Collagen 1 translation inhibitors and methods of use thereof

Abstract

The invention relates to collagen 1 translation inhibitors and methods of use thereof. The present invention relates to novel collagen 1 translation inhibitors, compositions and processes for their preparation and their use for the treatment of fibrosis, including pulmonary fibrosis, hepatic fibrosis, renal fibrosis, cardiac fibrosis and skin fibrosis; an IPF; wound healing; scar formation and gingival fibromatosis; systemic sclerosis; alcoholic steatohepatitis; and non-alcoholic steatohepatitis (NASH).

Description

[0001] This application is a divisional application of the application filed on April 21, 2021, with application number 202180029210.1 and invention title "Collagen 1 Translation Inhibitor and Method of Using Thereof". Technical Field

[0002] This invention relates to novel collagen 1 translation inhibitors, their compositions and methods of preparation, and their use in treating the following: 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). Background Art

[0003] The formation of fibrous connective tissue is part of the normal healing process following tissue injury or inflammation. During this process, activated immune cells, including macrophages, stimulate the proliferation and activation of fibroblasts, which then deposit connective tissue. However, abnormal or excessive production of connective tissue can lead to the accumulation of fibrous material, interfering with the normal function of the tissue. Fibrotic growth can proliferate and invade healthy surrounding tissues, even after the original injury has healed. This abnormal formation of excessive connective tissue during repair or response is called fibrosis.

[0004] Many drugs activate the fibrotic process and are released in response to tissue damage, inflammation, and oxidative stress. Regardless of the initiating event, a common feature of all fibrotic diseases is the transformation of tissue-resident fibroblasts into ECM-producing myofibroblasts that secrete type I collagen. The current program indirectly targets myofibroblast activation and collagen secretion by inhibiting a single fibrosis-inducing signal.

[0005] Physiologically, fibrosis involves the deposition of connective tissue, which can disrupt the structure and function of underlying organs or tissues. Defined by the pathological accumulation of extracellular matrix (ECM) proteins, fibrosis leads to scarring and thickening of affected tissues, thereby interfering with normal organ function. Among various conditions, the formation of fibrotic tissue is characterized by an abnormally large deposition of collagen. Collagen synthesis is also involved in many other pathological conditions. For example, clinical symptoms and conditions associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, and autoimmune diseases, are characterized by the overproduction of connective tissue, leading to the destruction of normal tissue structure and function. These diseases can best be explained by disturbances in cellular function, primarily manifested as excessive collagen synthesis and deposition. The role of collagen in fibrosis has prompted efforts to develop drugs that inhibit its accumulation.

[0006] Excessive collagen accumulation is a major pathological feature of various clinical conditions characterized by tissue fibrosis. These conditions include localized processes (e.g., pulmonary fibrosis and cirrhosis) or more generalized processes (e.g., progressive systemic sclerosis). Collagen deposition is characteristic of different forms of cutaneous fibrosis, including, in addition to scleroderma, localized and generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenomas, and collagen-type connective tissue nevi. Recent advances in understanding the normal biochemistry of collagen allow us to define specific levels of collagen biosynthesis and degradation at which pharmacological interventions can lead to a reduction in collagen deposition in tissues. Such compounds could potentially provide novel approaches to reduce excessive collagen accumulation in disease.

[0007] Liver fibrosis (also referred to as liver fibrosis in this article) can be caused by various types of chronic liver injury, especially those involving inflammatory components. Self-limiting acute liver injury (e.g., acute viral hepatitis A), even if fulminant, does not necessarily disrupt the scaffold structure and therefore usually does not cause fibrosis, despite hepatocyte loss. However, factors such as chronic alcoholism, malnutrition, hemochromatosis, and exposure to toxins, poisons, or drugs can lead to chronic liver injury and liver fibrosis due to exposure to hepatotoxic chemicals. Liver scarring caused by surgery or other forms of injury associated with mechanical biliary obstruction can also lead to liver fibrosis.

[0008] Fibrosis itself is not necessarily asymptomatic; however, it can lead to the development of portal hypertension or cirrhosis. In portal hypertension, scarring disrupts blood flow through the liver, while in cirrhosis, scarring leads to the destruction of normal liver structure and impaired liver function. The extent of each of these pathologies determines the clinical presentation of liver fibrosis. For example, congenital liver fibrosis affects the portal vein branches but largely does not damage the parenchyma. The result is portal hypertension without impairing hepatocyte function.

[0009] treat

[0010] Attempts to develop antifibrotic agents for the treatment of various conditions have been reported. However, treating established fibrosis that has developed months or years after chronic or repeated injuries remains a challenge.

[0011] Treatments aimed at reversing fibrosis are often too toxic for long-term use (e.g., corticosteroids, penicillamine) or lack proven efficacy (e.g., colchicine).

[0012] Many patients do not respond to available treatments for fibrosis, and long-term treatment is limited by toxicity and side effects. Therefore, there remains a need to develop treatments aimed at reducing fibrosis. Developing safe and effective therapies for established cirrhosis and portal hypertension, as well as for alleviating fibrosis, would be highly beneficial.

[0013] 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, whose mechanism of action is unclear, and nintedanib, a tyrosine kinase inhibitor—were approved for IPF, primarily based on their ability to reduce the decline in forced vital capacity (FVC) and slow disease progression. However, to date, it remains unclear whether these drugs improve symptoms such as shortness of breath and cough, or whether their beneficial effects on functional decline translate into increased survival.

[0014] The compounds of the present invention target activated fibroblasts and excessive collagen production, 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 diseases, pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF), as well as localized processes (e.g., pulmonary fibrosis and cirrhosis) or more generalized processes (e.g., progressive systemic sclerosis). The compounds can be further used to treat various forms of cutaneous fibrosis, including, in addition to scleroderma, localized and generalized scleroderma, keloids, hypertrophic scars, familial cutaneous collagenomas, and collagenous connective tissue nevi. The compounds can also be used to treat pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF), as well as liver fibrosis resulting from liver scarring caused by surgical procedures 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 and other liver fibrosis conditions, including nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD), which can be similarly treated with the compounds of the present invention. Summary of the Invention

[0015] This invention provides a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (e.g., deuterated analog), pharmaceutical product, or any combination thereof, having a structure of Formula IX as defined below and a structural representation listed in Table 1. In various embodiments, the compound is a collagen I translation inhibitor.

[0016] The present invention further provides a pharmaceutical composition comprising: a compound or a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, a hydrate, an N-oxide thereof, a prodrug, an isotope variant (e.g., a deuterated analog), a pharmaceutical product thereof, or any combination thereof, having the structure of Formula IX as defined below and the structural representations listed in Table 1; and a pharmaceutically acceptable carrier.

[0017] The present invention further provides a method for treating, inhibiting, reducing the severity of fibrosis in a subject, reducing the risk of developing fibrosis in a subject, or suppressing fibrosis in a subject, the method comprising administering to the subject, under conditions of effectively treating, inhibiting, reducing the severity of fibrosis in a subject, reducing the risk of developing fibrosis in a subject, or suppressing fibrosis in a subject, a compound represented by a structure of Formula IX as defined below and a compound represented by a structure listed in Table 1. In some embodiments, the fibrosis is a systemic fibrotic disease. In some embodiments, the systemic fibrotic disease is systemic sclerosis, multifocal fibrosis (IgG4-associated fibrosis), renal systemic fibrosis, scleroderma graft-versus-host disease, or any combination thereof. In some embodiments, the fibrosis is an organ-specific fibrotic disease. In some embodiments, the organ-specific fibrotic disease is pulmonary fibrosis, cardiac fibrosis, renal fibrosis, hepatic and portal vein fibrosis, radiation-induced fibrosis, bladder fibrosis, intestinal fibrosis, peritoneal sclerosis, diffuse fasciitis, wound healing, scar formation, or any combination thereof. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, the cardiac fibrosis is hypertension-associated cardiac fibrosis, post-myocardial infarction, Chagas disease-induced myocardial fibrosis, or any combination thereof. In some embodiments, the renal fibrosis is diabetic and hypertensive nephropathy, urinary tract obstruction-induced renal fibrosis, inflammatory / autoimmune-induced renal fibrosis, aristolochic acid nephropathy, polycystic kidney disease, or any combination thereof. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis, silica-induced pneumoconiosis (silicosis), asbestos-induced pulmonary fibrosis (asbestosis), chemotherapy-induced pulmonary fibrosis, or any combination thereof. In some embodiments, the hepatic and portal 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 diseases, tissue damage, inflammation, oxidative stress, or any combination thereof. In some embodiments, the fibrosis is liver fibrosis, pulmonary fibrosis, or skin fibrosis. In some embodiments, the subject has cirrhosis.In some embodiments, the skin fibrosis is scleroderma. In some embodiments, the skin fibrosis is the result of localized or generalized scleroderma, keloids, hypertrophic scars, familial collagenoma, collagenous connective tissue nevi, or any combination thereof. In some embodiments, the liver fibrosis is the result of liver scarring or chronic liver injury. In some embodiments, the chronic liver injury is caused by alcoholism, malnutrition, hemochromatosis, exposure to toxins, or drug exposure.

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

[0019] The present invention further provides a method for treating a subject with idiopathic pulmonary fibrosis (IPF), inhibiting 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, the method comprising administering to the subject, under conditions of effectively treating the subject with idiopathic pulmonary fibrosis (IPF), inhibiting the subject's IPF, reducing the severity of the subject's IPF, reducing the risk of developing IPF in a subject with IPF, or inhibiting IPF in a subject with IPF, a compound represented by a structure of formula IX as defined below and a compound represented by a structure listed in Table 1.

[0020] The present invention further provides a method for treating, inhibiting, reducing the severity of, reducing the risk of developing or suppressing liver fibrosis in a subject, said method comprising administering to the subject, under conditions of effectively treating, inhibiting, reducing the severity of, reducing the risk of developing or suppressing liver fibrosis in a subject with liver fibrosis, a compound represented by a structure of Formula IX as defined below and a compound represented by a structure listed in Table 1. In some embodiments, said liver fibrosis is portal hypertension, cirrhosis, congenital liver fibrosis, or any combination thereof.

[0021] The present invention further provides a method for treating, inhibiting, reducing the severity of cirrhosis in a subject, reducing the risk of developing cirrhosis in a subject, or inhibiting cirrhosis in a subject, the method comprising administering to the subject, under conditions of effectively treating, inhibiting, reducing the severity of cirrhosis in a subject, reducing the risk of developing cirrhosis in a subject, or inhibiting cirrhosis in a subject, a compound represented by a structure of Formula IX as defined below and a compound represented by a structure listed in Table 1. In some embodiments, the cirrhosis is a result of hepatitis or alcoholism.

[0022] The present invention further provides a method for treating alcoholic steatohepatitis (ASH) in a subject, inhibiting ASH in a subject, reducing the severity of ASH in a subject, reducing the risk of a subject developing ASH, or inhibiting ASH in a subject, the method comprising administering to the subject, under conditions of effectively treating alcoholic steatohepatitis (ASH) in a subject, inhibiting ASH in a subject with ASH, reducing the severity of ASH in a subject with ASH, reducing the risk of a subject with ASH developing ASH, or inhibiting ASH in a subject with ASH, a compound represented by a structure of formula IX as defined below and a compound represented by a structure listed in Table 1.

[0023] The present invention further provides a method for treating a subject with non-alcoholic steatohepatitis (NASH), inhibiting 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, under conditions of effectively treating a subject with non-alcoholic steatohepatitis (NASH), inhibiting 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, a compound represented by a structure of Formula IX as defined below and a compound represented by a structure listed in Table 1.

[0024] The present invention further provides a method for treating alcoholic fatty liver disease (AFLD) in a subject, inhibiting AFLD in a subject, reducing the severity of AFLD in a subject, reducing the risk of a subject developing AFLD, or inhibiting AFLD in a subject, the method comprising administering to the subject, under conditions of effectively treating alcoholic fatty liver disease (AFLD) in a subject, inhibiting AFLD in a subject with AFLD, reducing the severity of AFLD in a subject with AFLD, reducing the risk of a subject with AFLD developing AFLD, or inhibiting AFLD in a subject with AFLD, a compound represented by a structure of formula IX as defined below and a compound represented by a structure listed in Table 1.

[0025] The present invention further provides a method for treating a subject with non-alcoholic fatty liver disease (NAFLD), inhibiting 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, under conditions of effectively treating the non-alcoholic fatty liver disease (NAFLD) in a subject, inhibiting NAFLD in a subject with NAFLD, reducing the severity of NAFLD in a subject with NAFLD, reducing the risk of developing NAFLD in a subject with NAFLD, or inhibiting NAFLD in a subject with NAFLD, a compound represented by a structure of formula IX as defined below and a compound represented by a structure listed in Table 1.

[0026] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing an autoimmune disease or condition in a subject, or inhibiting an autoimmune disease or condition in a subject, the method comprising administering to the subject, under conditions of effectively treating, suppressing, reducing the severity of, reducing the risk of developing an autoimmune disease or condition in a subject, or inhibiting an autoimmune disease or condition in a subject, a compound represented by a structure of Formula IX as defined below and a compound represented by a structure listed in Table 1.

[0027] This invention provides a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (e.g., deuterated analog), pharmaceutical product, or any combination thereof, having a structure of Formula IX as defined below and a structural representation listed in Table 1. In various embodiments, the compound is a collagen I translation inhibitor.

[0028] The present invention further provides a pharmaceutical composition comprising: a compound or a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, a hydrate, an N-oxide thereof, a prodrug, an isotope variant (e.g., a deuterated analog), a pharmaceutical product thereof, or any combination thereof, having the structure of Formula IX as defined below and the structural representations listed in Table 1; and a pharmaceutically acceptable carrier.

[0029] The present invention further provides a method for treating, inhibiting, reducing the severity of fibrosis in a subject, reducing the risk of developing fibrosis in a subject, or suppressing fibrosis in a subject, the method comprising administering to the subject, under conditions of effectively treating, inhibiting, reducing the severity of fibrosis in a subject, reducing the risk of developing fibrosis in a subject, or suppressing fibrosis in a subject, a compound represented by a structure of Formula IX as defined below and a compound represented by a structure listed in Table 1. In some embodiments, the fibrosis is a systemic fibrotic disease. In some embodiments, the systemic fibrotic disease is systemic sclerosis, multifocal fibrosis (IgG4-associated fibrosis), renal systemic fibrosis, scleroderma graft-versus-host disease, or any combination thereof. In some embodiments, the fibrosis is an organ-specific fibrotic disease. In some embodiments, the organ-specific fibrotic disease is pulmonary fibrosis, cardiac fibrosis, renal fibrosis, hepatic and portal vein fibrosis, radiation-induced fibrosis, bladder fibrosis, intestinal fibrosis, peritoneal sclerosis, diffuse fasciitis, wound healing, scar formation, or any combination thereof. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, the cardiac fibrosis is hypertension-associated cardiac fibrosis, post-myocardial infarction, Chagas disease-induced myocardial fibrosis, or any combination thereof. In some embodiments, the renal fibrosis is diabetic and hypertensive nephropathy, urinary tract obstruction-induced renal fibrosis, inflammatory / autoimmune-induced renal fibrosis, aristolochic acid nephropathy, polycystic kidney disease, or any combination thereof. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis, silica-induced pneumoconiosis (silicosis), asbestos-induced pulmonary fibrosis (asbestosis), chemotherapy-induced pulmonary fibrosis, or any combination thereof. In some embodiments, the hepatic and portal 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, Peroni'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 diseases, tissue damage, inflammation, oxidative stress, or any combination thereof. In some embodiments, the fibrosis is hepatic fibrosis, pulmonary fibrosis, or skin fibrosis. In some embodiments, the subject has cirrhosis. In some embodiments, the skin fibrosis is scleroderma.In some embodiments, the skin fibrosis is the result of localized or generalized morphine scleroderma, keloids, hypertrophic scars, familial cutaneous collagenoma, collagenous connective tissue nevi, or any combination thereof. In some embodiments, the liver fibrosis is the result of liver scarring or chronic liver injury. In some embodiments, the chronic liver injury is caused by alcoholism, malnutrition, hemochromatosis, exposure to toxins, or drug exposure.

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

[0031] The present invention further provides a method for treating a subject with idiopathic pulmonary fibrosis (IPF), inhibiting 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, the method comprising administering to the subject, under conditions of effectively treating the subject with idiopathic pulmonary fibrosis (IPF), inhibiting the subject's IPF, reducing the severity of the subject's IPF, reducing the risk of developing IPF in a subject with IPF, or inhibiting IPF in a subject with IPF, a compound represented by a structure of formula IX as defined below and a compound represented by a structure listed in Table 1.

[0032] The present invention further provides a method for treating, inhibiting, reducing the severity of, reducing the risk of developing or suppressing liver fibrosis in a subject, said method comprising administering to the subject, under conditions of effectively treating, inhibiting, reducing the severity of, reducing the risk of developing or suppressing liver fibrosis in a subject with liver fibrosis, a compound represented by a structure of Formula IX as defined below and a compound represented by a structure listed in Table 1. In some embodiments, said liver fibrosis is portal hypertension, cirrhosis, congenital liver fibrosis, or any combination thereof.

[0033] The present invention further provides a method for treating, inhibiting, reducing the severity of cirrhosis in a subject, reducing the risk of developing cirrhosis in a subject, or inhibiting cirrhosis in a subject, the method comprising administering to the subject, under conditions of effectively treating, inhibiting, reducing the severity of cirrhosis in a subject, reducing the risk of developing cirrhosis in a subject, or inhibiting cirrhosis in a subject, a compound represented by a structure of Formula IX as defined below and a compound represented by a structure listed in Table 1. In some embodiments, the cirrhosis is a result of hepatitis or alcoholism.

[0034] The present invention further provides a method for treating alcoholic steatohepatitis (ASH) in a subject, inhibiting ASH in a subject, reducing the severity of ASH in a subject, reducing the risk of a subject developing ASH, or inhibiting ASH in a subject, the method comprising administering to the subject, under conditions of effectively treating alcoholic steatohepatitis (ASH) in a subject, inhibiting ASH in a subject with ASH, reducing the severity of ASH in a subject with ASH, reducing the risk of a subject with ASH developing ASH, or inhibiting ASH in a subject with ASH, a compound represented by a structure of formula IX as defined below and a compound represented by a structure listed in Table 1.

[0035] The present invention further provides a method for treating a subject with non-alcoholic steatohepatitis (NASH), inhibiting 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, under conditions of effectively treating a subject with non-alcoholic steatohepatitis (NASH), inhibiting 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, a compound represented by a structure of Formula IX as defined below and a compound represented by a structure listed in Table 1.

[0036] The present invention further provides a method for treating alcoholic fatty liver disease (AFLD) in a subject, inhibiting AFLD in a subject, reducing the severity of AFLD in a subject, reducing the risk of a subject developing AFLD, or inhibiting AFLD in a subject, the method comprising administering to the subject, under conditions of effectively treating alcoholic fatty liver disease (AFLD) in a subject, inhibiting AFLD in a subject with AFLD, reducing the severity of AFLD in a subject with AFLD, reducing the risk of a subject with AFLD developing AFLD, or inhibiting AFLD in a subject with AFLD, a compound represented by a structure of formula IX as defined below and a compound represented by a structure listed in Table 1.

[0037] The present invention further provides a method for treating a subject with non-alcoholic fatty liver disease (NAFLD), inhibiting 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, under conditions of effectively treating the non-alcoholic fatty liver disease (NAFLD) in a subject, inhibiting NAFLD in a subject with NAFLD, reducing the severity of NAFLD in a subject with NAFLD, reducing the risk of developing NAFLD in a subject with NAFLD, or inhibiting NAFLD in a subject with NAFLD, a compound represented by a structure of formula IX as defined below and a compound represented by a structure listed in Table 1.

[0038] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing an autoimmune disease or condition in a subject, or inhibiting an autoimmune disease or condition in a subject, the method comprising administering to the subject, under conditions of effectively treating, suppressing, reducing the severity of, reducing the risk of developing an autoimmune disease or condition in a subject, or inhibiting an autoimmune disease or condition in a subject, a compound represented by a structure of Formula IX as defined below and a compound represented by a structure listed in Table 1.

[0039] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing an autoimmune disease or condition in a subject, or inhibiting an autoimmune disease or condition in a subject, the method comprising administering to the subject, under conditions of effectively treating, suppressing, reducing the severity of, reducing the risk of developing an autoimmune disease or condition in a subject, or inhibiting an autoimmune disease or condition in a subject, a compound represented by a structure of Formula IX as defined below and a compound represented by a structure listed in Table 1. Attached Figure Description

[0040] Figure 1 This study demonstrates how protein synthesis monitoring (PSM) specifically monitors collagen 1 synthesis. The assay system consisted of the human lung fibroblast cell line WI-38, activated to produce higher levels of collagen. Two tRNAs (di-tRNAs) decoding a specific glycine codon and a specific proline codon were transfected using either control RNAi or collagen 1-targeted RNAi. FRET signaling specifically monitored collagen 1 translation, as FRET signaling was suppressed by 90% in cells treated with the collagen 1-targeted siRNA. Blue represents cell nuclei stained with DAPI; cyan represents FRET signals from tRNA pairs decoding the glycine-proline double codon.

[0041] Figure 2The selective regulation of collagen translation was depicted. In the top figure, the Y-axis represents the normalized values ​​of metabolic markers in control cells. Compounds showing minimal impact on total protein synthesis (relative to control ±20%) and collagen 1 protein accumulation in WI38 cells were selected as selective regulators of collagen synthesis by using di-tRNA collagen FRET and collagen 1-specific immunofluorescence. In the bottom 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 with high PSM scores are marked by dot size; compounds increasing collagen content are marked in red, and compounds decreasing collagen content are marked in green.

[0042] Figure 3 The compound's effects at the translational level were demonstrated. WI-38 human lung fibroblasts were incubated with the compound for 96 hours. Immunofluorescence: blue represents cell nuclei stained with DAPI; green represents collagen detected with an anti-collagen antibody.

[0043] Figure 4 The efficacy and toxicity of compounds 201, 256, and 213 were demonstrated. Figure 4 The pEC50 efficacy is plotted relative to the toxicity of pEC50. The dashed lines represent the x10 or x100 window between efficacy and toxicity. Figure 4 4B in the image is a representative image of compound 213. The image was taken with a x20 objective in an Operetta machine (Perkin Elmer). Green: Type I collagen; Gray: DAPI. Detailed Implementation

[0044] In various embodiments, the present invention relates to a compound represented by the structure of formula (I):

[0045]

[0046] in

[0047] 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, imidazolium, indazole), or a single or fused C3-C ring. 10 Cycloalkyl (e.g., cyclohexyl, cyclopentyl), or single or fused C3-C 10 Heterocyclic compounds (e.g., piperidine, tetrahydro-2H-pyran);

[0048] R1 and R2 are independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyridine), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0049] Or R2 and R1 can be linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0050] R3, R4, and R5 are each independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, and -R8-OR. 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0051] Or R3 and R4 are linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0052] R 20 It can be represented by the following structure:

[0053]

[0054] X1 is N or CR (e.g., CH, C-OH);

[0055] L1 is CH2, CHR, C(R)2, or C=O;

[0056] L2 is a bond or CH2, C=O, O, or S;

[0057] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 straight-chain or branched substituted or unsubstituted alkyl group (e.g., methyl, ethyl), C1-C5 straight-chain or branched alkoxy group, -R8-OR 10 (e.g., CH2-CH2-O-CH3), C1-C5 straight-chain or branched haloalkyl groups (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 groups (e.g., phenyl), substituted or unsubstituted heteroaryl groups (e.g., pyridine (2, 3, and 4-pyridine)); or

[0058] Two twin R-substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0059] R8 is [CH2] p

[0060] Where p is between 1 and 10 (e.g., 2);

[0061] R9 is [CH] q [C] q

[0062] Where q is between 2 and 10;

[0063] R 10 and R 11Each is independently a straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a straight-chain or branched alkoxy group (e.g., O-CH3), a C(O)R, or a S(O)2R, with or without H, substituted or unsubstituted C1-C5.

[0064] or R 10 and R 11 Linked to form substituted or unsubstituted C3-C8 heterocycles (e.g., piperazine, piperidine).

[0065] The substitutions include: F, Cl, Br, I, OH, SH, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain 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;

[0066] m, n, l, and k are each an independent integer between 0 and 4 (e.g., 0, 1, or 2);

[0067] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0068] In various embodiments, the present invention relates to a compound represented by the structure of formula I(a):

[0069]

[0070]

[0071] in

[0072] 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, imidazolium, indazole), or a single or fused C3-C ring. 10 Cycloalkyl (e.g., cyclohexyl, cyclopentyl), or single or fused C3-C 10 Heterocyclic compounds (e.g., piperidine, tetrahydro-2H-pyran);

[0073] R1 and R2 are independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10(e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyridine), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0074] Or R2 and R1 can be linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0075] R3, R4, and R5 are each independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, and -R8-OR. 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0076] Or R3 and R4 are linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0077] R 20 It can be represented by the following structure:

[0078]

[0079] X1 is N or CR (e.g., CH, C-OH);

[0080] L1 is CH2, CHR, C(R)2, or C=O;

[0081] L2 is a bond or CH2, C=O, O, or S;

[0082] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 straight-chain or branched substituted or unsubstituted alkyl group (e.g., methyl, ethyl), C1-C5 straight-chain or branched alkoxy group, -R8-OR 10 (e.g., CH2-CH2-O-CH3), C1-C5 straight-chain or branched haloalkyl groups (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 groups (e.g., phenyl), substituted or unsubstituted heteroaryl groups (e.g., pyridine (2, 3, and 4-pyridine)); or

[0083] Two twin R-substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0084] R8 is [CH2] p

[0085] Where p is between 1 and 10 (e.g., 1, 2);

[0086] R9 is [CH] q [C] q

[0087] Where q is between 2 and 10;

[0088] R 10 and R 11Each is independently a straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a straight-chain or branched alkoxy group (e.g., O-CH3), a C(O)R, or a S(O)2R, with or without H, substituted or unsubstituted C1-C5.

[0089] or R 10 and R 11 Linked to form substituted or unsubstituted C3-C8 heterocycles (e.g., piperazine, piperidine).

[0090] The substitutions include: F, Cl, Br, I, OH, SH, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain 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;

[0091] m, n, l, and k are each an independent integer between 0 and 4 (e.g., 0, 1, or 2);

[0092] W is 0, 1, or 2; where if w = 0, then there is no bridge on the ring.

[0093] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0094] In various embodiments, the present invention relates to a compound represented by the structure of Formula II.

[0095]

[0096] in

[0097] 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, imidazolium, indazole), or a single or fused C3-C ring. 10 Cycloalkyl (e.g., cyclohexyl, cyclopentyl), or single or fused C3-C 10 Heterocyclic compounds (e.g., piperidine, tetrahydro-2H-pyran);

[0098] R1 and R2 are independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10(e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyridine), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0099] Or R2 and R1 can be linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0100] R3, R4, and R5 are each independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, and -R8-OR. 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0101] Or R3 and R4 are linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0102] R 20 It can be represented by the following structure:

[0103]

[0104] X1 is N or CR (e.g., CH, C-OH);

[0105] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 straight-chain or branched substituted or unsubstituted alkyl group (e.g., methyl, ethyl), C1-C5 straight-chain or branched alkoxy group, -R8-OR 10 (e.g., CH2-CH2-O-CH3), C1-C5 straight-chain or branched haloalkyl groups (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 groups (e.g., phenyl), substituted or unsubstituted heteroaryl groups (e.g., pyridine (2, 3, and 4-pyridine)); or

[0106] Two twin R-substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0107] R8 is [CH2] p

[0108] Where p is between 1 and 10 (e.g., 2);

[0109] R9 is [CH] q [C] q

[0110] Where q is between 2 and 10;

[0111] R 10 and R 11 Each is independently a straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a straight-chain or branched alkoxy group (e.g., O-CH3), a C(O)R, or a S(O)2R, with or without H, substituted or unsubstituted C1-C5.

[0112] or R 10 and R 11Linked to form substituted or unsubstituted C3-C8 heterocycles (e.g., piperazine, piperidine).

[0113] The substitutions include: F, Cl, Br, I, OH, SH, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain 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;

[0114] m, n, l, and k are each an independent integer between 0 and 4 (e.g., 0, 1, or 2);

[0115] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0116] In various embodiments, the present invention relates to a compound represented by the structure of Formula III:

[0117]

[0118] in

[0119] The B ring 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 ring. 10 Cycloalkyl (e.g., cyclohexyl, cyclopentyl), or single or fused C3-C 10 Heterocyclic compounds (e.g., piperidine, tetrahydro-2H-pyran);

[0120] L1 is CH2, CHR, C(R)2, or C=O;

[0121] R1 and R2 are independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyridine), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0122] Or R2 and R1 can be linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0123] R3, R4, and R5 are each independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, and -R8-OR. 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0124] Or R3 and R4 are linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0125] R 20 It can be represented by the following structure:

[0126]

[0127] X1 is N or CC(R) (e.g., CH, C-OH);

[0128] X2 is NH, S, O, NR (e.g., N-CH2-CH2-O-CH3);

[0129] X3 is N, C(R) (e.g., CH, C-CH3, C-Cl, C-CN);

[0130] X4, X5, X6, and X7 are each independently C or N;

[0131] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 straight-chain or branched substituted or unsubstituted alkyl group (e.g., methyl, ethyl), C1-C5 straight-chain or branched alkoxy group, -R8-OR 10 (e.g., CH2-CH2-O-CH3), C1-C5 straight-chain or branched haloalkyl groups (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 groups (e.g., phenyl), substituted or unsubstituted heteroaryl groups (e.g., pyridine (2, 3, and 4-pyridine)); or

[0132] Two twin R-substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0133] R8 is [CH2] p

[0134] Where p is between 1 and 10 (e.g., 2);

[0135] R9 is [CH] q [C] q

[0136] Where q is between 2 and 10;

[0137] R 10 and R 11 Each is independently a straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a straight-chain or branched alkoxy group (e.g., O-CH3), a C(O)R, or a S(O)2R, with or without H, substituted or unsubstituted C1-C5.

[0138] or R 10 and R 11 Linked to form substituted or unsubstituted C3-C8 heterocycles (e.g., piperazine, piperidine).

[0139] The substitutions include: F, Cl, Br, I, OH, SH, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain 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;

[0140] m, n, l, and k are each an independent integer between 0 and 4 (e.g., 0, 1, or 2);

[0141] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0142] In various embodiments, if X3 is N, then X2 is not NH.

[0143] In various embodiments, the present invention relates to a compound represented by the structure of formula IV:

[0144]

[0145] in

[0146] 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 ring. 10 cycloalkyl, or single or fused C3-C 10 Heterocyclic compounds (e.g., piperidine, tetrahydro-2H-pyran);

[0147] L1 is CH2, CHR, C(R)2, or C=O;

[0148] R1 and R2 are independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyridine), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0149] Or R2 and R1 can be linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0150] R3, R4, and R5 are each independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, and -R8-OR. 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0151] Or R3 and R4 are linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0152] R 20 It can be represented by the following structure:

[0153]

[0154] X1 is N or CC(R) (e.g., CH, C-OH);

[0155] X8, X9, X 10 、X11 and X 12 Each can be either C or N independently;

[0156] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 straight-chain or branched substituted or unsubstituted alkyl group (e.g., methyl, ethyl), C1-C5 straight-chain or branched alkoxy group, -R8-OR 10 (e.g., CH2-CH2-O-CH3), C1-C5 straight-chain or branched haloalkyl groups (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 groups (e.g., phenyl), substituted or unsubstituted heteroaryl groups (e.g., pyridine (2, 3, and 4-pyridine)); or

[0157] Two twin R-substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0158] R8 is [CH2] p

[0159] Where p is between 1 and 10 (e.g., 2);

[0160] R9 is [CH] q [C] q

[0161] Where q is between 2 and 10;

[0162] R 10 and R 11 Each is independently a straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a straight-chain or branched alkoxy group (e.g., O-CH3), a C(O)R, or a S(O)2R, with or without H, substituted or unsubstituted C1-C5.

[0163] or R 10 and R 11 Linked to form substituted or unsubstituted C3-C8 heterocycles (e.g., piperazine, piperidine).

[0164] The substitutions include: F, Cl, Br, I, OH, SH, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain 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;

[0165] m, n, l, and k are each an independent integer between 0 and 4 (e.g., 0, 1, or 2);

[0166] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0167] In various embodiments, X8, X9, X 10 、X 11 and X 12 At least one of them is N.

[0168] In various embodiments, the present invention relates to a compound represented by the structure of formula V:

[0169]

[0170] in

[0171] L1 is CH2, CHR, C(R)2, or C=O;

[0172] R1 and R2 are independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyridine), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0173] Or R2 and R1 can be linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0174] R3, R4, and R5 are each independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, and -R8-OR. 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0175] Or R3 and R4 are linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0176] R 20 It can be represented by the following structure:

[0177]

[0178] X1 is N or CC(R) (e.g., CH, C-OH);

[0179] X2 is NH, S, O, NR (e.g., N-CH2-CH2-O-CH3);

[0180] X3 is N, C(R) (e.g., CH, C-CH3, C-Cl, C-CN);

[0181] X4, X5, X6, and X7 are each independently C or N;

[0182] X8, X9, X 10 、X 11 and X12 Each can be either C or N independently;

[0183] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 straight-chain or branched substituted or unsubstituted alkyl group (e.g., methyl, ethyl), C1-C5 straight-chain or branched alkoxy group, -R8-OR 10 (e.g., CH2-CH2-O-CH3), C1-C5 straight-chain or branched haloalkyl groups (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 groups (e.g., phenyl), substituted or unsubstituted heteroaryl groups (e.g., pyridine (2, 3, and 4-pyridine)); or

[0184] Two twin R-substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0185] R8 is [CH2] p

[0186] Where p is between 1 and 10 (e.g., 2);

[0187] R9 is [CH] q [C] q

[0188] Where q is between 2 and 10;

[0189] R 10 and R 11 Each is independently a straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a straight-chain or branched alkoxy group (e.g., O-CH3), a C(O)R, or a S(O)2R, with or without H, substituted or unsubstituted C1-C5.

[0190] or R 10 and R 11 Linked to form substituted or unsubstituted C3-C8 heterocycles (e.g., piperazine, piperidine).

[0191] The substitutions include: F, Cl, Br, I, OH, SH, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain 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;

[0192] m, n, l, and k are each an independent integer between 0 and 4 (e.g., 0, 1, or 2);

[0193] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0194] 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.

[0195] In various embodiments, the present invention relates to a compound represented by the structure of formula V(a):

[0196]

[0197]

[0198] in

[0199] L1 is CH2, CHR, C(R)2, or C=O;

[0200] R1 and R2 are independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyridine), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0201] Or R2 and R1 can be linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0202] R3, R4, and R5 are each independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, and -R8-OR. 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0203] Or R3 and R4 are linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0204] R 20 It can be represented by the following structure:

[0205]

[0206] X1 is N or CC(R) (e.g., CH, C-OH);

[0207] X2 is NH, S, O, NR (e.g., N-CH2-CH2-O-CH3);

[0208] X3 is N, C(R) (e.g., CH, C-CH3, C-Cl, C-CN);

[0209] X4, X5, X6, and X7 are each independently C or N;

[0210] X8, X9, X 10 、X 11 and X 12 Each can be either C or N independently;

[0211] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 straight-chain or branched substituted or unsubstituted alkyl group (e.g., methyl, ethyl), C1-C5 straight-chain or branched alkoxy group, -R8-OR 10 (e.g., CH2-CH2-O-CH3), C1-C5 straight-chain or branched haloalkyl groups (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 groups (e.g., phenyl), substituted or unsubstituted heteroaryl groups (e.g., pyridine (2, 3, and 4-pyridine)); or

[0212] Two twin R-substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0213] R8 is [CH2] p

[0214] Where p is between 1 and 10 (e.g., 2);

[0215] R9 is [CH] q [C] q

[0216] Where q is between 2 and 10;

[0217] R 10 and R 11 Each is independently a straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a straight-chain or branched alkoxy group (e.g., O-CH3), a C(O)R, or a S(O)2R, with or without H, substituted or unsubstituted C1-C5.

[0218] or R 10 and R 11 Linked to form substituted or unsubstituted C3-C8 heterocycles (e.g., piperazine, piperidine).

[0219] The substitutions include: F, Cl, Br, I, OH, SH, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain 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;

[0220] m, n, l, and k are each an independent integer between 0 and 4 (e.g., 0, 1, or 2);

[0221] W is 0, 1, or 2; where if w = 0, then there is no bridge on the ring.

[0222] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (e.g., deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0223] 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.

[0224] In various embodiments, the present invention relates to a compound represented by the structure of formula VI:

[0225]

[0226] in

[0227] L1 is CH2, CHR, C(R)2, or C=O;

[0228] 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 heterocyclic), 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-chain 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyridine), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0229] 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 heterocyclic), 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-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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0230] R 20 It can be represented by the following structure:

[0231]

[0232] X2 is NH, S, O, NR (e.g., N-CH2-CH2-O-CH3);

[0233] X3 is N, C(R) (e.g., CH, C-CH3, C-Cl, C-CN);

[0234] X8, X9, X 10 、X 11 and X 12 Each can be either C or N independently;

[0235] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 straight-chain or branched substituted or unsubstituted alkyl group (e.g., methyl, ethyl), C1-C5 straight-chain or branched alkoxy group, -R8-OR 10(e.g., CH2-CH2-O-CH3), C1-C5 straight-chain or branched haloalkyl groups (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 groups (e.g., phenyl), substituted or unsubstituted heteroaryl groups (e.g., pyridine (2, 3, and 4-pyridine)); or

[0236] Two twin R-substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0237] R8 is [CH2] p

[0238] Where p is between 1 and 10 (e.g., 2);

[0239] R9 is [CH] q [C] q

[0240] Where q is between 2 and 10;

[0241] R 10 and R 11 Each is independently a straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a straight-chain or branched alkoxy group (e.g., O-CH3), a C(O)R, or a S(O)2R, with or without H, substituted or unsubstituted C1-C5.

[0242] or R 10 and R 11 Linked to form substituted or unsubstituted C3-C8 heterocycles (e.g., piperazine, piperidine).

[0243] The substitutions include: F, Cl, Br, I, OH, SH, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain 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;

[0244] n and l are each an independent integer between 0 and 4 (e.g., 0, 1, or 2);

[0245] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0246] 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;

[0247] In various embodiments, the present invention relates to a compound represented by the structure of formula VII:

[0248]

[0249] in

[0250] L1 is CH2, CHR, C(R)2, or C=O;

[0251] R1, R2, and R6 are each independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, or -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 heterocyclic), 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-chain or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R) 10 (R) 11SO2R, SO2N(R) 10 (R) 11 ), NHSO2(R 10 (e.g., NHSO2CH3), CH(CF3)(NH-R) 10 ), C1-C5 straight-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyridine), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0252] Or R2 and R1 can be linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0253] Or R1 and R6 can be linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0254] R3 and R4 are independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, and -R8-OR. 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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 10C1-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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0255] Or R3 and R4 are linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0256] R 20 It can be represented by the following structure:

[0257]

[0258] X2 is NH, S, O, NR (e.g., N-CH2-CH2-O-CH3);

[0259] X3 is N, C(R) (e.g., CH, C-CH3, C-Cl, C-CN);

[0260] X 10 and X 12 Each can be either C or N independently;

[0261] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 straight-chain or branched substituted or unsubstituted alkyl group (e.g., methyl, ethyl), C1-C5 straight-chain or branched alkoxy group, -R8-OR 10(e.g., CH2-CH2-O-CH3), C1-C5 straight-chain or branched haloalkyl groups (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 groups (e.g., phenyl), substituted or unsubstituted heteroaryl groups (e.g., pyridine (2, 3, and 4-pyridine)); or

[0262] Two twin R-substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0263] R8 is [CH2] p

[0264] Where p is between 1 and 10 (e.g., 2);

[0265] R9 is [CH] q [C] q

[0266] Where q is between 2 and 10;

[0267] R 10 and R 11 Each is independently a straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a straight-chain or branched alkoxy group (e.g., O-CH3), a C(O)R, or a S(O)2R, with or without H, substituted or unsubstituted C1-C5.

[0268] or R 10 and R 11 Linked to form substituted or unsubstituted C3-C8 heterocycles (e.g., piperazine, piperidine).

[0269] The substitutions include: F, Cl, Br, I, OH, SH, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain 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;

[0270] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0271] In various embodiments, if X3 is N, then X2 is not NH.

[0272] In various embodiments, X8, X9, X 10 、X 11 and X 12 At least one of them is N.

[0273] In various embodiments, X 10 and X 12 At least one of them is N.

[0274] In various embodiments, the present invention relates to a compound represented by the structure of formula VIII:

[0275]

[0276] in

[0277] 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-chain 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 straight-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2);

[0278] 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-chain 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 straight-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2);

[0279] 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 straight-chain, branched, or cyclic haloalkyl groups (e.g., CHF2);

[0280] 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 straight-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl);

[0281] 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 straight-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl);

[0282] R 20 It can be represented by the following structure:

[0283]

[0284] X2 is NH, S, or O;

[0285] X3 is N, CH, or C-Cl;

[0286] X 10 and X 12 Each is independently either C or N; at least one of them is N;

[0287] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 straight-chain or branched substituted or unsubstituted alkyl group (e.g., methyl, ethyl), C1-C5 straight-chain or branched alkoxy group, -R8-OR 10(e.g., CH2-CH2-O-CH3), C1-C5 straight-chain or branched haloalkyl groups (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 groups (e.g., phenyl), substituted or unsubstituted heteroaryl groups (e.g., pyridine (2, 3, and 4-pyridine)); or

[0288] Two twin R-substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0289] R8 is [CH2] p

[0290] Where p is between 1 and 10 (e.g., 2);

[0291] R9 is [CH] q [C] q

[0292] Where q is between 2 and 10;

[0293] R 10 and R 11 Each is independently a straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a straight-chain or branched alkoxy group (e.g., O-CH3), a C(O)R, or a S(O)2R, with or without H, substituted or unsubstituted C1-C5.

[0294] or R 10 and R 11 Linked to form substituted or unsubstituted C3-C8 heterocycles (e.g., piperazine, piperidine).

[0295] The substitutions include: F, Cl, Br, I, OH, SH, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain 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;

[0296] If X3 is N, then X2 is not NH;

[0297] And X 10 and X 12 At least one of them is N;

[0298] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0299] In some embodiments, compounds of formulas I-VIII No It is 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole. In some embodiments, compounds of formulas I-VIII No It is PF-4708671.

[0300] In some embodiments, compounds of formulas I-VIII No It is a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), reverse amide, or 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzimidazole pharmaceutical product.

[0301] In some embodiments, if X3 of formula III and / or V-VIII is N, then X2 is not NH.

[0302] 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).

[0303] In some embodiments, X of formula IV-VIII 10 and X 12 At least one of them is N.

[0304] In some embodiments, if R2 of formulas I-VIII is CF3, then R3 is not ethyl.

[0305] In some embodiments, if R3 of formulas I-VIII is ethyl, then R2 is not CF3.

[0306] In some embodiments, at least one of R1 and R2 in formulas I-VIII is not H. In some embodiments, R1, R2, and R6 in formulas I-VIII are H. In some embodiments, R1, R2, or R6 is CF3. In some embodiments, R1, R2, or R6 is Cl. In some embodiments, R1, R2, or R6 is CN. In some embodiments, R1, R2, or R6 is NHC(O)Ph.

[0307] In some implementations, R3 is H, Cl, F, CF3, CHF2, CN, C(O)H, OR 20 CH3, C2H5, -R8-OR 10 , CH2-O-CH2-CH2-O-CH3, -O-R8-OR 10 Or O-CH2-CH2-O-CH3.

[0308] In some implementations, R1 is H, Cl, F, CN, CHF2, NH(CO)-Ph, -R8-OR 10 , CH2-O-CH2-CH2-O-CH3, -O-R8-OR 10 O-CH2-CH2-O-CH3, OR 20 Or CF3.

[0309] In some implementations, X2 is NH or O and X3 is CH or C-Cl.

[0310] In some implementations, L1 is CH2 and / or w is 1 or 0.

[0311] In some embodiments, at least one of R3 and R4 in formulas I-VIII is not H. In some embodiments, both R3 and R4 are methyl. In some embodiments, both R3 and R4 are H. In some embodiments, R3 is ethyl.

[0312] In some embodiments, R6 in formulas VII and VIII is Cl. In some embodiments, R6 is H.

[0313] In various embodiments, the present invention relates to a compound represented by the structure of formula IX:

[0314]

[0315] in

[0316] R1, R2, and R6 are each independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, or -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 heterocyclic), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R) 10 (R) 11 ), R9-R8-N(R10 (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-chain 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyridine), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0317] Or R2 and R1 can be linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0318] Or R1 and R6 can be linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., pyridine);

[0319] R3, R4, and R5 are each independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, and -R8-OR. 10(e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(C3-C8 heterocyclic), 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (e.g., CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups;

[0320] Or R3 and R4 are linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0321] X 10 and X 12 Each can be either C or N independently;

[0322] R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 straight-chain or branched substituted or unsubstituted alkyl group (e.g., methyl, ethyl), C1-C5 straight-chain or branched alkoxy group, -R8-OR 10 (e.g., CH2-CH2-O-CH3), C1-C5 straight-chain or branched haloalkyl groups (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 groups (e.g., phenyl), substituted or unsubstituted heteroaryl groups (e.g., pyridine (2, 3, and 4-pyridine)); or

[0323] Two twin R-substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0324] R8 is [CH2] p

[0325] Where p is between 1 and 10 (e.g., 2);

[0326] R9 is [CH] q [C] q

[0327] Where q is between 2 and 10;

[0328] R 10 and R 11 Each is independently a straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a straight-chain or branched alkoxy group (e.g., O-CH3), a C(O)R, or a S(O)2R; or R 10 and R 11 Linked to form substituted or unsubstituted C3-C8 heterocycles (e.g., piperazine, piperidine).

[0329] The substitutions include: F, Cl, Br, I, OH, SH, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain 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;

[0330] And X 10 and X 12At least one of them is N;

[0331] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0332] In some embodiments, if R3 is ethyl, then R2 is not CF3.

[0333] In some embodiments, if R2 is a CF 3， Therefore, R3 is not an ethyl group.

[0334] In some embodiments, at least one of R1, R2, R3, R4, and R6 is not H.

[0335] In some embodiments, at least one of R1, R2, and R6 is not H.

[0336] 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 is CF3. In some embodiments, R1, R2, or R6 is Cl. In some embodiments, R1, R2, or R6 is CN. In some embodiments, R1, R2, or R6 is NHC(O)Ph.

[0337] In some embodiments, at least one of R3 and R4 is not H. In some embodiments, both R3 and R4 are methyl. In some embodiments, both R3 and R4 are H. In some embodiments, R3 is ethyl.

[0338] In some embodiments, R6 is Cl. In some embodiments, R6 is H.

[0339] In some embodiments, compounds No It 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.

[0340] In some embodiments, compounds No It is a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), or pharmaceutical product of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzimidazole.

[0341] In various embodiments, the present invention relates to a compound represented by the structure of formula X:

[0342]

[0343] in

[0344] R1 and R2 are independently H, Cl, F, -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), OR 20 CHF2 or CF3;

[0345] R3 and R4 are independently H, Cl, F, OR 20 CHF2, CF3, C1-C5 straight-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), substituted or unsubstituted C3-C8 heterocycles (e.g., imidazole), (wherein the substitutions include: F, Cl, Br, I, C1-C5 straight-chain or branched alkyl groups, OH, alkoxy, CF3, aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO2 or any combination thereof);

[0346] Or R3 and R4 are linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic (e.g., cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole);

[0347] R 20 It can be represented by the following structure:

[0348]

[0349] X 12 It is C or N;

[0350] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

[0351] 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 either R2 or R1 is not CF3.

[0352] In some embodiments, if R2 is a CF 3， 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.

[0353] In some embodiments, at least one of R1, R2, R3, and R4 is not H.

[0354] In some embodiments, at least one of R1 and R2 is not H. In some embodiments, both R1 and R2 are 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.

[0355] In some embodiments, at least one of R3 and R4 is not H. In some embodiments, both R3 and R4 are methyl. In some embodiments, both R3 and R4 are H. In some embodiments, R3 is ethyl.

[0356] In some embodiments, R6 is Cl. In some embodiments, R6 is H.

[0357] In some embodiments, compounds No It 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.

[0358] In some embodiments, compounds No It is a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), or pharmaceutical product of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzimidazole.

[0359] In some embodiments, A in formulas 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 indole. 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]m-dioxane. 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 Cycloalkyl ring. In other embodiments, A is cyclohexyl.

[0360] In some embodiments, B in 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 indole. In other embodiments, B is benzimidazolyl. In other embodiments, B is benzothiazolyl. In other embodiments, B is quinoxalinyl. In other embodiments, B is tetrahydronaphthyl. In other embodiments, B is quinolinyl. In other embodiments, B is isoquinolinyl. In other embodiments, B is indene. 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 Cycloalkyl ring. In other embodiments, B is cyclohexyl.

[0361] In some embodiments, X1 of 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.

[0362] In some embodiments, X2 of 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.

[0363] In some embodiments, X3 of 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.

[0364] In each embodiment, if X3 of the compounds of formulas III, V, V(a), VI, VII and / or VIII is N, then X2 is not NH.

[0365] In some embodiments, X4 of compounds of formula III, V and / or V(a) is C. In other embodiments, X4 is N.

[0366] In some embodiments, X5 of compounds of formula III, V and / or V(a) is C. In other embodiments, X5 is N.

[0367] In some embodiments, X6 of compounds of formula III, V and / or V(a) is C. In other embodiments, X6 is N.

[0368] In some embodiments, X7 of compounds of formula III, V and / or V(a) is C. In other embodiments, X7 is N.

[0369] In some embodiments, X8 of compounds of formulas IV, V, V(a) and / or VI is C. In other embodiments, X8 is N.

[0370] In some embodiments, X9 of compounds of formulas IV, V, V(a) and / or VI is C. In other embodiments, X9 is N.

[0371] In some embodiments, the X of compounds of formulas IV-VIII and / or IX 10 It is C. In other embodiments, X 10 It's N.

[0372] In some embodiments, the X of compounds of formulas IV, V, V(a) and / or VI 11 It is C. In other embodiments, X 11 It's N.

[0373] In some embodiments, the X of compounds of formulas IV-VIII, IX, V and / or V(a) 12 It is C. In other embodiments, X 12 It's N.

[0374] In some embodiments, at least one of X4-X7 is N.

[0375] In some embodiments, X8-X 12 At least one of them is N. In some embodiments, X8-X 12 At least two of them are N.

[0376] It should be understood that if X4-X 12 If any one of them is N, then none of R1-R4 can be connected to it.

[0377] In some embodiments, R1 in 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.

[0378] In some embodiments, R1 of formulas I-IX is H. In some embodiments, R1 is a C1-C5 straight-chain 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.

[0379] In other embodiments, R1 in formulas 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 heterocyclic). In other embodiments, R1 is CH2-imidazolium. 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 a C1-C5 straight-chain, branched, or cyclic haloalkyl group. 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 10In other embodiments, R1 is NHSO2CH3. In other embodiments, R1 is a C1-C5 straight-chain 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 straight-chain 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 straight-chain, 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-oxacyclobutyl. In other embodiments, R1 is O-2-oxacyclobutyl. 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 straight-chain, branched, or cyclic alkoxy group, wherein at least one methylene (CH2) group of the alkoxy group is replaced by an oxygen atom (O). In other embodiments, R1 is O-1-oxetanebutyl. In other embodiments, R1 is O-2-oxetanebutyl. In other embodiments, R1 is a C1-C5 straight-chain 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 a phenyl group. In other embodiments, R1 is a substituted or unsubstituted C3-C8 heterocycle. In other embodiments, R1 is an oxazole. In other embodiments, R1 is a methyl-substituted oxazole. In other embodiments, R1 is an oxadiazole. In other embodiments, R1 is a methyl-substituted oxadiazole. In other embodiments, R1 is an imidazole. In other embodiments, R1 is a methyl-substituted imidazole.In other embodiments, R1 is pyridine. In other embodiments, R1 is 2-pyridine. In other embodiments, R1 is 3-pyridine. In other embodiments, R1 is 4-pyridine. In other embodiments, R1 is tetrazolium. 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 protonated pyridine oxide. In other embodiments, R1 is 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 a substituted or unsubstituted aryl group. In other embodiments, R1 is phenyl. In other embodiments, R1 is bromophenyl. In other embodiments, R1 is 2-bromophenyl. In other embodiments, R1 is 3-bromophenyl. In other embodiments, R1 is 4-bromophenyl. In other embodiments, R1 is a substituted or unsubstituted benzyl group. 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, substitutions include: C1-C5 straight-chain or branched alkyl groups (e.g., methyl), aryl, phenyl, heteroaryl (e.g., imidazole) and / or C3-C8 cycloalkyl groups, each being a separate embodiment of the invention.

[0380] In some embodiments, R2 in 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.

[0381] In some embodiments, R2 of formulas I-IX is H. In some embodiments, R2 is a C1-C5 straight-chain 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.

[0382] In some embodiments, R2 in formulas 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 heterocyclic). In other embodiments, R2 is CH2-imidazolium. 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 a C1-C5 straight-chain, branched, or cyclic haloalkyl group. 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 straight-chain 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 straight-chain 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 straight-chain, 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-oxacyclobutyl. In other embodiments, R2 is O-2-oxacyclobutyl. In other embodiments, R2 is 1-butoxy. In other embodiments, R2 is 2-butoxy. In other embodiments, R2 is O-tert-butyl. In other embodiments, R2 is a C1-C5 straight-chain or branched haloalkoxy group. 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 an oxazole or a methyl-substituted oxazole. In other embodiments, R2 is an oxadiazole or a methyl-substituted oxadiazole. In other embodiments, R2 is an 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 a tetrazolium. In other embodiments, R2 is a pyrimidine. In other embodiments, R2 is a pyrazine. In other embodiments, R2 is an oxetane. In other embodiments, R2 is 1-oxetane. In other embodiments, R2 is 2-oxetane. In other embodiments, R2 is indole. In other embodiments, R2 is a pyridine oxide. In other embodiments, R2 is a protonated pyridine oxide. In other embodiments, R2 is a deprotonated pyridine oxide. In other embodiments, R2 is 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 a phenyl group. In other embodiments, R2 is a bromophenyl group. In other embodiments, R2 is a 2-bromophenyl group. In other embodiments, R2 is a 3-bromophenyl group. In other embodiments, R2 is a 4-bromophenyl group. In other embodiments, R2 is a substituted or unsubstituted benzyl group. In other embodiments, R2 is a benzyl group. In other embodiments, R2 is R8-N(R 10 (R) 11 In other embodiments, R2 is CH2-NH2. In other embodiments, substitutions include: C1-C5 straight-chain or branched alkyl groups (e.g., methyl), aryl, phenyl, heteroaryl (e.g., imidazole) and / or C3-C8 cycloalkyl groups, each being a separate embodiment of the invention.

[0383] In some embodiments, R1 and R2 of formulas 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]-dioxane ring. In some embodiments, R1 and R2 are linked together to form a furanone ring (e.g., furan-2(3H)-one).

[0384] In some embodiments, R3 of formula X is H. In other embodiments, R3 is a C1-C5 straight-chain 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.

[0385] In some embodiments, R3 in 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 a C1-C5 straight-chain or branched C(O)-haloalkyl group. 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 straight-chain 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 straight-chain, 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 straight-chain, branched, or cyclic alkoxy group. In other embodiments, R3 is a methoxy group. In other embodiments, R3 is an isopropoxy group. In other embodiments, R3 is a substituted or unsubstituted C3-C8 cycloalkyl group. In other embodiments, R3 is a cyclopropyl group. In other embodiments, R3 is a cyclopentyl group. In other embodiments, R3 is a substituted or unsubstituted C3-C8 heterocyclic group. In other embodiments, R3 is a pyrazole. In other embodiments, R3 is a thiazole. In other embodiments, R3 is a thiophene. In other embodiments, R3 is an oxazole. In other embodiments, R3 is an isoxazole. In other embodiments, R3 is an imidazole. In other embodiments, R3 is a furan. In other embodiments, R3 is a triazole. In other embodiments, R3 is a pyridine. In other embodiments, R3 is a 2-pyridine. In other embodiments, R3 is a 3-pyridine. In other embodiments, R3 is 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 a substituted or unsubstituted aryl group. In other embodiments, R3 is phenyl. In other embodiments, R3 is CH(CF3)(NH-R 10 ).

[0386] In some embodiments, R4 of formula X is H. In other embodiments, R4 is a C1-C5 straight-chain 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 formula 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 a C1-C5 straight-chain or branched C(O)-haloalkyl group. 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 straight-chain 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 straight-chain, 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 straight-chain, branched, or cyclic alkoxy group. In other embodiments, R4 is a methoxy group. In other embodiments, R4 is an isopropoxy group. In other embodiments, R4 is a substituted or unsubstituted C3-C8 cycloalkyl group. In other embodiments, R4 is a cyclopropyl group. In other embodiments, R4 is a cyclopentyl group. In other embodiments, R4 is a substituted or unsubstituted C3-C8 heterocyclic group. In other embodiments, R4 is a pyrazole group. In other embodiments, R4 is a thiazole group. In other embodiments, R4 is a thiophene group. In other embodiments, R4 is an oxazole group. In other embodiments, R4 is an isoxazole group. In other embodiments, R4 is an imidazole group. In other embodiments, R4 is a furan group. In other embodiments, R4 is a triazole group. In other embodiments, R4 is a pyridine group. In other embodiments, R4 is a 2-pyridine group. In other embodiments, R4 is a 3-pyridine group. 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 a substituted or unsubstituted aryl group. In other embodiments, R4 is phenyl. In other embodiments, R4 is CH(CF3)(NH-R 10 ).

[0387] In some embodiments, R5 in formulas 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 a C1-C5 straight-chain or branched C(O)-haloalkyl group. 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 straight-chain 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 straight-chain, 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 straight-chain, 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 a substituted or unsubstituted aryl group. In other embodiments, R5 is phenyl. In other embodiments, R5 is CH(CF3)(NH-R 10 ).

[0388] In some embodiments, R3 and R4 of formulas I, I(a), II, III, IV, V, and V(a) are linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic ring. In some embodiments, R3 and R4 are linked together to form a cyclopentene. In some embodiments, R3 and R4 are linked together to form an aromatic carbide ring. In some embodiments, R3 and R4 are linked together to form a benzene. In some embodiments, R3 and R4 are linked together to form an aromatic heterocycle. In some embodiments, R3 and R4 are linked together to form a thiophene. In some embodiments, R3 and R4 are linked together to form a furan. In some embodiments, R3 and R4 are linked together to form a pyrrole. In some embodiments, R3 and R4 are linked together to form a pyrazole ring, a [1,3]-dioxane ring. In some embodiments, R3 and R4 are linked together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R3 and R4 are linked together to form a cyclopentene ring. In some embodiments, R3 and R4 are linked together to form an imidazole ring.

[0389] 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, a C1-C5 straight-chain or branched substituted or unsubstituted alkyl group, or a methyl group; each representing a separate embodiment according to the invention. In other embodiments, two twin R substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic ring. In other embodiments, two twin R substitutions are linked together to form a cyclopropyl ring.

[0390] In some embodiments, L2 in 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.

[0391] In some embodiments, R in 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 a C1-C5 straight-chain or branched substituted or unsubstituted alkyl group. In other embodiments, R is methyl. In other embodiments, R is ethyl. In other embodiments, R is a C1-C5 straight-chain or branched alkoxy group. 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-chain 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 a substituted or unsubstituted aryl group. In other embodiments, R is phenyl. In other embodiments, R is a substituted or unsubstituted heteroaryl group. In other embodiments, R is pyridine. In other embodiments, R is 2-pyridine, 3-pyridine, or 4-pyridine. In other embodiments, two twin R substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic or aromatic, carbocyclic or heterocyclic ring. In other embodiments, two twin R substitutions are linked together to form a 3- to 6-membered aliphatic ring. In other embodiments, two twin R substitutions are linked 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-chain or branched alkyl, OH, alkoxy, N(R)2, CF3, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2; each representing a separate embodiment according to the invention.

[0392] In some embodiments, R8 in formulas I-IX is CH2. In other embodiments, R8 is CH2CH2. In other embodiments, R8 is CH2CH2CH2.

[0393] In some embodiments, p in formulas I-IX is 1. In other embodiments, p is 2. In other embodiments, p is 3.

[0394] In some embodiments, R9 of formulas I-IX is C≡C.

[0395] In some embodiments, q in equation I-IX is 2.

[0396] In some embodiments, R of formulas I-IX 10 It is a C1-C5 substituted or unsubstituted straight-chain or branched alkyl group. In other embodiments, R 10 It is H. In other embodiments, R 10 It is CH3. In other embodiments, R 10 It is CH2CH3. In other embodiments, R 10 It is CH2CH2CH3. In other embodiments, R 10It is CH2-CH2-O-CH3. In other embodiments, R 10 It is a C1-C5 straight-chain or branched alkoxy group. In other embodiments, R 10 It's O-CH3.

[0397] In some embodiments, R of formulas I-IX 11 It is a C1-C5 straight-chain or branched alkyl group. In other embodiments, R 10 It is H. In other embodiments, R 11 It is CH3.

[0398] In some embodiments, R of formulas I-IX 10 and R 11 The linkage forms substituted or unsubstituted C3-C8 heterocycles. In other embodiments, R 10 and R 11 Connect to form a piperazine ring. In other embodiments, R 10 and R 11 Linkage is used to form a piperidine ring. In some embodiments, substitutions include: F, Cl, Br, I, OH, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycles (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof; each representing a separate embodiment according to the invention.

[0399] In some embodiments, m in formula IV is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0400] In some embodiments, n is 0 in formulas I-VI. In other embodiments, n is 1. In other embodiments, n is 2.

[0401] In some embodiments, k in formula IV is 0. In other embodiments, k is 1. In other embodiments, k is 2.

[0402] In some embodiments, l in formulas I-VI is 0. In other embodiments, l is 1. In other embodiments, l is 2.

[0403] In some embodiments, w in equations I(a) and / or V(a) is 0 and the bridging portion is absent. In other embodiments, w is 1. In other embodiments, w is 2.

[0404] In various embodiments, the present invention relates to the compounds presented in Table 1, their pharmaceutical compositions, and / or methods of use:

[0405] Table 1:

[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]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441] As is well known, in the structures presented in this invention where carbon atoms have fewer than four bonds, H atoms are present to complete the valence of carbon. As is well known, in the structures presented in this invention where nitrogen atoms have fewer than three bonds, H atoms are present to complete the valence of nitrogen.

[0442] In some embodiments, the present invention relates to the compounds listed above, pharmaceutical compositions thereof, and / or methods of use, wherein the compounds are pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N-oxides, prodrugs, isotope variants (deuterated analogs), pharmaceutical products, or any combination thereof. In some embodiments, the compounds are collagen I translation inhibitors.

[0443] In various embodiments, ring A of formulas I, I(a), II, and / or IV is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, tetraazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazolyl, isoquinoline, pyrazolyl, pyrroleyl, furanyl, thiophene, isoquinoline, indoleyl, 1H-indole, isoyndoleyl, naphthyl, anthraceneyl, benzimidazolyl, indoleyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indole-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzoisoxazolyl, benzothiazolyl, 1,3-benzothiazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indole-3-one, purineyl, benzoxazolyl, 1,3-benzoxazolyl, benzoisoxazolyl, benzothiazolyl, 1,3-benzothiazolyl, 4,5,6,7-tetrahydro -1,3-Benzothiazole, quinazolinyl, quinoxalinyl, cycloazinyl, phthalazinyl, quinolinyl, isoquinolinyl, 2,3-dihydroindene, indene, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxacycloheptene, benzo[d][1,3]m-dioxacyclopentene, acridineyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzofuran-2(3H)-one, benzothiophene, benzooxadiazole, benzo[c][1,2,5]oxadiazoleyl, benzo[c]thiopheneyl, benzo[m-dioxacyclopentenyl, benzo[d][1,3]m-dioxacyclopentene, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiazoleyl, imidazole [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]thiazo[4,5-d]pyrimidine, [1,3]thiazo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2-d]pyrimidine-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, quinoxaline-2(1H)-one, pyrrolopyridine, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazo[5,4-b]pyridine, thieno[3,2-c]pyridine, each representing a separate embodiment according to the invention;A may be a C3-C8 cycloalkyl (e.g., cyclohexyl, cyclopentyl) or a C3-C8 heterocycle, including but not limited to: tetrahydropyran, piperidine, 1-piperacline, tetrahydrothiophene 1,1-dioxide, 1-(piperidin-1-yl)acetone, or morpholine; each representing a separate embodiment according to the invention. In some embodiments, A is a C3-C8 heterocycle.

[0444] In various embodiments, the B ring of formulas I, I(a), II, III and / or IV is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetraazinyl, thiazolyl, isothiazinyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazolium, isoquinoline, pyrazolyl, pyrroleyl, triazolyl, furanyl, thiophene-yl, isoquinoline, indoleyl, 1H-indole, isoydinolyl, naphthyl, anthraceneyl, benzimidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, tetrahydronaphthyl-3,4-dihydro-2H-benzo[b][1,4]dioxane-heptene, benzofuran-2(3H)-one, benzo[d][1,3]m-dioxane-pentene, indazole, 2H-indazole, triazolyl, 4,5,6 7-Tetrahydro-2H-indazole, 3H-indol-3-one, purine group, benzoxazolyl group, 1,3-benzoxazolyl group, benzoisoxazolyl group, benzothiazolyl group, 1,3-benzothiazolyl group, 4,5,6,7-tetrahydro-1,3-benzothiazolyl group, quinazolinyl group, quinoxalinyl group, cycloazinyl group, phthalazinyl group, quinolinyl group, isoquinolinyl group, acridineyl group, benzofuranyl group, 1-benzene benzofuran, isobenzofuranyl, benzothiophene, benzoxadiazole, benzo[c][1,2,5]oxadiazoleyl, benzo[c]thiophene, benzo[m]dioxacyclopentenyl, thiadiazolyl, [1,3]oxazol[4,5-b]pyridine, oxadiazoleyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenten[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazo[4,5-d]pyrimidine, [1,3]thiazo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazo[3,2-d]pyrimidine-4(3H)-one, 4 -O-4H-thiopheno[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]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, quinoxaline-2(1H)-one, 1,2,3,4-tetrahydroquinoxaline, 1-(pyridin-1(2H)-yl)acetone, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazo[5,4-b]pyridine, thieno[3,2-c]pyridine, C3-C8 cycloalkyl or C3-C8 heterocycle, including but not limited to: tetrahydropyran, piperidine, 1-piperacline, tetrahydrothiophene 1,1-dioxide, 1-(piperidin-1-yl)acetone or morpholine;Each represents a separate embodiment of the invention. In some embodiments, B is a C3-C8 heterocycle. In some embodiments, B is a pyrimidine.

[0445] In various embodiments, compounds of formulas I, I(a), II, III, IV, V, V(a) and / or VI are substituted with R1, R2, R3, R4 and R5. A single substituent may be present at the ortho, meta or para position.

[0446] In each embodiment, R1 and / or R2 of formula I-IX are each independently H.

[0447] In each embodiment, R1 of formulas I, I(a), II, III, IV, V, V(a) and / or VI and / or R2 of formulas 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 heterocyclic), 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-chain 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 The following are examples of substituted or unsubstituted alkyl groups (e.g., methyl, ethyl) of C1-C5 straight or branched chains, substituted or unsubstituted alkenyl groups of C1-C5 straight, branched or cyclic haloalkyl groups (CHF2), C1-C5 straight, branched or cyclic alkoxy groups (e.g., methoxy), wherein optionally at least one methylene group (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight or branched thioalkoxy groups, C1-C5 straight or branched haloalkoxy groups, C1-C5 straight or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyridine), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups; each representing a separate embodiment according to the invention. In some embodiments, the substitutions include at least one of the following: F, Cl, Br, I, C1-C5 straight-chain 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 invention.

[0448] In some embodiments, R1 and R2 are linked 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 linked together to form a 5- or 6-membered heterocyclic ring. In some embodiments, R1 and R2 are linked together to form a pyrrole ring. In some embodiments, R1 and R2 are linked together to form a [1,3]-dioxacyclopentene ring. In some embodiments, R1 and R2 are linked together to form a furan-2(3H)-one 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 morpholine ring. In some embodiments, R1 and R2 are linked together to form a piperazine ring. In some embodiments, R1 and R2 are linked together to form an imidazole ring. In some embodiments, R1 and R2 are linked together to form a pyrrole ring. In some embodiments, R1 and R2 are linked together to form a cyclohexene ring. In some embodiments, R1 and R2 are linked together to form a pyrazine ring.

[0449] In various embodiments, compounds of formulas I, I(a), II, III, IV, V, V(a), and / or VI are substituted with R3 and / or R4. A single substituent may be present at the ortho, meta, or para position.

[0450] In each embodiment, R3 of formulas 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 heterocyclic), 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-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C1-C5 straight-chain or branched substituted or unsubstituted alkenyl groups, C1-C5 straight-chain, branched or cyclic haloalkyl groups (CHF2), C1-C5 straight-chain, branched or cyclic alkoxy groups (e.g., methoxy), optionally wherein at least one methylene group (CH2) of the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched thioalkoxy groups, C1-C5 straight-chain or branched haloalkoxy groups, C1-C5 straight-chain or branched alkoxyalkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycles (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups. In each embodiment, R3, R4, or R5 may each be further substituted independently with at least one of the following: F, Cl, Br, I, C1-C5 straight-chain 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 invention.

[0451] In some embodiments, R3 and R4 are linked 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 linked together to form a 5- or 6-membered carbocyclic ring. In some embodiments, R3 and R4 are linked together to form a 5- or 6-membered heterocyclic ring. In some embodiments, R3 and R4 are linked together to form a meta-dioxane ring. [1,3] meta-dioxane ring. In some embodiments, R3 and R4 are linked together to form a dihydrofuran-2(3H)-one ring. In some embodiments, R3 and R4 are linked together to form a furan-2(3H)-one ring. In some embodiments, R3 and R4 are linked together to form a benzene ring. In some embodiments, R3 and R4 are linked together to form an imidazole ring. In some embodiments, R3 and R4 are linked together to form a pyridine ring. In some embodiments, R3 and R4 are linked together to form a thiophene ring. In some embodiments, R3 and R4 are linked together to form a furan ring. In some embodiments, R3 and R4 are linked together to form a pyrrole ring. In some embodiments, R3 and R4 are joined together to form a pyrazine ring. In some embodiments, R3 and R4 are joined together to form a cyclohexene ring. In some embodiments, R3 and R4 are joined together to form a cyclopentene ring. In some embodiments, R4 and R3 are joined together to form a dioxane-heptene ring.

[0452] In various embodiments, n is 0 for compounds of formulas I, I(a), II, III, IV, V, V(a), and / or VI. 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.

[0453] In various embodiments, m is 0 for compounds of formulas I, I(a), II, III, IV, V, and / or V(a). 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.

[0454] In various embodiments, l is 0 for compounds of formulas I, I(a), II, III, IV, V, V(a), and / or VI. 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.

[0455] In various embodiments, k is 0 for compounds of formulas I, I(a), II, III, IV, V, and / or V(a). 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.

[0456] It should be understood that for heterocycles, n, m, l, and / or k are limited by the number of positions available for substitution, i.e., the number of CH or NH groups minus one. Therefore, if ring A and / or ring B are, for example, furanyl, thiophene, or pyrroleyl, then n, m, l, and k are between 0 and 2; and if ring A and / or ring B are, for example, oxazolyl, imidazolyl, or thiazolyl, then n, m, l, and k are 0 or 1; and if ring A and / or ring B are, for example, oxadiazolyl or thiadiazolyl, then n, m, l, and k are 0.

[0457] 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 CH2CH2CH2CH2.

[0458] In various embodiments, p is 1 for compounds of formulas I-IX. 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.

[0459] In some embodiments, R9 of compounds of formulas 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.

[0460] In some embodiments, q is 2 for compounds of formulas I-IX. 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.

[0461] In each embodiment, the R of the compounds of formulas I-IX 10 It is H. In some embodiments, R 10 It is a substituted or unsubstituted C1-C5 straight-chain or branched alkyl group. In some embodiments, R 10 It is methyl. In some embodiments, R 10 It is ethyl. In some embodiments, R 10 It is propyl. In some embodiments, R 10 It is isopropyl. In some embodiments, R 10 It is butyl. In some embodiments, R 10 It is isobutyl. In some embodiments, R 10 It is tert-butyl. In some embodiments, R 10 It is cyclopropyl. In some embodiments, R 10 It is pentyl. In some embodiments, R 10 It is isopentyl. In some embodiments, R 10 It is neopentyl. In some embodiments, R 10 It is benzyl. In some embodiments, R 10 It is CH2-CH2-O-CH3. In some embodiments, R 10 It is a C1-C5 straight-chain or branched alkoxy group. In some embodiments, R 10 It is O-CH3. In some embodiments, R 10 It is C(O)R. In some embodiments, R 10 It is S(O)2R.

[0462] In each embodiment, the R of the compounds of formulas I-IX 11 It is H. In some embodiments, R 11 It is a C1-C5 straight-chain or branched alkyl group. In some embodiments, R 11 It is methyl. In some embodiments, R 11 It is ethyl. In some embodiments, R 10 It is propyl. In some embodiments, R 11 It is isopropyl. In some embodiments, R 11 It is butyl. In some embodiments, R 11 It is isobutyl. In some embodiments, R 11 It is tert-butyl. In some embodiments, R 11 It is cyclopropyl. In some embodiments, R 11It is pentyl. In some embodiments, R 11 It is isopentyl. In some embodiments, R 11 It is neopentyl. In some embodiments, R 11 It is benzyl. In some embodiments, R 11 It is C(O)R. In some embodiments, R 11 It is S(O)2R.

[0463] In some embodiments, R of formulas I-IX 10 and R 11 The linkage forms substituted or unsubstituted C3-C8 heterocycles. In other embodiments, R 10 and R 11 Connect to form a piperazine ring. In other embodiments, R 10 and R 11 Linkage is used to form a piperidine ring. In some embodiments, substitutions include: F, Cl, Br, I, OH, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), C3-C8 heterocycles (e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, or any combination thereof; each representing a separate embodiment according to the invention.

[0464] In some embodiments, R in 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 a C1-C5 straight-chain or branched substituted or unsubstituted alkyl group. In other embodiments, R is methyl. In other embodiments, R is ethyl. In other embodiments, R is a C1-C5 straight-chain or branched alkoxy group. 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-chain 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 a substituted or unsubstituted aryl group. In other embodiments, R is phenyl. In other embodiments, R is a substituted or unsubstituted heteroaryl group. In other embodiments, R is pyridine. In other embodiments, R is 2-pyridine, 3-pyridine, or 4-pyridine. In other embodiments, two twin R substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic or aromatic, carbocyclic or heterocyclic ring. In other embodiments, two twin R substitutions are linked together to form a 3- to 6-membered aliphatic ring. In other embodiments, two twin R substitutions are linked together to form a cyclopropyl ring. In other embodiments, the substitution comprises at least one of the following: F, Cl, Br, I, OH, SH, C1-C5 straight-chain or branched alkyl, OH, alkoxy, N(R)2, CF3, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2; each representing a separate embodiment according to the invention.

[0465] 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, a C1-C5 straight-chain or branched substituted or unsubstituted alkyl group, or a methyl group; each representing a separate embodiment according to the invention. In other embodiments, two twin R substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic ring. In other embodiments, two twin R substitutions are linked together to form a cyclopropyl ring.

[0466] In some embodiments, L2 in 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.

[0467] In some embodiments, X1 of 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.

[0468] In some embodiments, X2 of 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.

[0469] In some embodiments, X3 of 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.

[0470] In some embodiments, X4 of compounds of formula III, V and / or V(a) is C. In other embodiments, X4 is N.

[0471] In some embodiments, X5 of compounds of formula III, V and / or V(a) is C. In other embodiments, X5 is N.

[0472] In some embodiments, X6 of compounds of formula III, V and / or V(a) is C. In other embodiments, X6 is N.

[0473] In some embodiments, X7 of compounds of formula III, V and / or V(a) is C. In other embodiments, X7 is N.

[0474] In some embodiments, X8 of compounds of formulas IV, V, V(a) and / or VI is C. In other embodiments, X8 is N.

[0475] In some embodiments, X9 of compounds of formulas IV, V, V(a) and / or VI is C. In other embodiments, X9 is N.

[0476] In some embodiments, the X of compounds of formula IV, V-VIII and / or IX 10 It is C. In other embodiments, X 10 It's N.

[0477] In some embodiments, the X of compounds of formulas IV, V, V(a) and / or VI 11 It is C. In other embodiments, X 11 It's N.

[0478] In some embodiments, the X of compounds of formula IV, V-VIII and / or IX 12 It is C. In other embodiments, X 12 It's N.

[0479] In some embodiments, at least one of X4-X7 is N.

[0480] In some embodiments, X8-X 12 At least one of them is N. In some embodiments, X8-X 12 At least two of them are N. In some embodiments, X 10 and X 12 At least one of them is N.

[0481] As used herein, “single or fused aromatic or heteroaromatic ring systems” can be any such ring, including but not limited to phenyl, naphthyl, pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), quinolinyl, pyrimidinyl, pyridazinyl, triazinyl, tetraazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazolyl, pyrazolyl, pyrroleyl, furanyl, thiophen-yl, quinolinyl, isoquinolinyl, 2,3-dihydroindenyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxacycloheptenyl, benzo[d][1,3]dioxacyclopentenyl, tetrahydronaphthyl, indoleyl, 1H-indole, isoyindoleyl, anthraceneyl, ...b][1,4]dioxacycloheptenyl, benzo[b][1,4]dioxacycloheptenyl, tetrahydronaphthyl, indoleyl, 1H-indole, isoyindoleyl, anthraceneyl, benzo[b][1,4]dioxacycloheptenyl, benzo Imidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indol-3-one, purine, benzoxazolyl, 1,3-benzoxazolyl, benzoisoxazolyl, benzothiazolyl, 1,3-benzothiazolyl, 4,5,6,7-tetrahydro-1,3-benzothiazolyl Azazole, quinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxalin, 1-(pyridin-1(2H)-yl)acetone, pyrazinyl, phthalazinyl, quinolinyl, isoquinolinyl, acridineyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzofuran-2(3H)-one, benzothiophene, benzoxadiazole, benzo[c][1,2,5]oxadiazole Benz[c]thiophene, benzo[m]dioxacyclopentenyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiazolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenten[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazo[4,5-d]pyrimidine, [1,3]thiazo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2-d]pyrimidine-4(3H)-one, 4-oxo-4H-thieno[3,2-d][1,3]thiazine, imidazo[1,2-a]pyridine, 1H-Imidazolo[4,5-b]pyridine, 1H-Imidazolo[4,5-c]pyridine, 3H-Imidazolo[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, quinoxaline-2(1H)-one, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazo[5,4-b]pyridine, thieno[3,2-c]pyridine, 3-methyl-4H-1,2,4-Triazole, 5-Methyl-1,2,4-oxadiazole, etc.

[0482] As used herein, unless otherwise stated, the term "alkyl" can be any straight-chain or branched alkyl group containing up to about 30 carbon atoms. In various embodiments, the alkyl group comprises C1-C5 carbon atoms. In some embodiments, the alkyl group comprises C1-C6 carbon atoms. In some embodiments, the alkyl group comprises C1-C8 carbon atoms. In some embodiments, the alkyl group comprises C1-C6 carbon atoms. 10 Carbon. In some embodiments, the alkyl group is C1-C. 12 Carbon. 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 carbons. 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, thio, thioalkyl, C1-C5 straight-chain 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.

[0483] Alkyl groups can be the only substituent or can be components with larger substituents, such as alkoxy, alkoxyalkyl, haloalkyl, arylalkyl, alkylamino, dialkylamino, alkylamide, alkylurea, etc. Preferred alkyl groups are methyl, ethyl, and propyl, and therefore halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, halopropyl, dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl, arylethyl, arylpropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, formamido, acetamito, propamido, halomethylamide, haloethylamide, halopropylamide, methylurea, ethylurea, propylurea, 2-CH2-C6H4-Cl, 3-CH2-C6H4-Cl or 4-CH2-C6H4-Cl, C(OH)(CH3)(Ph), etc.

[0484] As used herein, the term "aryl" refers to any aromatic ring directly bonded to another group and may be substituted or unsubstituted. An aryl group may be the only substituent, or it may be a component of larger substituents, such as in arylalkyl, arylamino, arylamide, etc. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, xylyl, furanyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiophene-yl, pyrroleyl, indolyl, phenylmethyl, phenylethyl, phenylamino, benzamido, 3-methyl-4H-1,2,4-triazolyl, 5-methyl-1,2,4-oxadiazolyl, etc. The substitutions include, but are not limited to: F, Cl, Br, I, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain or branched haloalkyl, C1-C5 straight-chain or branched alkoxy, C1-C5 straight-chain 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.

[0485] 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 alkoxy groups. Non-limiting examples of alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, and tert-butoxy.

[0486] As used herein, the term "aminoalkyl" refers to an amine substituted with an alkyl group as defined above. Aminoalkyl means monoalkylamine, dialkylamine, or trialkylamine. Non-limiting examples of aminoalkyl are -N(Me)2, -NHMe, and -NH3.

[0487] In some embodiments, "haloalkyl" refers to an alkyl group as defined above, which is substituted with one or more halogen atoms, such as F, Cl, Br, or I. The term "haloalkyl" includes, but is not limited to, fluoroalkyl, i.e., an alkyl group having at least one fluorine atom. Non-limiting examples of haloalkyl groups are CF3, CF2CF3, and CF2CH. 3、 CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2 and CF(CH3)-CH(CH3)2.

[0488] In some embodiments, "halophenyl" refers to a phenyl substituent that is replaced by one or more halogen atoms, such as F, Cl, Br, or I. In one embodiment, the halophenyl is a 4-chlorophenyl.

[0489] In some embodiments, "alkoxyalkyl" refers to an alkyl group as defined above, which is substituted with an alkoxy group as defined above, such as 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, and -CH2-CH2-OC(CH3)3.

[0490] In various embodiments, a "cycloalkyl" or "carbocyclic" group refers to a ring structure comprising a carbon atom as a ring atom, 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 the following: halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amide, alkylamide, dialkylamide, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C1-C5 straight-chain 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 with 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), etc.

[0491] In various embodiments, a "heterocycle" or "heterocyclic" group refers to a ring structure that includes sulfur, oxygen, nitrogen, or any combination thereof as part of a ring in addition to a carbon atom. In various embodiments, a "heteroaromatic ring" refers to an aromatic ring structure that includes sulfur, oxygen, nitrogen, or any combination thereof as part of a ring in addition to a carbon atom. 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 with the following: halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amide, alkylamide, dialkylamide, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C1-C5 straight-chain 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 with 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]m-dioxacyclopentene, indole, oxazole, isoxazole, imidazole and 1-methylimidazolium, 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.

[0492] In various embodiments, the present invention provides compounds of the present invention or isomers thereof, metabolites, pharmaceutically acceptable salts, pharmaceutical products, tautomers, hydrates, N-oxides, prodrugs, isotope variants (deuterated analogs), polymorphs, or crystals or combinations thereof. In various embodiments, the present invention provides isomers of the compounds of the present invention. In some embodiments, the present invention provides metabolites of the compounds of the present invention. In some embodiments, the present invention provides pharmaceutically acceptable salts of the compounds of the present invention. In some embodiments, the present invention provides pharmaceutical products of the compounds of the present invention. In some embodiments, the present invention provides tautomers of the compounds of the present invention. In some embodiments, the present invention provides hydrates of the compounds of the present invention. In some embodiments, the present invention provides N-oxides of the compounds of the present invention. In some embodiments, the present invention provides prodrugs of the compounds of the present invention. In some embodiments, the present invention provides isotope variants of the compounds of the present invention (including but not limited to deuterated analogs). In some embodiments, the present invention provides PROTACs (proteolytic-targeting chimeras) of the compounds of the present invention. In some embodiments, the present invention provides polymorphs of the compounds of the present invention. In some embodiments, the present invention provides crystals of the compounds of the present invention. In some embodiments, the present invention provides compositions comprising the compounds of the present invention as described herein, or in some embodiments, combinations of isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, tautomers, hydrates, N-oxides, prodrugs, isotope variants (deuterated analogs), polymorphs, or crystals of the compounds of the present invention.

[0493] In various embodiments, the term "isomer" includes, but is not limited to, stereoisomers and the like, structural isomers and the like, conformational isomers and the like. In some embodiments, the isomer is an optical isomer. In some embodiments, the isomer is a stereoisomer.

[0494] In various embodiments, the present invention covers the use of various stereoisomers of the compounds of the present invention. Those skilled in the art will understand that the compounds of the present invention may contain at least one chiral center. Therefore, compounds used in the methods of the present invention may be present in optically active or racemic forms and isolated in said forms. Thus, compounds according to the present invention may be present in optically active isomers (enantiomers or diastereomers, including but not limited to: (R), (S), (R)(R), (R)(S), (S)(S), (S)(R), (R)(R)(R), (R)(R)(S), (R)(S)(R), (S)(R)(R), (R)(S)(S), (S)(R)(S), (S)(R)(S), or (S)(S)(S) isomers); in racemic mixtures; or in enantiomerically concentrated mixtures. Some compounds may also exhibit polymorphism. It should be understood that the present invention covers any racemic, optically active, polymorphic, or stereoisomeric form or mixture thereof, said forms having properties suitable for treating the various conditions described herein.

[0495] It is well known in the field how to prepare optically active forms (e.g., by resolving racemic forms using recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using chiral stationary phases).

[0496] The compounds of the present invention may also exist as racemic mixtures containing substantially equal amounts of stereoisomers. In some embodiments, the compounds of the present invention may be prepared using known procedures or otherwise isolated to obtain stereoisomers substantially free of their corresponding stereoisomers (i.e., substantially pure). "Substantially pure" means that the purity of the stereoisomer is at least about 95%, more preferably at least about 98%, and most preferably at least about 99%.

[0497] The compounds of the present invention may also be in hydrate form, which means that the compounds further contain stoichiometric or nonstoichiometric amounts of water bound by noncovalent intermolecular forces.

[0498] As used herein, when some chemical functional group (e.g., alkyl or aryl) is referred to as “substituted”, this document defines one or more substitutions as possible.

[0499] The compounds of the present invention can exist in one or more possible tautomers, and depending on the symptoms, it is possible to isolate some or all of the tautomers into separate and distinct entities. It should be understood that this document covers all possible tautomers, including all additional enol and ketone tautomers and / or isomers. For example, it includes (but is not limited to) the following tautomers:

[0500] Tautomerization of the imidazole ring:

[0501]

[0502] Tautomerization of the pyrazolinone ring:

[0503]

[0504] This invention comprises "pharmaceutically acceptable salts" of the compounds of this invention, which can be produced by reacting the compounds of this invention with an acid or base. Certain compounds, particularly those having acidic or basic groups, may also be in the form of salts, preferably pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to those salts that retain the bioavailability and properties of a free base or free acid, which are not biologically or otherwise undesirable. The salts are formed from inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, ferric acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. Other salts are known to those skilled in the art and can be readily adapted for use according to this invention.

[0505] Suitable pharmaceutically acceptable salts of the amines of the compounds of the present invention can be prepared from inorganic or organic acids. Examples of inorganic salts of the amines in various embodiments are hydrogen sulfates, borates, bromides, chlorides, hemisulfates, hydrobroms, hydrochlorides, 2-hydroxyethyl sulfonates (hydroxyethane sulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphates, sulfates, aminosulfonates, sulfanamides, sulfonic acids (alkyl sulfonates, aryl sulfonates, halogenated alkyl sulfonates, halogenated aryl sulfonates), sulfonates, and thiocyanates.

[0506] In various embodiments, examples of organic salts of amines may be selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic acid, and sulfonic acid organic acids.Examples include acetate, arginine, aspartate, ascorbate, adipate, anthranilate, alginate, alkane carboxylates, substituted alkane carboxylates, alginate, benzenesulfonate, benzoate, hydrogen sulfate, butyrate, bicarbonate, tartrate, citrate, camphorate, camphor sulfonate, cyclohexylaminosulfonate, cyclopentanepropionate, and calcium edetate. edetate), camphor sulfonate, carbonate, clavulanate, cinnamate, dicarboxylate, digluconate, dodecyl sulfonate, dihydrochloride, decanoate, heptanoate, ethanesulfonate, edetate, ethanedisulfonate, propionate, estolate, esylate, fumarate, formate, fluoride, galacturonate, gluconate, glutamate, glycolate, glucorate, glucohepate tanoate, glycerol phosphate, gluceptate, glycolyllarsanilate, glutamate, glutamate, heptaate, hexanoate, hydroxymaleate, hydroxycarboxylic acid, hexylresorcinol, hydroxybenzoate, hydroxynaphthyl carboxate, hydrofluoric acid, lactate, lactobionate, laurate, malate, maleate, methylenebis(beta-oxynaphthoate), malonate, mandelate, mesylate, methanesulfonate sulfonate), methyl bromide, methyl nitrate, methanesulfonate, monopotassium maleate, mucate, monocarboxylate, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, napsylate, N-methylglucosamine, oxalate, octanoate, oleate, dihydroxynaphthalate, phenylacetate, picrate, phenylbenzoate, pivalate, propionate, phthalate, styrene Salts, pectates, phenylpropionates, palmitates, pantothenates, polygalactosates, pyruvates, quinates, salicylates, succinates, stearates, sulfaniates, basic acetates, tartrates, theophylline acetates, p-toluenesulfonates (toluenesulfonates), trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates, triethyliodide, tricarboxylates, undecanoates, and valerates.

[0507] In various embodiments, examples of inorganic salts of carboxylic acids or hydroxyl groups may be selected from ammonium, alkali metals (including lithium, sodium, potassium, cesium); alkaline earth metals (including calcium, magnesium, aluminum; zinc, barium, choline, quaternary ammonium).

[0508] In some embodiments, examples of organic salts of carboxylic acids or hydroxyl groups may be selected from arginine; organic amines, including aliphatic organic amines, alicyclic organic amines, and aromatic organic amines; benzathine penicillin, tert-butylamine, phenethylbenzylamine (N-benzylphenylethylamine), dicyclohexylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, hydrabamine, imidazole, lysine, methylamine, meglumine, N-methyl-D-glucosamine, N,N'-dibenzylethylenediamine, nicotinamide, organic amines, ornithine, pyridine, picolides, piperazine, procaine, tri(hydroxymethyl)methylamine, triethylamine, triethanolamine, trimethylamine, aminobutanetriol, and urea.

[0509] In various embodiments, the salt can be formed in a conventional manner, such as by reacting the product in the form of a free base or free acid with one or more equivalents of a suitable acid or base in a solvent or medium in which the salt is insoluble, or in a solvent (such as water) that is removed in a vacuum or by freeze-drying or by ion exchange of an existing salt with another ion or a suitable ion exchange resin.

[0510] Pharmaceutical Composition

[0511] Another aspect of the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to various aspects of the invention. The pharmaceutical composition may contain one or more of the compounds identified above in this invention. Typically, the pharmaceutical compositions of the invention will comprise a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to any suitable adjuvant, carrier, excipient, or stabilizer, and may be in solid or liquid form, such as tablets, capsules, powders, solutions, suspensions, or emulsions.

[0512] Typically, the composition will contain about 0.01% to 99%, preferably about 20% to 75%, of the active compound, along with adjuvants, carriers, and / or excipients. Although individual needs may vary, determining the optimal range for the effective amount of each component is within the scope of the art. Typical doses include about 0.01 to about 100 mg / kg body weight. Preferred doses include about 0.1 to about 100 mg / kg body weight. Most preferred doses include about 1 to about 100 mg / kg body weight. Those skilled in the art can readily determine the therapeutic regimen for administering the compounds of the present invention. That is, preferably, the frequency and dosage of administration can be determined through conventional optimization while minimizing any side effects.

[0513] Solid dosage forms can be of conventional types. Solid forms can be capsules, etc., containing compounds of the present invention and carriers such as lubricants and inert fillers, such as common gelatin types like lactose, sucrose, or corn starch. In some embodiments, these compounds are combined with a conventional tablet base, such as lactose, sucrose, or corn starch; and a binder, such as gum arabic, corn starch, or gelatin; a disintegrant, such as corn starch, potato starch, or alginate; and a lubricant, such as stearic acid or magnesium stearate.

[0514] Tablets and capsules may also contain binders such as gum arabic, gum arabic, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose, or saccharin. When the unit dosage form is a capsule, in addition to the above types of materials, it may also contain a liquid carrier, such as fatty oil.

[0515] Various other materials may be present in coating form or used to adjust the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. In addition to the active ingredient, syrups may contain sucrose as a sweetener, methyl and propylparabens as preservatives, dyes, and flavorings (such as cherry or orange flavorings).

[0516] For oral therapeutic administration, these active compounds can be combined with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, etc. Such compositions and formulations should contain at least 0.1% of the active compound. Of course, the percentage of the compound in these compositions can vary and can conveniently range from about 2% to about 60% per unit weight. The amount of active compound in such therapeutically useful compositions ensures that a suitable dosage is obtained. Preferred compositions according to the invention are prepared such that an oral dose unit contains between about 1 mg and 800 mg of the active compound.

[0517] The active compounds of the present invention can be administered orally, for example, with an inert diluent or with an assimilated edible carrier, or the active compounds can be encapsulated in hard or soft-shell capsules, or the active compounds can be compressed into tablets, or the active compounds can be directly incorporated into dietary foods.

[0518] Suitable pharmaceutical forms for injection include sterile aqueous solutions or dispersions and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should have a degree of flowability sufficient for easy injection. It should be stable under the conditions of manufacture and storage and should be protected from contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0519] The compounds or pharmaceutical compositions of the present invention can also be administered in injectable doses via solutions or suspensions of these materials in physiologically acceptable diluents, along with pharmaceutical adjuvants, carriers, or excipients. Such adjuvants, carriers, and / or excipients, with or without the addition of surfactants and other pharmaceutically and physiologically acceptable components, comprise, but are not limited to, sterile liquids such as water and oils. Exemplary oils are petroleum, animal, plant, or synthetic oils, such as peanut oil, soybean oil, or mineral oil. Typically, water, saline solutions, aqueous solutions of dextran and associated sugar solutions, as well as ethylene glycol such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.

[0520] These active compounds can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water, suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also be prepared in oils containing glycerol, liquid polyethylene glycol, and mixtures thereof. Exemplary oils are petroleum, animal, plant, or synthetic oils, such as peanut oil, soybean oil, or mineral oil. Typically, water, brine, aqueous solutions of dextran and related sugar solutions, as well as diols such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under normal storage and use conditions, these formulations contain preservatives to prevent microbial growth.

[0521] For use as an aerosol, the compounds of the present invention in solution or suspension can be packaged with a suitable propellant, such as a hydrocarbon propellant, like propane, butane, or isobutane, along with conventional adjuvants, in a pressurized aerosol container. The materials of the present invention can also be applied in a non-pressurized form, such as in a sprayer or atomizer.

[0522] In various embodiments, the compounds of the present invention are administered in combination with agents for treating fibrosis. In some embodiments, the agents for treating pulmonary fibrosis are selected from at least one of the following: pirfenidone and nintedanib. Other examples of agents that can be used in combination with the compounds of the present invention to treat pulmonary fibrosis, including IPF, 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 agents for treating NASH.

[0523] When the compounds of the present invention are administered, they may be administered systemically, or alternatively, they may be administered directly to specific sites where fibrosis is present. Therefore, administration can be accomplished in any manner that effectively delivers the compound or pharmaceutical composition to fibrotic cells. Exemplary administration modes include, but are not limited to, oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, intracavitary or intravesical, intraocular, intra-arterial, intralesional, or administration of the compound or composition to mucous membranes (such as the mucous membranes of the nose, throat, and bronchi).

[0524] Bioactivity

[0525] 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 said compounds will be useful in inhibiting, suppressing, enhancing, or stimulating a subject's desired response, as will be understood by those skilled in the art. In some embodiments, the composition may further comprise additional active ingredients whose activity is useful for the specific application of administering the compounds of the present invention.

[0526] This invention relates to the treatment, inhibition, and relief of fibrosis, including pulmonary fibrosis and liver fibrosis. More specifically, embodiments of the invention provide compositions and methods for treating and inhibiting fibrotic conditions, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), and liver fibrotic symptoms associated with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) using compounds according to the invention or pharmaceutically acceptable salts thereof.

[0527] In another embodiment, the human subject had pulmonary fibrosis. In another embodiment, the human subject had idiopathic pulmonary fibrosis (IPF). In another embodiment, the human subject had non-alcoholic fatty liver disease (NAFLD). In another embodiment, the human subject had non-alcoholic steatohepatitis (NASH). In another embodiment, the human subject did not have non-alcoholic steatohepatitis (NASH).

[0528] Among various conditions, the formation of fibrotic tissue is characterized by an abnormally large deposition of collagen. Collagen synthesis is also involved in many other pathological conditions. For example, clinical symptoms and conditions associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, and autoimmune diseases, are characterized by the overproduction of connective tissue, leading to the destruction of normal tissue structure and function. These diseases can best be explained by cellular dysfunction, primarily manifested as excessive collagen synthesis and deposition. The role of collagen in fibrosis has prompted efforts to develop drugs that inhibit its accumulation.

[0529] Excessive collagen accumulation is a major pathological feature of various clinical conditions characterized by tissue fibrosis. These conditions include localized processes (e.g., pulmonary fibrosis and cirrhosis) or more generalized processes (e.g., progressive systemic sclerosis). Collagen deposition is characteristic of different forms of cutaneous fibrosis, including, in addition to scleroderma, localized and generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenomas, and collagen-type connective tissue nevi. Recent advances in understanding the normal biochemistry of collagen allow us to define specific levels of collagen biosynthesis and degradation at which pharmacological interventions can lead to a reduction in collagen deposition in tissues. Such compounds could potentially provide novel approaches to reduce excessive collagen accumulation in disease.

[0530] Therefore, in various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of fibrosis in a subject, reducing the risk of developing fibrosis in a subject, or suppressing fibrosis in a subject, the method comprising administering a compound according to the invention to the subject under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing fibrosis in, or suppress 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 a result of wound healing. In some embodiments, the fibrosis is a result of scar formation. In some embodiments, the fibrosis is primary or secondary fibrosis. In some embodiments, the fibrosis is a result of systemic sclerosis, progressive systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, autoimmune diseases, or any combination thereof; each representing a separate embodiment according to the invention. In another embodiment, the human subject has pulmonary fibrosis. In another embodiment, the human subject has idiopathic pulmonary fibrosis (IPF). In some embodiments, the fibrosis is pulmonary fibrosis. In some embodiments, the subject has cirrhosis. In some embodiments, the fibrosis is liver fibrosis, pulmonary fibrosis, or skin fibrosis. In some embodiments, the skin fibrosis is scleroderma. In some embodiments, the skin fibrosis is the result of localized or generalized scleroderma, keloids, hypertrophic scars, familial skin collagenoma, collagenous connective tissue nevi, or any combination thereof; each representing a separate embodiment of the invention. In some embodiments, the fibrosis is caused by tissue damage, inflammation, oxidative stress, or any combination thereof; each representing a separate embodiment of the 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 of the invention.

[0531] Human fibrosis constitutes a major health problem worldwide due to the large number of individuals affected, the incomplete understanding of the pathogenesis of fibrosis, the significant heterogeneity of its etiology and clinical manifestations, the lack of appropriate and well-validated biomarkers, and, most importantly, the current lack of effective treatments to alleviate the disease. Fibrotic disorders encompass a variety of clinical entities, including systemic fibrotic diseases such as systemic sclerosis (SSc), scleroderma-related graft-versus-host disease, and renal systemic fibrosis, as well as multi-organ-specific disorders including radiation-induced fibrosis and cardiac fibrosis, pulmonary fibrosis, hepatic fibrosis, and renal fibrosis. Although their pathogenic mechanisms are quite diverse and remain elusive in some cases, these diseases share a common characteristic: the uncontrolled and progressive accumulation of fibrotic tissue in the affected organs, leading to dysfunction and eventual failure. Although the etiological mechanisms and clinical manifestations responsible for the development of fibrotic diseases are highly heterogeneous, numerous studies have identified activated myofibroblasts as a common cellular element ultimately responsible for replacing normal tissue with nonfunctional fibrotic tissue.

[0532] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of developing, or suppressing systemic fibrosis in a subject, said method comprising administering a compound of the invention to the subject under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing, or suppress systemic fibrosis in a subject with systemic fibrosis. In some embodiments, systemic fibrosis is systemic sclerosis. In some embodiments, systemic fibrosis is multifocal fibrosis (IgG4-associated fibrosis). In some embodiments, systemic fibrosis is renal systemic fibrosis. In some embodiments, systemic fibrosis is scleroderma graft-versus-host disease.

[0533] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of developing or suppressing organ-specific fibrosis in a subject, wherein the method comprises administering a compound of the invention to the subject under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing or suppress organ-specific fibrosis in a subject, or suppress organ-specific fibrosis in a subject.

[0534] In some embodiments, organ-specific fibrotic disease is pulmonary fibrosis. In some embodiments, organ-specific fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0535] In some embodiments, organ-specific fibrotic disease is cardiac fibrosis. In some embodiments, cardiac fibrosis is hypertension-related cardiac fibrosis. In some embodiments, cardiac fibrosis is post-myocardial infarction. In some embodiments, cardiac fibrosis is Chagas disease-induced myocardial fibrosis.

[0536] In some embodiments, organ-specific fibrotic disease is renal fibrosis. In some embodiments, renal fibrosis is diabetic and hypertensive nephropathy. In some embodiments, renal fibrosis is urinary tract obstruction-induced renal fibrosis. In some embodiments, renal fibrosis is inflammatory / autoimmune-induced renal fibrosis. In some embodiments, renal fibrosis is aristolochic acid nephropathy. In some embodiments, renal fibrosis is polycystic kidney disease.

[0537] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of developing, or suppressing cardiac fibrosis in a subject, said method comprising administering a compound of the invention to the subject under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing, or suppress 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 of the invention.

[0538] In some embodiments, organ-specific fibrotic disease is pulmonary fibrosis. In some embodiments, pulmonary fibrosis is idiopathic pulmonary fibrosis. In some embodiments, pulmonary fibrosis is silica-induced pneumoconiosis (silicosis). In some embodiments, pulmonary fibrosis is asbestos-induced pulmonary fibrosis (asbestosis). In some embodiments, pulmonary fibrosis is chemotherapy-induced pulmonary fibrosis.

[0539] In some embodiments, organ-specific fibrotic diseases are hepatic and portal fibrosis. In some embodiments, hepatic and portal fibrosis is alcoholic and non-alcoholic liver fibrosis. In some embodiments, hepatic and portal fibrosis is hepatitis C-induced liver fibrosis. In some embodiments, hepatic and portal fibrosis is primary biliary cirrhosis. In some embodiments, hepatic and portal fibrosis is parasite-induced liver fibrosis (schistosomiasis).

[0540] In some embodiments, organ-specific fibrosis is radiation-induced fibrosis (in various organs). In some embodiments, organ-specific fibrosis is bladder fibrosis. In some embodiments, organ-specific fibrosis is intestinal fibrosis. In some embodiments, organ-specific fibrosis is peritoneal sclerosis.

[0541] In some embodiments, organ-specific fibrotic disease is diffuse fasciitis. In some embodiments, diffuse fasciitis is localized scleroderma or keloid scarring. In some embodiments, diffuse fasciitis is Dupuitren's disease. In some embodiments, diffuse fasciitis is Peroni's disease. In some embodiments, diffuse fasciitis is myelofibrosis. In some embodiments, diffuse fasciitis is oral submucosal fibrosis.

[0542] In some embodiments, organ-specific fibrosis is a result of wound healing. In some embodiments, organ-specific fibrosis is a result of scar formation.

[0543] Liver fibrosis (also referred to as liver fibrosis in this article) can be caused by various types of chronic liver injury, especially those involving inflammatory components. Self-limiting acute liver injury (e.g., acute viral hepatitis A), even if fulminant, does not necessarily disrupt the scaffold structure and therefore usually does not cause fibrosis, despite hepatocyte loss. However, factors such as chronic alcoholism, malnutrition, hemochromatosis, and exposure to toxins, poisons, or drugs can lead to chronic liver injury and liver fibrosis due to exposure to hepatotoxic chemicals. Liver scarring caused by surgery or other forms of injury associated with mechanical biliary obstruction can also lead to liver fibrosis.

[0544] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of developing liver fibrosis in a subject, or suppressing liver fibrosis in a subject, the method comprising administering a compound of the invention to the subject under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing liver fibrosis in a subject, or suppress liver fibrosis in a subject with liver fibrosis. In some embodiments, liver fibrosis is caused by liver scarring. In some embodiments, liver fibrosis is caused by chronic liver injury. In some embodiments, chronic liver injury is caused by chronic alcoholism, malnutrition, hemochromatosis, exposure to toxins, or drug exposure; each representing a separate embodiment of the 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 of the invention.

[0545] Fibrosis itself is not necessarily asymptomatic; however, it can lead to the development of portal hypertension or cirrhosis. In portal hypertension, scarring disrupts blood flow through the liver, while in cirrhosis, scarring leads to the destruction of normal liver structure and impaired liver function. The extent of each of these pathologies determines the clinical presentation of liver fibrosis. For example, congenital liver fibrosis affects the portal vein branches but largely does not damage the parenchyma. The result is portal hypertension without impairing hepatocyte function.

[0546] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of developing, or suppressing liver fibrosis in a subject, said method comprising administering a compound of the invention to the subject under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing, or suppress liver fibrosis in the subject. In some embodiments, the liver fibrosis is portal hypertension, cirrhosis, congenital liver fibrosis, or any combination thereof; each representing a separate embodiment of the 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 of the invention.

[0547] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of developing, or suppressing portal hypertension in a subject, said method comprising administering a compound of the invention to the subject under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing, or suppress portal hypertension 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 of the invention.

[0548] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of cirrhosis in a subject, reducing the risk of developing cirrhosis in a subject, or suppressing cirrhosis in a subject, the method comprising administering a compound of the invention to the subject under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing cirrhosis in a subject, or suppress cirrhosis in a subject with cirrhosis. In some embodiments, cirrhosis is a result of hepatitis. In some embodiments, cirrhosis is a result of alcohol poisoning. 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 of the invention.

[0549] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of developing, or suppressing human alcohol poisoning in a subject, said method comprising administering a compound of the invention to the subject under conditions that effectively treat, inhibit, reduce the severity, reduce the risk, or suppress human alcohol poisoning 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 of the invention.

[0550] Nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) share similar pathogenesis and histopathology, but differ in etiology and epidemiology. NASH and ASH are advanced nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD), respectively. NAFLD is characterized by excessive fat accumulation in the liver (steatodegeneration), without any other obvious cause of chronic liver disease (virus, autoimmune, genetic, etc.), and alcohol consumption ≤20-30 g / day. Conversely, AFLD is defined as the presence of steatosis and alcohol consumption >20-30 g / day.

[0551] In each embodiment, the compound is a collagen translation inhibitor.

[0552] In various embodiments, the present invention relates to a method for treating a subject with non-alcoholic steatohepatitis (NASH), 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 a compound of the invention to the subject under conditions of effectively treating non-alcoholic steatohepatitis (NASH) in a subject, 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 invention.

[0553] In various embodiments, the present invention relates to a method for treating alcoholic steatohepatitis (ASH) in a subject, inhibiting ASH in a subject, reducing the severity of ASH in a subject, reducing the risk of a subject developing ASH, or suppressing ASH in a subject, said method comprising administering a compound of the invention to the subject under conditions that effectively treat alcoholic steatohepatitis (ASH) in a subject, inhibit ASH in a subject with ASH, reduce the severity of ASH in a subject with ASH, reduce the risk of a subject with ASH developing ASH, or suppress ASH in a subject with 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 of the invention.

[0554] In various embodiments, the present invention relates to a method for treating a subject with non-alcoholic fatty liver disease (NAFLD), inhibiting 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 a compound of the invention to the subject under conditions of effectively treating, inhibiting, reducing the severity of, reducing the risk of developing 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 of the invention.

[0555] In various embodiments, the present invention relates to a method for treating a subject with alcoholic fatty liver disease (AFLD), inhibiting AFLD in a subject, reducing the severity of AFLD in a subject, reducing the risk of a subject developing AFLD, or inhibiting AFLD in a subject, said method comprising administering a compound of the invention to the subject under conditions that effectively treat alcoholic fatty liver disease (AFLD), inhibit AFLD in a subject with AFLD, reduce the severity of AFLD in a subject with AFLD, reduce the risk of a subject with AFLD developing AFLD, or inhibit AFLD in a subject with 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 of the invention.

[0556] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of pulmonary fibrosis in a subject, reducing the risk of developing pulmonary fibrosis in a subject, or suppressing pulmonary fibrosis in a subject, the method comprising administering a compound of the invention to the subject under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing pulmonary fibrosis in a subject, or suppress 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 of the invention.

[0557] Idiopathic pulmonary fibrosis (IPF) is an age-related, refractory lung disease with historically limited treatment options. In 2014, the United States Food and Drug Administration (FDA) recently approved two drugs, pirfenidone and nintedanib, heralding a new era in its regulation. Both drugs demonstrated efficacy in Phase III clinical trials by delaying the rate of IPF progression; neither appears to completely halt disease progression. Advances in the understanding of the pathobiology of IPF have led to an unprecedented expansion of the number of potential therapeutic targets. Drugs targeting several of these therapeutic targets are being investigated at various stages of clinical development.

[0558] In various embodiments, the present invention relates to a method for treating a subject with idiopathic pulmonary fibrosis (IPF), suppressing 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, said method comprising administering a compound of the invention to the subject under conditions of effectively treating, suppressing, reducing the severity of IPF in a subject with IPF, reducing the risk of a subject with IPF 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 of the 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 of the invention.

[0559] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of developing, or suppressing skin fibrosis in a subject, said method comprising administering a compound of the invention to the subject under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing, or suppress 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 scleroderma, keloids, hypertrophic scars, familial skin collagenoma, collagenous connective tissue nevi, or any combination thereof; each representing a separate embodiment of the 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 of the invention.

[0560] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of developing scleroderma in a subject, or suppressing scleroderma in a subject, the method comprising administering a compound of the invention to the subject under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing scleroderma in a subject with scleroderma, or suppress scleroderma in a subject with 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 of the invention.

[0561] In various embodiments, the present invention relates to a method for inhibiting excessive production of collagen I (Col I) in a subject, the method comprising administering a compound according to the invention to a subject suffering from excessive collagen I (Col I) production, provided that the excessive production of collagen I (Col I) in the subject is effectively inhibited. 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 invention.

[0562] In some embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, reducing the risk of developing an autoimmune disease or condition in a subject, or inhibiting an autoimmune disease or condition in a subject, the method comprising administering a compound of the invention to the subject under conditions that effectively treat, suppress, reduce the severity of, reduce the risk of developing an autoimmune disease or condition in a subject, or inhibit the autoimmune disease or condition in a 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 of the invention.

[0563] 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 may be used to treat either males or females.

[0564] The following examples are presented to more fully illustrate preferred embodiments of the invention. However, these examples should not in any way be construed as limiting the broad scope of the invention.

[0565] Examples

[0566] Example 1

[0567] Synthetic details of the compounds of the present invention (Schemes 1-32)

[0568] General methods

[0569] Unless otherwise specified, all reagents are commercial grade and used as is without further purification. Unless otherwise specified, reagent-grade solvents are used in all cases. Thin-layer chromatography was performed using pre-coated silica gel F-254 plates (thickness: 0.25 mm). Recordings were made on a Bruker Avance 400 MHz or Avance III 400 MHz spectrometer. 1 H-NMR and 19F-NMR spectra. Residual solvent was used as an internal standard, and chemical shifts are expressed in ppm. Splitting modes were designated as s (singlet), d (doublet), dd (double doublet), t (triplet), dt (double triplet), q (quartet), m (multiplet), and br s (broad singlet).

[0570] abbreviations

[0571] ACN Acetonitrile

[0572] AcOH (acetic acid)

[0573] amphos bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)

[0574] Boc tert-butoxycarbonyl

[0575] BuLi n-Butyllithium

[0576] t-BuLi tert-butyllithium

[0577] DAST diethylaminosulfur trifluoride

[0578] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0579] Dppb 1,4-bis(diphenylphosphine)butane

[0580] Dppf 1,1'-bis(diphenylphosphino)ferrocene

[0581] DCM dichloromethane

[0582] DIBAL-H Diisobutylaluminum Hydrogenation

[0583] DIPEA N,N-Diisopropylethylamine

[0584] DMF N,N-dimethylformamide

[0585] DMA dimethylacetamide

[0586] DME 1,2-dimethoxyethane

[0587] DMSO (dimethyl sulfoxide)

[0588] HATU [O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea-hexafluorophosphate]

[0589] HPLC (High Performance Liquid Chromatography)

[0590] MsCl methanesulfonyl chloride

[0591] NBS N-bromosuccinimide

[0592] NMP (N-methyl-2-pyrrolidone)

[0593] PPA polyphosphate

[0594] rt room temperature

[0595] SEM 2-(trimethylsilyl)ethoxymethyl

[0596] T3P Propionic Anhydride

[0597] TBAF Tetrabutylammonium Fluoride

[0598] TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetrafluoroborate tetramethylammonium

[0599] TCFH N,N,N',N'-Tetramethylchloromethylammonium hexafluorophosphate

[0600] THF Tetrahydrofuran

[0601] TMSCF3 Trimethyl(trifluoromethyl)silane

[0602] TMS-OTf trimethylsilyl trifluoromethanesulfonate

[0603] General synthesis of the compounds of the present invention

[0604] RHS piperazine headgroup modification

[0605] Schemes 1 and 2 show compounds for RHS modification (analogs of compound 212, see structure).

[0606] The original general synthesis of Table 1).

[0607]

[0608] Scheme 1. Synthetic route 1 of analogue 3

[0609] Compound 212 analogue 3 was synthesized by reductive amination chemistry (pathway 1) in the presence of DCM containing sodium triacetoxyborohydride and acetic acid, by reacting 1H-indole-2-carboxaldehyde 1 with the corresponding substituted piperazine 2.

[0610]

[0611] Scheme 2. Synthetic route 2 of analogue 3

[0612] Route 2 (Scheme 2) utilizes Buchwald chemistry to synthesize compound 212 analog 3 from (hetero)aryl halides and amine intermediate 6. Amine intermediate 6 is prepared in two steps from commercially available 1H-indole-2-carboxaldehyde 1 and N-Boc-piperazine 4 via N-Boc intermediate 5. After the first step of reductive amination, N-Boc intermediate 5 is deprotected under acidic conditions to yield amine intermediate 6 after generating a free base via SCX ion-exchange chromatography. The final Buchwald chemistry step utilizes various (hetero)aryl halides at 95°C in the presence of dioxane containing palladium(II) acetate, RuPhos, and cesium carbonate.

[0613] LHS modification

[0614] Scheme 3 outlines the synthesis of 5-carbon-linked LHS-modified analog 11.

[0615]

[0616] Scheme 3.5 - Synthesis of carbon-linked LHS-modified analog 11.

[0617] The synthesis of the 5-carbon-linked LHS-modified analog 11 involved an initial reductive amination of commercially available 5-bromo-1H-indole-2-carboxaldehyde 7 with a piperazine 8 substituted with R1, under similar conditions to a DCM containing sodium triacetoxyborohydride and acetic acid. The resulting 5-bromoindole intermediate 9 was then used in a final Suzuki reaction step using borate ester 10 to give the final compound analog 11 in moderate yield.

[0618] Scheme 4 illustrates the synthesis of 5-nitrogen-linked LHS-modified analogs 17a and 17b.

[0619]

[0620] Scheme 4.5 Synthesis of nitrogen-linked LHS-modified analogs 17a and 17b.

[0621] The synthesis begins with the chemical selective reduction of the ester functional group of commercial ethyl 5-nitro-1H-indole-2-carboxylate 12 using a DCM solution containing diisobutylaluminum hydride. The resulting alcohol 13 is then oxidized to an aldehyde 14 using THF containing manganese oxide (IV). Subsequently, the substituted piperazine 8 is reductively amination of the aldehyde intermediate 14 to give a 5-nitroindole intermediate 15. The nitro moiety of these intermediates 15 is reduced under mild iron powder conditions in the presence of ammonium chloride to give the key 5-aminoindole intermediate 16. The final step involves amidation of the 5-aminoindole intermediate 15 with a carboxylic acid under HATU coupling conditions (condition a) or sulfonation of the 5-aminoindole intermediate 15 with the corresponding sulfonyl chloride (condition b) to give the final compound analogs 17a and 17b (Scheme 4), respectively.

[0622] Scheme 5 shows the synthesis of reverse 5-indoleamide analog 22.

[0623]

[0624] Scheme 5. Synthesis of reverse 5-indoleamide analog 22

[0625] The synthesis of reverse amine analog 22 began with the reductive amination of substituted piperazine 8 with commercially available methyl 2-formyl-1H-indole-5-carboxylate 18 to yield 5-methyl ester indole intermediate 19. The ester moiety of intermediate 19 was hydrolyzed using sodium hydroxide to give carboxylic acid intermediate 20, which was isolated as its sodium salt. The resulting sodium carboxylic acid salt 20 intermediate was amidated with aniline 21 under HATU amide coupling conditions to give reverse 5-indole amide analog 22 in good yield.

[0626] Scheme 6 outlines the synthesis of LHS-modified, variable substituted indole scaffold analogue 26 with small R1 substituents.

[0627]

[0628] Scheme 6. Synthesis of LHS-modified variable substituted indole scaffold analog 26

[0629] The synthesis begins with a commercially available ester or carboxylic acid 23 carrying an R1 substituent at various indole positions. The commercial ester or carboxylic acid starting material 23 is converted to an aldehyde intermediate 25 in a two-step sequence via the corresponding primary alcohol intermediate 24. The first step of this sequence involves reducing the carboxylic acid / ester moiety with THF containing lithium aluminum hydride. The second step of this sequence involves oxidizing the primary alcohol intermediate 24 to the aldehyde intermediate 25 using manganese oxide (IV). The key aldehyde intermediate 25 is then converted to the target analog 26 under reductive amination conditions using a substituted piperazine 8.

[0630] Scheme 7 shows the synthesis of 5-methoxyethoxyindole analog 31.

[0631]

[0632] Synthesis of Scheme 7.5-Methoxyethoxyindole analog 31

[0633] The synthesis of 5-methoxyethoxyindole analog 31 begins with the O-alkylation of commercially available ethyl 5-hydroxy-1H-indole-2-carboxylate 27 using 1-bromo-2-methoxyethane and cesium carbonate to give intermediate 28. Intermediate 28 is then converted to aldehyde intermediate 30 in a two-step reduction (LiAlH4) / oxidation (MnO2) sequence similar to that of Scheme 6. The final step to obtain analog 31 involves the reductive amination of aldehyde intermediate 30 with a substituted piperazine 8 under conditions similar to those previously described.

[0634] As shown in Scheme 8, 3-cyanoindole analog 36 was synthesized.

[0635]

[0636] Scheme 8.3 Synthesis of cyanoindole analog 36

[0637] The synthesis of 3-cyanoyindole analog 36 began with N-protection of commercially available 3-cyanoyindole 32 by heating in a high-pressure tube at 160 °C in the presence of pure triethyl orthoformate. The resulting N-protected indole acetal 33 was formylated by deprotonation (t-BuLi) at position 2 of the indole and subsequent anion quenching with DMF. Intermediate aldehyde 34 was reductively amination with a substituted piperazine 8 without purification. Intermediate 35 was obtained using the previously used DCM conditions containing sodium triacetoxyborohydride and acetic acid. The target 3-cyanoyindole analog 36 was then obtained in a final step by acidic N-deprotection of the acetal moiety of intermediate 35.

[0638] Connector modification

[0639] Scheme 9 shows the synthesis of amide-linked analog 38.

[0640]

[0641] Scheme 9. Synthesis of amide-linked analog 38

[0642] 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.

[0643] Scheme 10 describes a general method for synthesizing the connector-modified analogue 43.

[0644]

[0645] Synthesis of analogue 43 for joint modification in Scheme 10

[0646] Type 42 amine precursors (monocyclic, fused bicyclic, or spirocyclic) are commercially available or prepared sequentially in two steps. N-Boc-protected amine 39 is reacted with a heteroaryl halide 40 in the presence of palladium(II) acetate, RuPhos, and cesium carbonate to provide an N-Boc-protected amine intermediate 41. These N-Boc-protected amine intermediates 41 are then N-deprotected under acidic conditions to yield the critical amine intermediate 42. A final reductive amination step with 1H-indole-2-carboxaldehyde 1 yields a linker-modified analog 43 in moderate to good yields.

[0647] bracket modification

[0648] Following the general synthetic route outlined in Scheme 11, compound analogs 47 with an additional nitrogen atom introduced at different positions in the indole core were prepared.

[0649]

[0650] Scheme 11. Synthesis of compound analog 47 with an additional nitrogen atom in the indole core.

[0651] The synthesis of compound analog 47 begins with the reduction of carboxylic acid or ester 44 to the resulting primary alcohol 45 using THF containing lithium aluminum hydride. The resulting primary alcohol intermediate 45 is then oxidized to an aldehyde 46 by treatment with THF containing manganese oxide (IV). Using the previously described conditions, the aldehyde intermediate 46 is reductively amination with a substituted piperazine 8 to obtain the final scaffold-modified compound analog 47.

[0652] Scheme 12 shows the synthesis of compound analog 49 with different heteroarylpiperazine methyl head indole linkages.

[0653]

[0654] Scheme 12. Synthesis of compound analog 49 with different indole linkage sites

[0655] Using DCM containing sodium triacetoxyborohydride and acetic acid, compound analogs 49 with all indole linkages modified were prepared by reductive amination of aldehyde intermediate 48 with substituted piperazine 8.

[0656] Scheme 13 illustrates the synthesis of scaffold-modified analogs of compound 202 (structures are shown in Table 1).

[0657]

[0658] Scheme 13. Synthesis of scaffold-modified analog 54 of compound 202

[0659] First, an amine precursor 52 is constructed via a two-step sequence involving Buchwald amination of commercial chloropyrimidine 50 with N-Boc-piperazine 4, followed by N-Boc deprotection of the resulting N-Boc-piperazine intermediate 51 under acidic conditions to yield the hydrochloride salt. Then, in the presence of potassium carbonate-containing acetonitrile, the key nucleophilic piperazine intermediate 52, serving as the hydrochloride salt, is reacted with several chloromethyl heterocycles 53 to deliver a target scaffold-modified compound analog 54.

[0660] Scheme 14 describes the synthesis of RHS-modified triazole analog 58.

[0661]

[0662] Scheme 14. Synthesis of RHS-modified triazole analog 58.

[0663] Triazole piperazine amine intermediate 57 was synthesized from N-Boc piperazine 4 in two steps. The first step involved the amination of bromotriazole 55 with N-Boc piperazine 4 at 120 °C using DMSO containing copper(I) iodide / L-proline / tripotassium phosphate. The second step involved acid-mediated N-Boc deprotection of N-Boc triazole piperazine intermediate 56 to obtain amine intermediate 57 as a free base. These amine intermediates 57 were then reductively aminationed with 1H-indole-2-carboxaldehyde 1 under previously used conditions containing sodium triacetoxyborohydride and acetic acid to obtain the final triazole piperazine analog 58.

[0664] Scheme 15 describes the synthesis of 2-((4-(5-(((2-methoxyethoxy)methyl)pyrimidin-4-yl)piperazin-1-yl)methyl)-1H-indole 287.

[0665]

[0666] Scheme 15.2 Synthesis of compound 287 of ((4-(5-(((2-methoxyethoxy)methyl)pyrimidin-4-yl)piperazin-1-yl)methyl)-1H-indole.

[0667] Starting from intermediate 59, amine intermediate 63 is synthesized in four steps. The vinyl group of intermediate 59 is oxidatively cleaved using an aqueous THF solution containing osmium tetroxide and sodium periodate to give aldehyde intermediate 60. The aldehyde moiety of 60 is reduced using sodium borohydride to give primary alcohol 61, which is then O-alkylated using DMF containing sodium hydride and 1-bromo-2-methoxyethane to give N-Boc piperazine intermediate 62. N-Boc deprotection of N-Boc piperazine intermediate 62 is performed using a dioxane solution containing hydrogen chloride to give amine piperazine intermediate 63, which is produced as a free base. Amine intermediate 63 is finally reductively amination with 1H-indole-2-carboxaldehyde 1 under typical conditions using DCM containing sodium triacetoxyborohydride and acetic acid to give the final compound 287.

[0668] Scheme 16 shows the synthesis of 5-ethyl-4-(piperazin-1-yl)pyrimidine intermediate 68 in four steps.

[0669]

[0670] Scheme 16. Synthesis of 5-ethyl-4-(piperazin-1-yl)pyrimidine intermediate 68.

[0671] Aromatic substitution of 5-bromo-4-chloropyrimidine 65 with N-Boc piperazine 4 yields intermediate 66. The 5-bromo substituent is replaced by vinyl substitution via Suzuki coupling of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxane to give vinylpyrimidine intermediate 59. The vinyl moiety of intermediate 59 is reduced to ethyl by palladium-catalyzed hydrogenation to give ethylpyrimidine intermediate 67. N-Boc deprotection of N-Boc piperazine intermediate 67 under acidic conditions yields amine piperazine intermediate 68, which is produced as a free base.

[0672] Scheme 17 outlines a seven-step synthesis of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-((2-methoxyethoxy)methyl)-1H-benzo[d]imidazolium compound 289, which uses the amine intermediate 68 previously synthesized in Scheme 16.

[0673]

[0674] Synthesis of compound 289 of scheme 17.2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-((2-methoxyethoxy)methyl)-1H-benzo[d]imidazolium compound 289.

[0675] An N-SEM-protected benzimidazole intermediate 75 was synthesized from commercial 5-bromo-3H-1,3-benzodiazole 69 in five steps, comprising: N-SEM protection of benzimidazole (step 1); introduction of a hydroxymethyl substituent via Stille coupling (step 2); conversion of benzyl alcohol to 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). The N-SEM-protected benzimidazole intermediate 75 was reductively amination with amine intermediate 68 under the previously described conditions, followed by TBAF-mediated N-SEM deprotection to yield the final target compound 289.

[0676] Scheme 18 outlines the five-step synthesis of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-(2-methoxyethoxy)-1H-benzo[d]imidazolium compound 290, the synthesis of which uses amine intermediate 68 previously described in Scheme 16.

[0677]

[0678] Synthesis of compound 290 of scheme 18.2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-(2-methoxyethoxy)-1H-benzo[d]imidazolium.

[0679] 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 in two steps from commercially available 4-amino-3-nitrophenol 80. Base-mediated O-alkylation of 4-amino-3-nitrophenol 80 with 1-bromo-2-methoxyethane yielded intermediate 81, which was then reduced to diamine intermediate 82 by palladium-catalyzed hydrogenation. Finally, an amide of diamine intermediate 82 and carboxylic acid intermediate 79 was formed using HATU coupling conditions, followed by acetic acid-mediated cyclization to give the desired benzimidazole compound 290.

[0680] 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.

[0681]

[0682] Synthesis of compound 291 of scheme 19.2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-((2-methoxyethoxy)methyl)-1H-indole.

[0683] Indole ethyl ester intermediate 87 was synthesized in three steps from commercially available 1-(chloromethyl)-3-nitrobenzene 84. 2-Methoxyethanol was O-alkylated with 1-(chloromethyl)-3-nitrobenzene 84 using DMF containing sodium hydride. The resulting nitrophenyl intermediate 85 was reduced to aniline intermediate 86 using iron-containing acetic acid. Then, aniline intermediate 86 was subjected to aerobic cross-dehydrogenation coupling with DMSO containing palladium(II) acetate, acetic acid, and ethyl 2-oxypropionate to obtain indole ethyl ester intermediate 87. The obtained indole ethyl ester intermediate 87 was hydrolyzed to carboxylic acid 88, which was subsequently reacted with amine intermediate 68 to form an amide to give indoleamide intermediate 89. Finally, indoleamide intermediate 89 was reduced with lithium aluminum hydride to synthesize the desired indolepiperazinamine compound 291.

[0684] Scheme 20 outlines the three-step synthesis of 2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-(2-methoxyethoxy)-1H-indole 292.

[0685]

[0686] Synthesis of compound 292 of scheme 20.2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-6-(2-methoxyethoxy)-1H-indole.

[0687] Amide intermediate 92 was synthesized from commercially available 6-hydroxy-1H-indole-2-carboxylic acid 91 and amine intermediate 68 using HATU coupling conditions. The phenolic moiety of amide intermediate 92 was then O-alkylated with 1-bromo-2-methoxyethane under basic conditions to give O-alkylated intermediate 93. The final step of the synthesis involved reducing indoleamide intermediate 93 with lithium aluminum hydride to obtain the desired indolepiperazinamine compound 292.

[0688]

[0689] Scheme 21. Synthesis of substituted 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-1-yl)methyl)benzo[d]oxazole analogues 98

[0690] The first step involves an amide coupling reaction with substituted 2-aminophenol 95 and chloroacetyl chloride to give substituted phenol intermediate 96. Intermediate 96 is then subjected to intramolecular cyclization in polyphosphoric acid at high temperature to give 2-chloromethylbenzoxazole intermediate 97. Intermediate 97 is then subjected to nucleophilic substitution with piperazine intermediate 52 in a mixture of DMF and DIPEA at high temperature to give the final compound 98.

[0691]

[0692] Synthesis of Scheme 22,6-(difluoromethyl)-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-1-yl)methyl)benzo[d]oxazole 304

[0693] The synthesis of vinylbenzoxazole intermediate 99 was carried out using palladium-catalyzed Suzuki cross-coupling with potassium vinyltrifluoroborate and 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-1-yl)methyl)benzo[d]oxazole 98. Vinyl intermediate 99 was then oxidized with potassium osmium tetroxide dihydrate (VI) to give aldehyde intermediate 100. Intermediate 100 was fluorinated with DCM containing DAST to give the final compound 304.

[0694]

[0695] Synthesis of Scheme 23.2-(5,6-dimethylpyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane 105

[0696] In a mixture of DIPEA and DMF, 4-chloro-5,6-dimethylpyrimidine 102 was initially substituted with N-Boc-2,5-diazabicyclo[2.2.1]heptane 103 to give N-Boc 2,5-diazabicyclo[2.2.1]heptane intermediate 104. N-Boc deprotection was then performed using a dioxane solution containing 4M HCl to give intermediate 105.

[0697]

[0698] Scheme 24. Synthesis of functionalized 4-(4-(benzo[d]oxazol-2-ylmethyl)piperazin-1-yl)pyrimidin-5-carboxynitrile analog 110

[0699] At high temperature, initial substitution of the substituted 4-chloropyrimidine analog 106 and N-Boc-protected piperazine 4 in dioxane yields a functionalized N-Boc piperazine intermediate 107. Acid-mediated deprotection of the N-Boc protecting group is achieved using a dioxane solution containing 4M HCl to give piperazine intermediate 108. Intermediate 108 is alkylated at high temperature in DMF and DIPEA with the substituted 2-(chloromethyl)benzo[d]oxazole 97 to give intermediate 109. Intermediate 109 is then subjected to microwave-assisted palladium-catalyzed cyanation at high temperature using DMF containing tetra(triphenylphosphine)palladium and zinc cyanide to obtain final target 110.

[0700]

[0701] Scheme 25. Synthesis of functionalized 4-(4-(benzo[d]oxazol-2-ylmethyl)piperazin-1-yl)pyrimidin-5-carboxynitrile analog 111

[0702] The intermediate 109 was reacted with trifluoromethyltrimethylsilane in the presence of DMF containing copper iodide and potassium fluoride to introduce trifluoromethyl groups, thereby yielding the final compound 111.

[0703]

[0704] Scheme 26. Synthesis of functionalized 4-(4-(benzo[d]oxazol-2-ylmethyl)piperazin-1-yl)pyrimidin-5-carboxynitrile analog 112

[0705] Halogenated intermediate 109 was reduced under palladium-catalyzed hydrogenation conditions to obtain the final compound 112.

[0706]

[0707] Scheme 27.2-((4-(5-(difluoromethyl)-6-methylpyrimidin-4-yl)piperazin-1-yl)methyl)benzo[d]oxazole 312

[0708] The synthesis of vinylpyrimidine intermediate 113 was accomplished using palladium-catalyzed Suzuki cross-coupling with potassium vinyltrifluoroborate and tert-butyl 4-(5-iodo-6-methylpyrimidin-4-yl)piperazine-1-carboxylate 107. The N-Boc protecting group was removed under acidic conditions using a dioxane solution containing HCl to give intermediate 114 as a hydrochloride. Substitution of intermediate 114 with 2-(chloromethyl)benzo[d]oxazole 53 in DMF and DIPEA yielded intermediate 115. Vinyl intermediate 115 was oxidized using potassium osmium tetroxide dihydrate (VI) to give aldehyde intermediate 336. Intermediate 336 was fluorinated with DAST to give 2-((4-(5-(difluoromethyl)-6-methylpyrimidin-4-yl)piperazine-1-yl)methyl)benzo[d]oxazole 312.

[0709]

[0710] Scheme 28.1 Synthesis of (1-methyl-1H-1,2,4-triazol-3-yl)piperazine 120

[0711] The Cbz-protected intermediate 119 was synthesized by reductive amination of 1-methyl-1H-1,2,4-triazol-3-ylamine 118 with N,N-bis(2-oxoethyl)carbamate phenylmethyl ester in the presence of sodium cyanoborohydride and acetic acid. The N-Cbz intermediate 119 was then deprotected by palladium-catalyzed hydrogenation in methanol to give compound 120.

[0712]

[0713] Synthesis of Scheme 29.2-(1-(piperazin-1-yl)cyclopropyl)benzo[d]oxazole 127

[0714] The ethyl ester intermediate 123 was synthesized by alkylation of ethyl 1-aminocyclopropanecarboxylate hydrochloride 121 in THF and triethylamine using N-benzyl-2-chloro-N-(2-chloroethyl)ethylamine 122. Intermediate 123 was hydrolyzed in an aqueous THF solution containing lithium hydroxide to give carboxylic acid intermediate 124. Intermediate 124 was subjected to HATU-mediated amide coupling with 2-aminophenol to give aminophenol intermediate 125. Intermediate 125 was intramolecularly cyclized in polyphosphoric acid to give benzene-protected benzoxazole intermediate 126. Deprotection of intermediate 126 was achieved in methanol using palladium-catalyzed hydrogenation to give intermediate 127.

[0715]

[0716] Synthesis of Scheme 30.2-(piperazin-1-ylmethyl)oxazolo[5,4-c]pyridine 131

[0717] Amide intermediate 129 was synthesized via TBTU-mediated coupling of acid 128 and 4-amino-3-pyridinol in a mixture of DIPEA and DMF. Intermediate 129 was intramolecularly cyclized using DCM containing triphenylphosphine, hexachloroethane, and triethylamine to give oxazolo[5,4-c]pyridine intermediate 130. Intermediate 130 was deprotected under acidic conditions using a dioxane solution containing 4M HCl to give intermediate 131.

[0718]

[0719] Synthesis of Scheme 31.2-((4-(5-(2-(3-(but-3-yn-1-yl)-3H-bisacryl-3-yl)ethoxy)pyrimidin-4-yl)piperazin-1-yl)methyl)-1H-indole 337

[0720] The synthesis of amide intermediate 132 was accomplished via a HATU-mediated coupling reaction between 1H-indole-2-carboxylic acid 37 and an analogue of intermediate 108. Amide intermediate 132 was reduced to the corresponding amine using lithium aluminum hydride-containing THF to give intermediate 133. Demethylation of intermediate 133 was performed at high temperature using boron tribromide-containing DCM to give intermediate 134. Base-mediated alkylation of intermediate 134 with DMF containing 3-(but-3-yn-1-yl)-3-(2-iodoethyl)-3H-bis(acrylidine) 135 yielded the final compound 337.

[0721]

[0722] Synthesis of Scheme 32.6-(2-(3-(but-3-yn-1-yl)-3H-bisacryl-3-yl)ethoxy)-2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-1H-indole 338

[0723] Alcohol intermediate 138 was synthesized by DIBAL-H reduction at -78 °C. Intermediate 138 was chlorinated with THF containing lithium chloride, methanesulfonyl chloride, and triethylamine to give tert-butyl 2-(chloromethyl)-6-methoxy-1H-indole-1-carboxylate 139. Intermediate 139 was coupled with piperazine 68 at high temperature in the presence of DMF containing potassium carbonate and potassium iodide to give intermediate 140. Intermediate 140 was subjected to parallel deprotection with boron tribromide in DCM at high temperature to give intermediate 141. Intermediate 141 was subjected to base-mediated alkylation with DMF containing 3-(but-3-yn-1-yl)-3-(2-iodoethyl)-3H-bisacrylidine 135 to give the final compound 338.

[0724] Detailed synthesis of intermediates of the compounds of the present invention

[0725] Synthesis of tert-butyl 4-((6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)piperazine-1-carboxylate

[0726]

[0727] 2-(chloromethyl)-6-(trifluoromethyl)-1H-benzi[d]imidazole (1 g, 4.26 mmol) was dissolved in anhydrous DMF (10 mL), followed by the addition of tert-butyl piperazine-1-carboxylate (873 mg, 4.69 mmol), and then 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 (MgSO4), filtered, and evaporated. The residue was purified by column chromatography (DCM containing 0–5% MeOH) on silica gel to give tert-butyl piperazine-1-carboxylate as an orange solid.

[0728] Yield: 1.6g (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).

[0729] Synthesis of 2-(piperazin-1-ylmethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole

[0730]

[0731] 4-((6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (1.6 g, 4.16 mmol) was treated with a solution of dioxane (4 M, 4.3 mL, 17.2 mmol) containing HCl at room temperature for 18 hours. The solvent was removed under vacuum to give 2-(piperazine-1-ylmethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazolium dihydrochloride as a light brown solid. This material (980 mg, 2.74 mmol) was dissolved in MeOH (10 mL), loaded into an SCX-2 box (20 g, 0.6 mmol / g loading), washed with MeOH, and eluted with ammonia / MeOH (2 M) to give 2-(piperazine-1-ylmethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazolium as a light brown solid.

[0732] 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).

[0733] Synthesis of tert-butyl 4-((6-chloro-1H-benzo[d]imidazol-2-yl)methyl)piperazine-1-carboxylate

[0734]

[0735] 6-Chloro-2-(chloromethyl)-1H-benzo[d]imidazole (300 mg, 1.49 mmol) and piperazine-1-carboxylic acid tert-butyl ester (306 mg, 1.64 mmol) were dissolved in anhydrous acetonitrile (4 mL), potassium carbonate (1.03 g, 7.46 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate (50 mL) and brine (30 mL), and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were dried (MgSO4), filtered, and evaporated to give 4-((6-chloro-1H-benzo[d]imidazole-2-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester as an orange solid.

[0736] 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).

[0737] Synthesis of 6-chloro-2-(piperazin-1-ylmethyl)-1H-benzo[d]imidazole

[0738]

[0739] The compound 6-chloro-2-(piperazin-1-ylmethyl)-1H-benzi[d]imidazole was prepared according to a procedure similar to that described for the synthesis of 2-(piperazin-1-ylmethyl)-6-(trifluoromethyl)-1H-benzi[d]imidazole, and the isolated compound was a beige solid.

[0740] 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).

[0741] Synthesis of tert-butyl 4-((1H-indol-2-yl)methyl)piperazine-1-carboxylate

[0742]

[0743] To anhydrous DCM (5 mL) containing 1H-indol-2-carboxaldehyde (250 mg, 1.72 mmol) and piperazine-1-carboxylate tert-butyl ester (353 mg, 1.89 mmol), sodium triacetoxyborohydride (913 mg, 4.31 mmol) and acetic acid (10 μL, 0.17 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (30 mL) and partitioned with saturated NaHCO3 solution (30 mL). The organic phase was dried (MgSO4), filtered, and evaporated. The residue was purified by column chromatography (cyclohexane containing 0-50% ethyl acetate) on silica gel to give 4-((1H-indol-2-yl)methyl)piperazine-1-carboxylate tert-butyl ester as a light brown solid.

[0744] Yield: 456 mg (84%). 1¹H NMR (400MHz, DMSO) δ 11.00 (br s, 1H), 7.45 (d, J = 7.8Hz, 1H), 7.33 (d, J = 8.0Hz, 1H), 7.03 (dd, J = 7.0, 7.0Hz, 1H), 6.95 (dd, J = 7.2, 7.2Hz, 1H), 6.28 (d, J = 1.4Hz, 1H), 3.63 (s, 2H), 2.37 (dd, J = 5.0, 5.0Hz, 4H), 1.40 (s, 9H). Four protons were masked by the solvent / water peak.

[0745] Synthesis of 2-(piperazin-1-ylmethyl)-1H-indole

[0746]

[0747] 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-benzis[d]imidazole, and the isolated compound was a brown solid.

[0748] 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).

[0749] Synthesis of tert-butyl 4-((5-chloro-1H-indol-2-yl)methyl)piperazine-1-carboxylate

[0750]

[0751] The compound 4-((5-chloro-1H-indol-2-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-chloro-1H-indol-2-carboxaldehyde according to a procedure similar to that described for the synthesis of 4-((1H-indol-2-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester, and the isolated compound was a yellow solid.

[0752] 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).

[0753] Synthesis of 5-chloro-2-(piperazin-1-ylmethyl)-1H-indole

[0754]

[0755] 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-benzi[d]imidazole, and the isolated compound was a brown solid.

[0756] 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).

[0757] Synthesis of 5-bromo-2-[[4-(4-pyridyl)piperazin-1-yl]methyl]-1H-indole (compound 215)

[0758]

[0759] To anhydrous DCM (25 mL) containing 5-bromo-1H-indole-2-carboxaldehyde (1 g, 4.46 mmol) and 1-(4-pyridyl)piperazine (801 mg, 4.91 mmol), sodium triacetoxyborohydride (2.36 g, 11.16 mmol) and acetic acid (26 μL, 0.446 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (30 mL) and washed with saturated NaHCO3 aqueous solution (30 mL) and brine (10 mL). The organic phase was dried (Na2SO4), filtered, and evaporated. The residue was purified by column chromatography on silica gel (containing 0–10% DCM in a methanol solution containing 10% ammonia / methanol) to give 5-bromo-2-[[4-(4-pyridyl)piperazin-1-yl]methyl]-1H-indole as a grayish-white solid.

[0760] Yield: 743 mg (45%). 1 ¹H NMR (400MHz, DMSO) δ 11.28 (s, 1H), 8.16 (d, J = 6.5Hz, 2H), 7.65 (d, J = 1.9Hz, 1H), 7.30 (d, J = 8.5Hz, 1H), 7.15 (dd, J = 1.9, 8.6Hz, 1H), 6.81 (d, J = 6.7Hz, 2H), 6.32 (d, J = 1.3Hz, 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).

[0761] Synthesis of tert-butyl 4-((1H-indol-2-yl)methyl)piperazine-1-carboxylate

[0762]

[0763] To an anhydrous DCM solution (25 mL) containing 1H-indol-2-carboxaldehyde (1.0 g, 6.89 mmol) and tert-butyl piperazine-1-carboxylate (1.41 g, 7.58 mmol), sodium triacetoxyborohydride (3.65 g, 17.2 mmol) and acetic acid (39 μL, 0.69 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (30 mL) and washed with saturated aqueous NaHCO3 solution (30 mL) and brine (10 mL). The organic phase was dried (Na2SO4), filtered, and evaporated to give tert-butyl 4-((1H-indol-2-yl)methyl)piperazine-1-carboxylate as a grayish-white solid.

[0764] Yield: 2.03g (94%). 1 ¹H NMR (400MHz, 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 masked by the solvent / water peak.

[0765] Synthesis of 2-(piperazin-1-ylmethyl)-1H-indole

[0766]

[0767] A solution of dioxane containing HCl (4 M, 10 mL, 40 mmol) was added to a solution of dioxane containing HCl (2.03 g, 6.45 mmol) in 4 mL, and the reaction mixture was stirred at room temperature for 2 hours. Another solution of dioxane containing HCl (4 M, 10 mL, 40 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under vacuum to obtain a residue, which was dissolved in MeOH (10 mL), placed in an SCX-2 container (20 g, 0.6 mmol / g loading), washed with MeOH, and eluted with ammonia / MeOH (1 M) to give 2-(piperazin-1-ylmethyl)-1H-indole as a light brown solid.

[0768] Yield: 1.35g (97%). 1 NH NMR (400MHz, DMSO) δ 10.98 (br s, 1H), 7.45 (d, J = 7.8Hz, 1H), 7.30 (d, J = 7.8Hz, 1H), 7.02 (dd, J = 7.1, 7.1Hz, 1H), 6.92 (dd, J = 7.1, 7.1Hz, 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). NH protons are obscured by residual water peaks.

[0769] Synthesis of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

[0770]

[0771] Sodium hydride (60%, 30 mg, 0.761 mmol) was added to an anhydrous DMF (2 mL) solution containing 4-bromo-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.508 mmol), and the mixture was stirred at this temperature for 10 min. Then, 2-(trimethylsilyl)ethoxymethyl chloride (0.11 mL, 0.609 mmol) was added, and the reaction mixture was heated to room temperature and stirred for 2 h. The reaction mixture was carefully quenched by adding water (0.1 mL) dropwise 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 / saline 1:1 (10 mL), and saline (10 mL). The organic layer was dried (Na2SO4), filtered and evaporated, and the residue was purified by column chromatography (cyclohexane containing 0-20% ethyl acetate) on silica gel to give 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine as a colorless oil.

[0772] 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).

[0773] Synthesis of 4-(4-((1H-indol-2-yl)methyl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrrolo[2,3-b]pyridine

[0774]

[0775] Palladium(II) acetate (7.3 mg, 0.033 mmol) and RuPhos (30 mg, 0.065 mmol) were added to a degassed suspension of anhydrous dioxane (3 mL) containing 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). The mixture was purged with nitrogen for 10 min and heated at 95 °C for 3 h in a sealed tube. 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 on silica gel by column chromatography (DCM containing 0-8% methanol) to give 4-(4-((1H-indol-2-yl)methyl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrrolo[2,3-b]pyridine, which was a brown glassy substance.

[0776] 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).

[0777] Synthesis of 6-bromo-2-[[4-(4-pyridyl)piperazin-1-yl]methyl]-1H-indole (compound 224)

[0778]

[0779] The compound 6-bromo-2-[[4-(4-pyridyl)piperazin-1-yl]methyl]-1H-indole was prepared from 5-bromo-1H-indole-2-carboxaldehyde according to a procedure similar to that described for the synthesis of 5-bromo-2-[[4-(4-pyridyl)piperazin-1-yl]methyl]-1H-indole, and the isolated compound was a brown solid.

[0780] 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%).

[0781] Synthesis of (5-(trifluoromethyl)-1H-indol-2-yl)methanol

[0782]

[0783] At 0 °C, a 1 M THF solution containing lithium aluminum hydride (3.8 mL, 3.84 mmol) was added dropwise to a 5 mL solution of 5-(trifluoromethyl)-1H-indole-2-carboxylic acid (800 mg, 3.49 mmol). 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 (approximately 20 mL) and extracted with ethyl acetate. The organic layer was washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated to give crude (5-(trifluoromethyl)-1H-indole-2-yl)methanol as a yellow solid. This material was used in the next step without further purification.

[0784] Yield: 661 mg (88%). m / z: [ESI] + 214 (MH) + .

[0785] Synthesis of 5-(trifluoromethyl)-1H-indole-2-carboxaldehyde

[0786]

[0787] MnO2 (3034 mg, 34.9 mmol) was added to a 25 mL solution of THF containing (751 mg, 3.49 mmol) of (5-(trifluoromethyl)-1H-indol-2-yl)methanol, and the mixture was stirred at room temperature for 18 hours. The mixture was then diluted with ethyl acetate and filtered through a diatomaceous earth mat to give 5-(trifluoromethyl)-1H-indol-2-carboxaldehyde as a yellow solid.

[0788] Yield: 541 mg (73%, obtained in 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).

[0789] Synthesis of (6-methoxy-1H-indol-2-yl)methanol

[0790]

[0791] Following a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indole-2-yl)methanol, the compound (6-methoxy-1H-indole-2-yl)methanol was prepared from 6-methoxy-1H-indole-2-carboxylic acid, and the isolated compound was a grayish-white solid. The intermediate was used in the next step without further purification.

[0792] Yield: 1.13g. m / z: [ESI] + 178 (M+H) + .

[0793] Synthesis of 6-methoxy-1H-indole-2-carboxaldehyde

[0794]

[0795] The compound 6-methoxy-1H-indole-2-carboxaldehyde was prepared from (6-methoxy-1H-indole-2-yl)methanol according to a procedure similar to that described for the synthesis of (5-trifluoromethyl)-1H-indole-2-carboxaldehyde, and the isolated compound was a brown solid.

[0796] Yield: 369 mg (51%, obtained in 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).

[0797] Synthesis of (6-(trifluoromethyl)-1H-indol-2-yl)methanol

[0798]

[0799] The compound (6-(trifluoromethyl)-1H-indole-2-yl)methanol was prepared from 6-(trifluoromethyl)-1H-indole-2-yl)carboxylic acid according to a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indole-2-yl)methanol, and the isolated compound was a brown oil.

[0800] 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).

[0801] Synthesis of 6-(trifluoromethyl)-1H-indole-2-carboxaldehyde

[0802]

[0803] Following a procedure similar to that described for the synthesis of 5-(trifluoromethyl)-1H-indole-2-carboxaldehyde, the compound 6-(trifluoromethyl)-1H-indole-2-carboxaldehyde was prepared from (6-(trifluoromethyl)-1H-indole-2-yl)methanol, and the isolated compound was a brown solid. The intermediate was used in the next step without further purification.

[0804] Yield 244 mg (63%). m / z: [ESI] + 212 (MH) + .

[0805] Synthesis of (5-nitro-1H-indol-2-yl)methanol

[0806]

[0807] At -60°C, a 1M solution of DCM (17 mL, 16.6 mmol) containing diisobutylaluminum hydride was added dropwise to a THF solution (44 mL) containing ethyl 5-nitro-1H-indole-2-carboxylate (1300 mg, 5.5 mmol). The mixture was stirred at -60°C for 4 hours, followed by stirring at -20°C for 1 hour. The mixture was quenched at 0°C with a saturated Rochelle salt solution (approximately 20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic matter was washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated to give (5-nitro-1H-indole-2-yl)methanol as a brown solid.

[0808] 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).

[0809] Synthesis of 5-nitro-1H-indole-2-carboxaldehyde

[0810]

[0811] The compound 5-nitro-1H-indole-2-carboxaldehyde was prepared from (5-nitro-1H-indole-2-yl)methanol according to a procedure similar to that described for the synthesis of 5-trifluoromethyl-1H-indole-2-carboxaldehyde, and the isolated compound was a brown solid.

[0812] 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).

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

[0814]

[0815] The compound 5-nitro-2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole was prepared from 5-nitro-1H-indole-2-carboxaldehyde according to a procedure similar to that described for the synthesis of 5-bromo-2-[[4-(4-pyridin-4-yl)piperazin-1-yl)methyl]-1H-indole, and the isolated compound was a brown solid.

[0816] 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).

[0817] Synthesis of (7-chloro-1H-indol-2-yl)methanol

[0818]

[0819] The compound (7-chloro-1H-indole-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-indole-2-yl)methanol, but the compound was further purified on silica gel by column chromatography (cyclohexane containing 0-100% ethyl acetate) to give (7-chloro-1H-indole-2-yl)methanol as a brown oil.

[0820] 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).

[0821] Synthesis of 7-chloro-1H-indole-2-carboxaldehyde

[0822]

[0823] The compound 7-chloro-1H-indole-2-carboxaldehyde was prepared from (7-chloro-1H-indole-2-yl)methanol according to a procedure similar to that described for the synthesis of 5-(trifluoroethyl)-1H-indole-2-carboxaldehyde, and the isolated compound was a brown solid.

[0824] 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).

[0825] Synthesis of methyl 2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole-5-carboxylate

[0826]

[0827] The compound methyl 2-((4-(pyridinyl)piperazin-1-yl)methyl)-1H-indole was prepared from methyl 2-formyl-1H-indole-5-carboxylate and 1-(pyridinyl-4-yl)piperazine according to a procedure similar to that described for the synthesis of 5-bromo-2-[[4-(4-pyridinyl-4-yl)piperazin-1-yl)methyl]-1H-indole-5-carboxylate, but the compound was purified by SCX-2 ion-exchange chromatography (2 g, 0.6 mmol / g loading, washed with MeOH and eluted with 1N ammonia / MeOH), and the isolated compound was a brown solid.

[0828] 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).

[0829] Synthesis of 2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole-5-carboxylic acid

[0830]

[0831] A solution of water (1 mL) containing 11 mg (0.28 mmol) of NaOH was added to a suspension of methyl 2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole-5-carboxylic acid (100 mg, 0.28 mmol) in 3 mL of THF. The reaction mixture was stirred at room temperature for 2 hours, and then stirred at 65 °C for 4 days. The reaction mixture was concentrated, dissolved in MeOH / water / DMSO, and purified by SAX-2 ion exchange chromatography (1 g, 0.6 mmol / g loading, washed with MeOH and eluted with 50% AcOH / MeOH). The purified solid was then purified by SCX-2 ion exchange chromatography (2 g, 0.6 mol / g loading, washed with MeOH and eluted with 1N ammonia / MeOH) to give 2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole-5-carboxylic acid as a brown solid.

[0832] Yield: 34 mg (33%). 1 ¹H NMR (400MHz, 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 acid OH proton is hidden.

[0833] Synthesis of 2-(hydroxymethyl)-1H-indole-5-carboxynitrile

[0834]

[0835] Following a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indole-2-yl)methanol, compound 2-(hydroxymethyl)-1H-indole-5-carboxylic acid was prepared from 5-cyano-1H-indole-2-carboxylic acid, and the isolated compound was a yellow solid. The intermediate was used in the next step without further purification.

[0836] Yield 727 mg. m / z: [ESI] + 171 (MH) + .

[0837] Synthesis of 2-formyl-1H-indole-5-carboxynitrile

[0838]

[0839] The compound 6-methoxy-1H-indole-2-carboxaldehyde was prepared from (6-methoxy-1H-indole-2-yl)methanol according to a procedure similar to that described for the synthesis of (5-trifluoromethyl)-1H-indole-2-carboxaldehyde, and the isolated compound was a yellow solid.

[0840] Yield 600mg (76%, processed 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).

[0841] Synthesis of ethyl 5-(2-methoxyethoxy)-1H-indole-2-carboxylate (I) and methyl 5-(2-methoxyethoxy)-1-(2-methoxyethyl)-1H-indole-2-carboxylate (II)

[0842]

[0843] 1-Bromo-2-methoxyethane (110 μL, 1.17 mmol) was added to an anhydrous DMF solution containing ethyl 5-hydroxy-1H-indole-2-carboxylate (200 mg, 0.98 mmol) and cesium carbonate (953 mg, 2.92 mmol) at room temperature, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The layers were separated, and the organic phase was washed with water (10 mL), water / saline 1:1 (10 mL), and saline (10 mL), respectively. The organic layer was dried (Na2SO4), filtered and evaporated, and the residue was purified by column chromatography (cyclohexane containing 0-100% ethyl acetate) on silica gel 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.

[0844] Yield 141 mg. I: m / z: [ESI] + ]264(M+H) + (Purity 68%). II: m / z: [ESI + ]322(M+H) + (Purity 30%).

[0845] Synthesis of (5-(2-methoxyethoxy)-1H-indol-2-yl)methanol (I) and (5-(2-methoxymethoxy)-1-(2-methoxyethyl)-1H-indol-2-yl)methanol (II)

[0846]

[0847] Following a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indole-2-yl)methanol, compounds (5-(2-methoxyethoxy)-1H-indole-2-yl)methanol and (5-(2-methoxyethoxy)-1-(2-methoxyethyl)-1H-indole-2-yl)methanol were prepared from ethyl 5-(2-methoxyethoxy)-1H-indole-2-yl)carboxylate and ethyl 5-(2-methoxyethoxy)-1-(2-methoxyethyl)-1H-indole-2-yl)methanol, and the isolated compounds were brown oily substances. The mixture was used in the next step without further purification.

[0848] Yield 120 mg. I: m / z: [ESI] + ]222(M+H) + (Purity 61%). II: m / z: [ESI + 280 (M+H) + (Purity 34%).

[0849] Synthesis of 5-(2-methoxyethoxy)-1H-indole-2-carboxaldehyde (I) and 5-(2-methoxyethoxy)-1-(2-methoxyethyl)-1H-indole-2-carboxaldehyde (II)

[0850]

[0851] Compounds 5-(2-methoxyethoxy)-1H-indole-2-carboxaldehyde and 5-(2-methoxyethoxy)-1H-indole-2-carboxaldehyde were prepared from (5-(2-methoxyethoxy)-1H-indole-2-yl)methanol and (5-(2-methoxyethoxy)-1-(2-methoxyethyl)-1H-indole-2-yl)methanol, and the isolated compounds were brown solids. The mixture was used in the next step without further purification.

[0852] Yield 120 mg. I: m / z: [ESI] - 218 (MH) - (Purity 66%). II: m / z: [ESI] + ]278(M+H) + (Purity 29%).

[0853] Synthesis of 1-(diethoxymethyl)-1H-indole-3-carboxynitrile

[0854]

[0855] A suspension of triethyl orthoformate (11.7 mL, 70.34 mmol) containing 1H-indole-3-carboxynitrile (1000 mg, 7.03 mmol) was heated to 160 °C and stirred for 3 days in a high-pressure tube. The reaction mixture was evaporated to dryness, and the residue was purified by column chromatography (isohexane containing 0-20% ethyl acetate) on silica gel to give 1-(diethoxymethyl)-1H-indole-3-carboxynitrile as a colorless oil.

[0856] 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).

[0857] Synthesis of 1-(diethoxymethyl)-2-formyl-1H-indole-3-carboxynitrile

[0858]

[0859] At -78°C, a 1.7M solution of pentane containing tert-butyllithium (0.53 mL, 0.90 mmol) was added to a THF solution (6 mL) containing 200 mg (0.82 mmol) of 1-(diethoxymethyl)-1H-indole-3-carboxynitrile (THF), and the mixture was heated to -10°C and stirred for 30 min. The mixture was then cooled to -78°C, DMF (0.57 mL, 7.32 mmol) was added, and the mixture was heated to -10°C and stirred for 2 h. The reaction mixture was quenched at 0°C with a saturated aqueous solution of NaHCO3 (10 mL) and extracted with Et2O (2 × 10 mL). The combined organic extracts were dried (Na2SO4), filtered, and evaporated to give 1-(diethoxymethyl)-2-formyl-1H-indole-3-carboxynitrile as a yellow oil. The intermediate was used in the next step without further purification.

[0860] Yield: 185 mg (crude).

[0861] Synthesis of 1-(diethoxymethyl)-2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole-3-carboxynitrile

[0862]

[0863] Following a procedure similar to that described for the synthesis of 5-bromo-2-[[4-(4-pyridyl)piperazin-1-yl]methyl]-1H-indole, the compound 1-(diethoxymethyl)-2-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-1H-indole-3-carboxynitrile was prepared from 1-(diethoxymethyl)-2-formyl-1H-indole-3-carboxynitrile, and the isolated compound was a yellow oil. The next step was carried out without further purification.

[0864] Yield 180 mg (crude). m / z: [ESI] + 420(M+H) + .

[0865] Synthesis of tert-butyl 6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0866]

[0867] To a degassed suspension of anhydrous dioxane (4 mL) containing 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), palladium(II) acetate (11 mg, 0.05 mmol) and RuPhos (46 mg, 0.10 mmol) were added. The mixture was purged with nitrogen for 10 min and heated in a sealed tube at 95 °C for 3 h. 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 on silica gel by column chromatography (DCM containing 0-10% 1N ammonia / methanol) to give tert-butyl 6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a brown gel.

[0868] 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).

[0869] Synthesis of 2-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane

[0870]

[0871] TFA (0.5 mL, 6.53 mmol) was added to an anhydrous DCM (3 mL) solution containing tert-butyl 6-(pyridin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (195 mg, 0.71 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by SCX-2 ion-exchange chromatography (2 g, 0.6 mmol / g loading, washed with MeOH and eluted with 1N ammonia / MeOH), and the isolated compound was a grayish-white solid.

[0872] Yield: 67 mg (54%). 1 NH NMR (400MHz, DMSO) 8.11 (dd, J = 1.6, 4.7Hz, 2H), 6.33 (dd, J = 1.6, 4.7Hz, 2H), 3.97 (s, 4H), 3.61 (s, 4H). NH protons are obscured by the residual water peak.

[0873] Synthesis of tert-butyl 7-(pyridin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

[0874]

[0875] 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, 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, and the isolated compound was a yellow gel.

[0876] 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).

[0877] Synthesis of 2-(pyridin-4-yl)-2,7-diazaspiro[4.4]nonane

[0878]

[0879] The compound 2-(pyridin-4-yl)-2,7-diazaspiro[4.4]nonane was prepared from 7-(pyridin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester, and the isolated compound was a colorless oil.

[0880] 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).

[0881] Synthesis of (3R,5S)-3,5-dimethyl-4-(pyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0882]

[0883] 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, the compound (3R,5S)-3,5-dimethyl-4-(pyridin-4-yl)piperazine-1-carboxylate was prepared from (3R,5S)-3,5-dimethylpiperazine-1-carboxylate and 4-iodopyridine, and the isolated compound was a brown glassy substance.

[0884] Yield 39 mg (14%). m / z: [ESI + ]292(M+H) +

[0885] Synthesis of (2R,6S)-2,6-dimethyl-1-(pyridin-4-yl)piperazine dihydrochloride

[0886]

[0887] A solution of dioxane (4M, 2 mL, 8 mmol) containing HCl was added to a solution of (3R,5S)-3,5-dimethyl-4-(pyridin-4-yl)piperazine-1-carboxylate (39 mg, 0.13 mmol) in 1 mL, 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 a grayish-white solid. This was then used for the next step without further purification.

[0888] Yield 35 mg (quantitative). m / z: [ESI] + 192(M+H) + .

[0889] Synthesis of tert-butyl (3aR,6aS)-5-(pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylate

[0890]

[0891] 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, the compound (3aR,6aS)-5-(pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylate was prepared from (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylate and 4-iodopyridine, and the isolated compound was a yellow oil.

[0892] 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).

[0893] Synthesis of (3aR,6aS)-2-(pyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole

[0894]

[0895] The compound (3aR,6aS)-2-(pyridin-4-yl)octahydropyrrolo[3,4-c]pyrrole was prepared from (3aR,6aS)-5-(pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester, and the isolated compound was a grayish-white solid.

[0896] Yield: 128 mg (70%). 1 NH NMR (400MHz, DMSO) δ 8.10 (dd, J = 1.6, 4.8Hz, 2H), 6.47 (dd, J = 1.6, 4.8Hz, 2H), 3.49 (dd, J = 8.1, 10.4Hz, 2H), 3.08 (dd, J = 3.7, 10.4Hz, 2H), 2.93 (dd, J = 8.1, 10.9Hz, 2H), 2.89–2.81 (m, 2H), 2.64 (dd, J = 2.9, 10.9Hz, 2H). NH protons are obscured by the residual water peak.

[0897] Synthesis of tert-butyl 4-(5,6-dimethylpyrimidin-4-yl)piperazine-1-carboxylate

[0898]

[0899] According to a procedure similar to that described for the synthesis of tert-butyl piperazine-1-carboxylate[3.3]heptane-2-carboxylate, the compound 4-(5,6-dimethylpyrimidin-4-yl)piperazine-1-carboxylate was prepared from piperazine-1-carboxylate and 4-chloro-5,6-dimethylpyrimidine, and the isolated compound was a grayish-white solid.

[0900] 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).

[0901] Synthesis of 4,5-dimethyl-6-(piperazin-1-yl)pyrimidine hydrochloride

[0902]

[0903] The compound 4,5-dimethyl-6-(piperazin-1-ylmethyl)-1H-indole was prepared from tert-butyl 4-(5,6-dimethylpyrimidin-4-yl)piperazin-1-carboxylate using a procedure similar to that described for the synthesis of 2-(piperazin-1-yl)-indole, but the compound was not purified by SCX-2 ion-exchange chromatography, and the isolated compound was a grayish-white solid. The intermediate was used as the hydrochloride in the next step without further purification.

[0904] Yield: 511 mg (crude). m / z: [ESI] + 193(M+H) + .

[0905] Synthesis of pyrazolo[1,5-a]pyridin-2-ylmethanol

[0906]

[0907] Following a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indol-2-yl)methanol, the compound pyrazolo[1,5-a]pyridin-2-ylmethanol was prepared from pyrazolo[1,5-a]pyridin-2-carboxylic acid, and the isolated compound was a brown oil. The intermediate was used in the next step without further purification.

[0908] Yield: 338 mg (crude). m / z: [ESI] + 149(M+H) + .

[0909] Synthesis of pyrazolo[1,5-a]pyridine-2-carboxaldehyde

[0910]

[0911] The compound pyrazolo[1,5-a]pyridine-2-carboxaldehyde was prepared from pyrazolo[1,5-a]pyridine-2-carboxaldehyde using a procedure similar to that described for the synthesis of 5-(trifluoromethyl)-1H-indole-2-carboxaldehyde, and the isolated compound was a yellow solid.

[0912] Yield 208 mg (crude). m / z: [ESI] + 147(M+H) + .

[0913] Synthesis of (1H-pyrrolo[2,3-b]pyridin-2-yl)methanol

[0914]

[0915] Following a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indol-2-yl)methanol, the compound (1H-pyrrolo[2,3-b]pyridin-2-yl)methanol was prepared from 1H-pyrrolo[2,3-b]pyridin-2-carboxylic acid, and the isolated compound was a brown solid. The intermediate was used in the next step without further purification.

[0916] Yield 248 mg (crude). m / z: [ESI] + 149(M+H) + .

[0917] Synthesis of 1H-pyrrolo[2,3-b]pyridine-2-carboxaldehyde

[0918]

[0919] The compound 1H-pyrrolo[2,3-b]pyridine-2-carboxaldehyde 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-carboxaldehyde, and the isolated compound was a yellow solid.

[0920] Yield 168 mg (crude). m / z: [ESI] + 147(M+H) + .

[0921] Synthesis of (1H-pyrrolo[2,3-c]pyridin-2-yl)methanol

[0922]

[0923] Following a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indol-2-yl)methanol, the compound (1H-pyrrolo[2,3-c]pyridin-2-yl)methanol was prepared from 1H-pyrrolo[2,3-c]pyridin-2-carboxylic acid, and the isolated compound was a brown solid. The intermediate was used in the next step without further purification.

[0924] Yield: 321 mg (crude). m / z: [ESI] + 149(M+H) + .

[0925] Synthesis of 1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde

[0926]

[0927] The compound 1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde 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-carboxaldehyde, and the isolated compound was a yellow solid.

[0928] Yield 214 mg (68%). m / z: [ESI] + 147(M+H) + .

[0929] Synthesis of (1H-pyrrolo[3,2-b]pyridin-2-yl)methanol

[0930]

[0931] Following a procedure similar to that described for the synthesis of (5-(trifluoromethyl)-1H-indol-2-yl)methanol, the compound (1H-pyrrolo[3,2-b]pyridin-2-yl)methanol was prepared from 1H-pyrrolo[3,2-b]pyridin-2-carboxylic acid, and the isolated compound was a yellow solid. The intermediate was used in the next step without further purification.

[0932] Yield 186 mg (crude). m / z: [ESI] + 149(M+H) + .

[0933] Synthesis of 1H-pyrrolo[3,2-b]pyridine-2-carboxaldehyde

[0934]

[0935] The compound 1H-pyrrolo[3,2-b]pyridine-2-carboxaldehyde 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-carboxaldehyde, and the isolated compound was a yellow solid.

[0936] Yield 164 mg (90%). m / z: [ESI] + 147(M+H) + .

[0937] Synthesis of tert-butyl 4-(5-formylpyrimidin-4-yl)piperazine-1-carboxylate

[0938]

[0939] Under a nitrogen atmosphere at room temperature, water (20 mL) and osmium tetroxide (35 mg, 0.138 mmol) were added to a 20 mL solution of THF containing 2.00 g (6.89 mmol) of 4-(5-vinylpyrimidin-4-yl)piperazine-1-carboxylate. The resulting mixture was stirred for 2 minutes under a nitrogen atmosphere at room temperature. Sodium periodate (2.95 g, 13.79 mmol) was added in portions to the mixture over 2 minutes at room temperature. The resulting mixture was stirred for another 16 hours at room temperature. 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 reversed-phase rapid 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-65% B over 20 min; detector: UV 254 / 220 nm. The fraction containing the desired product was collected and concentrated under reduced pressure to give tert-butyl 4-(5-formylpyrimidin-4-yl)piperazine-1-carboxylate as a brown solid.

[0940] Yield: 1.10g (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) + .

[0941] Synthesis of tert-butyl 4-(5-(hydroxymethyl)pyrimidin-4-yl)piperazine-1-carboxylate

[0942]

[0943] Sodium borohydride (52 mg, 1.374 mmol) was added to an ethanol (10 mL) solution containing 270 mg (0.924 mmol) of tert-butyl 4-(5-formylpyrimidin-4-yl)piperazine-1-carboxylate (270 mg, 0.924 mmol). The resulting mixture was stirred for 30 min at 0 °C under a nitrogen atmosphere. 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 reversed-phase rapid 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–55% B over 20 min; detector: UV 254 / 220 nm. The fraction containing the desired product was collected and concentrated under reduced pressure to obtain tert-butyl 4-[5-(hydroxymethyl)pyrimidin-4-yl)piperazine-1-carboxylate, which is a brown oil.

[0944] 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) + .

[0945] Synthesis of tert-butyl 4-(5-((2-methoxyethoxy)methyl)pyrimidin-4-yl)piperazine-1-carboxylate

[0946]

[0947] Sodium hydride (0.15 g, 3.75 mmol, 60% w / w dispersed in mineral oil) was added to an anhydrous DMF (10 mL) solution containing 0.73 g (2.48 mmol) of 4-[5-(hydroxymethyl)pyrimidin-4-yl]piperazine-1-carboxylic acid tert-butyl ester (6.73 g, 2.48 mmol) in mineral oil. 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 mixture 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 reversed-phase rapid 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-60% B over 20 min; detector: UV 254 / 220 nm. The fraction containing the desired product was collected and concentrated under reduced pressure to give tert-butyl 4-(5-[(2-methoxyethoxy)methyl]pyrimidin-4-yl]piperazine-1-carboxylate, a brown oil.

[0948] Yield: 0.70g (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) + .

[0949] Synthesis of 5-((2-methoxyethoxy)methyl)-4-(piperazin-1-yl)pyrimidine

[0950]

[0951] 4-[5-[(2-methoxyethoxy)methyl]pyrimidin-4-yl]piperazine-1-carboxylic acid tert-butyl ester (0.70 g, 1.99 mmol) was treated with dioxane (15 mL, 60.00 mmol) containing 4 M HCl for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid 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: 10% B–30% B over 20 min; detector: UV 254 / 220 nm. The fraction containing the desired product was collected and concentrated under reduced pressure to give 5-[(2-methoxyethoxy)methyl]-4-(piperazine-1-yl)pyrimidine as a brown oil.

[0952] Yield: 0.40g (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) + .

[0953] Synthesis of tert-butyl 4-(1-methyl-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate

[0954]

[0955] Under a nitrogen atmosphere at room temperature, tert-butyl piperazine-1-carboxylate (4.14 g, 22.23 mmol), copper iodide (I) (1.06 g, 5.57 mmol), tripotassium phosphate (11.80 g, 55.59 mmol), and L-proline (1.28 g, 11.12 mmol) were added to a 45 mL DMSO solution containing 3.00 g (18.52 mmol) of 4-bromo-1-methyl-1,2,3-triazole at room temperature. The resulting mixture was stirred at 120 °C for 16 hours under a nitrogen atmosphere. After cooling to ambient temperature, the mixture was filtered, and the collected filter cake was washed with acetonitrile (2 × 10 mL). The combined washes and filtrates were concentrated under reduced pressure. The residue was purified by reversed-phase rapid 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-55% B over 20 min; detector: 254 / 220 nm. The fraction containing the desired product was collected and concentrated under reduced pressure to give tert-butyl 4-(1-methyl-1,2,3-triazol-4-yl)piperazine-1-carboxylate as a grayish-white solid.

[0956] Yield: 0.16g (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) + .

[0957] Synthesis of 1-(1-methyl-1H-1,2,3-triazol-4-yl)piperazine

[0958]

[0959] 4-(1-methyl-1,2,3-triazol-4-yl)piperazine-1-carboxylic acid tert-butyl ester (159 mg, 0.561 mmol) was treated with dioxane (10 mL, 40.00 mmol) containing 4 M HCl for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid 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: 20% B–40% B over 20 min; detector: 254 / 220 nm. The fraction containing the desired product was collected and concentrated under reduced pressure to give 1-(1-methyl-1,2,3-triazol-4-yl)piperazine as a yellow solid.

[0960] 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) + .

[0961] Synthesis of tert-butyl 4-(5-bromopyrimidin-4-yl)piperazine-1-carboxylate

[0962]

[0963] Potassium carbonate (1.48 g, 10.71 mmol) was added to a 30 mL solution of DMF containing piperazine-1-carboxylic acid tert-butyl ester (2.00 g, 10.74 mmol) and 5-bromo-4-chloropyrimidine (2.08 g, 10.75 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 130 °C for 16 hours. After cooling to room temperature, the mixture was filtered. The collected filter cake was washed with ethyl acetate (3 × 30 mL). The combined washes and filtrates were concentrated under reduced pressure. The residue was purified by reversed-phase rapid 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-80% B over 20 min; detector: UV 254 / 220 nm. The fraction containing the desired product was collected and concentrated under reduced pressure to give tert-butyl 4-(5-bromopyrimidin-4-yl)piperazine-1-carboxylate as a yellow solid.

[0964] Yield: 3.20g (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) + .

[0965] Synthesis of tert-butyl 4-(5-vinylpyrimidin-4-yl)piperazine-1-carboxylate

[0966]

[0967] To a solution of DME (30 mL) and water (9 mL) containing tert-butyl 4-(5-bromopyrimidin-4-yl)piperazine-1-carboxylate (3.00 g, 8.74 mmol), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxane (1.48 g, 9.61 mmol), sodium carbonate (1.85 g, 17.45 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) were added, and the mixture was complexed with dichloromethane (0.36 g, 0.44 mmol) at room temperature under an argon atmosphere. The resulting mixture was stirred at 95 °C for 16 hours under an argon atmosphere. After cooling to room temperature, the resulting mixture was filtered, and the collected filter cake was washed with ethyl acetate (3 × 50 mL). The combined washes and filtrates were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and eluted with petroleum ether containing 1%-90% ethyl acetate to give tert-butyl 4-(5-vinylpyrimidin-4-yl)piperazine-1-carboxylate, which was a brown oil.

[0968] Yield: 2.00g (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) + .

[0969] Synthesis of tert-butyl 4-(5-ethylpyrimidin-4-yl)piperazine-1-carboxylate

[0970]

[0971] To a stirred solution of methanol (30 mL) containing 4.00 g (13.77 mmol) of tert-butyl 4-(5-vinylpyrimidin-4-yl)piperazine-1-carboxylate, 10% wt. palladium / carbon (600 mg) was added. The stirred mixture was degassed and then stirred with a balloon at room temperature under a hydrogen atmosphere for 18 hours. The resulting mixture was filtered through a diatomaceous earth filter and washed with ethyl acetate (3 × 30 mL). The combined washes and filtrates 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.

[0972] Yield: 3.80g (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).

[0973] m / z: [ESI] + ]293(M+H) + .

[0974] Synthesis of 5-ethyl-4-(piperazin-1-yl)pyrimidine

[0975]

[0976] A solution of dioxane (5 mL, 20.00 mmol) containing 4 M HCl was added to a 20 mL solution of THF containing 3.80 g (12.99 mmol) of tert-butyl piperazine-1-carboxylate. 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 reversed-phase rapid chromatography under the following conditions: column, C18, 20–40 μm, 330 g; mobile phase A: water (with 10 mM NH4HCO3); mobile phase B: ACN; flow rate: 80 mL / min; gradient: 30% B–50% B over 20 min; detector: UV 254 / 220 nm. The fraction containing the desired product was collected and concentrated under reduced pressure to give 5-ethyl-4-(piperazine-1-yl)pyrimidine as a brown solid.

[0977] Yield: 2.20g (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) + .

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

[0979]

[0980] Under a nitrogen atmosphere at room temperature, potassium carbonate (7.10 g, 51.37 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (6.80 g, 40.79 mmol) were added to a DMF (60 mL) solution containing 5-bromo-3H-1,3-benzodiazole (5.00 g, 25.38 mmol). After stirring for 16 hours, the resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid 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–75% B over 20 min; detector: UV 254 / 220 nm. The fraction containing the desired product was collected and concentrated under reduced pressure to give 6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole, which was a brown oil.

[0981] Yield: 3.40g (41%). 1 ¹H NMR (400MHz, 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). (A mixture of two regioisomers, in approximately a 1:1 ratio). m / z: [ESI] + 327,329(M+H) + .

[0982] Synthesis of (3-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazol-5-yl)methanol

[0983]

[0984] Under an argon atmosphere at room temperature, (tributyltinyl)methanol (7.90 g, 24.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.40 g, 1.21 mmol) were added to a degassed anhydrous dioxane (40 mL) solution containing 6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (4.00 g, 12.22 mmol). The resulting mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid 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–60% B over 20 min; detector: UV 254 / 220 nm. The fraction containing the desired product was collected and concentrated under reduced pressure to give (3-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazol-5-yl)methanol, which is a brown oil.

[0985] Yield: 0.90g (27%). 1 ¹H NMR (400MHz, DMSO) δ 9.13 (s, 1H), 7.80 (s, 1H), 7.75 (d, J = 8.4Hz, 1H), 7.43 (d, J = 8.4Hz, 1H), 5.79 (s, 2H), 4.67 (s, 2H), 3.57 (t, J = 3.2Hz, 2H), 0.89 (t, J = 3.2Hz, 2H), -0.064 (s, 9H), OH protons are invisible - below the water peak. m / z: [ESI] + ]279(M+H) + .

[0986] Synthesis of 6-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzi[d]imidazole

[0987]

[0988] A solution of DCM (20 mL) containing (0.90 g, 3.23 mmol) was treated with thionyl chloride (2.30 mL, 31.67 mmol) for 1.5 h at room temperature under an argon atmosphere. The reaction mixture was quenched with saturated aqueous NaHCO3 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 a crude, brown, oily product, which was used in the next step without further purification.

[0989] Yield: 0.80g (crude). m / z: [ESI] + 297,299(M+H) + .

[0990] Synthesis of 6-[(2-methoxyethoxy)methyl]-1-[[2-(trimethylsily...

Claims

1. A compound represented by the structure of formula V(a): in L1 is CH2, CHR, C(R)2 or C=O; 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 chain or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight chain or branched substituted or unsubstituted alkenyl, C1-C5 straight chain, branched or cyclic haloalkyl (e.g., CHF2), C1-C5 straight chain, 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 chain or branched thioalkoxy, C1-C5 straight chain or branched haloalkoxy, C1-C5 straight chain 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; 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); 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 chain or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight chain or branched substituted or unsubstituted alkenyl, C1-C5 straight chain, branched or cyclic haloalkyl (e.g., CHF2), C1-C5 straight chain, 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 chain or branched thioalkoxy, C1-C5 straight chain or branched haloalkoxy, C1-C5 straight chain or branched alkoxyalkyl, substituted or unsubstituted C3-C8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C3-C8 heterocycle (e.g., pyrazole, thiazole), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; 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 (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole); R 20 Represented by the following structure: X2 is NH, S, O, NR (e.g., N-CH2-CH2-O-CH3); X3 is N, C(R) (e.g., CH, C-CH3, C-Cl, C-CN); X4, X5, X6 and X7 are each independently C or N; X8, X9, X 10 , X 11 and X 12 each independently is C or N; R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 straight chain or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight chain 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 Two geminal R substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole); R8 is [CH2] p where p is between 1 and 10 (e.g., 2); R9 is [CH] q , [C] q Where q is between 2 and 10; R 10 and R 11 Each is independently H, substituted or unsubstituted C1-C5 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), 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; m, n, l, and k are each independently an integer between 0 and 4 (e.g., 0, 1, or 2); W is 0, 1 or 2; wherein if w=0, then the bridge on the ring does not exist; Wherein if X3 is N, then X2 is not NH; or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant (e.g., a deuterated analog), reverse amide, pharmaceutical product, or any combination thereof.

2. The compound according to claim 1, which is represented by the structure of formula VI:

3. A compound represented by the structure of formula VII: in L1 is CH2, CHR, C(R)2 or C=O; 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), 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 chain or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight chain or branched substituted or unsubstituted alkenyl, C1-C5 straight chain, branched or cyclic haloalkyl (e.g., CHF2), C1-C5 straight chain, 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 chain or branched thioalkoxy, C1-C5 straight chain or branched haloalkoxy, C1-C5 straight chain 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; 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 chain or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight chain or branched substituted or unsubstituted alkenyl, C1-C5 straight chain, branched or cyclic haloalkyl (e.g., CHF2), C1-C5 straight chain, 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 chain or branched thioalkoxy, C1-C5 straight chain or branched haloalkoxy, C1-C5 straight chain 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; 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 (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole); R 20 Represented by the following structure: X2 is NH, S, O, NR (e.g., N-CH2-CH2-O-CH3); X3 is N, C(R) (e.g., CH, C-CH3, C-Cl, C-CN); X 10 and X 12 each independently is C or N; R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5 straight chain or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5 straight chain 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 Two geminal R substitutions are linked together to form a 3- to 6-membered substituted or unsubstituted aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole); R8 is [CH2] p where p is between 1 and 10 (e.g., 2); R9 is [CH] q , [C] q Where q is between 2 and 10; R 10 and R 11 Each is 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), 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; Wherein if X3 is N, then X2 is not NH; 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.

4. The compound according to any one of claims 1 or 2, wherein X8, X9, X 10 , X 11 and X 12 At least one of them is N.

5. The compound according to any one of claims 3 or 4, wherein X 10 and X 12 At least one of them is N.

6. The compound according to claim 1, which is selected from the following:

7. A compound represented by the structure of formula X: in R1 and R2 are each independently H, Cl, -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), OR 20 or CF3; R3 and R4 are each independently H, OR 20 , C1-C5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl), substituted or unsubstituted C3-C8 heterocycle (e.g., imidazole), (wherein the 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); 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 (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole); R 20 Represented by the following structure: X 12 is C or N; in, If R3 is ethyl, then R1 or R2 is not CF3; or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, prodrug, isotopic variant (e.g., a deuterated analog), pharmaceutical product, or any combination thereof.

8. The compound according to claim 7, which is selected from the following:

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

10. The compound according to any one of claims 1 to 9, wherein the compound is a collagen translation inhibitor.

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