, intestinal fibrosis, peritoneal sclerosis, diffuse fasciitis, wound healing, scarring or any combination thereof. In certain embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In certain embodiments, the cardiac fibrosis is hypertension-related cardiac fibrosis, after myocardial infarction, myocardial fibrosis induced by Chagas disease (Chagas disease) or any combination thereof. In certain 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 certain embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis, silica-induced pneumoconiosis (silicosis), asbestos-induced pulmonary fibrosis (asbestosis), chemotherapeutic-induced pulmonary fibrosis or any combination thereof. In some embodiments, the liver and portal vein fibrosis is alcoholic and non-alcoholic 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, keloids, Dupuytren's disease, Peyronie's disease, myelofibrosis, oral submucosal fibrosis or any combination thereof. In some embodiments, the fibrosis is primary or secondary fibrosis. In some embodiments, the fibrosis is the result of systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, autoimmune disorders, tissue damage, inflammation, oxidative stress or any combination thereof. In some embodiments, the fibrosis is liver fibrosis, lung fibrosis or skin fibrosis. In some embodiments, the subject suffers from cirrhosis of the liver.In some embodiments, the skin fibrosis is scleroderma. In some embodiments, the skin fibrosis is the result of localized or generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenomas, collagenous 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 is caused by alcoholism, malnutrition, hemochromatosis, toxicant exposure, toxin exposure, or drug exposure.

[0017] The present invention further provides a method of treating, suppressing, reducing the severity of, reducing the risk of, or inhibiting pulmonary fibrosis in a subject, comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of, or inhibit pulmonary fibrosis in a subject having pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

[0018] The present invention further provides a method of treating idiopathic pulmonary fibrosis (IPF) in a subject, suppressing IPF in a subject, reducing the severity of IPF in a subject, reducing the risk of developing IPF in a subject, or inhibiting IPF in a subject, comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat idiopathic pulmonary fibrosis (IPF) in a subject having IPF, suppressing IPF in a subject having IPF, reducing the severity of IPF in a subject having IPF, reducing the risk of developing IPF in a subject having IPF, or inhibiting IPF in a subject having IPF.

[0019] The present invention further provides a method of treating, suppressing, reducing the severity of, reducing the risk of, or inhibiting a liver fibrosis disorder in a subject, comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of, or inhibit a liver fibrosis disorder in a subject having a liver fibrosis disorder. In some embodiments, the liver fibrosis disorder is portal hypertension, cirrhosis, idiopathic hepatic fibrosis, or any combination thereof.

[0020] The present invention further provides a method of treating, arresting, reducing the severity of, reducing the risk of, or inhibiting cirrhosis in a subject, comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat, arrest, reduce the severity of, reduce the risk of, or inhibit cirrhosis in a subject having cirrhosis. In some embodiments, the cirrhosis is the result of hepatitis or alcoholism.

[0021] The present invention further provides a method of treating alcoholic steatohepatitis (ASH) in a subject, suppressing ASH in a subject, reducing the severity of ASH in a subject, reducing the risk of developing ASH in a subject, or inhibiting ASH in a subject, the method comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1 as defined below, under conditions effective to treat alcoholic steatohepatitis (ASH) in a subject having ASH, suppressing ASH in a subject having ASH, reducing the severity of ASH in a subject having ASH, reducing the risk of developing ASH in a subject having ASH, or inhibiting ASH in a subject having ASH.

[0022] The present invention further provides a method of treating non-alcoholic steatohepatitis (NASH) in a subject, suppressing NASH in a subject, reducing the severity of NASH in a subject, reducing the risk of developing NASH in a subject, or inhibiting NASH in a subject, the method comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat non-alcoholic steatohepatitis (NASH) in a subject having NASH, suppressing NASH in a subject having NASH, reducing the severity of NASH in a subject having NASH, reducing the risk of developing NASH in a subject having NASH, or inhibiting NASH in a subject having NASH.

[0023] The present invention further provides a method of treating alcoholic fatty liver disease (AFLD) in a subject, suppressing AFLD in a subject, reducing the severity of AFLD in a subject, reducing the risk of developing AFLD in a subject, or inhibiting AFLD in a subject, the method comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat alcoholic fatty liver disease (AFLD) in a subject having AFLD, suppressing AFLD in a subject having AFLD, reducing the severity of AFLD in a subject having AFLD, reducing the risk of developing AFLD in a subject having AFLD, or inhibiting AFLD in a subject having AFLD.

[0024] The present invention further provides a method for treating non-alcoholic fatty liver disease (NAFLD) in a subject, curbing NAFLD in a subject, reducing the severity of NAFLD in a subject, reducing the risk of developing NAFLD in a subject, or inhibiting NAFLD in a subject, the method comprising administering to the subject a compound represented by the structure of Formula IX and the structures listed in Table 1 as defined below under conditions effective to treat non-alcoholic fatty liver disease (NAFLD) in a subject with NAFLD, curb NAFLD in a subject with NAFLD, reduce the severity of NAFLD in a subject with NAFLD, reduce the risk of developing NAFLD in a subject with NAFLD, or inhibit NAFLD in a subject with NAFLD.

[0025] The present invention further provides a method of treating, suppressing, reducing the severity of, reducing the risk of, or inhibiting an autoimmune disease or condition in a subject, comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of, or inhibit an autoimmune disease or condition in a subject having an autoimmune disease or condition.

[0026] The present invention provides a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., deuterated analog), pharmaceutical product, or any combination thereof, which is represented by the structure of Formula IX as defined below and the structures listed in Table 1. In various embodiments, the compound is a collagen I translation inhibitor.

[0027] The present invention further provides a pharmaceutical composition comprising: a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., deuterated analog), pharmaceutical product, or any combination thereof, represented by the structure of Formula IX and the structures listed in Table 1 as defined below; and a pharmaceutically acceptable carrier.

[0028] The present invention further provides a method of treating fibrosis in a subject, curbing fibrosis in a subject, reducing the severity of fibrosis in a subject, reducing the risk of a subject developing fibrosis, or inhibiting fibrosis in a subject, the method comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1 as defined below under conditions effective to treat fibrosis in a subject with fibrosis, curbing fibrosis in a subject with fibrosis, reducing the severity of fibrosis in a subject with fibrosis, reducing the risk of a subject developing fibrosis, or inhibiting fibrosis in a subject with fibrosis. In some embodiments, the fibrosis is a systemic fibrotic disease. In some embodiments, the systemic fibrotic disease is systemic sclerosis, multifocal fibrosing sclerosis (IgG4-related fibrosis), nephrogenic systemic fibrosis, scleroderma graft-versus-host disease, or any combination thereof. In some embodiments, the fibrosis is an organ-specific fibrotic disease. In certain embodiments, the organ-specific fibrotic disease is pulmonary fibrosis, cardiac fibrosis, renal fibrosis, pulmonary fibrosis, liver and portal vein fibrosis, radiation-induced fibrosis, bladder fibrosis, intestinal fibrosis, peritoneal sclerosis, diffuse fasciitis, wound healing, scarring or its any combination. In certain embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In certain embodiments, the cardiac fibrosis is hypertension-related cardiac fibrosis, after myocardial infarction, myocardial fibrosis induced by Chagas' disease or its any combination. In certain 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 its any combination. In certain embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis, silica-induced pneumoconiosis (silicosis), asbestos-induced pulmonary fibrosis (asbestosis), chemotherapeutic-induced pulmonary fibrosis or its any combination. In some embodiments, the liver and portal vein fibrosis is alcoholic and non-alcoholic 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, keloids, Dupuytren's disease, Peyronie's disease, myelofibrosis, oral submucosal fibrosis or any combination thereof. In some embodiments, the fibrosis is primary or secondary fibrosis. In some embodiments, the fibrosis is the result of systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, autoimmune disorders, tissue damage, inflammation, oxidative stress or any combination thereof. In some embodiments, the fibrosis is liver fibrosis, lung fibrosis or skin fibrosis. In some embodiments, the subject suffers from cirrhosis of the liver. In some embodiments, the skin fibrosis is scleroderma.In some embodiments, the skin fibrosis is the result of localized or generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenomas, collagenous 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 is caused by alcoholism, malnutrition, hemochromatosis, toxicant exposure, toxin exposure, or drug exposure.

[0029] The present invention further provides a method of treating, suppressing, reducing the severity of, reducing the risk of, or inhibiting pulmonary fibrosis in a subject, comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of, or inhibit pulmonary fibrosis in a subject having pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

[0030] The present invention further provides a method of treating idiopathic pulmonary fibrosis (IPF) in a subject, suppressing IPF in a subject, reducing the severity of IPF in a subject, reducing the risk of developing IPF in a subject, or inhibiting IPF in a subject, comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat idiopathic pulmonary fibrosis (IPF) in a subject having IPF, suppressing IPF in a subject having IPF, reducing the severity of IPF in a subject having IPF, reducing the risk of developing IPF in a subject having IPF, or inhibiting IPF in a subject having IPF.

[0031] The present invention further provides a method of treating, suppressing, reducing the severity of, reducing the risk of, or inhibiting a liver fibrosis disorder in a subject, comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of, or inhibit a liver fibrosis disorder in a subject having a liver fibrosis disorder. In some embodiments, the liver fibrosis disorder is portal hypertension, cirrhosis, idiopathic hepatic fibrosis, or any combination thereof.

[0032] The present invention further provides a method of treating, arresting, reducing the severity of, reducing the risk of, or inhibiting cirrhosis in a subject, comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat, arrest, reduce the severity of, reduce the risk of, or inhibit cirrhosis in a subject having cirrhosis. In some embodiments, the cirrhosis is the result of hepatitis or alcoholism.

[0033] The present invention further provides a method of treating alcoholic steatohepatitis (ASH) in a subject, suppressing ASH in a subject, reducing the severity of ASH in a subject, reducing the risk of developing ASH in a subject, or inhibiting ASH in a subject, the method comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1 as defined below, under conditions effective to treat alcoholic steatohepatitis (ASH) in a subject having ASH, suppressing ASH in a subject having ASH, reducing the severity of ASH in a subject having ASH, reducing the risk of developing ASH in a subject having ASH, or inhibiting ASH in a subject having ASH.

[0034] The present invention further provides a method of treating non-alcoholic steatohepatitis (NASH) in a subject, suppressing NASH in a subject, reducing the severity of NASH in a subject, reducing the risk of developing NASH in a subject, or inhibiting NASH in a subject, the method comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat non-alcoholic steatohepatitis (NASH) in a subject having NASH, suppressing NASH in a subject having NASH, reducing the severity of NASH in a subject having NASH, reducing the risk of developing NASH in a subject having NASH, or inhibiting NASH in a subject having NASH.

[0035] The present invention further provides a method of treating alcoholic fatty liver disease (AFLD) in a subject, suppressing AFLD in a subject, reducing the severity of AFLD in a subject, reducing the risk of developing AFLD in a subject, or inhibiting AFLD in a subject, the method comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat alcoholic fatty liver disease (AFLD) in a subject having AFLD, suppressing AFLD in a subject having AFLD, reducing the severity of AFLD in a subject having AFLD, reducing the risk of developing AFLD in a subject having AFLD, or inhibiting AFLD in a subject having AFLD.

[0036] The present invention further provides a method for treating non-alcoholic fatty liver disease (NAFLD) in a subject, curbing NAFLD in a subject, reducing the severity of NAFLD in a subject, reducing the risk of developing NAFLD in a subject, or inhibiting NAFLD in a subject, the method comprising administering to the subject a compound represented by the structure of Formula IX and the structures listed in Table 1 as defined below under conditions effective to treat non-alcoholic fatty liver disease (NAFLD) in a subject with NAFLD, curb NAFLD in a subject with NAFLD, reduce the severity of NAFLD in a subject with NAFLD, reduce the risk of developing NAFLD in a subject with NAFLD, or inhibit NAFLD in a subject with NAFLD.

[0037] The present invention further provides a method of treating, suppressing, reducing the severity of, reducing the risk of, or inhibiting an autoimmune disease or condition in a subject, comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of, or inhibit an autoimmune disease or condition in a subject having an autoimmune disease or condition.

[0038] The present invention further provides a method of treating, suppressing, reducing the severity of, reducing the risk of, or inhibiting an autoimmune disease or condition in a subject, comprising administering to the subject a compound represented by the structure of Formula IX and by the structures listed in Table 1, as defined below, under conditions effective to treat, suppress, reduce the severity of, reduce the risk of, or inhibit an autoimmune disease or condition in a subject having an autoimmune disease or condition. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This study demonstrates how protein synthesis monitoring (PSM) can specifically monitor collagen 1 synthesis. The assay system includes WI-38 cells, a human lung fibroblast cell line, which are activated to produce higher levels of collagen. Two tRNAs (di-tRNAs) that decode a specific glycine codon and a specific proline codon are transfected with control RNAi or RNAi targeting collagen 1. The FRET signal specifically monitors collagen 1 translation, as it is suppressed by 90% in cells treated with collagen 1-targeted siRNA. The blue color is the cell nucleus stained with DAPI; the cyan color is the FRET signal from the tRNA pair that decodes the glycine-proline dicodon.

[0040] Figure 2Depicted are hits that selectively regulate collagen translation. In the upper figure, the Y-axis depicts the normalized values ​​of metabolic markers in control cells. By di-tRNA collagen FRET and by collagen 1-specific immunofluorescence, only compounds that show minimal effect on whole protein synthesis (relative to control ± 20%) and collagen 1 protein accumulation in WI38 cells are selected as compounds that selectively regulate collagen synthesis; in the lower figure, the Y-axis shows the FRET score (PSM score) of collagen-specific di-tRNA, and the X-axis shows the normalized immunofluorescence value (relative to control). Compounds showing high PSM scores are marked by point size; compounds that increase collagen content are marked red, and compounds that reduce collagen content are marked green.

[0041] Figure 3 Demonstrates compound effects at the translational level. WI-38 human lung fibroblasts were incubated with compounds for 96 hours. Immunofluorescence: blue depicts nuclei stained with DAPI; green depicts collagen detected with an anti-collagen antibody.

[0042] Figure 4 The efficacy and toxicity of compounds 201, 256, and 213 are shown. Figure (4A) shows the pEC50 of efficacy plotted against the pEC50 of toxicity. The dashed lines represent the x10 or x100 window between efficacy and toxicity. Figure (4B) shows representative images from compound 213. Images were taken with a x20 objective lens in an Operetta machine (Perkin Elmer). Green: Collagen type I; Gray: DAPI. DETAILED DESCRIPTION

[0043] In various embodiments, the present invention is directed to a compound represented by the structure of formula (I):

[0044]

[0045] in

[0046] Ring A and Ring B are each independently a single or fused aromatic ring or heteroaromatic ring system (e.g., benzimidazole, indole, benzothiazole, benzoxazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine, phenyl, pyrimidine, 2-pyridine, 3-pyridine or 4-pyridine, pyridazine, pyrazine, thiazole, pyrrole, triazole, imidazole, indazole), or a single or fused C3-C 10 Cycloalkyl (e.g., cyclohexyl, cyclopentyl), or a single or fused C3-C 10 heterocycles (e.g., piperidine, tetrahydro-2H-pyran);

[0047] R1 and R2 are each 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), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), OR 20 , 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 (e.g., NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHCO-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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyridine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0048] or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0049] R3, R4 and R5 are each 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), OR 20 , 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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0050] or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0051] R 20 Represented by the following structure:

[0052]

[0053] X1 is N or CR (e.g., CH, C-OH);

[0054] L1 is CH2, CHR, C(R)2 or C=O;

[0055] L2 is a bond or CH2, C=O, O or S;

[0056] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched 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), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3 and 4-pyridine)); or

[0057] Two geminal R substituents are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0058] R8 is [CH2] p

[0059] where p is between 1 and 10 (e.g., 2);

[0060] R9 is [CH] q , [C] q

[0061] where q is between 2 and 10;

[0062] R 10 and R 11are each independently H, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R;

[0063] or R 10 and R 11 connected to form a substituted or unsubstituted C3-C8 heterocycle (e.g., piperazine, piperidine),

[0064] wherein the substitution comprises: F, Cl, Br, I, OH, SH, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof;

[0065] m, n, l, and k are each independently an integer between 0 and 4 (e.g., 0, 1, or 2);

[0066] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0067] In various embodiments, the present invention is directed to a compound represented by the structure of Formula I(a):

[0068]

[0069] in

[0070] Ring A and Ring B are each independently a single or fused aromatic ring or heteroaromatic ring system (e.g., benzimidazole, indole, benzothiazole, benzoxazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine, phenyl, pyrimidine, 2-pyridine, 3-pyridine or 4-pyridine, pyridazine, pyrazine, thiazole, pyrrole, triazole, imidazole, indazole), or a single or fused C3-C 10 Cycloalkyl (e.g., cyclohexyl, cyclopentyl), or a single or fused C3-C 10 heterocycles (e.g., piperidine, tetrahydro-2H-pyran);

[0071] R1 and R2 are each 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), -O-R8-OR 10(e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), OR 20 , 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 (e.g., NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHCO-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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyridine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0072] or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0073] R3, R4 and R5 are each 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), OR 20 , 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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0074] or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0075] R 20Represented by the following structure:

[0076]

[0077] X1 is N or CR (e.g., CH, C-OH);

[0078] L1 is CH2, CHR, C(R)2 or C=O;

[0079] L2 is a bond or CH2, C=O, O or S;

[0080] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched 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), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3 and 4-pyridine)); or

[0081] Two geminal R substituents are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0082] R8 is [CH2] p

[0083] where p is between 1 and 10 (e.g., 1, 2);

[0084] R9 is [CH] q , [C] q

[0085] where q is between 2 and 10;

[0086] R 10 and R 11 are each independently H, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R;

[0087] or R 10 and R 11connected to form a substituted or unsubstituted C3-C8 heterocycle (e.g., piperazine, piperidine),

[0088] wherein the substitution comprises: F, Cl, Br, I, OH, SH, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof;

[0089] m, n, l, and k are each independently an integer between 0 and 4 (e.g., 0, 1, or 2);

[0090] W is 0, 1 or 2; wherein if w=0, the bridge on the ring does not exist;

[0091] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0092] In various embodiments, the present invention relates to a compound represented by the structure of Formula II

[0093]

[0094] in

[0095] Ring A and Ring B are each independently a single or fused aromatic ring or heteroaromatic ring system (e.g., benzimidazole, indole, benzothiazole, benzoxazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine, phenyl, pyrimidine, 2-pyridine, 3-pyridine or 4-pyridine, pyridazine, pyrazine, thiazole, pyrrole, triazole, imidazole, indazole), or a single or fused C3-C 10 Cycloalkyl (e.g., cyclohexyl, cyclopentyl), or a single or fused C3-C 10 heterocycles (e.g., piperidine, tetrahydro-2H-pyran);

[0096] R1 and R2 are each 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), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), OR 20, 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 (e.g., NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHCO-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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyridine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0097] or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0098] R3, R4 and R5 are each 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), OR 20 , 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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0099] or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0100] R 20 Represented by the following structure:

[0101]

[0102] X1 is N or CR (e.g., CH, C-OH);

[0103] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched 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), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3 and 4-pyridine)); or

[0104] Two geminal R substituents are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0105] R8 is [CH2] p

[0106] where p is between 1 and 10 (e.g., 2);

[0107] R9 is [CH] q , [C] q

[0108] where q is between 2 and 10;

[0109] R 10 and R 11 are each independently H, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R;

[0110] or R 10 and R 11 connected to form a substituted or unsubstituted C3-C8 heterocycle (e.g., piperazine, piperidine),

[0111] wherein the substitution comprises: F, Cl, Br, I, OH, SH, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof;

[0112] m, n, l, and k are each independently an integer between 0 and 4 (e.g., 0, 1, or 2);

[0113] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0114] In various embodiments, the present invention is directed to a compound represented by the structure of Formula III:

[0115]

[0116] in

[0117] Ring B is a single or fused aromatic ring or heteroaromatic ring system (e.g., phenyl, pyrimidine, 2-pyridine, 3-pyridine or 4-pyridine, pyridazine or pyrazine, thiazole, pyrrole, triazole, imidazole, indazole), or a single or fused C3-C 10 Cycloalkyl (e.g., cyclohexyl, cyclopentyl), or a single or fused C3-C 10 heterocycles (e.g., piperidine, tetrahydro-2H-pyran);

[0118] L1 is CH2, CHR, C(R)2 or C=O;

[0119] R1 and R2 are each 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), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), OR 20 , 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 (e.g., NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHCO-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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyridine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0120] or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0121] R3, R4 and R5 are each 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), OR 20 , CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 )(R11 )、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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0122] or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0123] R 20 Represented by the following structure:

[0124]

[0125] X1 is N or CC(R) (e.g., CH, C-OH);

[0126] X2 is NH, S, O, NR (e.g., N-CH2-CH2-O-CH3);

[0127] X3 is N, C(R) (e.g., CH, C-CH3, C-Cl, C-CN);

[0128] X4, X5, X6 and X7 are each independently C or N;

[0129] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched 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), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3 and 4-pyridine)); or

[0130] Two geminal R substituents are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0131] R8 is [CH2] p

[0132] where p is between 1 and 10 (e.g., 2);

[0133] R9 is [CH] q , [C] q

[0134] where q is between 2 and 10;

[0135] R 10 and R 11 are each independently H, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R;

[0136] or R 10 and R 11 connected to form a substituted or unsubstituted C3-C8 heterocycle (e.g., piperazine, piperidine),

[0137] wherein the substitution comprises: F, Cl, Br, I, OH, SH, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof;

[0138] m, n, l, and k are each independently an integer between 0 and 4 (e.g., 0, 1, or 2);

[0139] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0140] In various embodiments, if X3 is N, then X2 is not NH.

[0141] In various embodiments, the present invention is directed to a compound represented by the structure of Formula IV:

[0142]

[0143] in

[0144] Ring A is a single or fused aromatic ring or heteroaromatic ring system (e.g., benzimidazole, indole, benzothiazole, benzoxazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine, phenyl, pyrimidine, 2-pyridine, 3-pyridine or 4-pyridine, pyridazine or pyrazine), or a single or fused C3-C 10 Cycloalkyl, or single or fused C3-C 10 heterocycles (e.g., piperidine, tetrahydro-2H-pyran);

[0145] L1 is CH2, CHR, C(R)2 or C=O;

[0146] R1 and R2 are each 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), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), OR 20 , 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 (e.g., NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHCO-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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyridine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0147] or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0148] R3, R4 and R5 are each 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), OR 20, 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 chain or branched 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0149] or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0150] R 20 Represented by the following structure:

[0151]

[0152] X1 is N or CC(R) (e.g., CH, C-OH);

[0153] X8, X9, X 10 、X11 and X 12 are each independently C or N;

[0154] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched 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), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3 and 4-pyridine)); or

[0155] Two geminal R substituents are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0156] R8 is [CH2] p

[0157] where p is between 1 and 10 (e.g., 2);

[0158] R9 is [CH] q , [C] q

[0159] where q is between 2 and 10;

[0160] R 10 and R 11 are each independently H, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R;

[0161] or R 10 and R 11 connected to form a substituted or unsubstituted C3-C8 heterocycle (e.g., piperazine, piperidine),

[0162] wherein the substitution comprises: F, Cl, Br, I, OH, SH, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof;

[0163] m, n, l, and k are each independently an integer between 0 and 4 (e.g., 0, 1, or 2);

[0164] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0165] In various embodiments, X8, X9, X 10 、X 11 and X 12 At least one of them is N.

[0166] In various embodiments, the present invention is directed to a compound represented by the structure of Formula V:

[0167]

[0168] in

[0169] L1 is CH2, CHR, C(R)2 or C=O;

[0170] R1 and R2 are each 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), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), OR 20 , 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 (e.g., NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHCO-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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyridine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0171] or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0172] R3, R4 and R5 are each 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), OR 20 , 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(R10 )(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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0173] or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0174] R 20 Represented by the following structure:

[0175]

[0176] X1 is N or CC(R) (e.g., CH, C-OH);

[0177] X2 is NH, S, O, NR (e.g., N-CH2-CH2-O-CH3);

[0178] X3 is N, C(R) (e.g., CH, C-CH3, C-Cl, C-CN);

[0179] X4, X5, X6 and X7 are each independently C or N;

[0180] X8, X9, X 10 、X 11 and X12 are each independently C or N;

[0181] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched 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), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3 and 4-pyridine)); or

[0182] Two geminal R substituents are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0183] R8 is [CH2] p

[0184] where p is between 1 and 10 (e.g., 2);

[0185] R9 is [CH] q , [C] q

[0186] where q is between 2 and 10;

[0187] R 10 and R 11 are each independently H, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R;

[0188] or R 10 and R 11 connected to form a substituted or unsubstituted C3-C8 heterocycle (e.g., piperazine, piperidine),

[0189] wherein the substitution comprises: F, Cl, Br, I, OH, SH, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof;

[0190] m, n, l, and k are each independently an integer between 0 and 4 (e.g., 0, 1, or 2);

[0191] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0192] In various embodiments, if X3 is N, then X2 is not NH. In various embodiments, X8, X9, X 10 、X 11 and X 12 At least one of them is N.

[0193] In various embodiments, the present invention is directed to a compound represented by the structure of Formula V(a):

[0194]

[0195] in

[0196] L1 is CH2, CHR, C(R)2 or C=O;

[0197] R1 and R2 are each 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), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), OR 20 , 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 (e.g., NHCO-Ph, NHCO-CH3), NHC(O)-R 10(e.g., NHCO-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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyridine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0198] or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0199] R3, R4 and R5 are each 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), OR 20 , 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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0200] or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0201] R 20 Represented by the following structure:

[0202]

[0203] X1 is N or CC(R) (e.g., CH, C-OH);

[0204] X2 is NH, S, O, NR (e.g., N-CH2-CH2-O-CH3);

[0205] X3 is N, C(R) (e.g., CH, C-CH3, C-Cl, C-CN);

[0206] X4, X5, X6 and X7 are each independently C or N;

[0207] X8, X9, X 10 、X 11 and X 12 are each independently C or N;

[0208] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched 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), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3 and 4-pyridine)); or

[0209] Two geminal R substituents are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0210] R8 is [CH2] p

[0211] where p is between 1 and 10 (e.g., 2);

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

[0213] where q is between 2 and 10;

[0214] R 10 and R 11 are each independently H, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R;

[0215] or R 10 and R 11 connected to form a substituted or unsubstituted C3-C8 heterocycle (e.g., piperazine, piperidine),

[0216] wherein the substitution comprises: F, Cl, Br, I, OH, SH, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof;

[0217] m, n, l, and k are each independently an integer between 0 and 4 (e.g., 0, 1, or 2);

[0218] W is 0, 1 or 2; wherein if w=0, the bridge on the ring does not exist;

[0219] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0220] In various embodiments, if X3 is N, then X2 is not NH. In various embodiments, X8, X9, X 10 、X 11 and X 12 At least one of them is N.

[0221] In various embodiments, the present invention is directed to a compound represented by the structure of Formula VI:

[0222]

[0223] in

[0224] L1 is CH2, CHR, C(R)2 or C=O;

[0225] R1 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), -O-R8-OR 10 (e.g. O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), OR 20 , 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 (e.g., NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHCO-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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyridine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0226] 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), OR 20 , 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)-R10 、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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0227] R 20 Represented by the following structure:

[0228]

[0229] X2 is NH, S, O, NR (e.g., N-CH2-CH2-O-CH3);

[0230] X3 is N, C(R) (e.g., CH, C-CH3, C-Cl, C-CN);

[0231] X8, X9, X 10 、X 11 and X 12 are each independently C or N;

[0232] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched 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), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3 and 4-pyridine)); or

[0233] Two geminal R substituents are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0234] R8 is [CH2] p

[0235] where p is between 1 and 10 (e.g., 2);

[0236] R9 is [CH] q , [C] q

[0237] where q is between 2 and 10;

[0238] R 10 and R 11 are each independently H, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R;

[0239] or R 10 and R 11 connected to form a substituted or unsubstituted C3-C8 heterocycle (e.g., piperazine, piperidine),

[0240] wherein the substitution comprises: F, Cl, Br, I, OH, SH, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof;

[0241] n and l are each independently an integer between 0 and 4 (e.g., 0, 1 or 2);

[0242] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0243] In various embodiments, if X3 is N, then X2 is not NH. In various embodiments, X8, X9, X 10 、X 11 and X 12 At least one of them is N;

[0244] In various embodiments, the present invention is directed to a compound represented by the structure of Formula VII:

[0245]

[0246] in

[0247] L1 is CH2, CHR, C(R)2 or C=O;

[0248] R1, R2 and R6 are each 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), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocycle), OR 20 , 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 (e.g., NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (e.g., NHCO-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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyridine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0249] or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0250] or R1 and R6 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0251] R3 and R4 are each 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), OR 20 , 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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0252] or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0253] R 20 Represented by the following structure:

[0254]

[0255] X2 is NH, S, O, NR (e.g., N-CH2-CH2-O-CH3);

[0256] X3 is N, C(R) (e.g., CH, C-CH3, C-Cl, C-CN);

[0257] X 10 and X 12 are each independently C or N;

[0258] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched 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), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3 and 4-pyridine)); or

[0259] Two geminal R substituents are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0260] R8 is [CH2] p

[0261] where p is between 1 and 10 (e.g., 2);

[0262] R9 is [CH] q , [C] q

[0263] where q is between 2 and 10;

[0264] R 10 and R 11 are each independently H, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R;

[0265] or R 10 and R 11 connected to form a substituted or unsubstituted C3-C8 heterocycle (e.g., piperazine, piperidine),

[0266] wherein the substitution comprises: F, Cl, Br, I, OH, SH, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof;

[0267] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0268] In various embodiments, if X3 is N, then X2 is not NH. In various embodiments, X 10 and X 12 At least one of them is N.

[0269] In various embodiments, the present invention is directed to a compound represented by the structure of Formula VIII:

[0270]

[0271] in

[0272] R1 is H, OR 20 ,CF3,F,Cl,Br,I,OH,SH,-R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), CN, NO2, COOH, C1-C5 straight or branched C(O)-haloalkyl, NHC(O)-R (e.g., NHCO-Ph), -C(O)NH2, C(O)NHR, C(O)N(R 10 )(R 11 )、SO2R、SO2N(R 10 )(R 11 ), C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear, branched or cyclic halogenated alkyl (e.g., CHF2);

[0273] R2 is H, OR 20 ,CF3,F,Cl,Br,I,OH,SH,-R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), CN, NO2, COOH, C1-C5 straight or branched C(O)-haloalkyl, NHC(O)-R (e.g., NHCO-Ph), -C(O)NH2, C(O)NHR, C(O)N(R 10 )(R 11 )、SO2R、SO2N(R 10 )(R 11 ), C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear, branched or cyclic halogenated alkyl (e.g., CHF2);

[0274] R6 is H, OR 20 ,CF3,F,Cl,Br,I,OH,SH,-R8-OR 10(e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), CN, NO2 or C1-C5 linear, branched or cyclic haloalkyl (e.g., CHF2);

[0275] R3 is H, F, Cl, Br, I, OH, SH, OR 20 、CF3、-R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear, branched or cyclic haloalkyl (e.g., CHF2), substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl);

[0276] R4 is H, F, Cl, Br, I, OH, SH, OR 20 、CF3、-R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear, branched or cyclic haloalkyl (e.g., CHF2), substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl);

[0277] R 20 Represented by the following structure:

[0278]

[0279] X2 is NH, S or O;

[0280] X3 is N, CH or C-Cl;

[0281] X 10 and X 12 are each independently C or N; at least one of which is N;

[0282] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched 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), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3 and 4-pyridine)); or

[0283] Two geminal R substituents are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0284] R8 is [CH2] p

[0285] where p is between 1 and 10 (e.g., 2);

[0286] R9 is [CH] q , [C] q

[0287] where q is between 2 and 10;

[0288] R 10 and R 11 are each independently H, C1-C5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R;

[0289] or R 10 and R 11 connected to form a substituted or unsubstituted C3-C8 heterocycle (e.g., piperazine, piperidine),

[0290] wherein the substitution comprises: F, Cl, Br, I, OH, SH, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof;

[0291] Wherein if X3 is N, then X2 is not NH;

[0292] And where X 10 and X 12 At least one of them is N;

[0293] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0294] In some embodiments, the compounds of Formula I-VIII No is 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole. In some embodiments, the compound of formula I-VIII No It is PF-4708671.

[0295] In some embodiments, the compounds of Formula I-VIII No A pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), reverse amide, or drug product of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole.

[0296] In some embodiments, if X3 of Formula III and / or V-VIII is N, then X2 is not NH.

[0297] In some embodiments, if X3 of Formula III and / or V-VIII is N, then X2 is O or S. In some embodiments, if X2 of Formula III and / or V-VIII is NH, then X3 is CH or C(R).

[0298] In some embodiments, X of Formula IV-VIII 10 and X 12 At least one of them is N.

[0299] In some embodiments, if R2 of Formulas I-VIII is CF3, then R3 is not ethyl.

[0300] In some embodiments, if R3 of Formulas I-VIII is ethyl, then R2 is not CF3.

[0301] In some embodiments, at least one of R1 and R2 of Formulas I-VIII is not H. In some embodiments, R1, R2, and R6 of Formulas I-VIII are H. In some embodiments, R1, R2, or R6 are CF3. In some embodiments, R1, R2, or R6 are Cl. In some embodiments, R1, R2, or R6 are CN. In some embodiments, R1, R2, or R6 are NHC(O)Ph.

[0302] In some embodiments, at least one of R3 and R4 of Formulas I-VIII is not H. In some embodiments, R3 and R4 are both methyl. In some embodiments, R3 and R4 are both H. In some embodiments, R3 is ethyl.

[0303] In some embodiments, R6 of Formula VII and VIII is Cl. In some embodiments, R6 is H.

[0304] In various embodiments, the present invention is directed to a compound represented by the structure of Formula IX:

[0305]

[0306] in

[0307] R1, R2 and R6 are each 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), -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 )、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., NHCO-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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyridine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0308] or R2 and R1 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0309] or R1 and R6 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0310] R3, R4 and R5 are each 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, 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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched 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 wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;

[0311] or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0312] X 10 and X 12 are each independently C or N;

[0313] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 linear or branched 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), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3 and 4-pyridine)); or

[0314] Two geminal R substituents are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0315] R8 is [CH2] p

[0316] where p is between 1 and 10 (e.g., 2);

[0317] R9 is [CH] q , [C]q

[0318] where q is between 2 and 10;

[0319] R 10 and R 11 are each independently H, C1-C5 substituted or unsubstituted straight or branched alkyl (e.g., methyl, ethyl, CH2-CH2-O-CH3), C1-C5 straight or branched alkoxy (e.g., O-CH3), C(O)R or S(O)2R; or R 10 and R 11 connected to form a substituted or unsubstituted C3-C8 heterocycle (e.g., piperazine, piperidine),

[0320] wherein the substitution comprises: F, Cl, Br, I, OH, SH, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof;

[0321] And where X 10 and X 12 At least one of them is N;

[0322] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0323] In some embodiments, if R3 is ethyl, then R2 is not CF3.

[0324] In some embodiments, if R2 is CF3, then R3 is not ethyl.

[0325] In some embodiments, at least one of R1, R2, R3, R4, and R6 is not H.

[0326] In some embodiments, at least one of R1, R2, and R6 is not H.

[0327] In some embodiments, at least one of R1 and R2 is not H. In some embodiments, R1, R2, and R6 are H. In some embodiments, R1, R2, or R6 are CF3. In some embodiments, R1, R2, or R6 are Cl. In some embodiments, R1, R2, or R6 are CN. In some embodiments, R1, R2, or R6 are NHC(O)Ph.

[0328] In some embodiments, at least one of R3 and R4 is not H. In some embodiments, R3 and R4 are both methyl. In some embodiments, R3 and R4 are both H. In some embodiments, R3 is ethyl.

[0329] In some embodiments, R6 is Cl. In some embodiments, R6 is H.

[0330] In some embodiments, the compound No is 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole. In some embodiments, the compound No It is PF-4708671.

[0331] In some embodiments, the compound No A pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., deuterated analog), or drug product of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole.

[0332] In various embodiments, the present invention is directed to a compound represented by the structure of Formula X:

[0333]

[0334] in

[0335] R1 and R2 are each independently H, Cl, F, CHF2 or CF3;

[0336] R3 and R4 are each independently H, Cl, F, CHF2, CF3, C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), substituted or unsubstituted C3-C8 heterocycle (e.g., imidazole), (wherein substitution comprises: F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy, CF3, aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof);

[0337] or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole);

[0338] X 12 is C or N;

[0339] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0340] In some embodiments, if R3 is ethyl, then R2 is not CF3. In some embodiments, if R3 is ethyl, then R1 is not CF3. In some embodiments, if R3 is ethyl, then R2 or R1 is not CF3.

[0341] In some embodiments, if R2 is CF3, then R3 is not ethyl. In some embodiments, if R1 is CF3, then R3 is not ethyl. In some embodiments, if R1 or R2 is CF3, then R3 is not ethyl.

[0342] In some embodiments, at least one of R1, R2, R3, and R4 is not H.

[0343] In some embodiments, at least one of R1 and R2 is not H. In some embodiments, R1 and R2 are both H. In some embodiments, R1 or R2 is CF3. In some embodiments, R1 or R2 is Cl. In some embodiments, R1 or R2 is CN. In some embodiments, R1 or R2 is NHC(O)Ph.

[0344] In some embodiments, at least one of R3 and R4 is not H. In some embodiments, R3 and R4 are both methyl. In some embodiments, R3 and R4 are both H. In some embodiments, R3 is ethyl.

[0345] In some embodiments, R6 is Cl. In some embodiments, R6 is H.

[0346] In some embodiments, the compound No is 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole. In some embodiments, the compound No It is PF-4708671.

[0347] In some embodiments, the compound No A pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., deuterated analog), or drug product of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole.

[0348] In some embodiments, A of Formula I, I(a), II, and / or IV is phenyl. In other embodiments, A is pyridyl. In other embodiments, A is 2-pyridyl. In other embodiments, A is 3-pyridyl. In other embodiments, A is 4-pyridyl. In other embodiments, A is pyrimidine. In other embodiments, A is pyridazine. In other embodiments, A is pyrazine. 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 other embodiments, A is tetrahydronaphthyl. In other embodiments, A is indenyl. In other embodiments, A is benzofuran-2(3H)-one. In other embodiments, A is benzo[d][1,3]dioxole. In other embodiments, A is tetrahydrothiophene 1,1-dioxide. In other embodiments, A is thiazole. In other embodiments, A is piperidine. In other embodiments, A is 1-methylpiperidine. In other embodiments, A is imidazole. In other embodiments, A is 1-methylimidazole. In other embodiments, A is thiophene. In other embodiments, A is isoquinoline. In other embodiments, A is 1,3-dihydroisobenzofuran. In other embodiments, A is benzofuran. In other embodiments, A is a single or fused C3-C 10 In other embodiments, A is cyclohexyl.

[0349] In some embodiments, B of Formula I, I(a), and / or II is a benzene ring. In other embodiments, B is pyridyl. In other embodiments, B is 2-pyridyl. In other embodiments, B is 3-pyridyl. In other embodiments, B is 4-pyridyl. In other embodiments, B is pyrimidine. In other embodiments, B is pyridazine. In other embodiments, B is pyrazine. 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 triazole. In other embodiments, B is naphthyl. In other embodiments, B is indolyl. In other embodiments, B is benzimidazolyl. In other embodiments, B is benzothiazolyl. In other embodiments, B is quinoxalinyl. In other embodiments, B is tetrahydronaphthyl. In other embodiments, B is quinolyl. In other embodiments, B is isoquinolyl. In other embodiments, B is indenyl. In other embodiments, B is naphthalene. In other embodiments, B is tetrahydrothiophene 1,1-dioxide. In other embodiments, B is benzimidazole. In other embodiments, B is piperidine. In other embodiments, B is 1-methylpiperidine. In other embodiments, B is 1-methylimidazole. In other embodiments, B is thiophene. In other embodiments, B is isoquinoline. In other embodiments, B is indole. In other embodiments, B is 1,3-dihydroisobenzofuran. In other embodiments, B is benzofuran. In other embodiments, B is a single or fused C3-C 10 In other embodiments, B is cyclohexyl.

[0350] In some embodiments, X1 of the compounds of Formula I, I(a), II, III, and / or IV is N. In other embodiments, X1 is CR. In other embodiments, X1 is CH. In other embodiments, X1 is C-OH.

[0351] In some embodiments, X2 of the compounds of Formula III, V, V(a), VI, VII, and / or VIII is NH. In other embodiments, X2 is S. In other embodiments, X2 is O. In other embodiments, X2 is NR. In other embodiments, X2 is N-CH2-CH2-O-CH3.

[0352] In some embodiments, X3 of the compounds of Formula III, V, V(a), VI, VII, and / or VIII is N. In other embodiments, X3 is C(R). In other embodiments, X3 is CH. In other embodiments, X3 is C-CH3. In other embodiments, X3 is C-Cl. In other embodiments, X3 is C-CN.

[0353] In various embodiments, if X3 of the compound of Formula III, V, V(a), VI, VII and / or VIII is N, then X2 is not NH.

[0354] In some embodiments, X4 of the compound of Formula III, V and / or V(a) is C. In other embodiments, X4 is N.

[0355] In some embodiments, X5 of the compound of Formula III, V and / or V(a) is C. In other embodiments, X5 is N.

[0356] In some embodiments, X6 of the compound of Formula III, V and / or V(a) is C. In other embodiments, X6 is N.

[0357] In some embodiments, X7 of the compound of Formula III, V and / or V(a) is C. In other embodiments, X7 is N.

[0358] In some embodiments, X8 of the compounds of Formula IV, V, V(a), and / or VI is C. In other embodiments, X8 is N.

[0359] In some embodiments, X9 of the compound of Formula IV, V, V(a), and / or VI is C. In other embodiments, X9 is N.

[0360] In some embodiments, X of the compound of Formula IV-VIII and / or IX 10 is C. In other embodiments, X 10 It's N.

[0361] In some embodiments, X of the compounds of Formula IV, V, V(a), and / or VI 11 is C. In other embodiments, X 11 It's N.

[0362] In some embodiments, X of the compound of Formula IV-VIII, IX, V and / or V(a) 12 is C. In other embodiments, X 12 It's N.

[0363] In some embodiments, at least one of X4-X7 is N.

[0364] In some embodiments, X8-X 12 At least one of is N. In some embodiments, X8-X 12 At least two of them are N.

[0365] It should be understood that if X4-X 12 If any one of is N, then any one of R1-R4 cannot be connected to it.

[0366] In some embodiments, R1 of Formula X is H. In some embodiments, R1 is Cl. In some embodiments, R1 is F. In some embodiments, R1 is CF3. In some embodiments, R1 is CHF2.

[0367] In some embodiments, R1 of Formulas I-IX is H. In some embodiments, R1 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R1 is methyl. In other embodiments, R1 is ethyl. In other embodiments, R1 is isopropyl. In other embodiments, R1 is tert-butyl. In other embodiments, R1 is isobutyl. In other embodiments, R1 is pentyl. In other embodiments, R1 is propyl. In other embodiments, R1 is benzyl. In other embodiments, R1 is in the ortho position. In other embodiments, R1 is o-methyl.

[0368] In other embodiments, R1 of Formula I-IX is F. In other embodiments, R1 is Cl. In other embodiments, R1 is Br. In other embodiments, R1 is -R8-OR 10 In other embodiments, R1 is CH2-CH2-O-CH3. In other embodiments, R1 is CH2-O-CH2-CH2-O-CH3. In other embodiments, R1 is -O-R8-OR 10 . In other embodiments, R1 is O-CH2-CH2-O-CH3. In other embodiments, R1 is I. In other embodiments, R1 is R8-(C3-C8 cycloalkyl). In other embodiments, R1 is CH2-cyclohexyl. In other embodiments, R1 is R8-(C3-C8 heterocycle). In other embodiments, R1 is CH2-imidazole. In other embodiments, R1 is CH2-indazole. In other embodiments, R1 is CF3. In other embodiments, R1 is CN. In other embodiments, R1 is NH2. In other embodiments, R1 is C1-C5 linear, branched, or cyclic haloalkyl. In other embodiments, R1 is CHF2. In other embodiments, R1 is CF2CH2CH3. In other embodiments, R1 is CH2CH2CF3. In other embodiments, R1 is CF2CH(CH3)2. In other embodiments, R1 is CF(CH3)-CH(CH3)2. In other embodiments, R1 is OCD3. In other embodiments, R1 is NO2. In other embodiments, R1 is NH2. In other embodiments, R1 is R8-N(R 10 )(R 11 In other embodiments, R1 is CH2-NH2. In other embodiments, R1 is CH2-N(CH3)2). In other embodiments, R1 is R9-R8-N(R 10)(R 11 ). In other embodiments, R1 is C≡C-CH2-NH2. In other embodiments, R1 is B(OH)2. In other embodiments, R1 is NHC(O)-R 10 In other embodiments, R1 is NHC(O)CH3. In other embodiments, R1 is NHC(O)-R. In other embodiments, R1 is NHCO-Ph. In other embodiments, R1 is NHCO-N(R 10 )(R 11 ). In other embodiments, R1 is NHC(O)N(CH3)2. In other embodiments, R1 is COOH. In other embodiments, R1 is C(O)OR 10 In other embodiments, R1 is C(O)O-CH(CH3)2. In other embodiments, R1 is C(O)O-CH3. In other embodiments, R1 is SO2N(R 10 )(R 11 ). In other embodiments, R1 is SO2N(CH3)2. In other embodiments, R1 is SO2NHC(O)CH3. In other embodiments, R1 is OR 20 In other embodiments, R1 is NHSO2 (R 10). In other embodiments, R1 is NHSO2CH3. In other embodiments, R1 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R1 is methyl. In other embodiments, R1 is ethyl. In other embodiments, R1 is isopropyl. In other embodiments, R1 is tert-butyl. In other embodiments, R1 is isobutyl. In other embodiments, R1 is pentyl. In other embodiments, R1 is propyl. In other embodiments, R1 is benzyl. In other embodiments, R1 is a C1-C5 linear or branched, substituted or unsubstituted alkenyl group. In other embodiments, R1 is CH═C(Ph)2. In other embodiments, R1 is 2-CH2-C6H4-Cl. In other embodiments, R1 is 3-CH2-C6H4-Cl. In other embodiments, R1 is 4-CH2-C6H4-Cl. In other embodiments, R1 is ethyl. In other embodiments, R1 is isopropyl. In other embodiments, R1 is tert-butyl. In other embodiments, R1 is isobutyl. In other embodiments, R1 is pentyl. In other embodiments, R1 is a substituted or unsubstituted C3-C8 cycloalkyl group (e.g., cyclopropyl, cyclopentyl). In other embodiments, R1 is a C1-C5 linear, branched, or cyclic alkoxy group. In other embodiments, R1 is methoxy. In other embodiments, R1 is ethoxy. In other embodiments, R1 is propoxy. In other embodiments, R1 is isopropoxy. In other embodiments, R1 is O-CH2-cyclopropyl. In other embodiments, R1 is O-cyclobutyl. In other embodiments, R1 is O-cyclopentyl. In other embodiments, R1 is O-cyclohexyl. In other embodiments, R1 is O-1-oxetanyl. In other embodiments, R1 is O-2-oxetanyl. In other embodiments, R1 is 1-butoxy. In other embodiments, R1 is 2-butoxy. In other embodiments, R1 is O-tert-butyl. In other embodiments, R1 is a C1-C5 linear, branched, or cyclic alkoxy group, wherein at least one methylene group (CH2) in the alkoxy group is replaced by an oxygen atom (O). In other embodiments, R1 is O-1-oxetanyl. In other embodiments, R1 is O-2-oxetanyl. In other embodiments, R1 is a C1-C5 linear or branched haloalkoxy group. In other embodiments, R1 is OCF3. In other embodiments, R1 is OCHF2. In other embodiments, R1 is a substituted or unsubstituted aryl group. In other embodiments, R1 is phenyl. In other embodiments, R1 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R1 is oxazole. In other embodiments, R1 is a methyl-substituted oxazole. In other embodiments, R1 is oxadiazole. In other embodiments, R1 is a methyl-substituted oxadiazole. In other embodiments, R1 is imidazole. In other embodiments, R1 is imidazole substituted with methyl.In other embodiments, R1 is pyridine. In other embodiments, R1 is 2-pyridine. In other embodiments, R1 is 3-pyridine. In other embodiments, R1 is 4-pyridine. In other embodiments, R1 is tetrazole. In other embodiments, R1 is pyrimidine. In other embodiments, R1 is pyrazine. In other embodiments, R1 is oxetane. In other embodiments, R1 is 1-oxetane. In other embodiments, R1 is 2-oxetane. In other embodiments, R1 is indole. In other embodiments, R1 is pyridine oxide. In other embodiments, R1 is a protonated pyridine oxide. In other embodiments, R1 is a deprotonated pyridine oxide. In other embodiments, R1 is 3-methyl-4H-1,2,4-triazole. In other embodiments, R1 is 5-methyl-1,2,4-oxadiazole. In other embodiments, R1 is substituted or unsubstituted aryl. In other embodiments, R1 is phenyl. In other embodiments, R1 is bromophenyl. In other embodiments, R1 is 2-bromophenyl. In other embodiments, R1 is 3-bromophenyl. In other embodiments, R1 is 4-bromophenyl. In other embodiments, R1 is substituted or unsubstituted benzyl. In other embodiments, R1 is benzyl. In other embodiments, R1 is R8-N(R). 10 )(R 11 ). In other embodiments, R1 is CH2-NH2. In other embodiments, the substitution comprises: C1-C5 straight or branched chain alkyl (e.g., methyl), aryl, phenyl, heteroaryl (e.g., imidazole), and / or C3-C8 cycloalkyl, each of which is a separate embodiment according to the present invention.

[0369] In some embodiments, R2 of Formula X is H. In some embodiments, R2 is Cl. In some embodiments, R2 is F. In some embodiments, R2 is CF3. In some embodiments, R2 is CHF2.

[0370] In some embodiments, R2 of Formulas I-IX is H. In some embodiments, R2 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R2 is methyl. In other embodiments, R2 is ethyl. In other embodiments, R2 is isopropyl. In other embodiments, R2 is tert-butyl. In other embodiments, R2 is isobutyl. In other embodiments, R2 is pentyl. In other embodiments, R2 is propyl. In other embodiments, R2 is benzyl. In other embodiments, R2 is in the ortho position. In other embodiments, R2 is o-methyl.

[0371] In some embodiments, R2 of Formula I-IX is F. In other embodiments, R2 is Cl. In other embodiments, R2 is Br. In other embodiments, R2 is I. In other embodiments, R2 is R8-OR10 In other embodiments, R2 is CH2-CH2-O-CH3. In other embodiments, R2 is CH2-O-CH2-CH2-O-CH3. In other embodiments, R2 is -O-R8-OR 10 In other embodiments, R2 is O-CH2-CH2-O-CH3. In other embodiments, R2 is I. In other embodiments, R2 is R8-(C3-C8 cycloalkyl). In other embodiments, R2 is CH2-cyclohexyl. In other embodiments, R2 is R8-(C3-C8 heterocycle). In other embodiments, R2 is CH2-imidazole. In other embodiments, R2 is CH2-indazole. In other embodiments, R2 is CF3. In other embodiments, R2 is CN. In other embodiments, R2 is NH2. In other embodiments, R2 is C1-C5 linear, branched, or cyclic haloalkyl. In other embodiments, R2 is CHF2. In other embodiments, R2 is CF2CH2CH3. In other embodiments, R2 is CH2CH2CF3. In other embodiments, R2 is CF2CH(CH3)2. In other embodiments, R2 is CF(CH3)-CH(CH3)2. In other embodiments, R2 is OCD3. In other embodiments, R2 is NO2. In other embodiments, R2 is NH2. In other embodiments, R2 is R8-N(R 10 )(R 11 In other embodiments, R2 is CH2-NH2. In other embodiments, R2 is CH2-N(CH3)2). In other embodiments, R2 is R9-R8-N(R 10 )(R 11 In other embodiments, R2 is C≡C-CH2-NH2. In other embodiments, R2 is B(OH)2. In other embodiments, R2 is NHC(O)-R 10 In other embodiments, R2 is NHC(O)CH3. In other embodiments, R2 is NHC(O)-R. In other embodiments, R2 is NHCO-Ph. In other embodiments, R2 is NHCO-N(R 10 )(R 11 ). In other embodiments, R2 is NHC(O)N(CH3)2. In other embodiments, R2 is COOH. In other embodiments, R2 is C(O)OR 10 In other embodiments, R2 is C(O)O-CH(CH3)2. In other embodiments, R2 is C(O)O-CH3. In other embodiments, R2 is SO2N(R 10 )(R 11In other embodiments, R2 is SO2N(CH3)2. In other embodiments, R2 is SO2NHC(O)CH3. In other embodiments, R2 is NHSO2(R 10 ). In other embodiments, R2 is NHSO2CH3. In other embodiments, R2 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R2 is methyl. In other embodiments, R2 is ethyl. In other embodiments, R2 is isopropyl. In other embodiments, R2 is tert-butyl. In other embodiments, R2 is isobutyl. In other embodiments, R2 is pentyl. In other embodiments, R2 is propyl. In other embodiments, R2 is benzyl. In other embodiments, R2 is a C1-C5 linear or branched, substituted or unsubstituted alkenyl group. In other embodiments, R2 is CH═C(Ph)2. In other embodiments, R2 is 2-CH2-C6H4-Cl. In other embodiments, R2 is 3-CH2-C6H4-Cl. In other embodiments, R2 is 4-CH2-C6H4-Cl. In other embodiments, R2 is ethyl. In other embodiments, R2 is isopropyl. In other embodiments, R2 is tert-butyl. In other embodiments, R2 is isobutyl. In other embodiments, R2 is pentyl. In other embodiments, R2 is a substituted or unsubstituted C3-C8 cycloalkyl group (e.g., cyclopropyl, cyclopentyl). In other embodiments, R2 is a C1-C5 linear, branched, or cyclic alkoxy group. In other embodiments, R2 is methoxy. In other embodiments, R2 is ethoxy. In other embodiments, R2 is propoxy. In other embodiments, R2 is isopropoxy. In other embodiments, R2 is O-CH2-cyclopropyl. In other embodiments, R2 is O-cyclobutyl. In other embodiments, R2 is O-cyclopentyl. In other embodiments, R2 is O-cyclohexyl. In other embodiments, R2 is O-1-oxetanyl. In other embodiments, R2 is O-2-oxetanyl. In other embodiments, R2 is 1-butoxy. In other embodiments, R2 is 2-butoxy. In other embodiments, R2 is O-tert-butyl. In other embodiments, R2 is C1-C5 straight or branched chain haloalkoxy. In other embodiments, R2 is OCF3. In other embodiments, R2 is OCHF2. In other embodiments, R2 is OR 20In other embodiments, R2 is a substituted or unsubstituted aryl group. In other embodiments, R2 is a phenyl group. In other embodiments, R2 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R2 is oxazole or a methyl-substituted oxazole. In other embodiments, R2 is oxadiazole or a methyl-substituted oxadiazole. In other embodiments, R2 is imidazole or a methyl-substituted imidazole. In other embodiments, R2 is pyridine. In other embodiments, R2 is 2-pyridine. In other embodiments, R2 is 3-pyridine. In other embodiments, R2 is 4-pyridine. In other embodiments, R2 is tetrazole. In other embodiments, R2 is pyrimidine. In other embodiments, R2 is pyrazine. In other embodiments, R2 is oxetane. In other embodiments, R2 is 1-oxetane. In other embodiments, R2 is 2-oxetane. In other embodiments, R2 is indole. In other embodiments, R2 is pyridine oxide. In other embodiments, R2 is a protonated pyridine oxide. In other embodiments, R2 is a deprotonated pyridine oxide. In other embodiments, R2 is 3-methyl-4H-1,2,4-triazole. In other embodiments, R2 is 5-methyl-1,2,4-oxadiazole. In other embodiments, R2 is a substituted or unsubstituted aryl group. In other embodiments, R2 is phenyl. In other embodiments, R2 is bromophenyl. In other embodiments, R2 is 2-bromophenyl. In other embodiments, R2 is 3-bromophenyl. In other embodiments, R2 is 4-bromophenyl. In other embodiments, R2 is a substituted or unsubstituted benzyl group. In other embodiments, R2 is benzyl. In other embodiments, R2 is R8-N(R 10 )(R 11 ). In other embodiments, R2 is CH2-NH2. In other embodiments, the substitution comprises: C1-C5 straight or branched chain alkyl (e.g., methyl), aryl, phenyl, heteroaryl (e.g., imidazole), and / or C3-C8 cycloalkyl, each of which is a separate embodiment according to the present invention.

[0372] In some embodiments, R1 and R2 of Formula I-IX are linked together to form a pyrrole ring. In some embodiments, R1 and R2 are linked together to form a benzene ring. In some embodiments, R1 and R2 are linked together to form a pyridine ring. In some embodiments, R1 and R2 are linked together to form a [1,3]dioxole ring. In some embodiments, R1 and R2 are linked together to form a furanone ring (e.g., furan-2(3H)-one).

[0373] In some embodiments, R3 of Formula X is H. In other embodiments, R3 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R3 is methyl. In other embodiments, R3 is ethyl. In other embodiments, R3 is F. In other embodiments, R3 is Cl. In other embodiments, R3 is CF3. In other embodiments, R3 is CHF2.

[0374] In some embodiments, R3 of Formulas I-IX is H. In other embodiments, R3 is Cl. In other embodiments, R3 is I. In other embodiments, R3 is F. In other embodiments, R3 is Br. In other embodiments, R3 is CF3. In other embodiments, R3 is CHF2. In other embodiments, R3 is CN. In other embodiments, R3 is OH. In other embodiments, R3 is CD3. In other embodiments, R3 is OCD3. In other embodiments, R3 is R8-OH. In other embodiments, R3 is CH2-OH. In other embodiments, R3 is -R8-OR 10 In other embodiments, R3 is CH2-O-CH2-CH2-O-CH3. In other embodiments, R3 is CH2-O-CH3. In other embodiments, R3 is R8-N(R 10 )(R 11 ). In other embodiments, R3 is CH2-NH2. In other embodiments, R3 is CH2-N(CH3)2. In other embodiments, R3 is COOH. In other embodiments, R3 is C(O)OR 10 In other embodiments, R3 is C(O)O-CH2CH3. In other embodiments, R3 is R8-C(O)-R 10 In other embodiments, R3 is CH2C(O)CH3. In other embodiments, R3 is C(O)-R 10 In other embodiments, R3 is C(O)-H. In other embodiments, R3 is C(O)-CH3. In other embodiments, R3 is C(O)-CH2CH3. In other embodiments, R3 is C(O)-CH2CH2CH3. In other embodiments, R3 is C1-C5 straight or branched C(O)-haloalkyl. In other embodiments, R3 is C(O)-CF3. In other embodiments, R3 is C(O)N(R 10 )(R 11 In other embodiments, R3 is C(O)N(CH3)2). In other embodiments, R3 is SO2N(R 10 )(R 11 ). In other embodiments, R3 is SO2N(CH3)2. In other embodiments, R3 is OR 20In other embodiments, R3 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R3 is methyl. In other embodiments, R3 is ethyl. In other embodiments, R3 is propyl. In other embodiments, R3 is isopropyl. In other embodiments, R3 is tert-butyl. In other embodiments, R3 is isobutyl. In other embodiments, R3 is pentyl. In other embodiments, R3 is C(OH)(CH3)(Ph). In other embodiments, R3 is a C1-C5 linear, branched, or cyclic haloalkyl group. In other embodiments, R3 is CF2CH3. In other embodiments, R3 is CF2-cyclobutyl. In other embodiments, R3 is CH2CF3. In other embodiments, R3 is CF2CH2CH3. In other embodiments, R3 is CF3. In other embodiments, R3 is CF2CH2CH3. In other embodiments, R3 is CH2CH2CF3. In other embodiments, R3 is CF2CH(CH3)2. In other embodiments, R3 is CF(CH3)-CH(CH3)2. In other embodiments, R3 is a C1-C5 linear, branched, or cyclic alkoxy group. In other embodiments, R3 is methoxy. In other embodiments, R3 is isopropoxy. In other embodiments, R3 is a substituted or unsubstituted C3-C8 cycloalkyl group. In other embodiments, R3 is cyclopropyl. In other embodiments, R3 is cyclopentyl. In other embodiments, R3 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R3 is pyrazole. In other embodiments, R3 is thiazole. In other embodiments, R3 is thiophene. In other embodiments, R3 is oxazole. In other embodiments, R3 is isoxazole. In other embodiments, R3 is imidazole. In other embodiments, R3 is furan. In other embodiments, R3 is triazole. In other embodiments, R3 is pyridine. In other embodiments, R3 is 2-pyridine. In other embodiments, R3 is 3-pyridine. In other embodiments, R3 is 4-pyridine. In other embodiments, R3 is pyrimidine. In other embodiments, R3 is pyrazine. In other embodiments, R3 is oxetane. In other embodiments, R3 is 1-oxetane. In other embodiments, R3 is 2-oxetane. In other embodiments, R3 is indole. In other embodiments, R3 is 3-methyl-4H-1,2,4-triazole. In other embodiments, R3 is 5-methyl-1,2,4-oxadiazole. In other embodiments, R3 is substituted or unsubstituted aryl. In other embodiments, R3 is phenyl. In other embodiments, R3 is CH(CF3)(NH-R 10 ).

[0375] In some embodiments, R4 of Formula X is H. In other embodiments, R4 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R4 is methyl. In other embodiments, R4 is ethyl. In other embodiments, R4 is F. In other embodiments, R4 is Cl. In other embodiments, R4 is CF3. In other embodiments, R4 is CHF2. In other embodiments, R4 is CN. In some embodiments, R4 of Formulas IV and / or VII-IX is H. In other embodiments, R4 is Cl. In other embodiments, R4 is I. In other embodiments, R4 is F. In other embodiments, R4 is Br. In other embodiments, R4 is CF3. In other embodiments, R4 is CHF2. In other embodiments, R4 is OH. In other embodiments, R4 is CD3. In other embodiments, R4 is OCD3. In other embodiments, R4 is R8-OH. In other embodiments, R4 is CH2-OH. In other embodiments, R4 is -R8-OR 10 In other embodiments, R4 is CH2-O-CH2-CH2-O-CH3. In other embodiments, R4 is CH2-O-CH3. In other embodiments, R4 is R8-N(R 10 )(R 11 ). In other embodiments, R4 is CH2-NH2. In other embodiments, R4 is CH2-N(CH3)2. In other embodiments, R4 is COOH. In other embodiments, R4 is C(O)OR 10 In other embodiments, R4 is C(O)O-CH2CH3. In other embodiments, R4 is R8-C(O)-R 10 In other embodiments, R4 is CH2C(O)CH3. In other embodiments, R4 is C(O)-R 10 In other embodiments, R4 is C(O)-H. In other embodiments, R4 is C(O)-CH3. In other embodiments, R4 is C(O)-CH2CH3. In other embodiments, R4 is C(O)-CH2CH2CH3. In other embodiments, R4 is C1-C5 straight or branched C(O)-haloalkyl. In other embodiments, R4 is C(O)-CF3. In other embodiments, R4 is C(O)N(R 10 )(R 11 In other embodiments, R4 is C(O)N(CH3)2). In other embodiments, R4 is SO2N(R 10 )(R 11 ). In other embodiments, R4 is SO2N(CH3)2. In other embodiments, R4 is OR 20In other embodiments, R4 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R4 is methyl. In other embodiments, R4 is C(OH)(CH3)(Ph). In other embodiments, R4 is ethyl. In other embodiments, R4 is propyl. In other embodiments, R4 is isopropyl. In other embodiments, R4 is tert-butyl. In other embodiments, R4 is isobutyl. In other embodiments, R4 is pentyl. In other embodiments, R4 is a C1-C5 linear, branched, or cyclic haloalkyl group. In other embodiments, R3 is CF2CH3. In other embodiments, R3 is CF2-cyclobutyl. In other embodiments, R4 is CH2CF3. In other embodiments, R4 is CF2CH2CH3. In other embodiments, R4 is CF3. In other embodiments, R4 is CF2CH2CH3. In other embodiments, R4 is CH2CH2CF3. In other embodiments, R4 is CF2CH(CH3)2. In other embodiments, R4 is CF(CH3)-CH(CH3)2. In other embodiments, R4 is a C1-C5 linear, branched, or cyclic alkoxy group. In other embodiments, R4 is methoxy. In other embodiments, R4 is isopropoxy. In other embodiments, R4 is a substituted or unsubstituted C3-C8 cycloalkyl group. In other embodiments, R4 is cyclopropyl. In other embodiments, R4 is cyclopentyl. In other embodiments, R4 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R4 is pyrazole. In other embodiments, R4 is thiazole. In other embodiments, R4 is thiophene. In other embodiments, R4 is oxazole. In other embodiments, R4 is isoxazole. In other embodiments, R4 is imidazole. In other embodiments, R4 is furan. In other embodiments, R4 is triazole. In other embodiments, R4 is pyridine. In other embodiments, R4 is 2-pyridine. In other embodiments, R4 is 3-pyridine. In other embodiments, R4 is 4-pyridine. In other embodiments, R4 is pyrimidine. In other embodiments, R4 is pyrazine. In other embodiments, R4 is oxetane. In other embodiments, R4 is 1-oxetane. In other embodiments, R4 is 2-oxetane. In other embodiments, R4 is indole. In other embodiments, R4 is 3-methyl-4H-1,2,4-triazole. In other embodiments, R4 is 5-methyl-1,2,4-oxadiazole. In other embodiments, R4 is substituted or unsubstituted aryl. In other embodiments, R4 is phenyl. In other embodiments, R4 is CH(CF3)(NH-R 10 ).

[0376] In some embodiments, R5 of Formula I, I(a), II, III, IV, V, and V(a) is H. In other embodiments, R5 is Cl. In other embodiments, R5 is I. In other embodiments, R5 is F. In other embodiments, R5 is Br. In other embodiments, R5 is OH. In other embodiments, R5 is CD3. In other embodiments, R5 is OCD3. In other embodiments, R5 is R8-OH. In other embodiments, R5 is CH2-OH. In other embodiments, R5 is -R8-OR 10 In other embodiments, R5 is CH2-O-CH3. In other embodiments, R5 is R8-N(R 10 )(R 11 ). In other embodiments, R5 is CH2-NH2. In other embodiments, R5 is CH2-N(CH3)2. In other embodiments, R5 is COOH. In other embodiments, R5 is C(O)OR 10 In other embodiments, R5 is C(O)O-CH2CH3. In other embodiments, R5 is R8-C(O)-R 10 In other embodiments, R5 is CH2C(O)CH3. In other embodiments, R5 is C(O)-R 10 In other embodiments, R5 is C(O)-CH3. In other embodiments, R4 is C(O)-CH2CH3. In other embodiments, R5 is C(O)-CH2CH2CH3. In other embodiments, R5 is C1-C5 straight or branched C(O)-haloalkyl. In other embodiments, R5 is C(O)-CF3. In other embodiments, R5 is C(O)N(R 10 )(R 11 In other embodiments, R5 is C(O)N(CH3)2). In other embodiments, R5 is SO2N(R 10 )(R 11 ). In other embodiments, R5 is SO2N(CH3)2. In other embodiments, R5 is OR 20In other embodiments, R4 is a C1-C5 linear or branched, substituted or unsubstituted alkyl group. In other embodiments, R5 is methyl. In other embodiments, R5 is C(OH)(CH3)(Ph). In other embodiments, R5 is ethyl. In other embodiments, R5 is propyl. In other embodiments, R5 is isopropyl. In other embodiments, R5 is tert-butyl. In other embodiments, R5 is isobutyl. In other embodiments, R5 is pentyl. In other embodiments, R5 is a C1-C5 linear, branched, or cyclic haloalkyl group. In other embodiments, R5 is CF2CH3. In other embodiments, R5 is CF2-cyclobutyl. In other embodiments, R5 is CH2CF3. In other embodiments, R5 is CHF2. In other embodiments, R5 is CF2CH2CH3. In other embodiments, R5 is CF3. In other embodiments, R4 is CF2CH2CH3. In other embodiments, R5 is CH2CH2CF3. In other embodiments, R5 is CF2CH(CH3)2. In other embodiments, R5 is CF(CH3)-CH(CH3)2. In other embodiments, R5 is a C1-C5 linear, branched, or cyclic alkoxy group. In other embodiments, R5 is methoxy. In other embodiments, R5 is isopropoxy. In other embodiments, R5 is a substituted or unsubstituted C3-C8 cycloalkyl group. In other embodiments, R5 is cyclopropyl. In other embodiments, R5 is cyclopentyl. In other embodiments, R5 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R5 is pyrazole. In other embodiments, R5 is thiazole. In other embodiments, R5 is thiophene. In other embodiments, R5 is oxazole. In other embodiments, R5 is isoxazole. In other embodiments, R5 is imidazole. In other embodiments, R5 is furan. In other embodiments, R5 is triazole. In other embodiments, R5 is pyridine. In other embodiments, R5 is 2-pyridine. In other embodiments, R4 is 3-pyridine. In other embodiments, R5 is 4-pyridine. In other embodiments, R5 is pyrimidine. In other embodiments, R5 is pyrazine. In other embodiments, R5 is oxetane. In other embodiments, R5 is 1-oxetane. In other embodiments, R5 is 2-oxetane. In other embodiments, R5 is indole. In other embodiments, R5 is 3-methyl-4H-1,2,4-triazole. In other embodiments, R5 is 5-methyl-1,2,4-oxadiazole. In other embodiments, R5 is substituted or unsubstituted aryl. In other embodiments, R5 is phenyl. In other embodiments, R5 is CH(CF3)(NH-R 10 ).

[0377] In some embodiments, R3 and R4 of Formulas I, I(a), II, III, IV, V, and V(a) are joined together to form a 5- or 6-membered substituted or unsubstituted aliphatic ring. In some embodiments, R3 and R4 are joined together to form a cyclopentene ring. In some embodiments, R3 and R4 are joined together to form an aromatic carbocyclic ring. In some embodiments, R3 and R4 are joined together to form benzene. In some embodiments, R3 and R4 are joined together to form an aromatic heterocyclic ring. In some embodiments, R3 and R4 are joined together to form thiophene. In some embodiments, R3 and R4 are joined together to form furan. In some embodiments, R3 and R4 are joined together to form a pyrrole ring. In some embodiments, R3 and R4 are joined together to form a pyrazole ring or a [1,3]dioxole ring. In some embodiments, R3 and R4 are joined together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R3 and R4 are joined together to form a cyclopentene ring. In some embodiments, R3 and R4 are joined together to form an imidazole ring.

[0378] In some embodiments, L1 of Formulas I, I(a), and / or III-VII is CH2. In other embodiments, L1 is C═O. In other embodiments, L1 is CHR. In other embodiments, L1 is C(R)2. In other embodiments, R is H, F, C1-C5 linear or branched, substituted or unsubstituted alkyl, or methyl; each represents a separate embodiment according to the present invention. In other embodiments, two geminal R substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic ring. In other embodiments, two geminal R substitutions are linked together to form a cyclopropyl ring.

[0379] In some embodiments, L2 of Formula I and / or I(a) is a bond. In other embodiments, L2 is CH2. In other embodiments, L2 is C=O. In other embodiments, L2 is O. In other embodiments, L2 is S.

[0380] In some embodiments, R of Formulas I-IX 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 CF3. In other embodiments, R is NO2. In other embodiments, R is C1-C5 straight or branched, substituted or unsubstituted alkyl. In other embodiments, R is methyl. In other embodiments, R is ethyl. In other embodiments, R is C1-C5 straight or branched alkoxy. In other embodiments, R is -R8-OR 10In other embodiments, R is CH2-CH2-O-CH3. In other embodiments, R is a C1-C5 straight or branched haloalkyl group. In other embodiments, R is CF3. In other embodiments, R is CF2CH3. In other embodiments, R is CH2CF3. In other embodiments, R is CF2CH2CH3. In other embodiments, R is CH2CH2CF3. In other embodiments, R is CF2CH(CH3)2. In other embodiments, R is CF(CH3)-CH(CH3)2. In other embodiments, R is R8-aryl. In other embodiments, R is CH2-Ph. In other embodiments, R is substituted or unsubstituted aryl. In other embodiments, R is phenyl. In other embodiments, R is substituted or unsubstituted heteroaryl. In other embodiments, R is pyridine. In other embodiments, R is 2-pyridine, 3-pyridine, or 4-pyridine. In other embodiments, two geminal R groups are substituted and joined together to form a 3- to 6-membered substituted or unsubstituted aliphatic or aromatic, carbocyclic, or heterocyclic ring. In other embodiments, two geminal R groups are substituted and joined together to form a 3- to 6-membered aliphatic ring. In other embodiments, two geminal R groups are substituted and joined together to form a cyclopropyl ring. In other embodiments, R may be further substituted with at least one of the following: F, Cl, Br, I, OH, SH, C1-C5 straight or branched alkyl, OH, alkoxy, N(R)2, CF3, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2; each represents a separate embodiment according to the present invention.

[0381] In some embodiments, R8 of Formulas I-IX is CH2. In other embodiments, R8 is CH2CH2. In other embodiments, R8 is CH2CH2CH2.

[0382] In some embodiments, p of Formulas I-IX is 1. In other embodiments, p is 2. In other embodiments, p is 3.

[0383] In some embodiments, R9 of Formula I-IX is C≡C.

[0384] In some embodiments, q of Formulas I-IX is 2.

[0385] In some embodiments, R of Formula I-IX 10 is a C1-C5 substituted or unsubstituted straight or branched chain alkyl. 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 10is CH2-CH2-O-CH3. In other embodiments, R 10 is a C1-C5 straight or branched chain alkoxy. 10 It's O-CH3.

[0386] In some embodiments, R of Formula I-IX 11 is a C1-C5 straight or branched chain alkyl group. 10 is H. In other embodiments, R 11 It is CH3.

[0387] In some embodiments, R of Formula I-IX 10 and R 11 are connected to form a substituted or unsubstituted C3-C8 heterocycle. 10 and R 11 In other embodiments, R 10 and R 11 Connected to form a piperidine ring. In some embodiments, the substitution comprises: F, Cl, Br, I, OH, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof; each represents a separate embodiment according to the present invention.

[0388] In some embodiments, m of Formula IV is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0389] In some embodiments, n of Formulas I-VI is 0. In other embodiments, n is 1. In other embodiments, n is 2.

[0390] In some embodiments, k of Formula IV is 0. In other embodiments, k is 1. In other embodiments, k is 2.

[0391] In some embodiments, l of Formulas I-VI is 0. In other embodiments, l is 1. In other embodiments, l is 2.

[0392] In some embodiments, w of Formula I(a) and / or V(a) is 0 and the bridging moiety is absent. In other embodiments, w is 1. In other embodiments, w is 2.

[0393] In various embodiments, the present invention relates to the compounds, pharmaceutical compositions and / or methods of use thereof presented in Table 1:

[0394] Table 1:

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430] As is well known, in the structures presented in the present invention where the carbon atom has fewer than 4 bonds, H atoms are present to complete the valences of the carbon. As is well known, in the structures presented in the present invention where the nitrogen atom has fewer than 3 bonds, H atoms are present to complete the valences of the nitrogen.

[0431] In some embodiments, the present invention relates to the compounds listed above, their pharmaceutical compositions and / or methods of use, wherein the compound is a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (deuterated analog), pharmaceutical product or any combination thereof. In some embodiments, the compound is a collagen I translation inhibitor.

[0432] In various embodiments, Ring A of Formula I, I(a), II, and / or IV is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, isoquinoline, pyrazolyl, pyrrolyl, furanyl, thienyl, isoquinolinyl, indolyl, 1H-indole, isoindolyl, naphthyl, anthracenyl, benzimidazolyl, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4,5,6,7-tetrahydro -1,3-Benzothiazole, quinazolinyl, quinoxalinyl, cinnozinyl, phthalazinyl, quinolinyl, isoquinolinyl, 2,3-dihydroindenyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepene, benzo[d][1,3]dioxole, acridinyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzofuran-2(3H)-one, benzothiophene, benzoxadiazole, benzo[c][1,2,5]oxadiazolyl, benzo[c]thienyl, benzodioxolyl, benzo[d][1,3]dioxole, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiazolyl, imidazole 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]pyrazine-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, thieno[3,2-c]pyridine, each representing a separate embodiment according to the present invention;or A is a C3-C8 cycloalkyl (e.g., cyclohexyl, cyclopentyl) or a C3-C8 heterocycle, including but not limited to tetrahydropyran, piperidine, 1-piperacolin, tetrahydrothiophene 1,1-dioxide, 1-(piperidin-1-yl)ethanone, or morpholine; each represents a separate embodiment according to the present invention. In some embodiments, A is a C3-C8 heterocycle. ;

[0433] In various embodiments, Ring B of Formula I, I(a), II, III, and / or IV is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, isoquinoline, pyrazolyl, pyrrolyl, triazolyl, furanyl, thienyl, isoquinolinyl, indolyl, 1H-indole, isoindolyl, naphthyl, anthracenyl, benzimidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepene, benzofuran-2(3H)-one, benzo[d][1,3]dioxole, indazolyl, 2H-indazole, triazolyl, 4,5,6 ,7-tetrahydro-2H-indazole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4,5,6,7-tetrahydro-1,3-benzothiazole, quinazolinyl, quinoxalinyl, cinnozinyl, phthalazinyl, quinolinyl, isoquinolinyl, acridinyl, benzofuranyl, 1-phenyl benzofuranyl, isobenzofuranyl, benzothiophenyl, benzoxadiazole, benzo[c][1,2,5]oxadiazolyl, benzo[c]thienyl, benzodioxolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiazolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2-d]pyrimidin-4(3H)-one, 4 -Oxo-4H-thieno[3,2-d][1,3]thiazine, imidazo[1,2-a]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine , pyrido[2,3-b]pyrazine or pyrido[2,3-b]pyrazine-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, thieno[3,2-c]pyridine, C3-C8 cycloalkyl or C3-C8 heterocycle, including but not limited to tetrahydropyran, piperidine, 1-piperacolin, tetrahydrothiophene 1,1-dioxide, 1-(piperidin-1-yl)ethanone or morpholine;Each represents a separate embodiment according to the present invention. In some embodiments, B is a C3-C8 heterocycle. In some embodiments, B is a pyrimidine.

[0434] In various embodiments, the compounds of Formula I, I(a), II, III, IV, V, V(a), and / or VI are substituted with R1, R2, R3, R4, and R5. A single substituent can be present in the ortho, meta, or para position.

[0435] In various embodiments, R1 of Formula I-IX and / or R2 of Formula I-IX are each independently H.

[0436] In various embodiments, R1 of Formula I, I(a), II, III, IV, V, V(a) and / or VI and / or R2 of Formula I, I(a), II, III, IV, V and / or V(a) are each 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), -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 )、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., NHCO-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 linear or branched 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-R10 ), C1-C5 straight or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched substituted or unsubstituted alkenyl, C1-C5 straight, branched or cyclic haloalkyl (CHF2), C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy), optionally wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyridine), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; each represents a separate embodiment according to the present invention. In some embodiments, the substitution comprises at least one of: F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy, N(R)2, CF3, aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO2; each representing a separate embodiment according to the present invention.

[0437] In some embodiments, R1 and R2 are joined together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring. In some embodiments, R1 and R2 are joined together to form a 5- or 6-membered heterocyclic ring. In some embodiments, R1 and R2 are joined together to form a pyrrole ring. In some embodiments, R1 and R2 are joined together to form a [1,3]dioxole ring. In some embodiments, R1 and R2 are joined together to form a furan-2(3H)-one ring. In some embodiments, R1 and R2 are joined together to form a benzene ring. In some embodiments, R1 and R2 are joined together to form a pyridine ring. In some embodiments, R1 and R2 are joined together to form a morpholine ring. In some embodiments, R1 and R2 are joined together to form a piperazine ring. In some embodiments, R1 and R2 are joined together to form an imidazole ring. In some embodiments, R1 and R2 are joined together to form a pyrrole ring. In some embodiments, R1 and R2 are joined together to form a cyclohexene ring. In some embodiments, R1 and R2 are joined together to form a pyrazine ring.

[0438] In various embodiments, the compounds of Formula I, I(a), II, III, IV, V, V(a), and / or VI are substituted with R3 and / or R4. A single substituent can be present in the ortho, meta, or para position.

[0439] In various embodiments, R3 of Formula I-IX; R4 of Formula IV(a) and / or VII-IX; and / or R5 of Formula IV(a) are each independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 、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、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 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 substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight or branched substituted or unsubstituted alkenyl, C1-C5 straight, branched or cyclic haloalkyl (CHF2), C1-C5 straight, branched or cyclic alkoxy (e.g., methoxy), optionally wherein at least one methylene (CH2) in the alkoxy is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy, C1-C5 straight or branched haloalkoxy, C1-C5 straight or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl. In various embodiments, R3, R4 or R5 can each independently be further substituted with at least one selected from the group consisting of F, Cl, Br, I, C1-C5 linear or branched alkyl, OH, alkoxy, N(R)2, CF3, aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO2; each representing a separate embodiment of the present invention.

[0440] In some embodiments, R3 and R4 are joined together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring. In some embodiments, R3 and R4 are joined together to form a 5- or 6-membered carbocyclic ring. In some embodiments, R3 and R4 are joined together to form a 5- or 6-membered heterocyclic ring. In some embodiments, R3 and R4 are joined together to form a dioxole ring. [1,3]dioxole ring. In some embodiments, R3 and R4 are joined together to form a dihydrofuran-2(3H)-one ring. In some embodiments, R3 and R4 are joined together to form a furan-2(3H)-one ring. In some embodiments, R3 and R4 are joined together to form a benzene ring. In some embodiments, R3 and R4 are joined together to form an imidazole ring. In some embodiments, R3 and R4 are joined together to form a pyridine ring. In some embodiments, R3 and R4 are joined together to form a thiophene ring. In some embodiments, R3 and R4 are joined together to form a furan ring. In some embodiments, R3 and R4 are joined together to form a pyrrole ring. In certain embodiments, R3 and R4 are linked together to form a pyrazine ring. In certain embodiments, R3 and R4 are linked together to form a cyclohexene ring. In certain embodiments, R3 and R4 are linked together to form a cyclopentene ring. In certain embodiments, R4 and R3 are linked together to form a dioxepene ring.

[0441] In various embodiments, n of the compounds of Formula I, I(a), II, III, IV, V, V(a), and / or VI is 0. In some embodiments, n is 0 or 1. In some embodiments, n is between 1 and 3. In some embodiments, n is between 1 and 4. In some embodiments, n is between 0 and 2. In some embodiments, n is between 0 and 3. In some embodiments, n is between 0 and 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0442] In various embodiments, m of the compounds of Formula I, I(a), II, III, IV, V, and / or V(a) is 0. In some embodiments, m is 0 or 1. In some embodiments, m is between 1 and 3. In some embodiments, m is between 1 and 4. In some embodiments, m is between 0 and 2. In some embodiments, m is between 0 and 3. In some embodiments, m is between 0 and 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0443] In various embodiments, l of the compounds of Formula I, I(a), II, III, IV, V, V(a), and / or VI is 0. In some embodiments, l is 0 or 1. In some embodiments, l is between 1 and 3. In some embodiments, l is between 1 and 4. In some embodiments, l is 1 or 2. In some embodiments, l is between 0 and 3. In some embodiments, l is between 0 and 4. In some embodiments, l is 1. In some embodiments, l is 2. In some embodiments, l is 3. In some embodiments, l is 4.

[0444] In various embodiments, k for compounds of Formula I, I(a), II, III, IV, V, and / or V(a) is 0. In some embodiments, k is 0 or 1. In some embodiments, k is between 1 and 3. In some embodiments, k is between 1 and 4. In some embodiments, k is between 0 and 2. In some embodiments, k is between 0 and 3. In some embodiments, k is between 0 and 4. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4.

[0445] It will be understood that for heterocycles, 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 one. Thus, if the A and / or B rings are, for example, furanyl, thienyl, or pyrrolyl, n, m, l, and k are between 0 and 2; and if the A and / or B rings are, for example, oxazolyl, imidazolyl, or thiazolyl, n, m, l, and k are 0 or 1; and if the A and / or B rings are, for example, oxadiazolyl or thiadiazolyl, n, m, l, and k are 0.

[0446] In various embodiments, R8 of the compounds of Formulas I-IX is CH2. In some embodiments, R8 is CH2CH2. In some embodiments, R8 is CH2CH2CH2. In some embodiments, R8 is CH2CH2CH2.

[0447] In various embodiments, p of the compounds of Formulas I-IX is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is between 1 and 3. In some embodiments, p is between 1 and 5. In some embodiments, p is between 1 and 10.

[0448] In some embodiments, R9 of the compounds of Formula I-IX is C≡C. In some embodiments, R9 is C≡CC≡C. In some embodiments, R9 is CH═CH. In some embodiments, R9 is CH═CH-CH═CH.

[0449] In some embodiments, q of the compound of Formula I-IX is 2. In some embodiments, q is 4. In some embodiments, q is 6. In some embodiments, q is 8. In some embodiments, q is between 2 and 6.

[0450] In various embodiments, the R 10 is H. In some embodiments, R 10 is a substituted or unsubstituted C1-C5 straight or branched chain alkyl. 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 is CH2-CH2-O-CH3. In some embodiments, R 10 is a C1-C5 straight or branched chain alkoxy group. In some embodiments, R 10 In some embodiments, R 10 is C(O)R. In some embodiments, R 10 It is S(O)2R.

[0451] In various embodiments, the R 11 is H. In some embodiments, R 11 is a C1-C5 straight or branched chain alkyl group. In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 10 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 is C(O)R. In some embodiments, R 11 It is S(O)2R.

[0452] In some embodiments, R of Formula I-IX 10 and R 11 are connected to form a substituted or unsubstituted C3-C8 heterocycle. 10 and R 11 In other embodiments, R 10 and R 11 Connected to form a piperidine ring. In some embodiments, the substitution comprises: F, Cl, Br, I, OH, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycle (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof; each represents a separate embodiment according to the present invention.

[0453] In some embodiments, R of Formulas I-IX 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 CF3. In other embodiments, R is NO2. In other embodiments, R is C1-C5 straight or branched, substituted or unsubstituted alkyl. In other embodiments, R is methyl. In other embodiments, R is ethyl. In other embodiments, R is C1-C5 straight or branched alkoxy. In other embodiments, R is -R8-OR 10In other embodiments, R is CH2-CH2-O-CH3. In other embodiments, R is a C1-C5 straight or branched haloalkyl group. In other embodiments, R is CF3. In other embodiments, R is CF2CH3. In other embodiments, R is CH2CF3. In other embodiments, R is CF2CH2CH3. In other embodiments, R is CH2CH2CF3. In other embodiments, R is CF2CH(CH3)2. In other embodiments, R is CF(CH3)-CH(CH3)2. In other embodiments, R is R8-aryl. In other embodiments, R is CH2-Ph. In other embodiments, R is substituted or unsubstituted aryl. In other embodiments, R is phenyl. In other embodiments, R is substituted or unsubstituted heteroaryl. In other embodiments, R is pyridine. In other embodiments, R is 2-pyridine, 3-pyridine, or 4-pyridine. In other embodiments, two geminal R groups are joined together to form a 3- to 6-membered, substituted or unsubstituted aliphatic or aromatic, carbocyclic, or heterocyclic ring. In other embodiments, two geminal R groups are joined together to form a 3- to 6-membered aliphatic ring. In other embodiments, two geminal R groups are joined together to form a cyclopropyl ring. In other embodiments, substitution comprises at least one of the following: F, Cl, Br, I, OH, SH, C1-C5 linear or branched alkyl, OH, alkoxy, N(R)2, CF3, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2; each represents a separate embodiment according to the present invention.

[0454] In some embodiments, L1 of Formulas I, I(a), and III to VII is CH2. In other embodiments, L1 is C═O. In other embodiments, L1 is CHR. In other embodiments, L1 is C(R)2. In other embodiments, R is H, F, C1-C5 linear or branched, substituted or unsubstituted alkyl, or methyl; each represents a separate embodiment according to the present invention. In other embodiments, two geminal R substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic ring. In other embodiments, two geminal R substitutions are linked together to form a cyclopropyl ring.

[0455] In some embodiments, L2 of Formula I and / or I(a) is a bond. In other embodiments, L2 is CH2. In other embodiments, L2 is C=O. In other embodiments, L2 is O. In other embodiments, L2 is S.

[0456] In some embodiments, X1 of the compounds of Formula I, I(a), II, III, and / or IV is N. In other embodiments, X1 is CR. In other embodiments, X1 is CH. In other embodiments, X1 is C-OH.

[0457] In some embodiments, X2 of the compounds of Formula III and / or V-VIII is NH. In other embodiments, X2 is S. In other embodiments, X2 is O. In other embodiments, X2 is NR. In other embodiments, X2 is N-CH2-CH2-O-CH3.

[0458] In some embodiments, X3 of the compounds of Formula III and / or V-VIII is N. In other embodiments, X3 is C(R). In other embodiments, X3 is CH. In other embodiments, X3 is C-CH3. In other embodiments, X3 is C-Cl. In other embodiments, X3 is C-CN.

[0459] In some embodiments, X4 of the compound of Formula III, V and / or V(a) is C. In other embodiments, X4 is N.

[0460] In some embodiments, X5 of the compound of Formula III, V and / or V(a) is C. In other embodiments, X5 is N.

[0461] In some embodiments, X6 of the compound of Formula III, V and / or V(a) is C. In other embodiments, X6 is N.

[0462] In some embodiments, X7 of the compound of Formula III, V and / or V(a) is C. In other embodiments, X7 is N.

[0463] In some embodiments, X8 of the compounds of Formula IV, V, V(a), and / or VI is C. In other embodiments, X8 is N.

[0464] In some embodiments, X9 of the compound of Formula IV, V, V(a), and / or VI is C. In other embodiments, X9 is N.

[0465] In some embodiments, X of the compound of Formula IV, V-VIII and / or IX 10 is C. In other embodiments, X 10 It's N.

[0466] In some embodiments, X of the compounds of Formula IV, V, V(a), and / or VI 11 is C. In other embodiments, X 11 It's N.

[0467] In some embodiments, X of the compound of Formula IV, V-VIII and / or IX 12 is C. In other embodiments, X 12 It's N.

[0468] In some embodiments, at least one of X4-X7 is N.

[0469] In some embodiments, X8-X 12 At least one of is N. In some embodiments, X8-X 12 At least two of are N. In some embodiments, X 10 and X 12 At least one of them is N.

[0470] As used herein, a "single or fused aromatic or heteroaromatic ring system" can be any such ring including, but not limited to, phenyl, naphthyl, pyridinyl (2-pyridinyl, 3-pyridinyl, and 4-pyridinyl), quinolyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, pyrazolyl, pyrrolyl, furanyl, thienyl, quinolyl, isoquinolyl, 2,3-dihydroindanyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxole, benzodioxolyl, benzo[d][1,3]dioxole, tetrahydronaphthyl, indolyl, 1H-indole, isoindolyl, anthracenyl, benzo[d][1,3]benzo[d] imidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4,5,6,7-tetrahydro-1,3-benzothiazolyl oxazole, quinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxaline, 1-(pyridin-1(2H)-yl)ethanone, cinnozinyl, phthalazinyl, quinolinyl, isoquinolinyl, acridinyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzofuran-2(3H)-one, benzothiophenyl, benzoxadiazole, benzo[c][1,2,5]oxadiazole yl, benzo[c]thienyl, benzodioxolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiazolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2-d]pyrimidin-4(3H)-one, 4-oxo-4H-thieno[3,2-d][1,3]thiazine, imidazo[1,2-a]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-imidazo[4,5-c]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrido[2,3-b]pyrazine, pyrido[2,3- b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thieno[3,2-c]pyridine, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole, etc.

[0471] As used herein, unless otherwise specified, the term "alkyl" can be any straight or branched chain alkyl group containing up to about 30 carbons. In various embodiments, the alkyl group contains C1-C5 carbons. In some embodiments, the alkyl group contains C1-C6 carbons. In some embodiments, the alkyl group contains C1-C8 carbons. In some embodiments, the alkyl group contains C1-C 10 In some embodiments, the alkyl group is C1-C 12 In some embodiments, the alkyl group is C1-C 20 carbon. In some embodiments, the branched alkyl group is an alkyl group substituted with an alkyl side chain having 1 to 5 carbon atoms. In various embodiments, the alkyl group may be unsubstituted. In some embodiments, the alkyl group may be substituted with halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amide, alkylamide, dialkylamide, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, sulfhydryl, sulfoalkyl, C1-C5 straight or branched 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.

[0472] The alkyl group may be the sole substituent or it may be a component of a larger substituent, as in alkoxy, alkoxyalkyl, haloalkyl, arylalkyl, alkylamino, dialkylamino, alkylamido, alkylurea, etc. Preferred alkyl groups are methyl, ethyl, and propyl, and thus halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, halopropyl, dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl, arylethyl, arylpropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, formamido, acetamido, propionamido, halomethylamido, haloethylamido, halopropylamido, methylurea, ethylurea, propylurea, 2-CH2-C6H4-Cl, 3-CH2-C6H4-Cl, or 4-CH2-C6H4-Cl, C(OH)(CH3)(Ph), and the like.

[0473] As used herein, the term "aryl" refers to any aromatic ring directly bonded to another group and can be substituted or unsubstituted. The aryl group can be the only substituent, or the aryl group can be a component of a larger substituent, such as in arylalkyl, arylamino, arylamide, etc. Exemplary aryl groups include but are not limited to phenyl, tolyl, xylyl, furyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thienyl-base, pyrrolyl, indolyl, phenylmethyl, phenylethyl, phenylamino, phenylamide, 3-methyl-4H-1,2,4-triazolyl, 5-methyl-1,2,4-oxadiazolyl, etc. Substitutions include, but are not limited to, F, Cl, Br, I, C1-C5 straight or branched alkyl, C1-C5 straight or branched haloalkyl, C1-C5 straight or branched alkoxy, C1-C5 straight or branched haloalkoxy, CF3, 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 any combination thereof.

[0474] 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 are methoxy, ethoxy, propoxy, isopropoxy, and tert-butoxy.

[0475] As used herein, the term "aminoalkyl" refers to an amine substituted with an alkyl group as defined above. Aminoalkyl refers to a monoalkylamine, a dialkylamine, or a trialkylamine. Non-limiting examples of aminoalkyl groups are -N(Me)2, -NHMe, -NH3.

[0476] In some embodiments, "haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halogen atoms, for example, F, Cl, Br, or I. The term "haloalkyl" includes, but is not limited to, fluoroalkyl, i.e., an alkyl group having at least one fluorine atom. Non-limiting examples of haloalkyl groups are CF3, CF2CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, and CF(CH3)-CH(CH3)2.

[0477] In some embodiments, "halophenyl" refers to a phenyl substituent substituted with one or more halogen atoms, such as F, Cl, Br, or I. In one embodiment, the halophenyl is 4-chlorophenyl.

[0478] In some embodiments, "alkoxyalkyl" refers to an alkyl group as defined above, substituted with an alkoxy group as defined above, for example, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, etc. Non-limiting examples of alkoxyalkyl groups are -CH2-O-CH3, -CH2-O-CH(CH3)2, -CH2-OC(CH3)3, -CH2-CH2-O-CH3, -CH2-CH2-O-CH(CH3)2, -CH2-CH2-OC(CH3)3.

[0479] In various embodiments, a "cycloalkyl" or "carbocyclic" group refers to a ring structure comprising carbon atoms as ring atoms, which may be saturated or unsaturated, substituted or unsubstituted, single or fused. In some embodiments, the cycloalkyl group is a 3- to 10-membered ring. In some embodiments, the cycloalkyl group is a 3- to 12-membered ring. In some embodiments, the cycloalkyl group is a 6-membered ring. In some embodiments, the cycloalkyl group is a 5- to 7-membered ring. In some embodiments, the cycloalkyl group is a 3- to 8-membered ring. In some embodiments, the cycloalkyl group may be unsubstituted or substituted with halogen, alkyl, haloalkyl, hydroxy, alkoxy, carbonyl, amide, alkylamide, dialkylamide, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, sulfenyl, thioalkyl, C1-C5 straight or branched 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. In some embodiments, the cycloalkyl ring may 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), cyclooctene (COE), and the like.

[0480] In various embodiments, a "heterocycle" or "heterocyclic" group refers to a ring structure that includes, in addition to carbon atoms, sulfur, oxygen, nitrogen, or any combination thereof, as part of the ring. In various embodiments, a "heteroaromatic ring" refers to an aromatic ring structure that includes, in addition to carbon atoms, 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, the heterocyclic group or heteroaromatic ring may be unsubstituted or substituted by halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amide, alkylamide, dialkylamide, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, sulfenyl, thioalkyl, C1-C5 straight or branched 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. In some embodiments, the heterocyclic or heteroaromatic ring may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3 to 8 membered ring. In some embodiments, the heterocyclic ring is a saturated ring. In some embodiments, the heterocyclic ring is an unsaturated ring. Non-limiting examples of heterocyclic or heteroaromatic ring systems include pyridine, piperidine, morpholine, piperazine, thiophene, pyrrole, benzodioxazole, benzofuran-2(3H)-one, benzo\[d]\[1,3]dioxole, indole, oxazole, isoxazole, imidazole and 1-methylimidazole, furan, triazole, pyrimidine, pyrazine, oxetane (1 or 2-oxetane), 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.

[0481] In various embodiments, the present invention provides a compound of the present invention or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant (deuterated analog), polymorph or crystal or a combination thereof. In various embodiments, the present invention provides an isomer of a compound of the present invention. In some embodiments, the present invention provides a metabolite of a compound of the present invention. In some embodiments, the present invention provides a pharmaceutically acceptable salt of a compound of the present invention. In some embodiments, the present invention provides a pharmaceutical product of a compound of the present invention. In some embodiments, the present invention provides a tautomer of a compound of the present invention. In some embodiments, the present invention provides a hydrate of a compound of the present invention. In some embodiments, the present invention provides an N-oxide of a compound of the present invention. In some embodiments, the present invention provides a prodrug of a compound of the present invention. In some embodiments, the present invention provides an isotopic variant (including but not limited to deuterated analog) of a compound of the present invention. In some embodiments, the present invention provides a PROTAC (proteolysis targeting chimera) of a compound of the present invention. In some embodiments, the present invention provides a polymorph of a compound of the present invention. In some embodiments, the present invention provides a crystal of a compound of the present invention. In some embodiments, the present invention provides compositions comprising a compound of the invention as described herein, or in some embodiments, an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, prodrug, isotopic variant (deuterated analog), polymorph, or combination of crystals of a compound of the invention.

[0482] In various embodiments, the term "isomer" includes but is not limited to stereoisomers and analogs, structural isomers and analogs, conformational isomers and analogs, etc. In some embodiments, the isomer is an optical isomer. In some embodiments, the isomer is a stereoisomer.

[0483] In various embodiments, the present invention encompasses the use of various stereoisomers of the compounds of the present invention. It will be understood by those skilled in the art that the compounds of the present invention may contain at least one chiral center. Therefore, the compounds used in the methods of the present invention may exist in optically active or racemic forms and be separated in said forms. Therefore, the compounds according to the present invention may exist in optically active isomeric forms (enantiomers or diastereomers, including but not limited to: (R), (S), (R)(R), (R)(S), (S)(S), (S)(R), (R)(R)(R), (R)(R)(S), (R)(S)(R), (S)(R)(R), (R)(S)(S), (S)(R)(S), (S)(R)(S), (S)(S)(R) or (S)(S)(S) isomers); in the form of racemic mixtures or in the form of enantiomeric enriched mixtures. Some compounds may also exhibit polymorphism. It should be understood that the present invention encompasses any racemic, optically active, polymorphic or stereoisomeric forms or mixtures thereof having properties suitable for treating the different conditions described herein.

[0484] It is well known in the art how to prepare optically active forms (e.g., by resolution of racemic forms using recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using chiral stationary phases).

[0485] 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 separated using known procedures to obtain stereoisomers that are substantially free of their corresponding stereoisomers (i.e., substantially pure). By substantially pure, it is meant that the purity of the stereoisomers is at least about 95%, more preferably at least about 98%, and most preferably at least about 99%.

[0486] The compounds of the present invention may also be in the form of a hydrate, which means that the compound further comprises a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0487] As used herein, when some chemical functional group (eg, alkyl or aryl) is referred to as "substituted," one or more substitutions are possible as defined herein.

[0488] The compounds of the present invention may exist in one or more possible tautomer forms, and depending on the condition, it may be possible to separate some or all tautomers into separate and distinct entities. It should be understood that all possible tautomers are encompassed herein, including all additional enol and keto tautomers and / or isomers. For example, the following tautomers are included (but are not limited to these tautomers):

[0489] Tautomerization of the imidazole ring:

[0490]

[0491] Tautomerization of the pyrazolone ring:

[0492]

[0493] The present invention includes "pharmaceutically acceptable salts" of the compounds of the present invention, which can be produced by reacting the compounds of the present invention with an acid or base. Certain compounds, particularly those having an acid or basic group, can also be in the form of salts, preferably pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the free base or free acid, which are not biologically or otherwise undesirable. Salts are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, carnitine, 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, and the like. Other salts are known to those skilled in the art and can be readily adapted for use in accordance with the present invention.

[0494] Suitable pharmaceutically acceptable salts of the amines of the compounds of the present invention can be prepared from inorganic or organic acids. In various embodiments, examples of inorganic salts of amines are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromides, hydrochlorides, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphates, sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen-substituted alkylsulfonates, halogen-substituted arylsulfonates), sulfonates, and thiocyanates.

[0495] In various embodiments, examples of organic salts of amines may be selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid organic acids.Examples thereof are acetate, arginine, aspartate, ascorbate, adipate, anthranilate, alginates, alkanecarboxylates, substituted alkanecarboxylates, alginate, benzenesulfonate, benzoate, hydrogen sulfate, butyrate, hydrogen carbonate, hydrogen tartrate, citrate, camphorate, camphorsulfonate, cyclamates, cyclopentanepropionate, calcium edetate, edetate), camsylate, carbonate, clavulanate, cinnamate, dicarboxylate, digluconate, dodecylsulfonate, dihydrochloride, decanoate, heptanoate, ethanesulfonate, edetate, edisylate, propionate, estolate, esylate, fumarate, formate, fluoride, galacturonate, gluconate, glutamate, glycolate, glucorate, glucoheptonate tanoate), glycerophosphate, gluceptate, glycollylarsanilate, glutarate, glutamate, heptanoate, hexanoate, hydroxymaleate, hydroxycarboxylic acid, hexylresorcinol, hydroxybenzoate, hydroxynaphthoate, hydrofluoride, lactate, lactobionate, laurate, malate, maleate, methylenebis(beta-oxynaphthoate), malonate, mandelate, mesylate, methanesulfonate sulfonate), methyl bromide, methyl nitrate, methyl sulfonate, monopotassium maleate, mucate, monocarboxylate, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, napsylate, N-methylglucamine, oxalate, octanoate, oleate, pamoate, phenylacetate, picrate, phenylbenzoate, pivalate, propionate, phthalate, phenylethyl , pectinate, phenylpropionate, palmitate, pantothenate, polygalactonate, pyruvate, quinate, salicylate, succinate, stearate, sulfanilate, subacetate, tartrate, theophylline acetate, p-toluenesulfonate (toluenesulfonate), trifluoroacetate, terephthalate, tannate, chlorophylline salt (teoclate), trihaloacetate, triethiodide, tricarboxylate, undecanoate and valerate.

[0496] In various embodiments, examples of inorganic salts of carboxylic acids or hydroxyls may be selected from ammonium, alkali metals (including lithium, sodium, potassium, cesium); alkaline earth metals (including calcium, magnesium, aluminum; zinc, barium, choline, quaternary ammonium).

[0497] In some embodiments, examples of organic salts of carboxylic acids or hydroxyl groups can be selected from arginine; organic amines including aliphatic organic amines, alicyclic organic amines, aromatic organic amines; benzathine, tert-butylamine, phenethylbenzylamine (N-benzylphenethylamine), dicyclohexylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, hydrabamine, imidazole, lysine, methylamine, meglamine, N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, nicotinamide, organic amines, ornithine, pyridine, picolines, piperazine, procaine, tris(hydroxymethyl)methylamine, triethylamine, triethanolamine, trimethylamine, tromethamine, and urea.

[0498] In various embodiments, salts can be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of an appropriate acid or base in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by ion exchange of the existing salt for another ion or a suitable ion exchange resin.

[0499] Pharmaceutical composition

[0500] Another aspect of the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to the various aspects of the present invention. The pharmaceutical composition may contain one or more of the above-identified compounds of the present invention. Typically, the pharmaceutical composition of the present invention will 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 can be in solid or liquid form, such as a tablet, capsule, powder, solution, suspension or emulsion.

[0501] Typically, the composition will contain about 0.01% to 99%, preferably about 20% to 75% of the active compound and an adjuvant, carrier and / or vehicle. Although individual needs may vary, it is within the skill of the art to determine the optimal range for the effective amount of each component. Typical dosages include about 0.01 to about 100 mg / kg body weight. Preferred dosages include about 0.1 to about 100 mg / kg body weight. Most preferred dosages include about 1 to about 100 mg / kg body weight. One of ordinary skill in the art can also readily determine a therapeutic regimen for administering the compounds of the present invention. That is, the frequency of administration and dose size can be determined by conventional optimization, preferably while minimizing any side effects.

[0502] Solid unit dosage forms can be conventional. Solid forms can be capsules, such as ordinary gelatin-type capsules, containing a compound of the invention and a carrier, such as a lubricant and an inert filler, such as lactose, sucrose, or corn starch. In some embodiments, these compounds are combined with conventional tablet bases, such as lactose, sucrose, or corn starch; binders, such as acacia, corn starch, or gelatin; disintegrants, such as corn starch, potato starch, or alginic acid; and lubricants, such as stearic acid or magnesium stearate.

[0503] Tablets, capsules, etc. may also contain a binder such as gum tragacanth, gum arabic, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, or alginic acid; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose, or saccharin. When the dosage unit is a capsule, it may contain, in addition to the above-mentioned materials, a liquid carrier such as a fatty oil.

[0504] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. In addition to the active ingredient, a syrup may contain sucrose as a sweetener, methyl and propylparabens as preservatives, dyes, and flavorings (such as cherry or orange flavoring).

[0505] For oral treatment use, these active compounds can be combined with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, etc. Such compositions and preparations should contain at least 0.1% active compound. Of course, the percentage of the compound in these compositions can vary, and can be conveniently between about 2% to about 60% of the unit weight. The amount of the active compound in such therapeutically useful compositions makes it possible to obtain a suitable dosage. Preparation according to the preferred composition of the present invention makes it possible for the oral dosage unit to contain the active compound between about 1mg and 800mg.

[0506] The active compound of the present invention may be administered orally, for example, with an inert diluent or with an assimilable edible carrier, or the active compound may be enclosed in a hard or soft shell capsule, or the active compound may be compressed into tablets, or the active compound may be incorporated directly with the food of the diet.

[0507] The pharmaceutical form suitable for injection purposes comprises sterile aqueous solution or dispersion and the sterile powder for extemporaneously preparing sterile injectable solution or dispersion.In all cases, the form should be sterile and should have the fluidity reaching the degree of being easy to inject.It should be stable under the conditions of manufacture and storage and should be preserved in order to avoid the contamination effect of microorganisms such as bacteria and fungi.Carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), its suitable mixture and vegetable oil.

[0508] Compound of the present invention or pharmaceutical composition can also be used with injectable dose by solution or suspension of these materials in physiologically acceptable diluent and pharmaceutical adjuvant, carrier or vehicle.Add or do not add surfactant and other pharmaceutically and physiologically acceptable components, such adjuvant, carrier and / or vehicle include but are not limited to sterile liquid, such as water and oil.Exemplary oil is the oil of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil or mineral oil.Usually, water, saline, dextran aqueous solution and relevant sugar solution and ethylene glycol such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solution.

[0509] These active compounds can also be administered parenterally. Can suitably with surfactant, as the solution or suspension of these active compounds in the water mixed with hydroxypropylcellulose. Dispersion can also be prepared in the oil containing glycerol, liquid polyethylene glycol and its mixture. Exemplary oil is the oil of petroleum, animal, plant or synthetic origin, for example peanut oil, soybean oil or mineral oil. Usually, water, saline, dextran aqueous solution and relevant sugar solution and as glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions. Under common storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms.

[0510] In order to be used as aerosol, the compound of the present invention in solution or suspension can be packaged in a pressurized aerosol container with a suitable propellant, for example a hydrocarbon propellant, such as propane, butane or isobutane, together with conventional co-adjuvants. The material of the present invention can also be used in a non-pressurized form, such as in a sprayer or atomizer.

[0511] In various embodiments, the compounds of the present invention are administered in combination with a pharmaceutical agent for treating fibrosis. In some embodiments, the pharmaceutical agent for treating pulmonary fibrosis is at least one selected from the following: pirfenidone and nintedanib. Other examples of pharmaceutical agents that can be used to treat pulmonary fibrosis including IPF 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 pharmaceutical agent for treating NASH.

[0512] When the compound of the present invention is applied, it can be systemically applied, or alternatively, it can be directly applied to a specific site where there is fibrosis. Therefore, administration can be completed in any manner that effectively compounds or pharmaceutical compositions are delivered to fibrotic cells. Exemplary modes of administration include but are not limited to oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, by intranasal instillation, by intracavitary or intravesical instillation, intraocular, intraarterial, intralesional or by being applied to mucosa (such as the mucosa of nose, throat and bronchus) to apply compound or composition.

[0513] Biological activity

[0514] In various embodiments, the present invention provides compounds and compositions for use in any of the methods of the present invention, including any of the embodiments described herein. In various embodiments, the use of the compounds of the present invention or compositions comprising the compounds 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 composition may further include an additional active ingredient whose activity is useful for the specific application for which the compound of the present invention is administered.

[0515] The present invention relates to the treatment, inhibition, and alleviation of fibrosis, including pulmonary fibrosis and liver fibrosis. More specifically, embodiments of the present invention provide compositions and methods for treating and inhibiting fibrotic conditions, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis conditions associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), using compounds according to the present invention or pharmaceutically acceptable salts thereof.

[0516] 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). In another embodiment, the human subject does not suffer from non-alcoholic steatohepatitis (NASH).

[0517] In various conditions of illness, the formation of fibrotic tissue is characterized by the deposition of a large amount of abnormal collagen. The synthesis of collagen also relates to many other pathological conditions of illness. For example, the clinical conditions and illnesses relevant to primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis and autoimmune disorders are characterized by the excessive production of connective tissue, which causes the destruction of normal tissue structure and function. These diseases are preferably explained according to the disorder of cell function, and their main manifestations are the excessive synthesis and deposition of collagen. The effect of collagen in fibrosis prompts people to attempt to develop drugs that suppress its accumulation.

[0518] Excessive accumulation of collagen is the main pathological feature of the various clinical conditions of illness that is characterised in tissue fibrosis. These conditions of illness comprise localised processes (e.g., pulmonary fibrosis and liver cirrhosis) or more generalised processes (e.g., progressive systemic sclerosis). Collagen deposition is the feature of different forms of skin fibrosis, which, in addition to scleroderma, also comprises localised and generalised morphea, keloids, hypertrophic scars, familial skin collagenomas and collagen type connective tissue nevi. The latest progress in the understanding of the normal biochemistry of collagen allows us to define the specific levels of collagen biosynthesis and degradation, and at these levels, pharmacological intervention can cause the collagen deposition in tissue to reduce. Such compounds can potentially provide us with novel means to reduce the excessive collagen accumulation in disease.

[0519] Therefore, in various embodiments, the present invention relates to a method of treating fibrosis in a subject, curbing fibrosis in a subject, reducing the severity of fibrosis in a subject, reducing the risk of a subject developing fibrosis, or inhibiting fibrosis in a subject, comprising administering a compound according to the present invention to the subject under conditions effective to treat fibrosis in a subject with fibrosis, curbing fibrosis in a subject with fibrosis, reducing the severity of fibrosis in a subject with fibrosis, reducing the risk of a subject developing fibrosis, or inhibiting fibrosis in a subject with fibrosis. 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 or secondary fibrosis. In some embodiments, the fibrosis is the result of systemic sclerosis, progressive systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, an autoimmune disorder, or any combination thereof; each representing a separate embodiment according to the present invention. In another embodiment, the human subject suffers from pulmonary fibrosis. In another embodiment, the human subject suffers from idiopathic pulmonary fibrosis (IPF). In some embodiments, the fibrosis is pulmonary fibrosis. In some embodiments, the subject suffers from cirrhosis of the liver. In some embodiments, the fibrosis is hepatic fibrosis, pulmonary fibrosis, or skin fibrosis. In some embodiments, the skin fibrosis is scleroderma. In some embodiments, the skin fibrosis is the result of localized or generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenomas, collagenous connective tissue nevi, or any combination thereof; each represents a separate embodiment according to the present invention. In some embodiments, the fibrosis is caused by tissue damage, inflammation, oxidative stress, or any combination thereof; each represents a separate embodiment according to the present invention. In some embodiments, the fibrosis is gingival fibromatosis. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0520] Due to the large number of affected individuals, incomplete understanding of the pathogenesis of the fibrotic process, the significant heterogeneity of its etiology and clinical manifestations, the lack of appropriate and well-validated biomarkers and, most importantly, the current lack of therapeutic agents that effectively alleviate the disease, human fibrotic diseases constitute a major health problem worldwide. Fibrotic disorders encompass a variety of clinical entities, including systemic fibrotic diseases such as systemic sclerosis (SSc), scleroderma graft-versus-host disease, and nephrogenic systemic fibrosis, as well as a variety of organ-specific disorders including radiation-induced fibrosis and cardiac fibrosis, pulmonary fibrosis, lung fibrosis, liver fibrosis, and renal fibrosis. Although its pathogenic mechanism is quite diverse and remains elusive in some cases, a common feature of these diseases is that the fibrotic tissue in the affected organs is uncontrolled and gradually accumulates, causing its dysfunction and ultimate failure. Despite the remarkable heterogeneity in the etiological mechanisms responsible for the development of fibrotic diseases and their clinical manifestations, numerous studies have identified activated myofibroblasts as the common cellular element ultimately responsible for the replacement of normal tissue with non-functional fibrotic tissue.

[0521] In various embodiments, the present invention relates to a method for treating a systemic fibrotic disease in a subject, curbing the systemic fibrotic disease in a subject, reducing the severity of the systemic fibrotic disease in a subject, reducing the risk of a subject developing a systemic fibrotic disease, or inhibiting the systemic fibrotic disease in a subject, the method comprising administering a compound of the present invention to the subject under conditions of effectively treating the systemic fibrotic disease in a subject with systemic fibrotic disease, curbing the systemic fibrotic disease in a subject with systemic fibrotic disease, reducing the severity of the systemic fibrotic disease in a subject with systemic fibrotic disease, reducing the risk of a subject developing a systemic fibrotic disease, or inhibiting the systemic fibrotic disease in a subject with systemic fibrotic disease. In some embodiments, the systemic fibrotic disease is systemic sclerosis. In some embodiments, the systemic fibrotic disease is multifocal fibrosing sclerosis (IgG4-related fibrosis). In some embodiments, the systemic fibrotic disease is nephrogenic systemic fibrosis. In some embodiments, the systemic fibrotic disease is scleroderma graft-versus-host disease.

[0522] In various embodiments, the present invention is directed to a method of treating, suppressing, reducing the severity of, reducing the risk of, or inhibiting an organ-specific fibrotic disease in a subject, comprising administering to the subject a compound of the present invention under conditions effective to treat, suppress, reduce the severity of, reduce the risk of, or inhibit an organ-specific fibrotic disease in a subject having, an organ-specific fibrotic disease, or an organ-specific fibrotic disease in a subject having, an organ-specific fibrotic disease, or an organ-specific fibrotic disease in a subject having.

[0523] In some embodiments, the organ-specific fibrotic disease is pulmonary fibrosis. In some embodiments, the organ-specific fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0524] In some embodiments, the organ-specific fibrotic disease is cardiac fibrosis. In some embodiments, the cardiac fibrosis is hypertension-related cardiac fibrosis. In some embodiments, the cardiac fibrosis is post-myocardial infarction. In some embodiments, the cardiac fibrosis is Chagas' disease-induced myocardial fibrosis.

[0525] In some embodiments, the organ-specific fibrotic disease 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.

[0526] In various embodiments, the present invention relates to a method of treating cardiac fibrosis in a subject, curbing cardiac fibrosis in a subject, reducing the severity of cardiac fibrosis in a subject, reducing the risk of a subject developing cardiac fibrosis, or inhibiting cardiac fibrosis in a subject, the method comprising administering a compound of the present invention to the subject under conditions effective to treat cardiac fibrosis in a subject with cardiac fibrosis, curbing cardiac fibrosis in a subject with cardiac fibrosis, reducing the severity of cardiac fibrosis in a subject with cardiac fibrosis, reducing the risk of a subject with cardiac fibrosis developing cardiac fibrosis, or inhibiting cardiac fibrosis in a subject with cardiac fibrosis. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0527] In some embodiments, the organ-specific fibrotic disease 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 chemotherapeutic-induced pulmonary fibrosis.

[0528] In some embodiments, the organ-specific fibrotic disease is liver and portal vein fibrosis. In some embodiments, the liver and portal vein fibrosis is alcoholic and non-alcoholic liver fibrosis. In some embodiments, the liver and portal vein fibrosis is hepatitis C-induced liver fibrosis. In some embodiments, the liver and portal vein fibrosis is primary biliary cirrhosis. In some embodiments, the liver and portal vein fibrosis is parasite-induced liver fibrosis (schistosomiasis).

[0529] In some embodiments, the organ-specific fibrotic disease is radiation-induced fibrosis (various organs). In some embodiments, the organ-specific fibrotic disease is bladder fibrosis. In some embodiments, the organ-specific fibrotic disease is intestinal fibrosis. In some embodiments, the organ-specific fibrotic disease is peritoneal sclerosis.

[0530] In some embodiments, the organ-specific fibrotic disease is diffuse fasciitis. In some embodiments, the diffuse fasciitis is localized scleroderma or keloids. 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.

[0531] In some embodiments, the organ-specific fibrotic disease is the result of wound healing. In some embodiments, the organ-specific fibrotic disease is the result of scar formation.

[0532] The fibrosis of the liver (also referred to as liver fibrosis in this article) can be caused by various types of chronic liver damage, especially when related to inflammatory components. Even if self-limiting acute liver damage (for example, acute viral hepatitis A) is fulminant, it is not necessarily distorted stent architecture, and therefore does not usually cause fibrosis, although liver cells are lost. However, factors such as chronic alcoholism, malnutrition, hemochromatosis and poison exposure, toxin exposure or drug exposure may cause chronic liver damage and liver fibrosis due to hepatotoxic chemical exposure. Liver scarring caused by surgery or other forms of damage relevant to mechanical biliary obstruction may also cause liver fibrosis.

[0533] In various embodiments, the present invention relates to a method of treating, curbing, reducing the severity of, reducing the risk of, or inhibiting liver fibrosis in a subject, comprising administering a compound of the present invention to the subject under conditions effective to treat, curb, reduce the severity of, reduce the risk of, or inhibit liver fibrosis in a subject with liver fibrosis. In some embodiments, liver fibrosis is caused by scarring. In some embodiments, liver fibrosis is caused by chronic liver damage. In some embodiments, chronic liver damage is caused by chronic alcoholism, malnutrition, hemochromatosis, toxic exposure, toxin exposure, or drug exposure; each represents a separate embodiment according to the present invention. In some embodiments, the subject has cirrhosis. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0534] Fibrosis itself is not necessarily symptomatic; however, it can lead to the development of portal hypertension, in which scarring distorts blood flow through the liver, or cirrhosis, in which scarring leads to disruption of normal liver architecture and liver dysfunction. The extent of each of these pathologies determines the clinical manifestations of liver fibrosis. For example, congenital hepatic fibrosis affects the branches of the portal vein, largely sparing the parenchyma. The result is portal hypertension without impairing liver cell function.

[0535] In various embodiments, the present invention relates to a method of treating, suppressing, reducing the severity of, reducing the risk of, or inhibiting a liver fibrosis disorder in a subject, comprising administering to the subject a compound of the present invention under conditions effective to treat, suppress, reduce the severity of, reduce the risk of, or inhibit a liver fibrosis disorder in a subject having a liver fibrosis disorder. In some embodiments, the liver fibrosis disorder is portal hypertension, cirrhosis, idiopathic hepatic fibrosis, or any combination thereof; each represents a separate embodiment according to the present invention. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0536] In various embodiments, the present invention relates to a method of treating, suppressing, reducing the severity of, reducing the risk of, or inhibiting portal hypertension in a subject, comprising administering to the subject a compound of the present invention under conditions effective to treat, suppress, reduce the severity of, reduce the risk of, or inhibit portal hypertension in a subject having portal hypertension. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0537] In various embodiments, the present invention relates to a method of treating, arresting, reducing the severity of, reducing the risk of, or inhibiting cirrhosis in a subject, comprising administering to the subject a compound of the present invention under conditions effective to treat, arrest, reduce the severity of, reduce the risk of, or inhibit cirrhosis in a subject with cirrhosis. In some embodiments, the cirrhosis is a result of hepatitis. In some embodiments, the cirrhosis is a result of alcoholism. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0538] In various embodiments, the present invention relates to a method of treating, curbing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholism in a subject, comprising administering to the subject a compound of the present invention under conditions effective to treat, curb, reduce, reduce the severity of, reduce the risk of developing, or inhibit alcoholism in a subject suffering from alcoholism. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0539] Nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) share similar pathogenesis and histopathology, but differ in etiology and epidemiology. NASH and ASH are advanced forms of nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is characterized by excessive fat accumulation in the liver (steatosis), the absence of any other obvious cause of chronic liver disease (viral, autoimmune, genetic, etc.), and alcohol consumption ≤20-30 g / day. In contrast, AFLD is defined by the presence of steatosis and alcohol consumption >20-30 g / day.

[0540] In various embodiments, the present invention relates to a method of treating non-alcoholic steatohepatitis (NASH) in a subject, suppressing NASH in a subject, reducing the severity of NASH in a subject, reducing the risk of developing NASH in a subject, or inhibiting NASH in a subject, comprising administering to the subject a compound of the present invention under conditions effective to treat non-alcoholic steatohepatitis (NASH) in a subject with NASH, suppressing NASH in a subject with NASH, reducing the severity of NASH in a subject with NASH, reducing the risk of developing NASH in a subject with NASH, or inhibiting NASH in a subject with NASH. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0541] In various embodiments, the present invention relates to a method of treating alcoholic steatohepatitis (ASH) in a subject, curbing ASH in a subject, reducing the severity of ASH in a subject, reducing the risk of developing ASH in a subject, or inhibiting ASH in a subject, the method comprising administering a compound of the present invention to the subject under conditions effective to treat alcoholic steatohepatitis (ASH) in a subject suffering from alcoholic steatohepatitis (ASH), curbing ASH in a subject suffering from ASH, reducing the severity of ASH in a subject suffering from ASH, reducing the risk of developing ASH in a subject suffering from ASH, or inhibiting ASH in a subject suffering from ASH. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0542] In various embodiments, the present invention relates to a method for treating non-alcoholic fatty liver disease (NAFLD) in a subject, curbing NAFLD in a subject, reducing the severity of NAFLD in a subject, reducing the risk of NAFLD in a subject, or inhibiting NAFLD in a subject, the method comprising administering a compound of the present invention to the subject under conditions that effectively treat non-alcoholic fatty liver disease (NAFLD) in a subject with NAFLD, curbing NAFLD in a subject with NAFLD, reducing the severity of NAFLD in a subject with NAFLD, reducing the risk of NAFLD in a subject with NAFLD, or inhibiting NAFLD in a subject with NAFLD. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0543] In various embodiments, the present invention relates to a method of treating, suppressing, reducing the severity of, reducing the risk of, or inhibiting alcoholic fatty liver disease (AFLD) in a subject, comprising administering to the subject a compound of the present invention under conditions effective to treat, suppress, reduce the severity of, reduce the risk of, or inhibit alcoholic fatty liver disease (AFLD) in a subject having AFLD. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0544] In various embodiments, the present invention relates to a method of treating pulmonary fibrosis in a subject, curbing pulmonary fibrosis in a subject, reducing the severity of pulmonary fibrosis in a subject, reducing the risk of a subject developing pulmonary fibrosis, or inhibiting pulmonary fibrosis in a subject, the method comprising administering a compound of the present invention to the subject under conditions effective to treat pulmonary fibrosis in a subject with pulmonary fibrosis, curbing pulmonary fibrosis in a subject with pulmonary fibrosis, reducing the severity of pulmonary fibrosis in a subject with pulmonary fibrosis, reducing the risk of a subject developing pulmonary fibrosis, or inhibiting pulmonary fibrosis in a subject with pulmonary fibrosis. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0545] Idiopathic pulmonary fibrosis (IPF) is a stubborn lung disease associated with aging with historically limited treatment options. The recent approval of two drugs by the United States Food and Drug Administration (FDA) in 2014, pirfenidone and nintedanib, heralds a new era in its management. Both drugs have demonstrated efficacy in Phase III clinical trials by delaying the rate of progression of IPF; neither drug appears to be able to completely halt disease progression. Advances in the understanding of the pathobiology of IPF have led to an unprecedented expansion in the number of potential therapeutic targets. Drugs targeting several of these therapeutic targets are being studied in various stages of clinical development.

[0546] In various embodiments, the present invention relates to a method for treating idiopathic pulmonary fibrosis (IPF) in a subject, curbing IPF in a subject, reducing the severity of IPF in a subject, reducing the risk of a subject developing IPF, or inhibiting IPF in a subject, the method comprising administering a compound of the present invention to the subject under conditions that effectively treat idiopathic pulmonary fibrosis (IPF) in a subject with idiopathic pulmonary fibrosis (IPF), curbing IPF in a subject with IPF, reducing the severity of IPF in a subject with IPF, reducing the risk of a subject developing IPF, or inhibiting IPF in a subject with IPF. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention. In some embodiments, the compound is administered in combination with an agent for treating IPF. In some embodiments, the compound is administered in combination with pirfenidone, nintedanib, or a combination thereof; each represents a separate embodiment according to the present invention.

[0547] In various embodiments, the present invention relates to a method of treating skin fibrosis in a subject, curbing skin fibrosis in a subject, reducing the severity of skin fibrosis in a subject, reducing the risk of developing skin fibrosis in a subject, or inhibiting skin fibrosis in a subject, comprising administering a compound of the present invention to the subject under conditions effective to treat skin fibrosis in a subject with skin fibrosis, curbing skin fibrosis in a subject with skin fibrosis, reducing the severity of skin fibrosis in a subject with skin fibrosis, reducing the risk of developing skin fibrosis in a subject with skin fibrosis, or inhibiting skin fibrosis in a subject with skin fibrosis. In some embodiments, the skin fibrosis is scleroderma. In some embodiments, the skin fibrosis is the result of localized or generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenomas, collagenous connective tissue nevi, or any combination thereof; each represents a separate embodiment according to the present invention. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0548] In various embodiments, the present invention relates to a method of treating, arresting, reducing the severity of, reducing the risk of, or inhibiting scleroderma in a subject, comprising administering to the subject a compound of the present invention under conditions effective to treat, arrest, reduce the severity of, reduce the risk of, or inhibit scleroderma in a subject having scleroderma. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0549] In various embodiments, the present invention is directed to a method of inhibiting overproduction of collagen I (Col I) in a subject, comprising administering to a subject suffering from overproduction of collagen I (Col I) a compound according to the present invention under conditions effective to inhibit overproduction of collagen I (Col I) in the subject. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0550] In some embodiments, the present invention relates to a method of treating an autoimmune disease or condition in a subject, suppressing an autoimmune disease or condition in a subject, reducing the severity of an autoimmune disease or condition in a subject, reducing the risk of a subject developing an autoimmune disease or condition, or inhibiting an autoimmune disease or condition in a subject, the method comprising administering a compound of the present invention to the subject under conditions effective to treat an autoimmune disease or condition in a subject suffering from an autoimmune disease or condition, suppressing an autoimmune disease or condition in a subject suffering from an autoimmune disease or condition, reducing the severity of an autoimmune disease or condition in a subject suffering from an autoimmune disease or condition, reducing the risk of a subject developing an autoimmune disease or condition, or inhibiting an autoimmune disease or condition in a subject suffering from an autoimmune disease or condition. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to the present invention.

[0551] As used herein, a subject or patient refers to any mammalian patient, including but not limited to humans and other primates, dogs, cats, horses, cattle, sheep, pigs, rats, mice, and other rodents. In various embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the methods described herein can be used to treat males or females.

[0552] The following examples are presented in order to more fully illustrate the preferred embodiments of the present invention. However, the examples should in no way be construed as limiting the broad scope of the present invention.

[0553] Examples

[0554] Example 1

[0555] Synthetic details of the compounds of the present invention (Schemes 1-32)

[0556] General approach

[0557] Unless otherwise specified, all reagents were of commercial grade and used as received without further purification. Unless otherwise specified, reagent grade solvents were used in all cases. Thin layer chromatography was performed using pre-coated silica gel F-254 plates (thickness: 0.25 mm). Spectrometers were recorded on a Bruker Avance 400 MHz or Avance III 400 MHz spectrometer. 1 H-NMR and 19F-NMR spectra. Chemical shifts are expressed in ppm using the residual solvent as an internal standard. Splitting patterns are designated as s (singlet), d (doublet), dd (double of doublets), t (triplet), dt (double of triplets), q (quartet), m (multiplet), and br s (broad singlet).

[0558] Abbreviations

[0559] ACN acetonitrile

[0560] AcOH acetic acid

[0561] amphos Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)

[0562] Boc tert-Butoxycarbonyl

[0563] BuLi n-butyllithium

[0564] t-BuLi tert-butyllithium

[0565] DAST Diethylaminosulfur trifluoride

[0566] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0567] Dppb 1,4-bis(diphenylphosphino)butane

[0568] Dppf 1,1'-bis(diphenylphosphino)ferrocene

[0569] DCM dichloromethane

[0570] DIBAL-H Diisobutylaluminum hydride

[0571] DIPEA N,N-Diisopropylethylamine

[0572] DMF N,N-dimethylformamide

[0573] DMA dimethylacetamide

[0574] DME 1,2-dimethoxyethane

[0575] DMSO dimethyl sulfoxide

[0576] HATU [O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate]

[0577] HPLC high-performance liquid chromatography

[0578] MsCl methanesulfonyl chloride

[0579] NBS N-bromosuccinimide

[0580] NMP N-Methyl-2-pyrrolidone

[0581] PPA Polyphosphoric Acid

[0582] rt room temperature

[0583] SEM 2-(Trimethylsilyl)ethoxymethyl

[0584] T3P Propyl Phosphoric Anhydride

[0585] TBAF Tetrabutylammonium fluoride

[0586] TBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate

[0587] TCFH N,N,N',N'-Tetramethylchloroformamidine hexafluorophosphate

[0588] THF Tetrahydrofuran

[0589] TMSCF3 trimethyl(trifluoromethyl)silane

[0590] TMS-OTf trimethylsilyl trifluoromethanesulfonate

[0591] General Synthesis of Compounds of the Invention

[0592] RHS piperazine head group modification

[0593] Schemes 1 and 2 show compounds for RHS modification (compound 212 analogs, see

[0594] Table 1) of the original general synthesis.

[0595]

[0596] Scheme 1. Synthesis route 1 of analogue 3

[0597] Compound 212 analogs 3 were synthesized via reductive amination chemistry (pathway 1) by reacting 1H-indole-2-carbaldehyde 1 and the corresponding substituted piperazine 2 in the presence of sodium triacetoxyborohydride and acetic acid in DCM (Scheme 1).

[0598]

[0599] Scheme 2. Synthetic route 2 of analogue 3

[0600] Route 2 (Scheme 2) uses Buchwald chemistry to synthesize compound 212 analogs 3 from (hetero)aryl halides and amine intermediates 6. Amine intermediates 6 were prepared in two steps from commercial 1H-indole-2-carbaldehyde 1 and N-Boc-piperazine 4 via N-Boc intermediate 5. After the first reductive amination step, N-Boc intermediate 5 was deprotected under acidic conditions to afford amine intermediate 6 after generating the free base by SCX ion exchange chromatography. The final Buchwald chemistry step utilized various (hetero)aryl halides in the presence of palladium(II) acetate, RuPhos, and cesium carbonate in dioxane at 95°C.

[0601] LHS modification

[0602] Scheme 3 outlines the synthesis of the 5-carbon linked LHS modified analog 11.

[0603]

[0604] Scheme 3.5 - Synthesis of Carbon-linked LHS-modified analog 11.

[0605] The synthesis of the 5-carbon-linked LHS-modified analog 11 involved an initial reductive amination of commercial 5-bromo-1H-indole-2-carboxaldehyde 7 with R1-substituted piperazine 8 using similar conditions with sodium triacetoxyborohydride and acetic acid in DCM. The resulting 5-bromoindole intermediate 9 was then used in a final Suzuki reaction step with boronate ester 10 to afford the final compound analog 11 in moderate yield.

[0606] The synthesis of 5-nitrogen-linked LHS-modified analogs 17a and 17b is shown in Scheme 4.

[0607]

[0608] Scheme 4.5 - Synthesis of nitrogen-linked LHS-modified analogs 17a and 17b.

[0609] The synthesis begins with the chemoselective reduction of the ester functionality of commercial ethyl 5-nitro-1H-indole-2-carboxylate 12 using diisobutylaluminum hydride in DCM. The resulting alcohol 13 is then oxidized to aldehyde 14 using manganese(IV) oxide in THF. Subsequent reductive amination of substituted piperazine 8 with aldehyde intermediate 14 affords 5-nitroindole intermediate 15. The nitro moiety of these intermediates 15 is reduced using mild iron powder conditions in the presence of ammonium chloride to afford the resulting key 5-aminoindole intermediate 16. The final step involves amidation of 5-aminoindole intermediate 15 using a carboxylic acid under HATU coupling conditions (condition a) or sulfonylation of 5-aminoindole intermediate 15 using the corresponding sulfonyl chloride (condition b) to afford the final compound analogs 17a and 17b, respectively (Scheme 4).

[0610] Scheme 5 shows the synthesis of the reverse 5-indoleamide analog 22.

[0611]

[0612] Scheme 5. Synthesis of reverse 5-indoleamide analog 22

[0613] The synthesis of reverse amine analog 22 begins with the reductive amination of substituted piperazine 8 with commercial methyl 2-formyl-1H-indole-5-carboxylate 18 to afford the 5-methyl ester indole intermediate 19. Hydrolysis of the ester moiety of intermediate 19 with sodium hydroxide affords the carboxylic acid intermediate 20, which is isolated as its sodium salt. The resulting sodium salt of the carboxylic acid intermediate 20 is amidated with aniline 21 using HATU amide coupling conditions to afford reverse 5-indole amide analog 22 in good yield.

[0614] Scheme 6 outlines the synthesis of LHS-modified variably substituted indole scaffold analogs 26 with small R1 substituents.

[0615]

[0616] Scheme 6. Synthesis of LHS-modified variably substituted indole scaffold analogue 26

[0617] The synthesis begins with commercial esters or carboxylic acids 23 bearing R1 substituents at various indole positions. The commercial ester or carboxylic acid starting material 23 is converted to the aldehyde intermediate 25 via the corresponding primary alcohol intermediate 24 in a two-step sequence. The first step in the sequence involves the reduction of the carboxylic acid / ester moiety with lithium aluminum hydride in THF. The second step in the sequence is the oxidation of the primary alcohol intermediate 24 to the aldehyde intermediate 25 using manganese (IV) oxide. The key aldehyde intermediate 25 is then converted to the target analog 26 using a substituted piperazine 8 under reductive amination reaction conditions.

[0618] Scheme 7 shows the synthesis of 5-methoxyethoxyindole analog 31.

[0619]

[0620] Scheme 7. Synthesis of 5-methoxyethoxyindole analog 31

[0621] The synthesis of 5-methoxyethoxyindole analog 31 begins with O-alkylation of commercial ethyl 5-hydroxy-1H-indole-2-carboxylate 27 using 1-bromo-2-methoxyethane and cesium carbonate to provide intermediate 28. Intermediate 28 is then converted to the aldehyde intermediate 30 in a two-step reduction (LiAlH4) / oxidation (MnO2) sequence similar to Scheme 6. The final step to provide analog 31 involves reductive amination of the aldehyde intermediate 30 with a substituted piperazine 8 using conditions similar to those described previously.

[0622] As shown in Scheme 8, 3-cyanoindole analog 36 was synthesized.

[0623]

[0624] Scheme 8.3-Synthesis of cyanoindole analog 36

[0625] The synthesis of 3-cyanoindole analog 36 begins with N-protection of commercial 3-cyanoindole 32 by heating in an autoclave at 160°C in the presence of neat triethyl orthoformate. The resulting N-protected indole acetal 33 is formylated by deprotonation of the indole at position 2 (t-BuLi) and subsequent quenching of the anion with DMF. Intermediate aldehyde 34 is subjected to reductive amination with substituted piperazine 8 without purification. Intermediate 35 is obtained using the previously used conditions containing sodium triacetoxyborohydride and acetic acid in DCM. The target 3-cyanoindole analog 36 is then obtained in the final step by acidic N-deprotection of the acetal moiety of intermediate 35.

[0626] Linker modification

[0627] Scheme 9 shows the synthesis of amide-linked analog 38.

[0628]

[0629] Scheme 9. Synthesis of amide-linked analog 38

[0630] The amide-linked analog 38 was synthesized in a single step by HATU amide coupling of commercial indole-2-carboxylic acid 37 with substituted piperazine 8.

[0631] Scheme 10 illustrates the general synthesis of linker-modified analogs 43.

[0632]

[0633] Scheme 10 Synthesis of linker-modified analog 43

[0634] Amine precursors of type 42 (monocyclic, fused bicyclic, or spirocyclic) are commercially available or can be prepared in a two-step sequence. N-Boc-protected amines 39 react with heteroaryl halides 40 in the presence of palladium(II) acetate, RuPhos, and cesium carbonate to provide N-Boc-protected amine intermediates 41. These N-Boc-protected amine intermediates 41 are then N-deprotected under acidic conditions to afford key amine intermediates 42. A final reductive amination step of amine intermediates 42 with 1H-indole-2-carboxaldehyde 1 affords linker-modified analogs 43 in moderate to good yields.

[0635] Stent modification

[0636] Following the general synthetic route outlined in Scheme 11, compound analogs 47 were prepared that incorporated an additional nitrogen atom at various positions in the indole core.

[0637]

[0638] Scheme 11. Synthesis of compound analogs 47 with additional nitrogen atoms in the indole core

[0639] The synthesis of compound analog 47 begins with the reduction of carboxylic acid or ester 44 to the resulting primary alcohol 45 using lithium aluminum hydride in THF. The resulting primary alcohol intermediate 45 is oxidized to aldehyde 46 by treatment with manganese (IV) oxide in THF. The final scaffold-modified compound analog 47 is obtained by reductive amination of aldehyde intermediate 46 with substituted piperazine 8 using previously described conditions.

[0640] Scheme 12 shows the synthesis of compound analogs 49 with different points of attachment of the heteroarylpiperazinemethyl head group indole.

[0641]

[0642] Scheme 12. Synthesis of compound analogs 49 with different indole attachment points

[0643] All indole attachment point modified compound analogs 49 were prepared by reductive amination of aldehyde intermediate 48 with substituted piperazine 8 using sodium triacetoxyborohydride and acetic acid in DCM.

[0644] Scheme 13 shows the synthesis of scaffold-modified analogs of compound 202 (see Table 1 for structures).

[0645]

[0646] Scheme 13. Synthesis of Scaffold-Modified Analog 54 of Compound 202

[0647] The amine precursor 52 was first constructed via a two-step sequence involving Buchwald amination of commercial chloropyrimidine 50 with N-Boc-piperazine 4 and subsequent N-Boc deprotection of the resulting N-Boc-piperazine intermediate 51 under acidic conditions to afford the hydrochloride salt. The key nucleophilic piperazine intermediate 52, as the hydrochloride salt, was then reacted with several chloromethyl heterocycles 53 in the presence of potassium carbonate in acetonitrile to deliver the target scaffold-modified compound analog 54.

[0648] The synthesis of RHS-modified triazole analog 58 is described in Scheme 14.

[0649]

[0650] Scheme 14. Synthesis of RHS-modified triazole analog 58.

[0651] Triazole piperazine amine intermediates 57 were synthesized in two steps from N-Boc piperazine 4. The first step involved the amination of bromotriazole 55 with N-Boc piperazine 4 using copper(I) iodide / L-proline / tripotassium phosphate reaction conditions in DMSO at 120°C. The second step involved acid-mediated N-Boc deprotection of N-Boc triazole piperazine intermediates 56 to afford amine intermediates 57 generated as the free base. Reductive amination of these amine intermediates 57 with 1H-indole-2-carboxaldehyde 1 using the previously used conditions of sodium triacetoxyborohydride and acetic acid in DCM provided the final triazole piperazine analogs 58.

[0652] Scheme 15 describes the synthesis of 2-((4-(5-((2-methoxyethoxy)methyl)pyrimidin-4-yl)piperazin-1-yl)methyl)-1H-indole 287.

[0653]

[0654] Scheme 15. Synthesis of 2-((4-(5-((2-methoxyethoxy)methyl)pyrimidin-4-yl)piperazin-1-yl)methyl)-1H-indole Compound 287.

[0655] Starting from intermediate 59, the amine intermediate 63 was synthesized in four steps. Oxidative cleavage of the vinyl group of intermediate 59 using aqueous THF containing osmium tetroxide and sodium periodate provided the aldehyde intermediate 60. Reduction of the aldehyde moiety of 60 using sodium borohydride provided the primary alcohol 61, which was O-alkylated using sodium hydride and 1-bromo-2-methoxyethane in DMF to provide the N-Boc piperazine intermediate 62. N-Boc deprotection of the N-Boc piperazine intermediate 62 using dioxane containing hydrogen chloride provided the amine piperazine intermediate 63, which was produced as the free base. Final reductive amination of the amine intermediate 63 with 1H-indole-2-carboxaldehyde 1 using typical conditions of sodium triacetoxyborohydride and acetic acid in DCM provided the final compound 287.

[0656] Scheme 16 shows the synthesis of 5-ethyl-4-(piperazin-1-yl)pyrimidine intermediate 68 in four steps.

[0657]

[0658] Scheme 16. Synthesis of 5-ethyl-4-(piperazin-1-yl)pyrimidine intermediate 68.

[0659] Aromatic substitution of 5-bromo-4-chloropyrimidine 65 with N-Boc piperazine 4 afforded intermediate 66. The 5-bromo substituent was replaced with a vinyl group via Suzuki coupling using 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane to afford vinyl pyrimidine intermediate 59. The vinyl moiety of intermediate 59 was reduced to an ethyl group via palladium-catalyzed hydrogenation to afford ethyl pyrimidine intermediate 67. N-Boc deprotection of N-Boc piperazine intermediate 67 under acidic conditions afforded amine piperazine intermediate 68, which was generated as the free base.

[0660] Scheme 17 outlines the seven-step synthesis of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-((2-methoxyethoxy)methyl)-1H-benzo[d]imidazole compound 289, which utilized the amine intermediate 68 previously synthesized in Scheme 16.

[0661]

[0662] Scheme 17. Synthesis of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-((2-methoxyethoxy)methyl)-1H-benzo[d]imidazole Compound 289.

[0663] The N-SEM benzimidazole-protected aldehyde intermediate 75 was synthesized from commercial 5-bromo-3H-1,3-benzodiazole 69 in a five-step process, including N-SEM protection of the benzimidazole (step 1); introduction of the hydroxymethyl substituent via Stille coupling (step 2); conversion of the benzyl alcohol to the benzyl chloride (step 3); base-mediated O-alkylation with 2-methoxyethane-1-ol (step 4); and formylation of intermediate 74 using n-BuLi and DMF (step 5). Reductive amination of the N-SEM benzimidazole-protected aldehyde intermediate 75 with the amine intermediate 68 using previously described conditions was followed by TBAF-mediated deprotection of the N-SEM group to afford the final target compound 289.

[0664] Scheme 18 outlines the five-step synthesis of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-(2-methoxyethoxy)-1H-benzo[d]imidazole compound 290 using the amine intermediate 68 previously described in Scheme 16.

[0665]

[0666] Scheme 18. Synthesis of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-(2-methoxyethoxy)-1H-benzo[d]imidazole Compound 290.

[0667] Carboxylic acid intermediate 79 was synthesized from amine intermediate 68 in two steps. Step 1 involved alkylation of amine intermediate 68 with ethyl 2-chloroacetate, followed by step 2, hydrolysis of the ethyl ester group of intermediate 78. Intermediate 82, 4-(2-methoxyethoxy)benzene-1,2-diamine, was readily prepared from commercial 4-amino-3-nitrophenol 80 in two steps. Base-mediated O-alkylation of 4-amino-3-nitrophenol 80 with 1-bromo-2-methoxyethane afforded intermediate 81, which was reduced to diamine intermediate 82 via palladium-catalyzed hydrogenation. Finally, amide formation of diamine intermediate 82 and carboxylic acid intermediate 79 was achieved using HATU coupling conditions, followed by acetic acid-mediated cyclization to afford the desired benzimidazole compound 290.

[0668] Scheme 19 outlines the six-step synthesis of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-((2-methoxyethoxy)methyl)-1H-indole compound 291.

[0669]

[0670] Scheme 19. Synthesis of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-((2-methoxyethoxy)methyl)-1H-indole Compound 291.

[0671] Indole ethyl ester intermediate 87 was synthesized in three steps from commercial 1-(chloromethyl)-3-nitrobenzene 84. 2-Methoxyethanol was O-alkylated with 1-(chloromethyl)-3-nitrobenzene 84 using sodium hydride in DMF. The resulting nitrophenyl intermediate 85 was reduced to aniline intermediate 86 using iron-containing acetic acid. Aniline intermediate 86 was then subjected to aerobic cross-dehydrogenative coupling using palladium(II) acetate, acetic acid, and ethyl 2-oxopropionate in DMSO to provide indole ethyl ester intermediate 87. The resulting indole ethyl ester intermediate 87 was hydrolyzed to carboxylic acid 88, which then formed an amide with amine intermediate 68 to provide indoleamide intermediate 89. Finally, reduction of indoleamide intermediate 89 with lithium aluminum hydride enabled the synthesis of the desired indolepiperazinamine compound 291.

[0672] Scheme 20 outlines the three-step synthesis of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-(2-methoxyethoxy)-1H-indole 292.

[0673]

[0674] Scheme 20. Synthesis of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-(2-methoxyethoxy)-1H-indole Compound 292.

[0675] Using HATU coupling conditions, amide intermediate 92 was synthesized from commercial 6-hydroxy-1H-indole-2-carboxylic acid 91 and amine intermediate 68. The phenol moiety of amide intermediate 92 was then O-alkylated with 1-bromo-2-methoxyethane under basic conditions to provide O-alkylated intermediate 93. The final step of the synthesis involved the reduction of indoleamide intermediate 93 with lithium aluminum hydride to provide the desired indolepiperazineamine compound 292.

[0676]

[0677] Scheme 21. Synthesis of Substituted 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-1-yl)methyl)benzo[d]oxazole Analogs

[0678] The first step involves an amide coupling reaction with substituted 2-aminophenol 95 and chloroacetyl chloride to provide substituted phenol intermediate 96. Intermediate 96 undergoes intramolecular cyclization in polyphosphoric acid at elevated temperature to provide 2-chloromethylbenzoxazole intermediate 97. Intermediate 97 undergoes nucleophilic substitution with piperazine intermediate 52 in a mixture of DMF and DIPEA at elevated temperature to provide final compound 98.

[0679]

[0680] Scheme 22. Synthesis of 6-(difluoromethyl)-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-1-yl)methyl)benzo[d]oxazole 304

[0681] The synthesis of vinylbenzoxazole intermediate 99 was accomplished using a palladium-catalyzed Suzuki cross-coupling with potassium vinyl trifluoroborate and 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-1-yl)methyl)benzo[d]oxazole 98. Vinyl intermediate 99 was then oxidized using potassium(VI)osmate dihydrate to provide aldehyde intermediate 100. Intermediate 100 was fluorinated using DAST in DCM to provide the final compound 304.

[0682]

[0683] Scheme 23. Synthesis of 2-(5,6-dimethylpyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane 105

[0684] Initial displacement of 4-chloro-5,6-dimethylpyrimidine 102 with N-Boc-2,5-diazabicyclo[2.2.1]heptane 103 in a mixture of DIPEA and DMF afforded N-Boc 2,5-diazabicyclo[2.2.1]heptane intermediate 104. N-Boc deprotection using 4M HCl in dioxane afforded intermediate 105.

[0685]

[0686] Scheme 24. Synthesis of Functionalized 4-(4-(Benzo[d]oxazol-2-ylmethyl)piperazin-1-yl)pyrimidine-5-carbonitrile Analog 110

[0687] Initial substitution of substituted 4-chloropyrimidine analog 106 and N-Boc protected piperazine 4 in dioxane at elevated temperature yielded functionalized N-Boc piperazine intermediate 107. Acid-mediated deprotection of the N-Boc protecting group was achieved using 4 M HCl in dioxane to provide piperazine intermediate 108. Intermediate 108 was alkylated with substituted 2-(chloromethyl)benzo[d]oxazole 97 in DMF and DIPEA at elevated temperature to provide intermediate 109. Microwave-assisted palladium-catalyzed cyanation of intermediate 109 using tetrakis(triphenylphosphine)palladium and zinc cyanide in DMF at elevated temperature afforded the final target 110.

[0688]

[0689] Scheme 25. Synthesis of Functionalized 4-(4-(Benzo[d]oxazol-2-ylmethyl)piperazin-1-yl)pyrimidine-5-carbonitrile Analog 111

[0690] Halide conversion was performed to introduce the trifluoromethyl group to give final compound 111 by reaction of intermediate 109 with trifluoromethyltrimethylsilane in the presence of copper iodide and potassium fluoride in DMF.

[0691]

[0692] Scheme 26. Synthesis of Functionalized 4-(4-(Benzo[d]oxazol-2-ylmethyl)piperazin-1-yl)pyrimidine-5-carbonitrile Analog 112

[0693] Reduction of the halogenated intermediate 109 was achieved under palladium catalyzed hydrogenation conditions to afford the final compound 112.

[0694]

[0695] Scheme 27. 2-((4-(5-(difluoromethyl)-6-methylpyrimidin-4-yl)piperazin-1-yl)methyl)benzo[d]oxazole 312

[0696] The synthesis of vinyl pyrimidine intermediate 113 was accomplished using a palladium-catalyzed Suzuki cross-coupling using potassium vinyl trifluoroborate and tert-butyl 4-(5-iodo-6-methylpyrimidin-4-yl)piperazine-1-carboxylate 107. Removal of the N-Boc protecting group using HCl in dioxane under acidic conditions afforded intermediate 114 as the hydrochloride salt. Substitution reaction of intermediate 114 with 2-(chloromethyl)benzo[d]oxazole 53 in DMF and DIPEA afforded intermediate 115. Oxidation of vinyl intermediate 115 using potassium(VI)osmate dihydrate afforded aldehyde intermediate 336. Fluorination of intermediate 336 with DAST afforded 2-((4-(5-(difluoromethyl)-6-methylpyrimidin-4-yl)piperazin-1-yl)methyl)benzo[d]oxazole 312

[0697]

[0698] Scheme 28. Synthesis of 1-(1-methyl-1H-1,2,4-triazol-3-yl)piperazine 120

[0699] The synthesis of Cbz-protected intermediate 119 was accomplished by reductive amination of 1-methyl-1H-1,2,4-triazol-3-ylamine 118 with phenylmethyl N,N-bis(2-oxoethyl)carbamate in the presence of sodium cyanoborohydride and acetic acid. The N-Cbz intermediate 119 was deprotected using palladium-catalyzed hydrogenation in methanol to afford compound 120.

[0700]

[0701] Scheme 29. Synthesis of 2-(1-(piperazin-1-yl)cyclopropyl)benzo[d]oxazole 127

[0702] The synthesis of ethyl ester intermediate 123 was accomplished by alkylation of ethyl 1-aminocyclopropanecarboxylate hydrochloride 121 with N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine 122 in THF and triethylamine. Intermediate 123 was hydrolyzed with aqueous THF containing lithium hydroxide to provide carboxylic acid intermediate 124. Intermediate 124 was subjected to HATU-mediated amide coupling conditions with 2-aminophenol to provide aminophenol intermediate 125. Intermediate 125 was intramolecularly cyclized in polyphosphoric acid to provide benzene-protected benzoxazole intermediate 126. Deprotection of intermediate 126 was achieved using palladium-catalyzed hydrogenation in methanol to provide intermediate 127.

[0703]

[0704] Scheme 30. Synthesis of 2-(piperazin-1-ylmethyl)oxazolo[5,4-c]pyridine 131

[0705] The synthesis of amide intermediate 129 was achieved by TBTU-mediated coupling of acid 128 and 4-amino-3-pyridinol in a mixture of DIPEA and DMF. Intermediate 129 underwent intramolecular cyclization using triphenylphosphine, hexachloroethane, and triethylamine in DCM to provide oxazolo[5,4-c]pyridine intermediate 130. Intermediate 130 was deprotected under acidic conditions using 4M HCl in dioxane to provide intermediate 131.

[0706]

[0707] Scheme 31. Synthesis of 2-((4-(5-(2-(3-(but-3-yn-1-yl)-3H-diaziridin-3-yl)ethoxy)pyrimidin-4-yl)piperazin-1-yl)methyl)-1H-indole 337

[0708] The synthesis of amide intermediate 132 was accomplished by a HATU-mediated coupling reaction between 1H-indole-2-carboxylic acid 37 and an analog of intermediate 108. Amide intermediate 132 was reduced to the corresponding amine using lithium aluminum hydride in THF to provide intermediate 133. Demethylation of intermediate 133 was achieved using boron tribromide in DCM at elevated temperature to provide intermediate 134. Base-mediated alkylation of intermediate 134 with 3-(but-3-yn-1-yl)-3-(2-iodoethyl)-3H-diaziridine 135 in DMF provided final compound 337.

[0709]

[0710] Scheme 32. Synthesis of 6-(2-(3-(but-3-yn-1-yl)-3H-diaziridin-3-yl)ethoxy)-2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-1H-indole 338

[0711] The synthesis of alcohol intermediate 138 was completed by DIBAL-H reduction at -78°C to give alcohol intermediate 138. Intermediate 138 was chlorinated using lithium chloride, methanesulfonyl chloride, and triethylamine in THF to give tert-butyl 2-(chloromethyl)-6-methoxy-1H-indole-1-carboxylate 139. Intermediate 139 was coupled with piperazine 68 in the presence of potassium carbonate and potassium iodide in DMF at elevated temperature to give intermediate 140. Intermediate 140 was deprotected in parallel with boron tribromide in DCM at elevated temperature to give intermediate 141. Base-mediated alkylation of intermediate 141 with 3-(but-3-yn-1-yl)-3-(2-iodoethyl)-3H-diaziridine 135 in DMF gave final compound 338.

[0712] Detailed Synthesis of Intermediates of the Compounds of the Invention

[0713] Synthesis of tert-Butyl 4-((6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)piperazine-1-carboxylate

[0714]

[0715] 2-(Chloromethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (1 g, 4.26 mmol) was dissolved in anhydrous DMF (10 mL), tert-butyl piperazine-1-carboxylate (873 mg, 4.69 mmol) was added, followed by DIPEA (1.5 mL, 8.52 mmol). The reaction mixture was stirred at 80 ° C for 18 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried (MgSO ), filtered and evaporated. The residue was purified by column chromatography on silica gel (DCM containing 0-5% MeOH) to give tert-butyl 4-((6-(trifluoromethyl)-1H benzo[d]imidazol-2-yl)methyl)piperazine-1-carboxylate as an orange solid.

[0716] Yield 1.6 g (97%). 1 H NMR(400MHz,DMSO)δ12.78(br s,1H),7.87(s,1H),7.76-7.70(m,1H),7.48(d,J=8.2Hz,1H),3.81(s,2H),3.38(m,4H),2.44(dd,J=5.0,5.0Hz,4H),1.39(s,9H).

[0717] Synthesis of 2-(piperazin-1-ylmethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole

[0718]

[0719] Tert-Butyl 4-((6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)piperazine-1-carboxylate (1.6 g, 4.16 mmol) was treated with a solution of HCl in dioxane (4 M, 4.3 mL, 17.2 mmol) at room temperature for 18 hours. The solvent was removed in vacuo to give 2-(piperazin-1-ylmethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole dihydrochloride as a light brown solid. This material (980 mg, 2.74 mmol) was dissolved in MeOH (10 mL), loaded onto an SCX-2 cartridge (20 g, 0.6 mmol / g loading), washed with MeOH, and eluted with ammonia / MeOH (2 M) to give 2-(piperazin-1-ylmethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole as a light brown solid.

[0720] Yield 475 mg (61%). 1 H NMR (400MHz, DMSO) δ7.90 (m, 1H), 7.73 (d, J = 7.1Hz, 1H), 7.52 (d, J = 8.3Hz, 1H), 3.78 (s, 2H), 2.78 (dd, J = 4.5, 4.5Hz, 4H), 2.47-2.40 (m, 4H).

[0721] Synthesis of tert-Butyl 4-((6-chloro-1H-benzo[d]imidazol-2-yl)methyl)piperazine-1-carboxylate

[0722]

[0723] 6- chloro-2- (chloromethyl) -1H- benzo [d] imidazole (300mg, 1.49mmol) and tert-butyl piperazine-1-carboxylate (306mg, 1.64mmol) were dissolved in anhydrous acetonitrile (4mL), potassium carbonate (1.03g, 7.46mmol) was added, and the reactants were stirred at room temperature for 18 hours. The reaction mixture was distributed between ethyl acetate (50mL) and brine (30mL), and the aqueous layer was extracted with ethyl acetate (2×30mL). The combined organic extracts were dried (MgSO ), filtered and evaporated to give tert-butyl 4- ((6- chloro- 1H- benzo [d] imidazole-2-yl) methyl) piperazine-1-carboxylate as an orange solid.

[0724] Yield 525 mg (quantitative). 1H NMR(400MHz,DMSO)δ12.52(br s,1H),7.59(m,1H),7.49(m,1H),7.21-7.16(m,1H),3.75(s,2H),3.23(dd,J= 5.0, 5.0Hz, 2H), 2.64-2.60 (m, 2H), 2.43 (dd, J = 5.0, 5.0Hz, 4H), 1.40 (s, 9H).

[0725] Synthesis of 6-chloro-2-(piperazin-1-ylmethyl)-1H-benzo[d]imidazole

[0726]

[0727] The compound 6-chloro-2-(piperazin-1-ylmethyl)-1H-benzo[d]imidazole was prepared according to a procedure similar to that described for the synthesis of 2-(piperazin-1-ylmethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole and isolated as a beige solid.

[0728] Yield 355 mg (95%). 1 H NMR (400MHz, DMSO) δ7.56 (m, 2H), 7.21 (d, J = 8.3Hz, 1H), 3.72 (s, 2H), 2.76 (m, 4H), 2.46-2.39 (m, 4H).

[0729] Synthesis of tert-Butyl 4-((1H-indol-2-yl)methyl)piperazine-1-carboxylate

[0730]

[0731] To anhydrous DCM (5mL) solution containing 1H-indole-2-carboxaldehyde (250mg, 1.72mmol) and piperazine-1-carboxylic acid tert-butyl ester (353mg, 1.89mmol) was added sodium triacetoxyborohydride (913mg, 4.31mmol) and acetic acid (10 μL, 0.17mmol) in sequence, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (30mL) and distributed with saturated NaHCO solution (30mL). The organic phase was dried (MgSO ), filtered and evaporated. The residue was purified by column chromatography (cyclohexane containing 0-50% ethyl acetate) on silica gel to obtain tert-butyl 4-((1H-indol-2-yl)methyl)piperazine-1-carboxylate as a light brown solid.

[0732] Yield 456 mg (84%). 1H NMR (400 MHz, DMSO) δ 11.00 (br s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.03 (dd, J = 7.0, 7.0 Hz, 1H), 6.95 (dd, J = 7.2, 7.2 Hz, 1H), 6.28 (d, J = 1.4 Hz, 1H), 3.63 (s, 2H), 2.37 (dd, J = 5.0, 5.0 Hz, 4H), 1.40 (s, 9H). Four protons were obscured by the solvent / water peak.

[0733] Synthesis of 2-(Piperazin-1-ylmethyl)-1H-indole

[0734]

[0735] The compound 2-(piperazin-1-ylmethyl)-1H-indole was prepared according to a procedure similar to that described for the synthesis of 2-(piperazin-1-ylmethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole and isolated as a brown solid.

[0736] Yield 260 mg (60%). 1 H NMR(400MHz,DMSO)δ11.02-10.95(br s,1H),7.45(d,J=7.8Hz,1H),7.33-7.27(m,1H),7.05-7.00(m,1H),6.96-6.89(m,1H ), 6.27 (d, J = 1.3Hz, 1H), 3.58 (s, 2H), 2.75 (dd, J = 4.8, 4.8Hz, 4H), 2.40-2.33 (m, 4H).

[0737] Synthesis of tert-Butyl 4-((5-chloro-1H-indol-2-yl)methyl)piperazine-1-carboxylate

[0738]

[0739] The compound tert-butyl 4-((5-chloro-1H-indol-2-yl)methyl)piperazine-1-carboxylate was prepared from 5-chloro-1H-indole-2-carbaldehyde according to a procedure similar to that described for the synthesis of tert-butyl 4-((1H-indol-2-yl)-methyl)piperazine-1-carboxylate and isolated as a yellow solid.

[0740] Yield 781 mg (quantitative). 1H NMR (400MHz, DMSO) δ11.22(s,1H),7.50(d,J=2.1Hz,1H),7.33(d,J=8.7Hz,1H),7.03(dd,J=2.1,8. 5Hz, 1H), 6.29 (d, J = 1.3Hz, 1H), 3.63 (s, 2H), 3.34 (m, 4H), 2.36 (dd, J = 5.0, 5.0Hz, 4H), 1.40 (s, 9H).

[0741] Synthesis of 5-chloro-2-(piperazin-1-ylmethyl)-1H-indole

[0742]

[0743] The compound 5-chloro-2-(piperazin-1-ylmethyl)-1H-indole was prepared according to a procedure similar to that described for the synthesis of 2-(piperazin-1-ylmethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole and isolated as a brown solid.

[0744] Yield 488 mg (87%). 1 H NMR(400MHz,DMSO)δ11.21(br s,1H),7.52(d,J=1.8Hz,1H),7.36(d,J=8.6Hz,1H),7.06(dd,J=2.0,8.6Hz,1H), 6.31(s,1H),3.60(s,2H),2.74(dd,J=4.5,4.5Hz,4H),2.41-2.33(m,4H),2.19(br s,1H).

[0745] Synthesis of 5-bromo-2-[[4-(4-pyridyl)piperazin-1-yl]methyl]-1H-indole (Compound 215)

[0746]

[0747] To anhydrous DCM (25mL) solution containing 5-bromo-1H-indole-2-carboxaldehyde (1g, 4.46mmol) and 1-(4-pyridyl)piperazine (801mg, 4.91mmol) was added sodium triacetoxyborohydride (2.36g, 11.16mmol) and acetic acid (26 μL, 0.446mmol) sequentially, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (30mL) and washed with saturated NaHCO aqueous solution (30mL) and salt solution (10mL). The organic phase was dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (containing 0-10% of a methanol solution containing 10% ammonia / methanol) to obtain 5-bromo-2-[[4-(4-pyridyl)piperazine-1-yl]methyl]-1H-indole as a pale solid.

[0748] Yield: 743 mg (45%). 1H NMR (400 MHz, DMSO) δ 11.28 (s, 1H), 8.16 (d, J = 6.5 Hz, 2H), 7.65 (d, J = 1.9 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.15 (dd, J = 1.9, 8.6 Hz, 1H), 6.81 (d, J = 6.7 Hz, 2H), 6.32 (d, J = 1.3 Hz, 1H), 3.68 (s, 2H). Eight protons are obscured by water and DMSO peaks. m / z: [ESI + ]371(M+H) + ,(C 18 H 19 BrN4).

[0749] Synthesis of tert-Butyl 4-((1H-indol-2-yl)methyl)piperazine-1-carboxylate

[0750]

[0751] To anhydrous DCM (25mL) solution containing 1H-indole-2-carboxaldehyde (1.0g, 6.89mmol) and piperazine-1-tert-butyl formate (1.41g, 7.58mmol) was added sodium triacetoxyborohydride (3.65g, 17.2mmol) and acetic acid (39 μL, 0.69mmol) sequentially, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (30mL) and washed with saturated NaHCO aqueous solution (30mL) and salt solution (10mL). The organic phase was dried (NaSO), filtered and evaporated to obtain tert-butyl 4-((1H-indol-2-yl) methyl) piperazine-1-carboxylate as an off-white solid.

[0752] Yield 2.03 g (94%).1 H NMR (400 MHz, DMSO) δ 11.00 (br s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.03 (dd, J = 7.0, 7.0 Hz, 1H), 6.95 (dd, J = 7.2, 7.2 Hz, 1H), 6.28 (d, J = 1.4 Hz, 1H), 3.63 (s, 2H), 2.37 (dd, J = 5.0, 5.0 Hz, 4H), 1.40 (s, 9H). Four protons were obscured by the solvent / water peak.

[0753] Synthesis of 2-(Piperazin-1-ylmethyl)-1H-indole

[0754]

[0755] To the dioxane solution (4mL) containing 4-((1H-indol-2-yl) methyl) piperazine-1-tert-butyl formate (2.03g, 6.45mmol), dioxane (4M, 10mL, 40mmol) solution containing HCl is added, and the reaction mixture is stirred at room temperature for 2 hours.Add other dioxane (4M, 10mL, 40mmol) containing HCl, and reactant is stirred at room temperature for 18 hours.Remove solvent in a vacuum to obtain residue, the residue is dissolved in MeOH (10mL), load SCX-2 boxes (20g, 0.6mmol / g load), wash with MeOH and elute with ammonia / MeOH (1M) to obtain 2-(piperazine-1-ylmethyl)-1H-indoles as light brown solid.

[0756] Yield 1.35 g (97%). 1 H NMR (400 MHz, DMSO) δ 10.98 (br s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.02 (dd, J = 7.1, 7.1 Hz, 1H), 6.92 (dd, J = 7.1, 7.1 Hz, 1H), 6.27 (d, J = 1.3 Hz, 1H), 3.58 (s, 2H), 2.75 (dd, J = 4.8, 4.8 Hz, 4H), 2.40-2.33 (m, 4H). The NH protons were obscured by the residual water peak.

[0757] Synthesis of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

[0758]

[0759] At 0 ° C, sodium hydride (60%, 30 mg, 0.761 mmol) was added to a solution of anhydrous DMF (2 mL) containing 4-bromo-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.508 mmol), and the mixture was stirred at this temperature for 10 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (0.11 mL, 0.609 mmol) was then added, and the reactants were warmed to room temperature and stirred for 2 hours. The reaction mixture was carefully quenched by dropwise addition of water (0.1 mL) and partitioned between ethyl acetate (20 mL) and water (20 mL). The layers were separated, and the organic phase was washed with water (10 mL), water / brine 1: 1 (10 mL), and brine (10 mL). The organic layer was dried (Na2SO4), filtered and evaporated, and the residue was purified by column chromatography on silica gel (0-20% ethyl acetate in cyclohexane) to give 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine as a colorless oil.

[0760] Yield 111 mg (69%). 1 H NMR (400MHz, DMSO) δ8.27(d,J=5.1Hz,1H),7.90(d,J=3.6Hz,1H),7.54(d,J=5.1Hz,1H) ,6.63(d,J=3.6Hz,1H),5.74(s,2H),3.64-3.59(m,2H),0.94-0.90(m,2H),0.00(s,9H).

[0761] Synthesis of 4-(4-((1H-indol-2-yl)methyl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

[0762]

[0763] To a degassed suspension of 2-(piperazin-1-ylmethyl)-1H-indole (70 mg, 0.325 mmol), 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (117 mg, 0.358 mmol) and cesium carbonate (212 mg, 0.65 mmol) in anhydrous dioxane (3 mL) was added palladium(II) acetate (7.3 mg, 0.033 mmol) and RuPhos (30 mg, 0.065 mmol). The mixture was sparged with nitrogen for 10 minutes and heated at 95°C in a sealed tube for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (2×15 mL), and the combined organic extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography on silica gel (0-8% methanol in DCM) to give 4-(4-((1H-indol-2-yl)methyl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine as a brown glass.

[0764] Yield 144 mg (96%). 1 H NMR (400MHz, DMSO) δ11.14(s,1H),8.09(d,J=5.5Hz,1H),7.55(d,J=8.0Hz,1H),7.49(d, J=3.8Hz,1H),7.43(d,J=8.0Hz,1H),7.12(dd,J=7.0,7.0Hz,1H),7.04(dd,J=7.2,7.2Hz, 1H),6.65(d,J=3.6Hz,1H),6.58(d,J=5.6Hz,1H),6.41(d,J=1.3Hz,1H),5.64(s,2H),3.8 0(s,2H),3.60-3.50(m,6H),2.72(dd,J=4.6,4.6Hz,4H),0.93-0.88(m,2H),0.00(s,9H).

[0765] Synthesis of 6-bromo-2-[[4-(4-pyridyl)piperazin-1-yl]methyl]-1H-indole (Compound 224)

[0766]

[0767] The compound 6-bromo-2-[[4-(4-pyridinyl)piperazin-1-yl]methyl]-1H-indole was prepared from 5-bromo-1H-indole-2-carbaldehyde according to a procedure similar to that described for the synthesis of 5-bromo-2-[[4-(4-pyridinyl)pyrazin-1-yl]methyl]-1H-indole and isolated as a brown solid.

[0768] Yield 644 mg (39%). 1 H NMR (400MHz, DMSO) δ11.20(s,1H),8.20(br s,2H),7.51(d,J=1.3Hz,1H),7.43(d,J=8.4Hz,1H),7.09(dd,J=1.9,8.4Hz,1H),6.87(br s, 2H), 6.35 (d, J = 1.3Hz, 1H), 3.67 (s, 2H), 3.35-3.29 (m, 4H), 2.55-2.52 (m, 4H). m / z:[ESI + ]371(M+H) + ,(C 18 H 19 BrN4),R t =2.41(98.2%).

[0769] Synthesis of (5-(Trifluoromethyl)-1H-indol-2-yl)methanol

[0770]

[0771] At 0 ° C, 1M THF (3.8 mL, 3.84 mmol) solution containing lithium aluminum hydride was added dropwise to a THF solution (5 mL) containing 5- (trifluoromethyl) -1H- indole -2- carboxylic acid (800 mg, 3.49 mmol), and the mixture was stirred at room temperature for 2 hours, then heated to 65 ° C and stirred for 2 hours. After cooling to 0 ° C, the mixture was quenched with a saturated Rochelle salt solution (about 20 mL) and extracted with ethyl acetate. The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to give a crude (5- (trifluoromethyl) -1H- indole -2- bases) methanol as a yellow solid. The material was used for the next step without further purification.

[0772] Yield 661 mg (88%). m / z: [ESI + ]214(MH) + .

[0773] Synthesis of 5-(Trifluoromethyl)-1H-indole-2-carbaldehyde

[0774]

[0775] To a solution of (5-(trifluoromethyl)-1H-indol-2-yl)methanol (751 mg, 3.49 mmol) in THF (25 mL) was added MnO (3034 mg, 34.9 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was then diluted with ethyl acetate and filtered through a pad of celite to give 5-(trifluoromethyl)-1H-indole-2-carbaldehyde as a yellow solid.

[0776] Yield 541 mg (73%, 2 steps). 1 H NMR (400MHz, DMSO) δ12.40 (s, 1H), 9.95 (s, 1H), 8.23 ​​(s, 1H), 7.66 (d, J = 8.9Hz, 1H), 7.62 (dd, J = 1.5, 8.9Hz, 1H), 7.58 (d, J = 1.5Hz, 1H).

[0777] Synthesis of (6-methoxy-1H-indol-2-yl)methanol

[0778]

[0779] The compound (6-methoxy-1H-indol-2-yl)methanol was prepared from 6-methoxy-1H-indole-2-carboxylic acid according to a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indol-2-yl)methanol and isolated as an off-white solid. The intermediate was used in the next step without further purification.

[0780] Yield 1.13g. m / z: [ESI + ]178(M+H) + .

[0781] Synthesis of 6-methoxy-1H-indole-2-carbaldehyde

[0782]

[0783] Compound 6-methoxy-1H-indole-2-carbaldehyde was prepared from (6-methoxy-1H-indol-2-yl)methanol according to a procedure similar to that described for the synthesis of (5-trifluoromethyl)-1H-indole-2-carbaldehyde and isolated as a brown solid.

[0784] Yield 369 mg (51%, 2 steps). 1H NMR (400MHz, DMSO) δ11.79(s,1H),9.72(s,1H),7.63(d,J=8.8Hz,1H),7.33(dd,J =0.8, 2.1Hz, 1H), 6.86 (d, J = 2.3Hz, 1H), 6.78 (dd, J = 2.3, 8.8Hz, 1H), 3.82 (s, 3H).

[0785] Synthesis of (6-(Trifluoromethyl)-1H-indol-2-yl)methanol

[0786]

[0787] The compound (6-(trifluoromethyl)-1H-indol-2-yl)methanol was prepared from 6-(trifluoromethyl)-1H-indole-2-carboxylic acid according to a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indol-2-yl)methanol and isolated as a brown oil.

[0788] Yield 391 mg (83%). 1 H NMR (400MHz, DMSO) δ 11.47 (s, 1H), 7.66 (d, J = 7.4Hz, 2H), 7.25 (d, J = 8.4Hz, 1H), 6.42 (d, J = 1.1Hz, 1H), 5.43 (t, J = 5.5Hz, 1H), 4.67 (d, J = 5.5Hz, 2H).

[0789] Synthesis of 6-(Trifluoromethyl)-1H-indole-2-carbaldehyde

[0790]

[0791] Compound 6-(trifluoromethyl)-1H-indole-2-carbaldehyde was prepared from (6-(trifluoromethyl)-1H-indole-2-yl)methanol according to a procedure similar to that described for the synthesis of 5-(trifluoromethyl)-1H-indole-2-carbaldehyde and isolated as a brown solid. The intermediate was used in the next step without further purification.

[0792] Yield 244 mg (63%). m / z: [ESI + ]212(MH) + .

[0793] Synthesis of (5-nitro-1H-indol-2-yl)methanol

[0794]

[0795] At -60 ° C, to a solution of ethyl 5-nitro-1H-indole-2-carboxylate (1300 mg, 5.5 mmol) in THF (44 mL) was added dropwise a 1 M solution of diisobutylaluminum hydride in DCM (17 mL, 16.6 mmol), and the mixture was stirred at -60 ° C for 4 hours, then at -20 ° C for 1 hour. The mixture was quenched with saturated Rochelle salt solution (about 20 mL) at 0 ° C and extracted with ethyl acetate (3 × 50 mL). The combined organics were washed with brine (20 mL), dried (Na SO ), filtered and concentrated to give (5-nitro-1H-indol-2-yl) methanol as a brown solid.

[0796] Yield 1068 mg (quantitative). 1 H NMR (400MHz, DMSO) δ11.82(s,1H),8.50(d,J=2.3Hz,1H),7.97(dd,J=2.3,9.0Hz,1H ), 7.49 (d, J = 9.0Hz, 1H), 6.58 (s, 1H), 5.46 (t, J = 5.3Hz, 1H), 4.66 (d, J = 5.3Hz, 2H).

[0797] Synthesis of 5-Nitro-1H-Indole-2-Carbaldehyde

[0798]

[0799] The compound 5-nitro-1H-indole-2-carbaldehyde was prepared from (5-nitro-1H-indol-2-yl)methanol according to a procedure similar to that described for the synthesis of 5-trifluoromethyl-1H-indole-2-carbaldehyde and isolated as a brown solid.

[0800] Yield 893 mg (84%). 1 H NMR (400MHz, DMSO) δ12.68 (s, 1H), 9.98 (s, 1H), 8.85 (s, 1H), 8.20 (d, J = 9.0Hz, 1H), 7.70 (s, 1H), 7.63 (d, J = 9.0Hz, 1H).

[0801] Synthesis of 5-nitro-2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole

[0802]

[0803] The compound 5-nitro-2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole was prepared from 5-nitro-1H-indole-2-carbaldehyde according to a procedure similar to that described for the synthesis of 5-bromo-2-[[4-(4-pyridinyl)piperazol-1-yl]methyl]-1H-indole and isolated as a brown solid.

[0804] Yield 1053 mg (67%). 1 H NMR (400MHz, DMSO) δ11.90(s,1H),8.56(d,J=2.3Hz,1H),8.21(d,J=6.5Hz,2H),8.03(dd,J=2.3,9.0Hz,1H), 7.55(d,J=9.0Hz,1H),6.86(d,J=6.5Hz,2H),6.69(s,1H),3.79(s,2H),3.43-3.39(m,4H),2.63-2.58(m,4H).

[0805] Synthesis of (7-chloro-1H-indol-2-yl)methanol

[0806]

[0807] The compound (7-chloro-1H-indol-2-yl)methanol was prepared from 7-chloro-1H-indole-2-carboxylic acid according to a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indol-2-yl)methanol, but the compound was further purified by column chromatography on silica gel (0-100% ethyl acetate in cyclohexane) to give (7-chloro-1H-indol-2-yl)methanol as a brown oil.

[0808] Yield 264 mg (57%). 1 H NMR (400MHz, DMSO) δ11.24(s,1H),7.46(d,J=7.9Hz,1H),7.12(d,J=7.9Hz,1H),6.97(dd ,J=7.7,7.7Hz,1H),6.42(d,J=1.8Hz,1H),5.19(t,J=5.8Hz,1H),4.63(d,J=5.8Hz,2H).

[0809] Synthesis of 7-chloro-1H-indole-2-carbaldehyde

[0810]

[0811] Compound 7-chloro-1H-indole-2-carbaldehyde was prepared from (7-chloro-1H-indol-2-yl)methanol according to a procedure similar to that described for the synthesis of 5-(trifluoroethyl)-1H-indole-2-carbaldehyde and isolated as a brown solid.

[0812] Yield 222 mg (86%). 1 H NMR (400MHz, DMSO) δ12.34(s,1H),9.94(s,1H),7.76(d,J=7.8Hz,1H),7.50(d,J=2.0Hz,1H),7.45(d,J=7.8Hz,1H),7.15(dd,J=7.8,7.8Hz,1H).

[0813] Synthesis of methyl 2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole-5-carboxylate

[0814]

[0815] Compound 2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole-5-carboxylic acid methyl ester was prepared from 2-formyl-1H-indole-5-carboxylic acid methyl ester and 1-(pyridin-4-yl)piperazine according to a procedure similar to that described for the synthesis of 5-bromo-2-[[4-(4-pyridinyl)piperazin-1-yl]methyl]-1H-indole, but the compound was purified by SCX-2 ion exchange chromatography (2 g, 0.6 mmol / g loading, washing with MeOH and eluting with 1 N ammonia in MeOH) and the compound was isolated as a brown solid.

[0816] Yield 342 mg (79%). 1 H NMR (400MHz, DMSO) δ11.49(s,1H),8.20(d,J=1.1Hz,1H),8.16(d,J=6.5Hz,2H),7.70(dd,J=1.6,8.5Hz,1H),7.42(d,J=8.5 Hz,1H),6.82(dd,J=1.6,6.5Hz,2H),6.49(d,J=1.1Hz,1H),3.85(s,3H),3.71(s,2H),3.36-3.32(m,4H),2.58-2.52(m,4H).

[0817] Synthesis of 2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole-5-carboxylic acid

[0818]

[0819] To a suspension of methyl 2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole-5-carboxylate (100 mg, 0.28 mmol) in THF (3 mL) was added a solution of NaOH (11 mg, 0.28 mmol) in water (1 mL), and the reaction was stirred at room temperature for 2 hours and then at 65° C. for 4 days. The reaction mixture was concentrated, redissolved in MeOH / water / DMSO, and purified by SAX-2 ion exchange chromatography (1 g, 0.6 mmol / g loading, washing with MeOH and eluting with 50% AcOH / MeOH), followed by SCX-2 ion exchange chromatography (2 g, 0.6 mol / g loading, washing with MeOH and eluting with 1N ammonia / MeOH) to give 2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole-5-carboxylic acid as a brown solid.

[0820] Yield 34 mg (33%). 1 H NMR (400 MHz, DMSO) δ 11.42 (s, 1H), 8.17-8.15 (m, 3H), 7.69 (dd, J = 1.6, 8.5 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 6.82 (d, J = 6.7 Hz, 2H), 6.47 (d, J = 1.1 Hz, 1H), 3.70 (s, 2H), 3.39-3.31 (m, 4H), 2.58-2.53 (m, 4H). The acidic OH proton is hidden.

[0821] Synthesis of 2-(Hydroxymethyl)-1H-indole-5-carbonitrile

[0822]

[0823] The compound 2-(hydroxymethyl)-1H-indole-5-carbonitrile was prepared from 5-cyano-1H-indole-2-carboxylic acid according to a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indol-2-yl)methanol and isolated as a yellow solid. The intermediate was used in the next step without further purification.

[0824] Yield: 727 mg. m / z: [ESI + ]171(MH) + .

[0825] Synthesis of 2-Formyl-1H-indole-5-carbonitrile

[0826]

[0827] Compound 6-methoxy-1H-indole-2-carbaldehyde was prepared from (6-methoxy-1H-indol-2-yl)methanol according to a procedure similar to that described for the synthesis of (5-trifluoromethyl)-1H-indole-2-carbaldehyde and isolated as a yellow solid.

[0828] Yield 600 mg (76% in 2 steps). 1 H NMR (400MHz, DMSO) δ12.50(s,1H),9.95(s,1H),8.39(dd,J=0.8,1.5Hz,1H),7.67(dd,J=1.5,8.6Hz,1H),7.62(d,J=8.6Hz,1H),7.56(s,1H).

[0829] Synthesis of 5-(2-methoxyethoxy)-1H-indole-2-carboxylic acid ethyl ester (I) and 5-(2-methoxyethoxy)-1-(2-methoxyethyl)-1H-indole-2-carboxylic acid methyl ester (II)

[0830]

[0831] To anhydrous DMF (2 mL) solution of ethyl 5-hydroxy-1H-indole-2-carboxylate (200 mg, 0.98 mmol) and cesium carbonate (953 mg, 2.92 mmol) was added 1-bromo-2-methoxyethane (110 μL, 1.17 mmol) at room temperature, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was distributed between ethyl acetate (20 mL) and water (10 mL). The layers were separated and the organic phase was washed with water (10 mL), water / brine 1: 1 (10 mL) and brine (10 mL). The organic layer was dried (Na2SO4), filtered and evaporated, and the residue was purified by column chromatography on silica gel (0-100% ethyl acetate in cyclohexane) to give ethyl 5-(2-methoxyethoxy)-1H-indole-2-carboxylate and ethyl 5-(2-methoxyethoxy)-1-(2-methoxyethyl)-1H-indole-2-carboxylate as white solids.

[0832] Yield 141 mg. I: m / z: [ESI + ]264(M+H) + (Purity 68%). II: m / z: [ESI + ]322(M+H) + (Purity 30%).

[0833] Synthesis of (5-(2-methoxyethoxy)-1H-indol-2-yl)methanol (I) and (5-(2-methoxymethoxy)-1-(2-methoxyethyl)-1H-indol-2-yl)methanol (II)

[0834]

[0835] The compounds (5-(2-methoxyethoxy)-1H-indol-2-yl)methanol and (5-(2-methoxyethoxy)-1-(2-methoxyethyl)-1H-indol-2-yl)methanol were prepared from ethyl 5-(2-methoxyethoxy)-1H-indole-2-carboxylate and ethyl 5-(2-methoxyethoxy)-1-(2-methoxyethyl)-1H-indole-2-carboxylate according to a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indol-2-yl)methanol and isolated as brown oils. The mixture was used in the next step without further purification.

[0836] Yield 120 mg. I: m / z: [ESI + ]222(M+H) + (Purity 61%). II: m / z: [ESI + ]280(M+H) + (Purity 34%).

[0837] Synthesis of 5-(2-methoxyethoxy)-1H-indole-2-carbaldehyde (I) and 5-(2-methoxyethoxy)-1-(2-methoxyethyl)-1H-indole-2-carbaldehyde (II)

[0838]

[0839] Compounds 5-(2-methoxyethoxy)-1H-indole-2-carbaldehyde and 5-(2-methoxyethoxy)-1-(2-methoxyethyl)-1H-indole-2-carbaldehyde were prepared from (5-(2-methoxyethoxy)-1H-indole-2-yl)methanol and (5-(2-methoxyethoxy)-1-(2-methoxyethyl)-1H-indole-2-yl)methanol according to procedures similar to those described for the synthesis of 5-(trifluoromethyl)-1H-indole-2-carbaldehyde, and the isolated compounds were obtained as brown solids. The mixture was used in the next step without further purification.

[0840] Yield 120 mg. I: m / z: [ESI - ]218(MH) - (Purity 66%). II: m / z: [ESI + ]278(M+H) + (Purity 29%).

[0841] Synthesis of 1-(diethoxymethyl)-1H-indole-3-carbonitrile

[0842]

[0843] A suspension of 1H-indole-3-carbonitrile (1000 mg, 7.03 mmol) in triethyl orthoformate (11.7 mL, 70.34 mmol) was heated to 160° C. in a pressure tube and stirred for 3 days. The reaction mixture was evaporated to dryness, and the residue was purified by column chromatography on silica gel (0-20% ethyl acetate in isohexane) to give 1-(diethoxymethyl)-1H-indole-3-carbonitrile as a colorless oil.

[0844] Yield 1806 mg (quantitative). 1 H NMR (400MHz, DMSO) δ8.41(s,1H),7.80(d,J=7.7Hz,1H),7.68(d,J=7.7Hz,1H),7.38(dd,J=7.5,7 .5Hz,1H),7.33(dd,J=7.5,7.5Hz,1H),6.59(s,1H),3.62(q,J=7.0Hz,4H),1.17(t,J=7.0Hz,6H).

[0845] Synthesis of 1-(diethoxymethyl)-2-formyl-1H-indole-3-carbonitrile

[0846]

[0847] At -78 DEG C, to the THF solution (6mL) containing 1- (diethoxymethyl) -1H- indole -3- carbonitrile (200mg, 0.82mmol) add 1.7M pentane (0.53mL, 0.90mmol) solution containing tert-butyl lithium, and the mixture is warmed to -10 DEG C and stirred for 30 minutes.Then the mixture is cooled to -78 DEG C, DMF (0.57mL, 7.32mmol) is added, and the mixture is warmed to -10 DEG C and stirred for 2 hours.The reaction mixture is quenched with saturated NaHCO at 0 DEG C Aqueous solution (10mL) is quenched and extracted with EtO (2 × 10mL).The combined organic extracts are dried (NaSO), filtered and evaporated to obtain 1- (diethoxymethyl) -2- formyl -1H- indole -3- carbonitrile as a yellow oil.The intermediate is used for the next step without further purification.

[0848] Yield 185 mg (crude).

[0849] Synthesis of 1-(diethoxymethyl)-2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole-3-carbonitrile

[0850]

[0851] The compound 1-(diethoxymethyl)-2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole-3-carbonitrile was prepared from 1-(diethoxymethyl)-2-formyl-1H-indole-3-carbonitrile according to a procedure similar to that described for the synthesis of 5-bromo-2-[[4-(4-pyridinyl)piperazin-1-yl]methyl]-1H-indole and isolated as a yellow oil. It was carried on to the next step without further purification.

[0852] Yield 180 mg (crude). m / z: [ESI + ]420(M+H) + .

[0853] Synthesis of tert-Butyl 6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0854]

[0855] To a degassed suspension of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (106 mg, 0.54 mmol), 4-iodopyridine (100 mg, 0.49 mmol) and cesium carbonate (318 mg, 0.98 mmol) in anhydrous dioxane (4 mL) was added palladium (II) acetate (11 mg, 0.05 mmol) and RuPhos (46 mg, 0.10 mmol). The mixture was sparged with nitrogen for 10 minutes and heated at 95 ° C in a sealed tube for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (2×15 mL), and the combined organic extracts were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (0-10% 1 N ammonia in methanol in DCM) to give tert-butyl 6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a brown gum.

[0856] Yield 195 mg (97%). 1 H NMR (400MHz, DMSO) 8 8.13 (dd, J = 1.6, 4.7 Hz, 2H), 6.34 (dd, J = 1.6, 4.7 Hz, 2H), 4.04 (s, 8H), 1.39 (s, 9H).

[0857] Synthesis of 2-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane

[0858]

[0859] To anhydrous DCM (3mL) solution of tert-butyl 6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-formate (195mg, 0.71mmol) was added TFA (0.5mL, 6.53mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by SCX-2 ion exchange chromatography (2g, 0.6mmol / g loading, washed with MeOH and eluted with 1N ammonia / MeOH), and the isolated compound was a pale white solid.

[0860] Yield 67 mg (54%). 1 H NMR (400 MHz, DMSO) δ 8.11 (dd, J = 1.6, 4.7 Hz, 2H), 6.33 (dd, J = 1.6, 4.7 Hz, 2H), 3.97 (s, 4H), 3.61 (s, 4H). The NH protons are obscured by the residual water peak.

[0861] Synthesis of tert-Butyl 7-(pyridin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

[0862]

[0863] The compound tert-butyl 7-(pyridin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate was prepared from tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate and 4-iodopyridine according to a procedure similar to that described for the synthesis of tert-butyl 6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and isolated as a yellow gum.

[0864] Yield 235 mg (79%). 1 H NMR (400MHz, DMSO) δ8.09 (dd, J=1.6, 4.9Hz, 2H), 6.45 (dd, J=1.6, 4.9Hz, 2H), 3.41-3.31 (m,4H),3.27-3.22(m,4H),1.99-1.94(m,2H),1.89-1.83(m,2H),1.41(d,J=5.6Hz,9H).

[0865] Synthesis of 2-(pyridin-4-yl)-2,7-diazaspiro[4.4]nonane

[0866]

[0867] The compound 2-(pyridin-4-yl)-2,7-diazaspiro[4.4]nonane was prepared from tert-butyl 7-(pyridin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate according to a procedure similar to that described for the synthesis of 2-(piperazin-1-ylmethyl)-1H-indole and isolated as a colorless oil.

[0868] Yield 100 mg (65%). 1 H NMR (400MHz, DMSO) δ8.08 (dd, J=1.5, 4.9Hz, 2H), 6.42 (dd, J=1.5, 4.9Hz, 2H), 4.11 (br s,1H),3.32-3.14(m,4H),2.86(t,J=7.1Hz,2H),2.67(s,2H),1.98-1.89(m,2H),1.72-1.66(m,2H).

[0869] Synthesis of tert-Butyl (3R,5S)-3,5-dimethyl-4-(pyridin-4-yl)piperazine-1-carboxylate

[0870]

[0871] The compound (3R,5S)-tert-butyl 3,5-dimethyl-4-(pyridin-4-yl)piperazine-1-carboxylate was prepared from tert-butyl (3R,5S)-3,5-dimethylpiperazine-1-carboxylate and 4-iodopyridine according to a procedure similar to that described for the synthesis of tert-butyl 6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and isolated as a brown glass.

[0872] Yield 39 mg (14%). m / z: [ESI + ]292(M+H) +

[0873] Synthesis of (2R,6S)-2,6-dimethyl-1-(pyridin-4-yl)piperazine dihydrochloride

[0874]

[0875] To a solution of tert-butyl (3R, 5S)-3,5-dimethyl-4-(pyridin-4-yl)piperazine-1-carboxylate (39 mg, 0.13 mmol) in dioxane (1 mL) was added a solution of HCl in dioxane (4 M, 2 mL, 8 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to give (2R, 6S)-2,6-dimethyl-1-(pyridin-4-yl)piperazine dihydrochloride as an off-white solid. The next step was carried out without further purification.

[0876] Yield: 35 mg (quantitative). m / z: [ESI + ]192(M+H) + .

[0877] Synthesis of tert-Butyl (3aR,6aS)-5-(pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0878]

[0879] The compound (3aR,6aS)-5-(pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester was prepared from (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate and 4-iodopyridine according to a procedure similar to that described for the synthesis of tert-butyl 6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and isolated as a yellow oil.

[0880] Yield 281 mg (quantitative). 1 H NMR (400MHz, DMSO) δ8.10 (dd, J = 1.6, 4.9 Hz, 2H), 6.45 (dd, J = 1.6, 4.9 Hz, 2H), 3.58-3.50 (m, 4H), 3.20-3.16 (m, 4H), 3.04-3.00 (m, 2H), 1.40 (s, 9H).

[0881] Synthesis of (3aR,6aS)-2-(pyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0882]

[0883] The compound (3aR,6aS)-2-(pyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole was prepared from tert-butyl (3aR,6aS)-5-(pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate according to a procedure similar to that described for the synthesis of 2-(piperazin-1-ylmethyl)-1H-indole and isolated as an off-white solid.

[0884] Yield 128 mg (70%). 1 H NMR (400 MHz, DMSO) δ 8.10 (dd, J = 1.6, 4.8 Hz, 2H), 6.47 (dd, J = 1.6, 4.8 Hz, 2H), 3.49 (dd, J = 8.1, 10.4 Hz, 2H), 3.08 (dd, J = 3.7, 10.4 Hz, 2H), 2.93 (dd, J = 8.1, 10.9 Hz, 2H), 2.89-2.81 (m, 2H), 2.64 (dd, J = 2.9, 10.9 Hz, 2H). The NH protons are obscured by the residual water peak.

[0885] Synthesis of tert-Butyl 4-(5,6-dimethylpyrimidin-4-yl)piperazine-1-carboxylate

[0886]

[0887] The compound tert-butyl 4-(5,6-dimethylpyrimidin-4-yl)piperazine-1-carboxylate was prepared from tert-butyl piperazine-1-carboxylate and 4-chloro-5,6-dimethylpyrimidine according to a procedure similar to that described for the synthesis of tert-butyl 6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and isolated as an off-white solid.

[0888] Yield 459 mg (40%). 1 H NMR (400MHz, CDCl3) δ8.54(s,1H),3.57-3.53(m,4H),3.27-3.23(m,4H),2.42(s,3H),2.16(s,3H),1.48(s,9H).

[0889] Synthesis of 4,5-dimethyl-6-(piperazin-1-yl)pyrimidine hydrochloride

[0890]

[0891] Compound 4,5-dimethyl-6-(piperazin-1-yl)pyrimidine hydrochloride was prepared from tert-butyl 4-(5,6-dimethylpyrimidin-4-yl)piperazine-1-carboxylate according to a procedure similar to that described for the synthesis of 2-(piperazin-1-ylmethyl)-1H-indole, except that the compound was not purified by SCX-2 ion exchange chromatography and was isolated as an off-white solid. The intermediate was used in the next step as the hydrochloride salt without further purification.

[0892] Yield: 511 mg (crude). m / z: [ESI + ]193(M+H) + .

[0893] Synthesis of Pyrazolo[1,5-a]pyridin-2-ylmethanol

[0894]

[0895] The compound pyrazolo[1,5-a]pyridin-2-ylmethanol was prepared from pyrazolo[1,5-a]pyridine-2-carboxylic acid according to a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indol-2-yl)methanol and isolated as a brown oil. The intermediate was used in the next step without further purification.

[0896] Yield: 338 mg (crude). m / z: [ESI + ]149(M+H) + .

[0897] Synthesis of Pyrazolo[1,5-a]pyridine-2-carboxaldehyde

[0898]

[0899] The compound pyrazolo[1,5-a]pyridine-2-carbaldehyde was prepared from pyrazolo[1,5-a]pyridin-2-ylmethanol according to a procedure similar to that described for the synthesis of 5-(trifluoromethyl)-1H-indole-2-carbaldehyde and isolated as a yellow solid.

[0900] Yield: 208 mg (crude). m / z: [ESI + ]147(M+H) + .

[0901] Synthesis of (1H-pyrrolo[2,3-b]pyridin-2-yl)methanol

[0902]

[0903] The compound (1H-pyrrolo[2,3-b]pyridin-2-yl)methanol was prepared from 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid according to a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indol-2-yl)methanol and isolated as a brown solid. The intermediate was used in the next step without further purification.

[0904] Yield 248 mg (crude). m / z: [ESI + ]149(M+H) + .

[0905] Synthesis of 1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde

[0906]

[0907] Compound 1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde was prepared from (1H-pyrrolo[2,3-b]pyridin-2-yl)methanol according to a procedure similar to that described for the synthesis of 5-(trifluoromethyl)-1H-indole-2-carbaldehyde and isolated as a yellow solid.

[0908] Yield 168 mg (crude). m / z: [ESI + ]147(M+H) + .

[0909] Synthesis of (1H-pyrrolo[2,3-c]pyridin-2-yl)methanol

[0910]

[0911] The compound (1H-pyrrolo[2,3-c]pyridin-2-yl)methanol was prepared from 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid according to a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indol-2-yl)methanol and isolated as a brown solid. The intermediate was used in the next step without further purification.

[0912] Yield: 321 mg (crude). m / z: [ESI + ]149(M+H) + .

[0913] Synthesis of 1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde

[0914]

[0915] Compound 1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde was prepared from (1H-pyrrolo[2,3-c]pyridin-2-yl)methanol according to a procedure similar to that described for the synthesis of 5-(trifluoromethyl)-1H-indole-2-carbaldehyde and isolated as a yellow solid.

[0916] Yield 214 mg (68%). m / z: [ESI + ]147(M+H) + .

[0917] Synthesis of (1H-pyrrolo[3,2-b]pyridin-2-yl)methanol

[0918]

[0919] The compound (1H-pyrrolo[3,2-b]pyridin-2-yl)methanol was prepared from 1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid according to a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indol-2-yl)methanol and isolated as a yellow solid. The intermediate was used in the next step without further purification.

[0920] Yield 186 mg (crude). m / z: [ESI + ]149(M+H) + .

[0921] Synthesis of 1H-pyrrolo[3,2-b]pyridine-2-carboxaldehyde

[0922]

[0923] Compound 1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde was prepared from (1H-pyrrolo[3,2-b]pyridin-2-yl)methanol according to a procedure similar to that described for the synthesis of 5-(trifluoromethyl)-1H-indole-2-carbaldehyde and isolated as a yellow solid.

[0924] Yield 164 mg (90%). m / z: [ESI + ]147(M+H) + .

[0925] Synthesis of tert-Butyl 4-(5-Formylpyrimidin-4-yl)piperazine-1-carboxylate

[0926]

[0927] To a solution of tert-butyl 4-(5-vinylpyrimidin-4-yl)piperazine-1-carboxylate (2.00 g, 6.89 mmol) in THF (20 mL) was added water (20 mL) and osmium tetroxide (35 mg, 0.138 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for 2 minutes under a nitrogen atmosphere. Sodium metaperiodate (2.95 g, 13.79 mmol) was added portionwise to the above mixture over 2 minutes at room temperature. The resulting mixture was stirred at room temperature for another 16 hours. The resulting solution was diluted with water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile phase A: Water; Mobile phase B: ACN; Flow rate: 80 ml / min; Gradient: 45% B to 65% B over 20 minutes; Detector: UV 254 / 220 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to afford tert-butyl 4-(5-formylpyrimidin-4-yl)piperazine-1-carboxylate as a brown solid.

[0928] Yield 1.10 g (55%). 1 H NMR (400MHz, DMSO) δ9.84 (s, 1H), 8.80 (s, 1H), 8.66 (s, 1H), 3.63 (t, J = 5.2Hz, 4H), 3.47 (t, J = 5.2Hz, 4H), 1.43 (s, 9H). m / z:[ESI + ]293(M+H) + .

[0929] Synthesis of tert-Butyl 4-(5-(Hydroxymethyl)pyrimidin-4-yl)piperazine-1-carboxylate

[0930]

[0931] To a solution of tert-butyl 4-(5-formylpyrimidin-4-yl)piperazine-1-carboxylate (270 mg, 0.924 mmol) in ethanol (10 mL) was added sodium borohydride (52 mg, 1.374 mmol) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C under a nitrogen atmosphere for 30 minutes. The resulting mixture was extracted with acetic acid (0.15 mL, 2.623 mmol). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile phase A: Water (with 10 mM NH4HCO3); Mobile phase B: ACN; Flow rate: 80 mL / min; Gradient: 35% B to 55% B over 20 minutes; Detector: UV 254 / 220 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to give tert-butyl 4-[5-(hydroxymethyl)pyrimidin-4-yl)piperazine-1-carboxylate as a brown oil.

[0932] Yield 200 mg (74%). 1 H NMR (400MHz, DMSO) δ 8.53 (s, 1H), 8.30 (s, 1H), 5.44 (t, J = 5.2Hz, 1H), 4.43 (d, J = 5.2Hz, 2H), 3.55 (t, J = 4.8Hz, 4H), 3.43 (t, J = 4.8Hz, 4H), 1.43 (s, 9H). m / z:[ESI + ]295(M+H) + .

[0933] Synthesis of tert-Butyl 4-(5-((2-methoxyethoxy)methyl)pyrimidin-4-yl)piperazine-1-carboxylate

[0934]

[0935] To a solution of tert-butyl 4-[5-(hydroxymethyl)pyrimidin-4-yl]piperazine-1-carboxylate (0.73 g, 2.48 mmol) in anhydrous DMF (10 mL) was added sodium hydride (0.15 g, 3.75 mmol, 60% w / w dispersion in mineral oil) under a nitrogen atmosphere at 0°C. After stirring for another 30 minutes, 2-bromoethyl methyl ether (0.35 mL, 3.72 mmol) was added dropwise over 5 minutes. The resulting mixture was stirred at ambient temperature for another 2 hours. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile phase A: Water (plus 10 mM NH4HCO3); Mobile phase B: ACN; Flow rate: 80 ml / min; Gradient: 40% B to 60% B over 20 minutes; Detector: UV 254 / 220 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to afford tert-butyl 4-(5-[(2-methoxyethoxy)methyl]pyrimidin-4-yl]piperazine-1-carboxylate as a brown oil.

[0936] Yield 0.70 g (80%). 1 H NMR(400MHz,DMSO)δ8.54(s,1H),8.26(s,1H),4.41(s,2H),3.60-3.55(m,6 H), 3.48 (t, J = 4.4Hz, 2H), 3.42 (t, J = 5.0Hz, 4H), 3.26 (s, 3H), 1.43 (s, 9H). m / z:[ESI + ]353(M+H) + .

[0937] Synthesis of 5-((2-methoxyethoxy)methyl)-4-(piperazin-1-yl)pyrimidine

[0938]

[0939] Tert-butyl 4-[5-[(2-methoxyethoxy)methyl]pyrimidin-4-yl]piperazine-1-carboxylate (0.70 g, 1.99 mmol) was treated with 4M HCl in dioxane (15 mL, 60.00 mmol) at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column: spherical C18, 20-40 μm, 330 g; mobile phase A: water (plus 10 mM NH4HCO3); mobile phase B: ACN; flow rate: 80 ml / min; gradient: 10% B to 30% B in 20 minutes; detector: UV 254 / 220 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to give 5-[(2-methoxyethoxy)methyl]-4-(piperazin-1-yl)pyrimidine as a brown oil.

[0940] Yield 0.40 g (80%). 1 H NMR (400MHz, DMSO) δ8.50 (s, 1H), 8.21 (s, 1H), 4.28 (s, 2H), 3.58-3.42 (m, 8H), 3.22 (s, 3H), 2.76 (t, J = 4.8Hz, 4H), NH not visible-under waterpeak. m / z:[ESI + ]253(M+H) + .

[0941] Synthesis of tert-Butyl 4-(1-methyl-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate

[0942]

[0943] To a solution of 4-bromo-1-methyl-1,2,3-triazole (3.00 g, 18.52 mmol) in DMSO (45 mL) was added tert-butyl piperazine-1-carboxylate (4.14 g, 22.23 mmol), copper (I) iodide (1.06 g, 5.57 mmol), tripotassium phosphate (11.80 g, 55.59 mmol), and L-proline (1.28 g, 11.12 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120°C under a nitrogen atmosphere for 16 hours. After cooling to ambient temperature, the resulting mixture was filtered, and the collected filter cake was washed with acetonitrile (2 x 10 mL). The combined washings and filtrate were concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile phase A: Water (plus 10 mM NH4HCO3); Mobile phase B: ACN; Flow rate: 80 ml / min; Gradient: 35% B to 55% B over 20 minutes; Detector: 254 / 220 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to afford tert-butyl 4-(1-methyl-1,2,3-triazol-4-yl)piperazine-1-carboxylate as an off-white solid.

[0944] Yield 0.16 g (3%). 1 H NMR (400MHz, DMSO) δ7.46 (s, 1H), 3.93 (s, 3H), 3.44 (t, J = 4.8Hz, 4H), 3.01 (t, J = 4.8Hz, 4H), 1.41 (s, 9H). m / z:[ESI + ]268(M+H) + .

[0945] Synthesis of 1-(1-methyl-1H-1,2,3-triazol-4-yl)piperazine

[0946]

[0947] tert-Butyl 4-(1-methyl-1,2,3-triazol-4-yl)piperazine-1-carboxylate (159 mg, 0.561 mmol) was treated with 4M HCl in dioxane (10 mL, 40.00 mmol) at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile Phase A: Water (plus 10 mM NH4HCO3); Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 20% B to 40% B over 20 minutes; Detector: 254 / 220 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to yield 1-(1-methyl-1,2,3-triazol-4-yl)piperazine as a yellow solid.

[0948] Yield 25 mg (25%). 1 H NMR (400MHz, DMSO) δ7.41 (s, 1H), 3.93 (s, 3H), 3.05 (t, J = 5.2Hz, 4H), 2.85 (t, J = 5.2Hz, 4H), NH not visible-under water peak. m / z:[ESI + ]168(M+H) + .

[0949] Synthesis of tert-Butyl 4-(5-bromopyrimidin-4-yl)piperazine-1-carboxylate

[0950]

[0951] To a solution of tert-butyl piperazine-1-carboxylate (2.00 g, 10.74 mmol) and 5-bromo-4-chloropyrimidine (2.08 g, 10.75 mmol) in DMF (30 mL) was added potassium carbonate (1.48 g, 10.71 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 130°C for 16 hours. After cooling to room temperature, the resulting mixture was filtered. The collected filter cake was washed with ethyl acetate (3 x 30 mL). The combined washings and filtrate were concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase A: water (with 10 mM NH4HCO3); mobile phase B: ACN; flow rate: 80 mL / min; gradient: 60% B to 80% B over 20 minutes; detector: UV 254 / 220 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to give tert-butyl 4-(5-bromopyrimidin-4-yl)piperazine-1-carboxylate as a yellow solid.

[0952] Yield 3.20 g (87%). 1H NMR (400MHz, DMSO) δ8.63 (s, 1H), 8.57 (s, 1H), 3.60 (t, J = 5.2Hz, 4H), 3.46 (t, J = 5.2Hz, 4H), 1.43 (s, 9H). m / z:[ESI + ]343,345(M+H) + .

[0953] Synthesis of tert-Butyl 4-(5-vinylpyrimidin-4-yl)piperazine-1-carboxylate

[0954]

[0955] To a solution of tert-butyl 4-(5-bromopyrimidin-4-yl)piperazine-1-carboxylate (3.00 g, 8.74 mmol) in DME (30 mL) and water (9 mL) were added 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.48 g, 9.61 mmol), sodium carbonate (1.85 g, 17.45 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (0.36 g, 0.44 mmol) at room temperature under an argon atmosphere. The resulting mixture was stirred at 95°C under an argon atmosphere for 16 hours. After cooling to room temperature, the resulting mixture was filtered, and the collected filter cake was washed with ethyl acetate (3 x 50 mL). The combined washings and filtrate were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 1%-90% ethyl acetate in petroleum ether to give tert-butyl 4-(5-vinylpyrimidin-4-yl)piperazine-1-carboxylate as a brown oil.

[0956] Yield 2.00 g (79%). 1 H NMR (400MHz, CDCl3) δ8.64(s,1H),8.36(s,1H),6.62-6.50(m,1H),5.69(dd,J= 1.1, 17.6Hz, 1H), 5.38 (dd, J = 1.0, 11.0Hz, 1H), 3.56-3.52 (m, 8H), 1.50 (s, 9H). m / z:[ESI + ]291(M+H) + .

[0957] Synthesis of tert-Butyl 4-(5-ethylpyrimidin-4-yl)piperazine-1-carboxylate

[0958]

[0959] To a stirred solution of tert-butyl 4-(5-vinylpyrimidin-4-yl)piperazine-1-carboxylate (4.00 g, 13.77 mmol) in methanol (30 mL) was added 10% wt. of palladium on carbon (600 mg). After the stirred mixture was degassed, it was stirred with a balloon under a hydrogen atmosphere at room temperature for 18 hours. The resulting mixture was filtered through a pad of celite and washed with ethyl acetate (3×30 mL). The combined washings and filtrate were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether containing 33% EtOAc to give tert-butyl 4-(5-ethylpyrimidin-4-yl)piperazine-1-carboxylate as a brown solid.

[0960] Yield 3.80 g (94%). 1 H NMR (400MHz, CDCl3) δ8.64(s,1H),8.28(s,1H),3.57(t,J=4.8Hz,4H),3.41(t,J=4.8Hz,4H),2.62(q,J=7.5Hz,2H),1.50(s,9H),1.30(t,J=7.5Hz,3H).

[0961] m / z: [ESI + ]293(M+H) + .

[0962] Synthesis of 5-ethyl-4-(piperazin-1-yl)pyrimidine

[0963]

[0964] To a solution of tert-butyl 4-(5-ethylpyrimidin-4-yl)piperazine-1-carboxylate (3.80 g, 12.99 mmol) in THF (20 mL) was added a solution of 4 M HCl in dioxane (5 mL, 20.00 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18, 20-40 μm, 330 g; mobile phase A: water (plus 10 mM NH4HCO3); mobile phase B: ACN; flow rate: 80 ml / min; gradient: 30% B to 50% B in 20 minutes; detector: UV 254 / 220 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to give 5-ethyl-4-(piperazin-1-yl)pyrimidine as a brown solid.

[0965] Yield 2.20 g (88%). 1H NMR (400MHz, DMSO) δ8.58(s,1H),8.32(s,1H),3.48(t,J=4.4Hz,4H),3.10(t,J=4.4Hz,4H),2.60(q,J=7.5Hz,2H),1.20(t,J=7.5Hz,3H), NH invisible-under water peak. m / z:[ESI + ]193(M+H) + .

[0966] Synthesis of 6-Bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole

[0967]

[0968] To a solution of 5-bromo-3H-1,3-benzodiazole (5.00 g, 25.38 mmol) in DMF (60 mL) was added potassium carbonate (7.10 g, 51.37 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (6.80 g, 40.79 mmol) at room temperature under a nitrogen atmosphere. After stirring for 16 hours, the resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile phase A: Water (with 10 mM NH4HCO3); Mobile phase B: ACN; Flow rate: 80 mL / min; Gradient: 55% B to 75% B over 20 minutes; Detector: UV 254 / 220 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to give 6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole as a brown oil.

[0969] Yield 3.40 g (41%). 1 H NMR (400 MHz, CDCl3) δ 7.99-7.97 (m, 1.5H), 7.73-7.68 (m, 1H), 7.48-7.42 (m, 1.5H), 5.54 (s, 1H), 5.52 (s, 1H), 3.57-3.49 (m, 2H), 0.95-0.90 (m, 2H), -0.031 (s, 4.5H), -0.039 (s, 4.5H). (Mixture of two regioisomers, ratio = about 1:1). m / z: [ESI + ]327,329(M+H) + .

[0970] Synthesis of (3-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazol-5-yl)methanol

[0971]

[0972] To a solution of 6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (4.00 g, 12.22 mmol) in degassed anhydrous dioxane (40 mL) under an argon atmosphere at room temperature were added (tributylstannyl)methanol (7.90 g, 24.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.40 g, 1.21 mmol). The resulting mixture was stirred at 80°C for 16 hours. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile phase A: Water (with 10 mM NH4HCO3); Mobile phase B: ACN; Flow rate: 80 mL / min; Gradient: 40% B to 60% B over 20 minutes; Detector: UV 254 / 220 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to give (3-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazol-5-yl)methanol as a brown oil.

[0973] Yield 0.90 g (27%). 1 H NMR (400 MHz, DMSO) δ 9.13 (s, 1H), 7.80 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 5.79 (s, 2H), 4.67 (s, 2H), 3.57 (t, J = 3.2 Hz, 2H), 0.89 (t, J = 3.2 Hz, 2H), -0.064 (s, 9H), OH proton is not visible - below the water peak. m / z: [ESI + ]279(M+H) + .

[0974] Synthesis of 6-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole

[0975]

[0976] Under argon atmosphere, a solution of (3-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazol-5-yl)methanol (0.90 g, 3.23 mmol) in DCM (20 mL) was treated with thionyl chloride (2.30 mL, 31.67 mmol) for 1.5 hours at room temperature. The reactant was quenched with saturated NaHCO3 aqueous solution (20 mL) and the resulting mixture was extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product as a brown oil, which was used in the next step without further purification.

[0977] Yield 0.80 g (crude). m / z: [ESI + ]297,299(M+H) + .

[0978] Synthesis of 6-[(2-methoxyethoxy)methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole

[0979]

[0980] A solution of 2-methoxyethanol (0.51 g, 6.70 mmol) in DMF (10 mL) was treated with sodium hydride (0.23 g, 5.75 mmol, 60% wt dispersion in mineral oil) at 0°C for 30 minutes, followed by the addition of the above-mentioned 6-(chloromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (0.80 g, crude). The resulting solution was stirred at room temperature for another 16 hours. The reaction was quenched with saturated aqueous NH4Cl solution (15 mL). The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile phase A: Water (plus 10 mM NH4HCO3); Mobile phase B: ACN; Flow rate: 80 ml / min; Gradient: 30% B to 50% B over 20 minutes; Detector: UV 254 / 220 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to yield 6-[(2-methoxyethoxy)methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole as a brown oil.

[0981] Yield 0.23 g (21% in 2 steps). 1H NMR (400MHz, CDCl3) δ8.02(s,1H),7.80(d,J=8.4Hz,1H),7.56(d,J=1.6Hz,1H),7.33(dd,J=1.6,8.4Hz,1H),5.56 (s,2H),4.74(s,2H),3.70-3.57(m,4H),3.51(t,J=4.4Hz,2H),3.42(s,3H),0.97(t,J=4.4Hz,2H),-0.03(s,9H). m / z:[ESI + ]337(M+H) + .

[0982] Synthesis of 6-[(2-methoxyethoxy)methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole-2-carbaldehyde

[0983]

[0984] Under an argon atmosphere at -40 ° C, a solution of 6-[(2-methoxyethoxy)methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (0.47 g, 1.40 mmol) in THF (30 mL) was added dropwise over 40 minutes. 1.6M of a solution of n-butyllithium in THF (1.80 mL, 2.88 mmol) was then added dropwise to the stirred reaction mixture at -40 ° C within 5 minutes. After stirring for another 1 hour at room temperature, the reactant was quenched with a saturated aqueous NH4Cl solution (10 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a crude product as a brown oil, which was used in the next step without further purification.

[0985] Yield 0.37 g (crude). m / z: [ESI +] 365(M+H) + .

[0986] Synthesis of 2-[[4-(5-ethylpyrimidin-4-yl)piperazin-1-yl]methyl]-6-[(2-methoxyethoxy)methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole

[0987]

[0988] To a solution of crude 6-[(2-methoxyethoxy)methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole-2-carbaldehyde (0.37 g) in DCM (15 mL) was added 5-ethyl-4-(piperazin-1-yl)pyrimidine (0.19 g, 0.99 mmol), sodium triacetoxyborohydride (0.43 g, 2.03 mmol) and acetic acid (0.01 mL, 0.173 mmol) at room temperature under an argon atmosphere. After stirring at room temperature for 1 hour, the reaction was quenched with saturated aqueous NH4Cl solution (5 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile phase A: Water (plus 10 mM NH4HCO3); Mobile phase B: ACN; Flow rate: 80 ml / min; Gradient: 60% B to 80% B over 20 minutes; Detector: UV 254 / 220 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to give 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-((2-methoxyethoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-benzo[d]imidazole as a brown oil.

[0989] Yield 0.23 g (31% in 2 steps). 1 H NMR (400MHz, DMSO) δ8.52(s,1H),8.25(s,1H),7.63-7.51(m,2H),7.19(d,J=8.8Hz,1H),5.74(s,2H),4.59(s,2H),3.86(s,2H),3.63-3.53( m,4H),3.49(t,J=5.8Hz,2H),3.40-3.30(m,4H),3.26(s,3H),2.65-2.56(m,6H),1.19(t,J=7.5Hz,3H),0.93(t,J=4.4Hz,2H),-0.08(s,9H). m / z:[ESI + ]541(M+H) + .

[0990] Synthesis of ethyl 2-[4-(5-ethylpyrimidin-4-yl)piperazin-1-yl]acetate

[0991]

[0992] To a solution of 5-ethyl-4-(piperazin-1-yl)pyrimidine (0.50 g, 2.60 mmol) in DMF (10 mL) at room temperature were added potassium carbonate (0.72 g, 5.21 mmol) and ethyl chloroacetate (0.31 mL, 2.90 mmol). The resulting mixture was stirred at 50°C for 16 hours. After cooling to room temperature, the resulting mixture was filtered. The filter cake was washed with DMF (3 x 2 mL). The combined washings and filtrate were concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile phase A: Water (with 10 mM NH4HCO3); Mobile phase B: ACN; Flow rate: 80 mL / min; Gradient: 25% B to 45% B over 20 minutes; Detector: UV 254 / 220 nm. Fractions containing the desired product were collecte...

Claims

1. A compound represented by the structure of the following formula III: in Ring B is a 6-membered nitrogen-containing heteroaromatic ring; X1 is N; L1 is CH2, CHR or C(R)2; R1 and R2 are each independently H; F; Cl; Br; I; OH; SH; R8-OH; R8-SH; -R8-OR 10 ;-O-R8-OR 10 ;CF3; CD3; OCD3; CN; NO2; NH2; NHR; N(R)2; NHC(O)-R; C(O)H; C(O)NHR; C(O)N(R 10 )(R 11 );SO2R;SO2N(R 10 )(R 11 );NHSO2(R 10 ); C1-C5 straight chain or branched substituted or unsubstituted alkyl; C1-C5 straight chain, branched or cyclic haloalkyl; C1-C5 straight chain, branched or cyclic alkoxy; C1-C5 straight chain or branched haloalkoxy; C1-C5 straight chain or branched alkoxyalkyl; substituted or unsubstituted C3-C8 cycloalkyl; or substituted or unsubstituted C3-C8 heterocycle; R3, R4 and R5 are each independently H; F; Cl; Br; I; OH; SH; R8-OH; R8-SH; CF3; CD3; OCD3; CN; NO2; NH2; NHR; N(R)2; NHC(O)-R 10 ;COOH;C(O)-R 10 ; SO2R; SO2N(R 10 )(R 11 ); C1-C5 straight chain or branched substituted or unsubstituted alkyl; or C1-C5 straight chain, branched or cyclic halogenated alkyl; X2 is S or O; X3 is N; X4, X5 and X7 are C; X6 is C or N; R is OH; F; Cl; Br; I; CN; CF3; NO2; C1-C5 straight chain or branched substituted or unsubstituted alkyl; C1-C5 straight chain or branched alkoxy; C1-C5 straight chain or branched haloalkyl; substituted or unsubstituted C3-C8 aryl; or substituted or unsubstituted 3- to 8-membered heteroaryl; or Two geminal Rs are substituted and linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring; R8 is [CH2] p Where p is between 1 and 3; R 10 and R 11 Each is independently H or a substituted or unsubstituted C1-C5 straight or branched chain alkyl group; or R 10 and R 11 connected to form a substituted or unsubstituted C3-C8 heterocycle, Wherein the "substituted or unsubstituted" substituent is selected from: F; Cl; Br; I; OH; SH; C1-C5 straight chain or branched alkyl; C1-C5 straight chain or branched alkyl-OH; C3-C8 heterocycle; C1-C5 alkoxy; N(R)2; CF3; C3-C8 aryl; CN; NO2 or any combination thereof; m, n, l and k are each independently an integer between 0 and 4; or a pharmaceutically acceptable salt, stereoisomer, tautomer or any combination thereof.

2. A compound represented by the structure of the following formula III: in Ring B is pyrimidine, 3-pyridine or 4-pyridine, pyrazine, thiazole, pyrrole, triazole, imidazole or pyrazole; in X1 is N; L1 is CH2; R1 and R2 are each independently H; Cl; I; OH; SH; R8-OH; R8-SH; -R8-OR 10 ;-O-R8-OR 10 ;OR 20 ;CF3; CD3; OCD3; CN; NO2; NH2; NHR; N(R)2; NHC(O)-R; NHC(O)-R 10 NHCO-N(R 10 )(R 11 ); -C(O)Ph; C(O)OR 10 ; C(O)-R 10 ; C(O)NHR; C(O)N(R 10 )(R 11 );SO2R;SO2N(R 10 )(R 11 );NHSO2(R 10); C1-C5 straight chain or branched substituted alkyl; C1-C5 straight chain, branched or cyclic haloalkyl; C1-C5 branched or cyclic alkoxy; C1-C5 straight chain or branched thioalkoxy; C1-C5 straight chain or branched haloalkoxy; C1-C5 straight chain or branched alkoxyalkyl; or substituted or unsubstituted C3-C8 cycloalkyl; R3, R4 and R5 are each independently H; F; Cl; Br; I; OH; SH; R8-OH; R8-SH; OR 20 ;CF3; CD3; OCD3; CN; NO2; NH2; COOH; C(O)-R 10 ; -C(O)NH2; SO2R; C1-C5 linear or branched substituted or unsubstituted alkyl; or C1-C5 linear, branched or cyclic halogenated alkyl; or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring; R 20 Represented by the following structure: X2 is NH; X3 is CH or C(R); X4, X5, X6 and X7 are C; R is OH; F; Cl; Br; I; CF3; NO2; C1-C5 straight chain or branched substituted or unsubstituted alkyl; C1-C5 straight chain or branched alkoxy; C1-C5 straight chain or branched haloalkyl; substituted or unsubstituted C3-C8 aryl; or substituted or unsubstituted 3- to 8-membered heteroaryl; R8 is [CH2] p Where p is between 1 and 5; R 10 and R 11 Each is independently H, substituted or unsubstituted C1-C5 straight chain or branched chain alkyl or C1-C5 straight chain or branched chain alkoxy; Wherein the "substituted or unsubstituted" substituent is selected from: F; Cl; Br; I; OH; SH; C1-C5 straight or branched alkyl; C3-C8 heterocycle; C1-C5 alkoxy; N(R)2; CF3; C3-C8 aryl; CN; NO2 or any combination thereof; m, n, l and k are each independently an integer between 0 and 2; or a pharmaceutically acceptable salt, stereoisomer, tautomer or any combination thereof; in, The compound does not include 3. A compound represented by the structure of the following formula V(a): in L1 is CH2, CHR or C(R)2; R1 and R2 are each independently H; F; Cl; Br; I; OH; SH; R8-OH; R8-SH; -R8-OR 10 ;-O-R8-OR 10 ;CF3; CD3; OCD3; CN; NO2; NH2; NHR; N(R)2; NHC(O)-R 10 ; C(O)-R 10 ; C(O)NHR; C(O)N(R 10 )(R 11 );SO2R;SO2N(R 10 )(R 11 );NHSO2(R 10 ); C1-C5 straight chain or branched substituted or unsubstituted alkyl; C1-C5 straight chain, branched or cyclic haloalkyl; C1-C5 straight chain, branched or cyclic alkoxy; C1-C5 straight chain or branched haloalkoxy; C1-C5 straight chain or branched alkoxyalkyl; substituted or unsubstituted C3-C8 cycloalkyl; or substituted or unsubstituted C3-C8 heterocycle; R3 is F; Cl; Br; I; OH; SH; R8-OH; R8-SH; CF3; CD3; OCD3; CN; NO2; NH2; COOH; C(O)-R 10 ;-C(O)NH2;SO2R;SO2N(R 10 )(R 11 ); C1-C5 straight chain or branched unsubstituted alkyl; or C1-C5 straight chain, branched or cyclic halogenated alkyl; R4 and R5 are each independently H; F; Cl; Br; I; OH; SH; R8-OH; R8-SH; CF3; CD3; OCD3; CN; NO2; NH2; COOH; C(O)-R 10 ;-C(O)NH2;SO2R;SO2N(R 10 )(R 11 ); C1-C5 straight chain or branched unsubstituted alkyl; or C1-C5 straight chain, branched or cyclic halogenated alkyl; or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring; X2 is NH, S or O; X3 is N or CH; Wherein if X3 is N, then X2 is not NH; X4, X5, X6 and X7 are C; X8, X9, X 10 , X 11 and X 12 are each independently C or N, wherein if X9 is N, then X 11 is C, and if X9 is C, then X 11 is N; R is OH; F; Cl; Br; I; CN; CF3; NO2; C1-C5 straight chain or branched substituted or unsubstituted alkyl; C1-C5 straight chain or branched alkoxy; or C1-C5 straight chain or branched haloalkyl; R8 is [CH2] p Where p is between 1 and 5; R 10 and R 11 Each is independently H or a substituted or unsubstituted C1-C5 straight or branched chain alkyl group; Wherein the "substituted or unsubstituted" substituent is selected from: F; Cl; Br; I; OH; SH; C1-C5 straight or branched alkyl; C3-C8 heterocycle; C1-C5 alkoxy; N(R)2; CF3; C3-C8 aryl; CN; NO2 or any combination thereof; m, n and k are each independently an integer between 0 and 2; w is 0 or 1; l is an integer between 1 and 2; or a pharmaceutically acceptable salt, stereoisomer, tautomer or any combination thereof.

4. A compound represented by the structure of the following formula VII: in L1 is CH2, CHR or C(R)2; R1 and R2 are each independently H; F; Cl; Br; I; OH; SH; R8-OH; R8-SH; -R8-OR 10 ;-O-R8-OR 10 ;OR 20 ;CF3; CD3; OCD3; CN; NO2; NH2; NHR; N(R)2; NHC(O)-R 10 ; C(O)-R 10 ; C(O)NHR; C(O)N(R 10 )(R 11 );SO2R;SO2N(R 10 )(R 11); C1-C5 straight chain or branched substituted or unsubstituted alkyl; C1-C5 straight chain, branched or cyclic haloalkyl; C1-C5 straight chain, branched or cyclic alkoxy; C1-C5 straight chain or branched haloalkoxy; C1-C5 straight chain or branched alkoxyalkyl; substituted or unsubstituted C3-C8 cycloalkyl; or substituted or unsubstituted C3-C8 heterocycle; R6 is H; F; Cl; Br; I; OH; SH; R8-OH; R8-SH; -R8-OR 10 ;-O-R8-OR 10 ;OR 20 ;CF3; CD3; OCD3; CN; NO2; NH2; NHR; N(R)2; NHC(O)-R 10 ; C(O)-R 10 ;-C(O)NH2;SO2R;SO2N(R 10 )(R 11 ); C1-C5 straight chain or branched substituted or unsubstituted alkyl; C1-C5 straight chain, branched or cyclic haloalkyl; or C1-C5 straight chain, branched or cyclic alkoxy; and R3 and R4 are each independently H; F; Cl; Br; I; OH; SH; R8-OH; R8-SH; OR 20 ;CF3; CD3; OCD3; CN; NO2; NH2; NHC(O)-R 10 ;C(O)OR 10 ; C(O)-R 10 ;-C(O)NH2;C(O)NHR;SO2R;SO2N(R 10 )(R 11 ); C1-C5 straight chain or branched unsubstituted alkyl; or C1-C5 straight chain, branched or cyclic halogenated alkyl; R 20 Represented by the following structure: X2 is NH, S or O; X3 is N, CH or C(R); Wherein if X3 is N, then X2 is not NH; X 10 and X 12 Each independently is N; R is OH; F; Cl; Br; I; CN; CF3; NO2; C1-C5 straight chain or branched substituted or unsubstituted alkyl; C1-C5 straight chain or branched alkoxy; or C1-C5 straight chain or branched haloalkyl; or Two geminal Rs are substituted and linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring; R8 is [CH2] p Where p is between 1 and 3; R 10 and R 11 Each is independently H or a substituted or unsubstituted C1-C5 straight or branched chain alkyl group; Wherein the "substituted or unsubstituted" substituent is selected from: F; Cl; Br; I; OH; SH; C1-C5 straight or branched alkyl; C3-C8 heterocycle; C1-C5 alkoxy; N(R)2; CF3; C3-C8 aryl; CN; NO2 or any combination thereof; or a pharmaceutically acceptable salt, stereoisomer, tautomer or any combination thereof.

5. The compound according to claim 1, wherein: The ring system of Ring B is pyrimidine or 2-pyridine, 3-pyridine or 4-pyridine; R1 is H, Cl, F or C1-C5 straight chain, branched or cyclic halogenated alkyl; R3 is H, Cl, F, CN, C(O)H or C1-C5 linear or branched substituted or unsubstituted alkyl; L1 is CH2, CHF or C(CH3)2; l is 1 or 2; or any combination thereof.

6. The compound according to claim 5, wherein: R1 is CHF2 or CF3; R3 is CF3, CHF2, CH3 or C2H5.

7. The compound according to claim 2, wherein: Ring B is 2,4-pyrimidine, 3-pyridine or 4-pyridine, thiazole or triazole; R1 is H; Cl; CN; NH2; C(O)NHR; C1-C5 straight or branched unsubstituted alkyl; NHC(O)-Ph; -R8-O-R 10 ; -O-R8-O-R 10 or O-R 20 ; R3 is H, OR 20 , CH3, C2H5 or R3 and R4 are linked together to form a 5-membered or 6-membered aromatic carbocyclic or heterocyclic ring; X3 is CH, C-CH3 or C-Cl; l is 1 or 2; or any combination thereof.

8. The compound according to claim 7, wherein: R1 is CH2-O-CH2-CH2-O-CH3, O-CH2-CH2-O-CH3 or CF3.

9. The compound according to claim 3, wherein: X8, X9, X 10 , X 11 and X 12 At least one of them is N; R3 is a C1-C5 straight or branched unsubstituted alkyl group; R4 is H, a C1-C5 straight or branched unsubstituted alkyl group, or R3 and R4 are linked together to form a 5-membered or 6-membered aromatic carbocyclic or heterocyclic ring; R1 is H or F; X2 is NH or O; L1 is CH2; l is 1 or 2; or any combination thereof.

10. The compound according to claim 9, wherein: R3 is CF3 or methyl.

11. The compound according to claim 4, wherein: R3 is H; Cl; F; CN; C(O)H; OR 20 ; C(O)NH2; C1-C5 straight chain or branched unsubstituted alkyl; or C1-C5 straight chain, branched or cyclic halogenated alkyl; R1 is H; Cl; F; CN; -C(O)NH2; C1-C5 linear or branched substituted or unsubstituted alkyl; C1-C5 straight chain, branched or cyclic halogenated alkyl; -R8-OR 10 ;-O-R8-OR 10 OR 20 ; X3 is N, CH or C-Cl; L1 is CH2, CH-CH3, CHF or cyclopropyl; or any combination thereof.

12. The compound according to claim 11, wherein: R3 is CF3, CHF2, CH3 or C2H5; R1 is CHF2, CH2-O-CH2-CH2-O-CH3, O-CH2-CH2-O-CH3 or CF3.

13. A compound according to any one of claims 1, 2, 3 and 4, wherein if present: -R8-OR of R, R1, R2, R3, R4 or R5 10 is CH2-O-CH3, CH2-CH2-O-CH3 or CH2-O-CH2-CH2-O-CH3; R1 or R2-O-R8-OR 10 It is O-CH2-CH2-O-CH3; R1 NHC(O)-R or NHC(O)-R 10 is NHC(O)-Ph or NHCO-CH3; C(O)NHR of R1 or R2 is C(O)NH-Ph, R1 or R2 NHSO2 (R 10 ) is NHSO2CH3; The alkyl group of R, R1, R2, R3, R4 or R5 is methyl or ethyl, R 10 or R 11 The substituted or unsubstituted alkyl group is methyl, ethyl or CH2-CH2-O-CH3; The haloalkyl group of R1, R2, R3, R4 or R5 is CHF2; The haloalkyl group of R is CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2 or CF(CH3)-CH(CH3)2, R1, R2, R 10 or R 11 The alkoxy group is methoxy; The heterocycle of R3, R4 or R5 is imidazole, pyrazole or thiazole; The heteroaryl group of R is pyridine; The aryl group of R is phenyl, C(R) of X3 is C-CH3 or C-Cl; R2 and R1 are linked together to form a benzene or pyridine ring; R3 and R4 are linked together to form a cyclopentene, benzene, thiophene, furan, pyrrole or pyrazole ring; and / or Two geminal R substituents are linked together to form a cyclopropyl group.

14. A compound according to claim 1, 2, 3 or 4, wherein the heteroaryl group of R, if present, is 2-pyridine, 3-pyridine or 4-pyridine.

15. The compound according to claim 3, wherein X 10 and X 12 At least one of them is N.

16. A compound represented by the structure of Formula IX below: in R1 is Cl, -R8-OR 10 、-O-R8-OR 10 , OR 20 or CF3; R2 is H, Cl, -R8-OR 10 、-O-R8-OR 10 , OR 20 or CF3; R6 is H; R3 and R4 are each independently H, OR 20 , C1-C5 straight or branched chain substituted or unsubstituted alkyl or substituted or unsubstituted C3-C8 heterocycle, Wherein the "substituted or unsubstituted" substituent is selected from: F; Cl; Br; I; C1-C5 straight chain or branched alkyl; OH; C1-C5 alkoxy; CF3; C3-C8 aryl; 3-membered to 8-membered heteroaryl; C3-C8 cycloalkyl; CN; NO2 or any combination thereof; or R3 and R4 are linked together to form a 5-membered or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic or heterocyclic ring; R 20 Represented by the following structure: X 10 and X 12 is N; in, If R3 is ethyl, then R1 or R2 is not CF3; or a pharmaceutically acceptable salt, stereoisomer, tautomer or any combination thereof.

17. A compound represented by the structure of the following compound:

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

19. Use of a compound according to any one of claims 1 to 17 or a compound described by the following structure for preparing a medicament for treating fibrosis in a subject, curbing fibrosis in a subject, reducing the severity of fibrosis in a subject, reducing the risk of fibrosis in a subject, or inhibiting fibrosis in a subject:

20. The use according to claim 19, wherein the fibrosis is a systemic fibrosing disease; wherein the fibrosis is an organ-specific fibrotic disease; wherein the fibrosis is primary fibrosis or secondary fibrosis; wherein the fibrosis is the result of systemic sclerosis, graft-versus-host disease, pulmonary fibrosis, an autoimmune disorder, tissue damage, inflammation, oxidative stress, or any combination thereof; or The fibrosis is liver fibrosis, lung fibrosis or skin fibrosis.

21. The use according to claim 20, wherein the systemic fibrotic disease is systemic sclerosis, multifocal fibrosing sclerosis, IgG4-related fibrosis, nephrogenic systemic fibrosis, scleroderma graft-versus-host disease, or any combination thereof; wherein the organ-specific fibrotic disease is pulmonary fibrosis, cardiac fibrosis, renal fibrosis, lung fibrosis, liver and portal vein fibrosis, radiation-induced fibrosis, bladder fibrosis, intestinal fibrosis, peritoneal sclerosis, diffuse fasciitis, wound healing, scarring, or any combination thereof; wherein the skin fibrosis is scleroderma; wherein the skin fibrosis is the result of localized or generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenomas, collagenous connective tissue nevi, or any combination thereof; or The liver fibrosis is the result of liver scarring or chronic liver damage.

22. The use according to claim 21, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis; wherein the cardiac fibrosis is hypertension-associated cardiac fibrosis, post-myocardial infarction, Chagas' disease-induced cardiac fibrosis, or any combination thereof; wherein 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; wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, silica-induced pneumoconiosis, silicosis, asbestos-induced pulmonary fibrosis, asbestosis, chemotherapeutic agent-induced pulmonary fibrosis, or any combination thereof; wherein the liver and portal vein fibrosis is alcoholic and non-alcoholic liver fibrosis, hepatitis C-induced liver fibrosis, primary biliary cirrhosis, parasite-induced liver fibrosis, schistosomiasis, or any combination thereof; wherein the diffuse fasciitis is localized scleroderma, keloid, Dupuytren's disease, Peyronie's disease, myelofibrosis, oral submucous fibrosis, or any combination thereof; or The chronic liver damage is caused by alcoholism, malnutrition, hemochromatosis, poison exposure, toxin exposure or drug exposure.

23. The use according to any one of claims 19 to 22, wherein the subject suffers from liver cirrhosis.

24. Use of a compound according to any one of claims 1 to 17 for the preparation of a medicament for: Treating pulmonary fibrosis in a subject, arresting pulmonary fibrosis in a subject, reducing the severity of pulmonary fibrosis in a subject, reducing the risk of developing pulmonary fibrosis in a subject, or inhibiting pulmonary fibrosis in a subject; Treating idiopathic pulmonary fibrosis in a subject, arresting idiopathic pulmonary fibrosis in a subject, reducing the severity of idiopathic pulmonary fibrosis in a subject, reducing the risk of developing idiopathic pulmonary fibrosis in a subject, or inhibiting idiopathic pulmonary fibrosis in a subject; treating a liver fibrosis disorder in a subject, arresting a liver fibrosis disorder in a subject, reducing the severity of a liver fibrosis disorder in a subject, reducing the risk of a subject developing a liver fibrosis disorder, or inhibiting a liver fibrosis disorder in a subject; Treating cirrhosis of the liver in a subject, arresting cirrhosis of the liver in a subject, reducing the severity of cirrhosis of the liver in a subject, reducing the risk of developing cirrhosis of the liver in a subject, or inhibiting cirrhosis of the liver in a subject; treating alcoholic steatohepatitis in a subject, arresting alcoholic steatohepatitis in a subject, reducing the severity of alcoholic steatohepatitis in a subject, reducing the risk of developing alcoholic steatohepatitis in a subject, or inhibiting alcoholic steatohepatitis in a subject; treating nonalcoholic steatohepatitis in a subject, arresting nonalcoholic steatohepatitis in a subject, reducing the severity of nonalcoholic steatohepatitis in a subject, reducing the risk of developing nonalcoholic steatohepatitis in a subject, or inhibiting nonalcoholic steatohepatitis in a subject; treating alcoholic fatty liver disease in a subject, arresting alcoholic fatty liver disease in a subject, reducing the severity of alcoholic fatty liver disease in a subject, reducing the risk of developing alcoholic fatty liver disease in a subject, or inhibiting alcoholic fatty liver disease in a subject; Treating, arresting, reducing the severity of, reducing the risk of, or inhibiting non-alcoholic fatty liver disease in a subject; or Treating an autoimmune disease or condition in a subject, suppressing an autoimmune disease or condition in a subject, reducing the severity of an autoimmune disease or condition in a subject, reducing the risk of developing an autoimmune disease or condition in a subject, or inhibiting an autoimmune disease or condition in a subject.

25. The use according to claim 24, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis; wherein the liver fibrosis disorder is portal hypertension, liver cirrhosis, idiopathic hepatic fibrosis or any combination thereof; or The cirrhosis is the result of hepatitis or alcoholism.

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