Collagen 1 translation inhibitors and their usage

Abstract

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, hepatic fibrosis, renal fibrosis, cardiac fibrosis, and dermal fibrosis; IPF; wound healing; scar formation and gingival fibromatosis; systemic sclerosis; and alcoholic steatohepatitis and non-alcoholic steatohepatitis (NASH).

Description

[0001] Invention Field 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, hepatic fibrosis, renal fibrosis, cardiac fibrosis, and dermal fibrosis; IPF; wound healing; scar formation and gingival fibromatosis; systemic sclerosis; and alcoholic steatohepatitis and non-alcoholic steatohepatitis (NASH). Background of the Invention The formation of fibrous connective tissue is part of the normal healing process following tissue damage caused by injury or inflammation. During this process, activated immune cells, including macrophages, stimulate the proliferation and activation of fibroblasts, which in turn leads to the deposition of connective tissue. However, abnormal or excessive production of connective tissue can result in 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. Such abnormal formation of excessive connective tissue during a reparative or reactive process is called fibrosis.

[0003] Many agents induce activation of the fibrotic process and are released in response to tissue injury, inflammation, and oxidative stress. Regardless of the initiating event, a common feature of all fibrotic diseases is the transformation of tissue-resident fibroblasts into ECM-producing myofibroblasts that secrete type I collagen. The current procedure indirectly targets myofibroblast activation and collagen secretion by inhibiting a single fibrosis-inducing signal.

[0004] Physiologically, fibrosis involves the deposition of connective tissue, which can disrupt the structure and function of basal organs or tissues. Limited by the pathological accumulation of extracellular matrix (ECM) proteins, fibrosis leads to scarring and thickening of affected tissues, interfering with normal organ function. In many conditions, the formation of fibrotic tissue is characterized by the deposition of abnormally large amounts of collagen. Collagen synthesis is also associated with many other pathological conditions. For example, clinical conditions and disorders associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, and autoimmune disorders, are identified by the excessive production of connective tissue, leading to the disruption of normal tissue structure and function. These diseases are best explained by interference with 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.

[0005] Excessive collagen accumulation is a major pathological feature in a variety of clinical conditions characterized by tissue fibrosis. These conditions include localized processes such as pulmonary fibrosis and cirrhosis, or more generalized processes such as progressive systemic sclerosis. Collagen deposition is characteristic of various forms of dermal 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 means to reduce excessive collagen accumulation in disease.

[0006] Liver fibrosis, also referred to herein as hepatic fibrosis, can be caused by a variety of types of chronic liver injury, particularly those involving inflammatory components. Self-limiting acute liver injury (e.g., acute hepatitis A), even when fulminant, does not necessarily distort 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.

[0007] Fibrosis itself is not necessarily asymptomatic; however, it can lead to the development of portal hypertension or cirrhosis, in which scarring distorts blood flow through the liver, and in which scarring causes destruction of normal liver structure and impaired liver function. The extent of each of these conditions determines the clinical presentation of liver fibrosis disorders. For example, congenital liver fibrosis affects the portal vein branches, which largely preserves the parenchyma. The result is portal hypertension with preserved hepatocellular function.

[0008] treat Attempts to develop antifibrotic agents for the treatment of a variety of disorders have been reported. However, treating established fibrosis that has developed months or years after chronic or repeated injuries remains a challenge.

[0009] Treatments aimed at reversing fibrosis are often too toxic for long-term use (e.g., corticosteroids, penicillamine) or lack proven efficacy (e.g., colchicine).

[0010] Many patients do not respond to available treatments for fibrotic disorders, 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.

[0011] Attempts to treat idiopathic pulmonary fibrosis (IPF) with a combination of anti-inflammatory drugs (prednisone, azathioprine, and N-acetyl-L-cysteine ​​(NAC)) failed to improve outcomes and instead increased mortality. In 2014, two drugs, pirfenidone (a drug with a poorly understood mechanism) and nintedanib (a tyrosine kinase inhibitor), were approved for the treatment of IPF, primarily based on their ability to reduce the decline in forced vital capacity (FVC) and slow the rate of disease progression. However, to date, it 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.

[0012] The compounds of this invention target and activate 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, lung fibrosis and idiopathic pulmonary fibrosis (IPF), as well as localized processes such as pulmonary fibrosis and cirrhosis or more generalized processes such as progressive systemic sclerosis. The compounds can also be used to treat various forms of dermal fibrosis, including, in addition to scleroderma, localized and generalized scleroderma, keloids, hypertrophic scars, familial skin 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. Such fibrosis can lead to portal hypertension or cirrhosis and other liver fibrosis disorders, in which scarring causes distorted blood flow through the liver. These other liver fibrosis disorders include non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). The portal hypertension, cirrhosis, and other liver fibrosis disorders can be similarly treated with the compounds of the present invention. Invention Overview This invention provides compounds of formulas I-V as defined below and compounds represented by the structures listed in Table 1, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates thereof. N-Oxides, reverse amide analogs, prodrugs, isotope variants (e.g., deuterated analogs), PROTACs, pharmaceutical products, or any combination thereof. In many embodiments, the compound is a collagen I translation inhibitor.

[0014] This invention provides compounds represented by the structure of compound 100, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates thereof. N -Oxides, reverse amide analogs, prodrugs, isotope variants (e.g., deuterated analogs), PROTACs, pharmaceutical products, or any combination thereof.

[0015] This invention provides compounds represented by the structure of compound 118, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates thereof. N -Oxides, reverse amide analogs, prodrugs, isotope variants (e.g., deuterated analogs), PROTACs, pharmaceutical products, or any combination thereof.

[0016] The present invention also provides a pharmaceutical composition comprising a compound of formulas I-V as defined below and a compound represented by the structures listed in Table 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate thereof. N -Oxides, prodrugs, isotope variants (e.g., deuterated analogs), PROTACs, pharmaceutical products or any combination thereof, and pharmaceutically acceptable carriers.

[0017] This invention also provides methods 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 a subject suffering from fibrosis, under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing fibrosis in the subject, or suppress fibrosis in the subject, a compound represented by a structure of formulas I-V 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, organ-specific fibrotic diseases are 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, pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, cardiac fibrosis is hypertension-related cardiac fibrosis, post-myocardial infarction, Chagas disease-induced myocardial fibrosis, or any combination thereof. In some embodiments, 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, pulmonary fibrosis is idiopathic pulmonary fibrosis, silica-induced pneumoconiosis (silicosis), asbestos-induced pulmonary fibrosis (asbestosis), chemotherapeutic agent-induced pulmonary fibrosis, or any combination thereof. In some embodiments, 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, diffuse fasciitis is localized scleroderma, keloids, Dupuytren's disease, Peyronie's disease, myelofibrosis, oral submucosal fibrosis, or any combination thereof. In some embodiments, fibrosis is primary or secondary fibrosis. In some embodiments, fibrosis is the result of systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, autoimmune disorders, tissue damage, inflammation, oxidative stress, or any combination thereof. In some embodiments, fibrosis is liver fibrosis, pulmonary fibrosis, or dermal fibrosis. In some embodiments, the subject has cirrhosis.In some embodiments, dermal fibrosis is scleroderma. In some embodiments, dermal 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, liver fibrosis is the result of liver scarring or chronic liver injury. In some embodiments, chronic liver injury is caused by: alcoholism, malnutrition, hemochromatosis, or exposure to toxins, poisons, or drugs.

[0018] The present invention also 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 a subject suffering from pulmonary fibrosis, a compound represented by a structure of formulas I-V as defined below and a compound represented by a structure listed in Table 1, under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing, or suppress pulmonary fibrosis in the subject. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

[0019] The present invention also provides a method for treating, inhibiting, reducing the severity of, or reducing the risk of developing idiopathic pulmonary fibrosis (IPF) in a subject, or suppressing IPF in a subject, comprising administering, to a subject suffering from IPF, compounds of formulas I-V as defined below and those represented by structures listed in Table 1, under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing, or suppress IPF in the subject.

[0020] This invention also provides a method for treating, inhibiting, reducing the severity of, reducing the risk of developing or suppressing liver fibrosis in a subject, comprising administering to a subject with liver fibrosis a compound represented by a structure of formulas I-V as defined below and a structure listed in Table 1, 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, liver fibrosis is portal hypertension, cirrhosis, congenital liver fibrosis, or any combination thereof.

[0021] The present invention also 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 a subject with cirrhosis, under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing cirrhosis in the subject, or inhibit cirrhosis in the subject, a compound represented by a structure of formulas I-V as defined below and a compound represented by a structure listed in Table 1. In some embodiments, cirrhosis is a result of hepatitis or alcohol poisoning.

[0022] The present invention also provides a method for treating, inhibiting, reducing the severity of, reducing the risk of developing or suppressing alcoholic steatohepatitis (ASH) in a subject, comprising administering to a subject suffering from alcoholic steatohepatitis (ASH) a compound represented by a structure of formulas I-V as defined below and a structure listed in Table 1, under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing or suppress alcoholic steatohepatitis (ASH) in the subject.

[0023] The present invention also provides a method for treating, inhibiting, reducing the severity of, or reducing the risk of developing non-alcoholic steatohepatitis (NASH) in a subject, comprising administering to a subject suffering from non-alcoholic steatohepatitis (NASH) a compound represented by a structure of formulas I-V as defined below and a structure listed in Table 1, under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing, or inhibit the non-alcoholic steatohepatitis (NASH) in the subject.

[0024] The present invention also provides a method for treating, inhibiting, reducing the severity of, reducing the risk of developing AFLD in a subject, or suppressing AFLD in a subject, comprising administering to a subject suffering from AFLD compounds, as defined below, representing structures of formulas I-V and those listed in Table 1, under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing AFLD in the subject, or suppress AFLD in the subject.

[0025] The present invention also provides a method for treating, inhibiting, reducing the severity of, or reducing the risk of developing non-alcoholic fatty liver disease (NAFLD) in a subject, comprising administering to a subject suffering from NAFLD a compound represented by the structures of Formulas I-V as defined below and the structures listed in Table 1, under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing, or reduce the subject's NAFLD.

[0026] The present invention also provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing an autoimmune disease or disorder in a subject, or inhibiting an autoimmune disease or disorder in a subject, the method comprising administering, to a subject suffering from an autoimmune disease or disorder, compounds of the structures defined below as Formulas I-V and those listed in Table 1, to a subject suffering from an autoimmune disease or disorder, under conditions that effectively treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the subject's autoimmune disease or disorder.

[0027] The present invention also provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing an autoimmune disease or disorder in a subject, or inhibiting an autoimmune disease or disorder in a subject, the method comprising administering, to a subject suffering from an autoimmune disease or disorder, compounds of the structures defined below as Formulas I-V and those listed in Table 1, to a subject suffering from an autoimmune disease or disorder, under conditions that effectively treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the subject's autoimmune disease or disorder. Brief description of the attached diagram The subject matter considered to be the present invention is specifically pointed out and expressly claimed in the concluding section of the specification. However, when combined with the appendix... Figure 1 When reading this invention, both its organization and operation methods, along with its objects, features, and advantages, can be best understood together with the following detailed description, in conjunction with the accompanying drawings: Figure 1 The effect of compound 100 on collagen 1 expression in WI-38 human lung fibroblasts was demonstrated. WI-38 cells were plated in 384-well plates and activated with a fibroblast activation mixture for 72 hours, followed by treatment with the compound for the last 48 hours. Compound 100 was tested at specified concentrations (0.005 mM, 0.014 mM, 0.12 mM, 0.37 mM, 1 mM, 3 mM, and 10 mM). Collagen 1 levels were determined by immunofluorescence microscopy using an anti-collagen 1 antibody. Relative collagen expression was determined and normalized against control cells treated with DMSO. Normalized collagen expression is plotted on the Y-axis. EC50 of compound 100 was also shown. 50 It is 163 nM.

[0029] Figure 2 The short-term stability of the nano-suspension of compound 100, as observed by the dynamic light scattering Z-potential of the size particle, was described.

[0030] Figure 3 The short-term stability of the compound 100 nano-suspension, as observed by HPLC determination, was depicted, and the change in sample purity over time was measured. The compound 100 nano-suspension exhibited chemical and physical stability for up to 6 weeks under both storage conditions. An increase in the dissolved fraction was observed from t=3 days under both storage conditions. The standard purity at 254 nm is 99.33%.

[0031] Figures 4A-4B The nano-suspension of compound 100 was depicted at 25°C ( Figure 4A ) and at 2℃-8℃ ( Figure 4B XRPD of the compound was observed to be unchanged in physical form after 6 weeks under both storage conditions.

[0032] Figure 5 The pharmacokinetic profile of compound 100 in Balb / C mice was described using single-dose administration. The pharmacokinetic profiles of compound 100 were as follows: IV at 10 mg / kg (triangle), PO at 3 mg / kg (circle with solid line), 10 mg / kg (circle with large shadow), and 30 mg / kg (circle with small shadow).

[0033] Figure 6A multi-dose 5-day pharmacokinetic (PK) study of compound 100 in Balb / C mice was depicted (days 1 and 5). PK profile: IV at 10 mg / kg, PO at 3 mg / kg, 10 mg / kg, 30 mg / kg, and 100 mg / kg (as indicated on the right side of the figure). IV administration of compound 100 showed low clearance (11% LBF, assuming a mouse LBF of 120 mL / min / kg) and a half-life of 1.9 h; and a moderate volume of distribution of 1.5 L / kg. The PO multi-dose PK study was conducted on a BID basis for 5 consecutive days, with plasma collected only on days 1 and 5, but the drug administered daily at midnight and 8 am. A nanosuspension formulation was used and was freshly prepared each day of administration.

[0034] Figure 7 A single-dose PK study comparison of intravenous administration of compound 100 and compound A was depicted. PK plot administration: IV administration of compound 100 and compound A at 10 mg / kg. IV administration of compound 100 and compound A shows similar exposure levels for both compounds, with compound 100 showing a lower observed clearance value.

[0035] Figure 8 A single-dose pharmacokinetic (PK) study comparing compound 100 and compound A via PO administration was described. Both compound 100 and compound A were administered via PO at 3 mg / kg, 10 mg / kg, and 30 mg / kg. Compound 100 showed stable PO bioavailability at all three administration levels. In contrast, compound A showed an increase in bioavailability from 32.3% to 273% as the administration level increased from 3 mg / kg to 100 mg / kg. This phenomenon may be related to efflux saturation of compound A during the absorption phase.

[0036] Figure 9 The research timeline is outlined.

[0037] Figure 10 H&E staining of lung tissue sections was depicted. G1 (Group 1) was treated with saline solution instead of bleomycin; G2 (Group 2) was treated with bleomycin 0.66 mg / kg; G3 (Group 3) was treated with bleomycin 0.66 mg / kg followed by administration of compound 100 at 10 mg / kg; G4 (Group 4) was treated with bleomycin 0.66 mg / kg followed by administration of compound 100 at 30 mg / kg; G5 (Group 5) was treated with bleomycin 0.66 mg / kg followed by administration of nintedanib 60 mg / kg; arrows point to fibrotic tissue in the lung sections. Images are from two different mice in each group.

[0038] Figure 11Quantitative morphological determination of H&E staining was described. Statistical significance was calculated using the Mann-Whitney one-tailed test.

[0039] Figure 12 Masson's trichrome staining of lung sections was depicted. G1 (Group 1) was treated with saline solution instead of bleomycin; G2 (Group 2) was treated with bleomycin 0.66 mg / kg; G3 (Group 3) was treated with bleomycin 0.66 mg / kg followed by administration of compound 100 at 10 mg / kg; G4 (Group 4) was treated with bleomycin 0.66 mg / kg followed by administration of compound 100 at 30 mg / kg; G5 (Group 5) was treated with bleomycin 0.66 mg / kg followed by administration of nintedanib 60 mg / kg. Compared to G2, G3 and G4 showed an increased reduction in fibrotic tissue. G4 had less fibrotic area than nintedanib (the main commercially approved treatment for fibrosis). Arrows point to fibrotic tissue in lung sections. Images are of two different mice in each group.

[0040] Figure 13 Quantitative morphological determination using Masson's trichrome staining was described. Statistical significance was calculated using the Mann-Whitney one-tailed test.

[0041] Figure 14 A modified Ashcroft score was used to characterize bleomycin-induced pulmonary fibrosis. Statistical significance was calculated using the Mann-Whitney one-tailed test relative to the model-mediated control. p=0.0001 , p<0.0001.

[0042] Figure 15 Compound 102 of the present invention is described. 5-(4-acetylpiperazin-1-yl)-N-(4-(2-(methoxymethyl) 2-yl)phenyl)thiazolyl)pyridine amide Cytotoxicity window of (compound B).

[0043] Figures 16A-16B The kinetic solubility of compound 102 of the present invention at pH 7.4 was described compared to compound B. Figure 16A ) and hERG channel inhibition ( Figure 16B ). Invention Details In various embodiments, the present invention relates to compounds represented by the structure of Formula I: in Rings A and B are each independently a single or fused aromatic or heteroaromatic ring system (e.g., A: phenyl, thiophene, imidazole, pyrazole, pyrimidine, 2-pyridine, 3-pyridine or 4-pyridine, benzimidazole, indole, benzothiazole, benzoxazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine, pyridazine or pyrazine; B: phenyl, pyrimidine, 2-pyridine, 3-pyridine or 4-pyridine, pyridazine or pyrazine, thiophene, thiazole, pyrrole, imidazole, indazole), or a single or fused C3-C ring. 10 Cycloalkyl (e.g., A: pyrrolidone-2-one; B: bicyclo[1.1.1]pentyl, cyclobutyl, cyclohexyl, cyclopentyl) or single or fused C3-C 10 Heterocyclic compounds (e.g., morpholine, piperidine, piperazine, tetrahydro-2H-pyran, azacyclic butane, pyrrolidine-2-one); R1 and R2 are independently H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2OH), R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3, CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), -R8-O-R6-R 30 (For example, CH2O-tetrahydro-) 2H -Pyran, CH2O-CH2-CCH, CH2O-CH2CH2O-CH3, CH2O-CH2CH2NH-CH3, CH2O-CH2CH2S-CH3, CH2O-CH2CH2S(O)CH3, CH2O-CH2CH2SO2-CH3, CH2O-CH2CF2H, CH2-O-CH2-CH2-O-CH3, CH2O-CH2-C(H)(OH)-CH3), R8-(C3-C8 cycloalkyl), R8-(3-8 membered heterocyclic), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 (R) 11 (e.g., CH2-NH-CH3, CH2-NH-C(O)CH3, CH2-N(CH3)2), R9-R8-N(R 10 (R) 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R (e.g., NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (For example, 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), C2-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 group (CH2) in 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 3-8 membered heterocycles (e.g., aziridine, pyridine), substituted or unsubstituted aryl groups (e.g., phenyl) or substituted or unsubstituted benzyl groups; Alternatively, 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., 1,4-dioxane, 2,3-dihydro-1,4-dioxane, dioxol, dioxolpyridine). R3 and R4 are independently H, F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), R8-(C3-C8 cycloalkyl), R8-(3-8 membered heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, N(R) 10 (R) 11 (e.g., morpholine, piperazine, 1-(methanesulfonyl)piperazine or 4-(methanesulfonyl)piperazine, 1-(piperazin-1-yl)acetone), 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 (e.g., C(O)NH(CH3)2O-CH3), C(O)N(R) 10 (R) 11 (e.g., C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH3)2, C(O)-piperazine), SO2R, SO2N(R) 10 (R) 11 ), CH(CF3)(NH-R 10 C1-C5 straight-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C2-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, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethyl)piperidin-4-oxy, 1-(methyl ... (ketone)piperidine-4-oxy), optionally wherein at least one methylene group (CH2) in the alkoxy group 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 single, spirocyclic, fused or bridged C3-C 10 Heterocyclic compounds (e.g., piperazine, 1-(2-methoxyethyl)piperazine, 1-methylpiperazine or 4-methylpiperazine, 1-(methylsulfonyl)piperazine or 4-(methylsulfonyl)piperazine, 1-(methylsulfonyl)piperidine or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ketene, 1-(piperazin-1-yl)ethyl ketene, 2-(dimethylamino)-1-(piperazin-1-yl)ethyl ketene, 2-(dimethylamino)-1-(piperazin-1-yl)acetone, 2-hydroxy-1-(piperazin-1-yl)ketene, N 1-Methylpiperazine-1-carboxamide, piperidine-4-ol, piperidine-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro- 2H-Pyran, tetrahydro-2H-thiaran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]hept-2-yl)ethenone, 2-methoxy-1-(2,6-diazaspiro[3.3]hept-2-yl)ethenone, 2,8-diazaspiro[4.5]dec-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g., phenyl) or substituted or unsubstituted benzyl; Alternatively, R3 and R4 can be linked together to form a 5- or 6-membered substituted or unsubstituted aliphatic carbocyclic ring (e.g., cyclopentene), aromatic carbocyclic ring (e.g., benzene), or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole). R5 is H, R 20 ,F,Cl,Br,I,OH,SH,R8-OH,R8-SH,-R8-OR 10 R8-(C3-C8 cycloalkyl), R8-(3-8 membered 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 10C1-C5 straight-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C2-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 group (CH2) in 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 3-8 membered heterocycles, substituted or unsubstituted aryl groups or substituted or unsubstituted benzyl groups; R6 is [CH2] w , Where w is between 0 and 10 (e.g., 0, 1, 2); R8 is [CH2] p , Where p is between 1 and 10 (e.g., 1); R9 is [CH] q [C] q , Where q is between 2 and 10; R 10 and R 11 Each of the following is independently H, OH, a substituted or unsubstituted C1-C5 straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a C1-C5 straight-chain or branched alkoxy group (e.g., O-CH3), or a substituted or unsubstituted 3-8 membered heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro- 2H -pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl or S(O)2-alkyl; Or R 10 and R 11 Linked to form substituted or unsubstituted 3-8 membered heterocycles (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidine-2-one, oxetane, azirbutane, 1-methylazirbutane, 1-(piperazin-1-yl)acetone); R 20 It can be represented by the following structure: ; R 30It is H, OH, substituted or unsubstituted C1-C5 straight-chain or branched alkyl (e.g., methyl, C(H)(OH)(CH3), methyl, ethyl, CH2-CH2-O-CH3), C2-C5 straight-chain or branched substituted or unsubstituted alkynyl (e.g., CCH), C1-C5 straight-chain or branched alkoxy (e.g., O-CH3), C1-C5 straight-chain or branched thioalkoxy (e.g., S-CH3), C1-C5 straight-chain, branched or cyclic haloalkyl (e.g., CHF2), substituted or unsubstituted 3-8 membered heterocycles (e.g., tetrahydro- 2H -pyran), N(R) 10 (R) 11 (e.g., N(H)(CH3)), S(O)R (e.g., S(O)-CH3), SO2R (e.g., SO2-CH3) or C(O)R; Q1 is NH, S, or O; G=X means C=O, C=S, S=O or SO2; R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 (e.g., NH(CH3)), N(R) 10 (R) 11 ), R 20 C1-C5 straight-chain or branched C1-C5 substituted or unsubstituted alkyl groups (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R 10 (e.g., CH2-OH, CH2CH2-OH), C(O)-R 10 (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl groups (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)). 2、 C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10 (e.g., C(O)-CH2CH2-OH), C(O)-substituted or unsubstituted 3-8 membered heterocycles (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight-chain or branched C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight-chain or branched alkoxy, -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) or substituted or unsubstituted heteroaryl groups (e.g., pyridine (2-pyridine, 3-pyridine, and 4-pyridine); or Two substituted Rs are linked together to form a 3-6 substituted or unsubstituted aliphatic carbocyclic ring (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole). n and l are each an integer between 1 and 3 (e.g., 1 or 2); m and k are each an integer between 0 and 3 (e.g., 0, 1); Or its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N -Oxides, prodrugs, isotope variants (e.g., deuterated analogs), PROTACs, reverse amides, pharmaceutical products, or any combination thereof.

[0045] In various embodiments, non-limiting examples of substitutions included by the term "substituted" as defined herein include: F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight-chain or branched alkyl groups (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight-chain or branched C(O)-alkyl groups (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl groups (e.g., SO2-CH3), amides (e.g., C(O)-NH-alkyl or NH-C(O)-alkyl), C1-C5 straight-chain or branched alkyl-OH groups (e.g., C(CH3)2CH2-OH, CH2CH2-OH), 3-8 membered heterocycles (e.g., piperidine), substituted or unsubstituted C1-C5 straight-chain or branched alkoxy groups, NH2, N(H)(R), N(R)2, N(R) 10 (R) 11), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl or any combination thereof. In some embodiments, the term "substituted" according to the invention refers to at least one group selected from the group consisting of: F, Cl, Br, I, OH, CF3, CN, NO2, C1-C5 straight-chain or branched alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl), C1-C5 straight-chain or branched alkoxy groups (e.g., OCH3), C2-C5 straight-chain or branched alkynyl groups (e.g., CCH), C1-C5 straight-chain or branched thioalkoxy groups (e.g., SCH3), C1-C5 straight-chain or branched alkylsulfinyl groups (e.g., S(O)CH3), C1-C5 straight-chain or branched alkylsulfonyl groups (e.g., S(O)2-CH3), NH2, and C1-C5 straight-chain or branched N(H) (alkyl) groups. (e.g., N(H)(CH3)) and C1-C5 straight-chain or branched N(alkyl)2; each representing a separate embodiment according to the invention. In some embodiments, the substitution includes at least one group selected from: F, Cl, Br, I, OH, CF3, CN, NO2, C1-C5 straight-chain or branched alkoxy (e.g., OCH3), C2-C5 straight-chain or branched alkynyl (e.g., CCH), C1-C5 straight-chain or branched thioalkoxy (e.g., SCH3), C1-C5 straight-chain or branched alkylsulfinyl (e.g., S(O)CH3), C1-C5 straight-chain or branched alkylsulfonyl (e.g., S(O)2-CH3), C1-C5 straight-chain or branched N(H)(alkyl) (e.g., N(H)(CH3)) and C1-C5 straight-chain or branched N(alkyl)2; each representing a separate embodiment according to the invention.

[0046] In various embodiments, the present invention relates to compounds represented by the structure of formula II: in R1 can be H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2OH), R8-SH, or -R8-OR. 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3, CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), -R8-O-R6-R 30 (For example, CH2O-tetrahydro-) 2H-Pyran, CH2O-CH2-CCH, CH2O-CH2CH2O-CH3, CH2O-CH2CH2NH-CH3, CH2O-CH2CH2S-CH3, CH2O-CH2CH2S(O)CH3, CH2O-CH2CH2SO2-CH3, CH2O-CH2CF2H, CH2-O-CH2-CH2-O-CH3, CH2O-CH2-C(H)(OH)-CH3), R8-(C3-C8 cycloalkyl), R8-(3-8 membered heterocyclic), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 (R) 11 (e.g., CH2-NH-CH3, CH2-NH-C(O)CH3, CH2-N(CH3)2), R9-R8-N(R 10 (R) 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R (e.g., NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (For example, 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) 10C1-C5 straight-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C2-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 group (CH2) in 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 3-8 membered heterocycles (e.g., aziridine, pyridine), substituted or unsubstituted aryl groups (e.g., phenyl) or substituted or unsubstituted benzyl groups; 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-(3-8 membered heterocycle), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, N(R) 10 (R) 11 (e.g., morpholine, piperazine, 1-(piperazin-1-yl)ketene, 1-(methanesulfonyl)piperazine, or 4-(methanesulfonyl)piperazine), R8-N(R 10 (R) 11 ), R9-R8-N(R 10 (R) 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R 10 NHCO-N(R) 10 (R) 11 ), COOH, -C(O)Ph, C(O)OR 10 R8-C(O)-R 10 C(O)H, C(O)-R 10 C1-C5 straight-chain or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR (e.g., C(O)NH(CH3)2O-CH3), C(O)N(R) 10 (R) 11 (e.g., C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH3)2, C(O)-piperazine), SO2R, SO2N(R) 10 (R) 11 ), CH(CF3)(NH-R 10C1-C5 straight-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl); C2-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, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethyl)piperidin-4-oxy, 1-(methyl ... (ketone)piperidine-4-oxy), optionally wherein at least one methylene group (CH2) in the alkoxy group 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 single, spirocyclic, fused or bridged C3-C 10 Heterocyclic compounds (e.g., piperazine, 1-(2-methoxyethyl)piperazine, 1-methylpiperazine or 4-methylpiperazine, 1-(methylsulfonyl)piperazine or 4-(methylsulfonyl)piperazine, 1-(methylsulfonyl)piperidine or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ketene, 1-(piperazin-1-yl)ethyl ketene, 2-(dimethylamino)-1-(piperazin-1-yl)ethyl ketene, 2-(dimethylamino)-1-(piperazin-1-yl)acetone, 2-hydroxy-1-(piperazin-1-yl)ketene, N 1-Methylpiperazine-1-carboxamide, piperidine-4-ol, piperidine-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2- H -Pyran, tetrahydro-2H-thiaran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]hept-2-yl)ethenone, 2-methoxy-1-(2,6-diazaspiro[3.3]hept-2-yl)ethenone, 2,8-diazaspiro[4.5]dec-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g., phenyl) or substituted or unsubstituted benzyl; X1, X2, X3, X4, and X5 are each independently C or N; R6 is [CH2] w , Where w is between 0 and 10 (e.g., 0, 1, 2); 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 of the following is independently H, OH, a substituted or unsubstituted C1-C5 straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a C1-C5 straight-chain or branched alkoxy group (e.g., O-CH3), or a substituted or unsubstituted 3-8 membered heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro- 2H -pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl or S(O)2-alkyl; Or R 10 and R 11 Linked to form substituted or unsubstituted 3-8 membered heterocycles (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidine-2-one, oxetane, azirbutane, 1-methylazirbutane, 1-(piperazin-1-yl)acetone); R 20 It can be represented by the following structure: ; R 30 It is H, OH, substituted or unsubstituted C1-C5 straight-chain or branched alkyl (e.g., methyl, C(H)(OH)(CH3), methyl, ethyl, CH2-CH2-O-CH3), C2-C5 straight-chain or branched substituted or unsubstituted alkynyl (e.g., CCH), C1-C5 straight-chain or branched alkoxy (e.g., O-CH3), C1-C5 straight-chain or branched thioalkoxy (e.g., S-CH3), C1-C5 straight-chain, branched or cyclic haloalkyl (e.g., CHF2), substituted or unsubstituted 3-8 membered heterocycles (e.g., tetrahydro- 2H -pyran), N(R) 10 (R) 11 (e.g., N(H)(CH3)), S(O)R (e.g., S(O)-CH3), SO2R (e.g., SO2-CH3) or C(O)R; R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 (e.g., NH(CH3)), N(R) 10 (R) 11 ), R 20 C1-C5 straight-chain or branched C1-C5 substituted or unsubstituted alkyl groups (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R10 (e.g., CH2-OH, CH2CH2-OH), C(O)-R 10 (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl groups (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)2, C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10 (e.g., C(O)-CH2CH2-OH), C(O)-substituted or unsubstituted 3-8 membered heterocycles (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight-chain or branched C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight-chain or branched alkoxy, -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-pyridine, 3-pyridine, and 4-pyridine); or Two substituted Rs are linked together to form a 3-6 substituted or unsubstituted aliphatic carbocyclic ring (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole). Or its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N -Oxides, prodrugs, isotope variants (e.g., deuterated analogs), PROTACs, reverse amides, pharmaceutical products, or any combination thereof.

[0047] In various embodiments, the present invention relates to compounds represented by the structure of Formula III: in R1 can be H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2OH), R8-SH, or -R8-OR. 10(e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3, CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), -R8-O-R6-R 30 (For example, CH2O-tetrahydro-) 2H -Pyran, CH2O-CH2-CCH, CH2O-CH2CH2O-CH3, CH2O-CH2CH2NH-CH3, CH2O-CH2CH2S-CH3, CH2O-CH2CH2S(O)CH3, CH2O-CH2CH2SO2-CH3, CH2O-CH2CF2H, CH2-O-CH2-CH2-O-CH3, CH2O-CH2-C(H)(OH)-CH3), R8-(C3-C8 cycloalkyl), R8-(3-8 membered heterocyclic), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 (R) 11 (e.g., CH2-NH-CH3, CH2-NH-C(O)CH3, CH2-N(CH3)2), R9-R8-N(R 10 (R) 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R (e.g., NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (For example, 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) 10C1-C5 straight-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C2-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 group (CH2) in 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 3-8 membered heterocycles (e.g., aziridine, pyridine), substituted or unsubstituted aryl groups (e.g., phenyl), substituted or unsubstituted benzyl groups; X1, X2, X3, X4, and X5 are each independently C or N; X6 is O, CH2, CHR (e.g., CH(OH), CH(NH2), CH(NH(CH3))), C(R) 10 (R) 11 (e.g., C(H)CH2CH2-OH, C(H)CH2-OH, 1-methylazacyclobutane), NH, NS(O)2-R 10 (e.g., N-SO2-CH3), NR (e.g., N-CH3, N-SO2-CH3, NR) 20 (N-CH2CH2-OCH3) or NC(O)-R 10 (For example, NC(O)O-tBu, NC(O)-CH2CH2-OCH3, NC(O)-CH3, NC(O)-CH2-N(CH3)2, NC(O)-CH2-CH2-N(CH3)2, NC(O)-CH2-OH, NC(O)-CH2CH2-OH, NC(O)-NH-CH3, NC(O)-1-methyl-2-pyrrolidine, NC(O)-1-methyl-3-pyrrolidine, NC(O)-1-methyl-3-piperidine, NC(O)-1-methyl-4-piperidine; R6 is [CH2] w , Where w is between 0 and 10 (e.g., 0, 1, 2); 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 of the following is independently H, OH, a substituted or unsubstituted C1-C5 straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a C1-C5 straight-chain or branched alkoxy group (e.g., O-CH3), or a substituted or unsubstituted 3-8 membered heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro- 2H -pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl or S(O)2-alkyl; Or R 10 and R 11 Linked to form substituted or unsubstituted 3-8 membered heterocycles (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidine-2-one, oxetane, azirbutane, 1-methylazirbutane, 1-(piperazin-1-yl)acetone); R 20 It can be represented by the following structure: ; R 30 It is H, OH, substituted or unsubstituted C1-C5 straight-chain or branched alkyl (e.g., methyl, C(H)(OH)(CH3), methyl, ethyl, CH2-CH2-O-CH3), C2-C5 straight-chain or branched substituted or unsubstituted alkynyl (e.g., CCH), C1-C5 straight-chain or branched alkoxy (e.g., O-CH3), C1-C5 straight-chain or branched thioalkoxy (e.g., S-CH3), C1-C5 straight-chain, branched or cyclic haloalkyl (e.g., CHF2), substituted or unsubstituted 3-8 membered heterocycles (e.g., tetrahydro- 2H -pyran), N(R) 10 (R) 11 (e.g., N(H)(CH3)), S(O)R (e.g., S(O)-CH3), SO2R (e.g., SO2-CH3) or C(O)R; R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 (e.g., NH(CH3)), N(R) 10 (R) 11 ), R 20 C1-C5 straight-chain or branched C1-C5 substituted or unsubstituted alkyl groups (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R 10(e.g., CH2-OH, CH2CH2-OH), C(O)-R 10 (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl groups (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)2, C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10 (e.g., C(O)-CH2CH2-OH), C(O)-substituted or unsubstituted 3-8 membered heterocycles (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight-chain or branched C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight-chain or branched alkoxy, -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) or substituted or unsubstituted heteroaryl groups (e.g., pyridine (2-pyridine, 3-pyridine, and 4-pyridine); or Two substituted Rs are linked together to form a 3-6 substituted or unsubstituted aliphatic carbocyclic ring (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole). Or its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N -Oxides, prodrugs, isotope variants (e.g., deuterated analogs), PROTACs, reverse amides, pharmaceutical products, or any combination thereof.

[0048] In various embodiments, the present invention relates to compounds represented by the structure of formula IV: in X2 is C or N; X 10 It is O, S, NH, NR, N(H)C(O), C(O)NH, S(O)2NH, NHS(O)2; w is between 0 and 10 (e.g., 0, 1, 2); p is between 0 and 10 (e.g., 1); G'=X' is C=O, S=O or S(O)2; R 10 and R 11 Each of the following is independently H, OH, a substituted or unsubstituted C1-C5 straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a C1-C5 straight-chain or branched alkoxy group (e.g., O-CH3), or a substituted or unsubstituted 3-8 membered heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro- 2H -pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl or S(O)2-alkyl; Or R 10 and R 11 Linked to form substituted or unsubstituted 3-8 membered heterocycles (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidine-2-one, oxetane, azirbutane, 1-methylazirbutane, 1-(piperazin-1-yl)acetone); R 12 It is H or a substituted or unsubstituted C1-C5 straight-chain or branched alkyl group (e.g., methyl, ethyl); R 20 It can be represented by the following structure: ; R 30 It is H, OH, substituted or unsubstituted C1-C5 straight-chain or branched alkyl (e.g., methyl, C(H)(OH)(CH3), methyl, ethyl, CH2-CH2-O-CH3), C2-C5 straight-chain or branched substituted or unsubstituted alkynyl (e.g., CCH), C1-C5 straight-chain or branched alkoxy (e.g., O-CH3), C1-C5 straight-chain or branched thioalkoxy (e.g., S-CH3), C1-C5 straight-chain, branched or cyclic haloalkyl (e.g., CHF2), substituted or unsubstituted 3-8 membered heterocycles (e.g., tetrahydro- 2H -pyran), N(R) 10 (R) 11 (e.g., N(H)(CH3)), S(O)R (e.g., S(O)-CH3), SO2R (e.g., SO2-CH3) or C(O)R; R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 (e.g., NH(CH3)), N(R)10 (R) 11 ), R 20 C1-C5 straight-chain or branched C1-C5 substituted or unsubstituted alkyl groups (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R 10 (e.g., CH2-OH, CH2CH2-OH), C(O)-R 10 (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl groups (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)2, C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10 (e.g., C(O)-CH2CH2-OH), C(O)-substituted or unsubstituted 3-8 membered heterocycles (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight-chain or branched C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight-chain or branched alkoxy, -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) or substituted or unsubstituted heteroaryl groups (e.g., pyridine (2-pyridine, 3-pyridine, and 4-pyridine); or Two substituted Rs are linked together to form a 3-6 substituted or unsubstituted aliphatic carbocyclic ring (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole). Or its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N -Oxides, prodrugs, isotope variants (e.g., deuterated analogs), PROTACs, reverse amides, pharmaceutical products, or any combination thereof.

[0049] In various implementations, G'=X' is S(O)2. In various implementations, G'=X' is C(O). In various implementations, R 12It is a C1-C5 straight-chain or branched alkyl group. In various embodiments, R 12 It is methyl. In various embodiments, (G'=X')(R 12 ) is C(O)-CH3. In various implementations, (G'=X')(R 12 The compound is S(O)2-CH3. In many embodiments, the compound is not... 5-(4-acetylpiperazin-1-yl)-N-(4-(2-(methoxymethyl)pyridin-3-yl)thiazolyl-2-yl)pyridine Pyridine In many implementations, the compound is not 5-(4-acetylpiperazin-1-yl)-N-(4-(2-(methoxymethyl)) (Phenyl)thiazolyl)pyridine amide In many implementations, the compound is not 5-(4-acetylpiperazin-1-yl)-N- (4-(2-(hydroxymethyl)pyridin-3-yl)thiazo-2-yl)pyridineamide In many implementations, the compound is not 5-(4- Acetylpiperazine-1-yl)-N-(4-(2-(hydroxymethyl)phenyl)thiazo-2-yl)pyridineamide In many implementations, the compound is not N-(4-(2-(methoxymethyl)phenyl)thiazo-2-yl)-5-(4-(methylsulfonyl)piperazin-1-yl)pyridine amide In many implementations, the compound is not N-(4-(2-(hydroxymethyl)phenyl)thiazolyl-2-yl)-5-(4-(methyl) sulfonyl)piperazin-1-yl)pyridine amide In many implementations, the compound is not N-(4-(2-(acetaminomethyl)benzene) (2-yl)-5-(4-(methylsulfonyl)piperazin-1-yl)pyridineamide In many implementations, the compound is not N-(4-(2-(dimethylaminomethyl)phenyl)thiazo-2-yl)-5-(4-(methylsulfonyl)piperazin-1-yl)pyridineamide .

[0050] In various embodiments, the present invention relates to compounds represented by the structure of formula IV(a): in X2 is C or N; X 10 It is O, S, NH, NR, N(H)C(O), C(O)NH, S(O)2NH, NHS(O)2; w is between 0 and 10 (e.g., 0, 1, 2); p is between 0 and 10 (e.g., 1); R 10 and R 11 Each of the following is independently H, OH, a substituted or unsubstituted C1-C5 straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a C1-C5 straight-chain or branched alkoxy group (e.g., O-CH3), or a substituted or unsubstituted 3-8 membered heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro- 2H -pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl or S(O)2-alkyl; Or R 10 and R 11Linked to form substituted or unsubstituted 3-8 membered heterocycles (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidine-2-one, oxetane, azirbutane, 1-methylazirbutane, 1-(piperazin-1-yl)acetone); R 30 It is H, OH, substituted or unsubstituted C1-C5 straight-chain or branched alkyl (e.g., methyl, C(H)(OH)(CH3), methyl, ethyl, CH2-CH2-O-CH3), C2-C5 straight-chain or branched substituted or unsubstituted alkynyl (e.g., CCH), C1-C5 straight-chain or branched alkoxy (e.g., O-CH3), C1-C5 straight-chain or branched thioalkoxy (e.g., S-CH3), C1-C5 straight-chain, branched or cyclic haloalkyl (e.g., CHF2), substituted or unsubstituted 3-8 membered heterocycles (e.g., tetrahydro- 2H -pyran), N(R) 10 (R) 11 (e.g., N(H)(CH3)), S(O)R (e.g., S(O)-CH3), SO2R (e.g., SO2-CH3) or C(O)R; R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 (e.g., NH(CH3)), N(R) 10 (R) 11 ), R 20 C1-C5 straight-chain or branched C1-C5 substituted or unsubstituted alkyl groups (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R 10 (e.g., CH2-OH, CH2CH2-OH), C(O)-R 10 (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl groups (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)2, C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10(e.g., C(O)-CH2CH2-OH), C(O)-substituted or unsubstituted 3-8 membered heterocycles (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight-chain or branched C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight-chain or branched alkoxy, -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) or substituted or unsubstituted heteroaryl groups (e.g., pyridine (2-pyridine, 3-pyridine, and 4-pyridine); or Two substituted Rs are linked together to form a 3-6 substituted or unsubstituted aliphatic carbocyclic ring (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole). R8 is [CH2] p , Where p is between 1 and 10 (e.g., 1); R 20 It can be represented by the following structure: ; Or its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N -Oxides, prodrugs, isotope variants (e.g., deuterated analogs), PROTACs, reverse amides, pharmaceutical products, or any combination thereof.

[0051] In various implementations, the compound is not 5-(4-acetylpiperazin-1-yl)-N-(4-(2-(methoxymethyl)) Pyridine-3-yl)thiazolyl)pyridineamide In many implementations, the compound is not 5-(4-acetylpiperazine-1- 4-(2-(methoxymethyl)phenyl)thiazolyl-2-yl)pyridine amide In many implementations, the compound is not 5- (4-acetylpiperazin-1-yl)-N-(4-(2-(hydroxymethyl)pyridin-3-yl)thiazo-2-yl)pyridineamide In many implementations, the compound is not 5-(4-acetylpiperazin-1-yl)-N-(4-(2-(hydroxymethyl)phenyl)thiazo-2-yl)pyridine amide .

[0052] In various embodiments, the present invention relates to compounds represented by the structure of formula IV(b): in X2 is C or N; X 10 It is O, S, NH, NR, N(H)C(O), C(O)NH, S(O)2NH, NHS(O)2; w is between 0 and 10 (e.g., 0, 1, 2); p is between 0 and 10 (e.g., 1); R 10 and R 11 Each of the following is independently H, OH, a substituted or unsubstituted C1-C5 straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a C1-C5 straight-chain or branched alkoxy group (e.g., O-CH3), or a substituted or unsubstituted 3-8 membered heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro- 2H -pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl or S(O)2-alkyl; Or R 10 and R 11 Linked to form substituted or unsubstituted 3-8 membered heterocycles (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidine-2-one, oxetane, azirbutane, 1-methylazirbutane, 1-(piperazin-1-yl)acetone); R 30 It is H, OH, substituted or unsubstituted C1-C5 straight-chain or branched alkyl (e.g., methyl, C(H)(OH)(CH3), methyl, ethyl, CH2-CH2-O-CH3), C2-C5 straight-chain or branched substituted or unsubstituted alkynyl (e.g., CCH), C1-C5 straight-chain or branched alkoxy (e.g., O-CH3), C1-C5 straight-chain or branched thioalkoxy (e.g., S-CH3), C1-C5 straight-chain, branched or cyclic haloalkyl (e.g., CHF2), substituted or unsubstituted 3-8 membered heterocycles (e.g., tetrahydro- 2H -pyran), N(R) 10 (R) 11 (e.g., N(H)(CH3)), S(O)R (e.g., S(O)-CH3), SO2R (e.g., SO2-CH3) or C(O)R; R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 (e.g., NH(CH3)), N(R) 10 (R) 11 ), R 20C1-C5 straight-chain or branched C1-C5 substituted or unsubstituted alkyl groups (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R 10 (e.g., CH2-OH, CH2CH2-OH), C(O)-R 10 (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl groups (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)2, C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10 (e.g., C(O)-CH2CH2-OH), C(O)-substituted or unsubstituted 3-8 membered heterocycles (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight-chain or branched C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight-chain or branched alkoxy, -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) or substituted or unsubstituted heteroaryl groups (e.g., pyridine (2-pyridine, 3-pyridine, and 4-pyridine); or Two substituted Rs are linked together to form a 3-6 substituted or unsubstituted aliphatic carbocyclic ring (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole). R8 is [CH2] p , Where p is between 1 and 10 (e.g., 1); R 20 It can be represented by the following structure: ; Or its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N -Oxides, prodrugs, isotope variants (e.g., deuterated analogs), PROTACs, reverse amides, pharmaceutical products, or any combination thereof.

[0053] In various implementations, the compound is not N-(4-(2-(methoxymethyl)phenyl)thiazolyl-2-yl)-5-(4- (methylsulfonyl)piperazin-1-yl)pyridineamide In many implementations, the compound is not N-(4-(2-(hydroxymethyl)) (Phenyl)thiazolyl)-5-(4-(methylsulfonyl)piperazin-1-yl)pyridineamide In many implementations, the compound is not N-(4-(2-(acetaminomethyl)phenyl)thiazo-2-yl)-5-(4-(methylsulfonyl)piperazin-1-yl)pyridineamide In many implementations, the compound is not N-(4-(2-(dimethylaminomethyl)phenyl)thiazolyl-2-yl)-5-(4-(methyl) sulfonyl)piperazin-1-yl)pyridine amide .

[0054] In various embodiments, the present invention relates to compounds represented by the structure of formula V: in X2 is C or N; w is between 0 and 10 (e.g., 0, 1, 2); R 30 It is H, OH, substituted or unsubstituted C1-C5 straight-chain or branched alkyl (e.g., methyl, C(H)(OH)(CH3), methyl, ethyl, CH2-CH2-O-CH3), C2-C5 straight-chain or branched substituted or unsubstituted alkynyl (e.g., CCH), C1-C5 straight-chain or branched alkoxy (e.g., O-CH3), C1-C5 straight-chain or branched thioalkoxy (e.g., S-CH3), C1-C5 straight-chain, branched or cyclic haloalkyl (e.g., CHF2), substituted or unsubstituted 3-8 membered heterocycles (e.g., tetrahydro- 2H -pyran), N(R) 10 (R) 11 (e.g., N(H)(CH3)), S(O)R (e.g., S(O)-CH3), SO2R (e.g., SO2-CH3) or C(O)R; R 10 and R 11 Each of the following is independently H, OH, a substituted or unsubstituted C1-C5 straight-chain or branched alkyl group (e.g., methyl, ethyl, CH2-CH2-O-CH3), a C1-C5 straight-chain or branched alkoxy group (e.g., O-CH3), or a substituted or unsubstituted 3-8 membered heterocycle (e.g., 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro- 2H -pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, methyl-piperidine), C(O)-alkyl or S(O)2-alkyl; Or R 10 and R 11Linked to form substituted or unsubstituted 3-8 membered heterocycles (e.g., morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidine-2-one, oxetane, azirbutane, 1-methylazirbutane, 1-(piperazin-1-yl)acetone); R is H, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NH(R 10 (e.g., NH(CH3)), N(R) 10 (R) 11 ), R 20 C1-C5 straight-chain or branched C1-C5 substituted or unsubstituted alkyl groups (e.g., methyl, ethyl, CH2CH2OH, CH2CH2OCH3), R8-R 10 (e.g., CH2-OH, CH2CH2-OH), C(O)-R 10 (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH3), C1-C5 substituted or unsubstituted C(O)-alkyl groups (e.g., C(O)-CH2CH2-OCH3, C(O)-CH3, C(O)-CH2-N(CH3)2, C(O)-CH2-CH2-N(CH3)2, C(O)-CH2-OH), C(O)-R8-R 10 (e.g., C(O)-CH2CH2-OH), C(O)-substituted or unsubstituted 3-8 membered heterocycles (e.g., C(O)-methylpyrrolidine, C(O)-methylpiperidine), C1-C5 substituted or unsubstituted SO2-alkyl (e.g., SO2-CH3), C1-C5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH3), C1-C5 straight-chain or branched C(O)-O-alkyl (e.g., C(O)-O-tBu), C1-C5 straight-chain or branched alkoxy, -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) or substituted or unsubstituted heteroaryl groups (e.g., pyridine (2-pyridine, 3-pyridine, and 4-pyridine); or Two substituted Rs are linked together to form a 3-6 substituted or unsubstituted aliphatic carbocyclic ring (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole). R8 is [CH2]p , Where p is between 1 and 10 (e.g., 1); R 20 It can be represented by the following structure: ; Or its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N -Oxides, prodrugs, isotope variants (e.g., deuterated analogs), PROTACs, reverse amides, pharmaceutical products, or any combination thereof.

[0055] In various implementations, the compound is not 5-(4-acetylpiperazin-1-yl)-N-(4-(2-(methoxymethyl)) Pyridine-3-yl)thiazolyl)pyridineamide In many implementations, the compound is not 5-(4-acetylpiperazine-1- 4-(2-(methoxymethyl)phenyl)thiazolyl-2-yl)pyridine amide In many implementations, the compound is not 5- (4-acetylpiperazin-1-yl)-N-(4-(2-(hydroxymethyl)pyridin-3-yl)thiazo-2-yl)pyridineamide In many implementations, the compound is not 5-(4-acetylpiperazin-1-yl)-N-(4-(2-(hydroxymethyl)phenyl)thiazo-2-yl)pyridine amide .

[0056] In some embodiments, A of Formula I 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 phenyl or pyridyl. In other embodiments, A is phenyl or 3-pyridyl. In other embodiments, A is 4-pyridyl.

[0057] In some embodiments, B of Formula I is a phenyl ring. In other embodiments, B is pyridyl. In other embodiments, B is 2-pyridyl. In other embodiments, B is 3-pyridyl. In other embodiments, B is 4-pyridyl.

[0058] In various embodiments, compounds of formulas I-III are substituted with R1. In various embodiments, compounds of formula I are substituted with R2. In various embodiments, compounds of formulas I-II are substituted with R3. In various embodiments, compounds of formula I are substituted with R4. A single substituent may be present at the ortho, meta, or para position.

[0059] In some embodiments, at least one of R2 and R4 of the compound of formula I is H. In some embodiments, both R2 and R4 of the compound of formula I are H. In some embodiments, R2 of the compound of formula I is H. In some embodiments, R4 of the compound of formula I is H. In some embodiments, at least one of R1 and R3 of the compounds of formulas I-II is not H. In some embodiments, neither R1 nor R3 of the compounds of formulas I-II is H. In some embodiments, R1 of the compound of formula III is not H. In some embodiments, R3 of the compound of formula I or formula II is not H.

[0060] In some embodiments, R1 of the compounds of formula I is in the ortho position. In some embodiments, R1 of the compounds of formulas I-III is -R8-O-R6-R 30 In some implementations, -R8-O-R6-R 30 It is CH2O-tetrahydro- 2H -Pyran. In some implementations, -R8-O-R6-R 30 It is CH2O-CH2-CCH. In some implementations, -R8-O-R6-R 30 It is CH2O-CH2CH2O-CH3. In some implementations, -R8-O-R6-R 30 It is CH2O-CH2CH2NH-CH3. In some implementations, -R8-O-R6-R 30 It is CH2O-CH2CH2S-CH3. In some implementations, -R8-O-R6-R 30 It is CH2O-CH2CH2S(O)CH3. In some implementations, -R8-O-R6-R 30 It is CH2O-CH2CH2SO2-CH3. In some implementations, -R8-O-R6-R 30 It is CH2O-CH2CF2H. In some implementations, -R8-O-R6-R 30 It is CH2-O-CH2-CH2-O-CH3. In some implementations, -R8-O-R6-R 30 It is CH2O-CH2-C(H)(OH)-CH3). In some embodiments, the R1 of compounds of formulas I-III is -R8-O-R6-R 30 In some embodiments, R8 is CH2. For compounds of formulas I-III, R1 is -R8-O-R6-R 30 Where R8 is CH2 and R6 is CH2-CH2 (i.e., w is 2). In some embodiments, R1 of compounds of formulas I-III is -R8-O-R6-R30 Where R8 is CH2, R6 does not exist (i.e., w is 0), and R 30 It is tetrahydro- 2H -Pyran. In some embodiments, R1 of compounds of formulas I-III is -R8-O-R6-R 30 R8 is CH2, and R 30 It is tetrahydro- 2H -Pyran. In some embodiments, R1 of compounds of formulas I-III is -R8-O-R6-R 30 Where R8 is CH2, R6 is CH2CH2 (i.e., w is 2), and R 30 These are OCH3, N(H)CH3, S-CH3, S(O)CH3, and S(O)2CH3; each is a separate embodiment according to the invention. In some embodiments, R1 of the compounds of formulas I-III is -R8-O-R6-R 30 Where R8 is CH2, R6 is CH2 (i.e., w is 1), and R 30 It is methyl, CCH, CF2H, or C(H)(OH)-CH3; each is a separate embodiment according to the invention. In some embodiments, R1 of the compounds of formulas I-III is -R8-OR. 10 In some embodiments, R1 of compounds of formulas I-III is -R8-OR 10 In some embodiments, R8 is CH2. For compounds of formulas I-III, R1 is -R8-OR. 10 , where R 10 It is tetrahydro- 2H -Pyran. In some embodiments, R1 of compounds of formulas I-III is -R8-OR 10 R8 is CH2, and R 10 It is tetrahydro- 2H -Pyran.

[0061] In some embodiments, the R2 of the compound of formula I is H.

[0062] In some embodiments, R3 of compounds of formulas I-II is a substituted or unsubstituted, single, spirocyclic, fused, or bridged C3-C. 10 Heterocyclic. In some embodiments, R3 is a substituted piperazine. In some embodiments, R3 is 1-(piperazin-1-yl)ethyl ketone. In some embodiments, R3 is 1-(methylsulfonyl)piperazine or 4-(methylsulfonyl)piperazine. In some embodiments, R3 is N(R 10 (R) 11In some implementations, R1 is R8-O-R6-R. 30 And R3 is N(R 10 (R) 11 In some implementations, N(R) 10 (R) 11 N(R) is a substituted or unsubstituted 3-8 membered heterocyclic ring. In some embodiments, N(R) is a substituted or unsubstituted heterocyclic ring. 10 (R) 11 N(R) is a substituted or unsubstituted 6-membered heterocyclic ring. In some embodiments, N(R) is a substituted or unsubstituted 6-membered heterocyclic ring. 10 (R) 11 ) is an amide-substituted piperazine (e.g., 1-(methylsulfonyl)piperazine or 4-(methylsulfonyl)piperazine, N -methylpiperazine-1-carboxamide or 1-(piperazine-1-yl)ethyl ketone), sulfonyl-substituted piperazines (e.g., 1-(methylsulfonyl)piperazine or 4-(methylsulfonyl)piperazine); each is a separate embodiment according to the invention. In some embodiments, N(R 10 (R) 11 ) is 1-(piperazin-1-yl)ketene. In some embodiments, N(R) 10 (R) 11 R1 is 1-(methanesulfonyl)piperazine or 4-(methanesulfonyl)piperazine. In some embodiments, R1 is -R8-O-R6-R 30 And R3 is 1-(piperazin-1-yl)ketene. In some embodiments, R1 is -R8-OR 10 Furthermore, R3 is 1-(piperazin-1-yl)ethenone.

[0063] In some implementations, if R3 is a heterocyclic ring, then R1 cannot be H. In some implementations, if R3 is a heterocyclic ring, then R1 is -R8-OR. 10 In some implementations, if R3 is a heterocyclic ring, then R1 is -R8-O-R6-R. 30 .

[0064] In some embodiments, R4 of the compound of formula I is H.

[0065] In some embodiments, R5 of the compound of formula I is H.

[0066] In some embodiments, R6 is absent in compounds of formulas I-III (i.e., w is 0). In some embodiments, R6 is CH2 (i.e., w is 1). In some embodiments, R6 is CH2CH2 (i.e., w is 2).

[0067] In some embodiments, w is 0 for compounds of formulas I-V. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4. In some embodiments, w is 5.

[0068] In some embodiments, R8 of compounds of formulas I-V is CH2 (i.e., p is 1). In some embodiments, R8 is CH2CH2 (i.e., p is 2).

[0069] In some embodiments, p is 1 for compounds of formulas I-V. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 0.

[0070] In some implementations, R of formulas I-V 10 It is a substituted or unsubstituted 3-8 membered heterocyclic ring. In other embodiments, R 10 It is tetrahydro- 2H -Pyran.

[0071] In some implementations, R of formulas I-V 11 It's H.

[0072] In some implementations, R of formulas I-V 10 and R 11 They are linked to form substituted or unsubstituted 3-8 membered heterocycles. In other embodiments, R 10 and R 11 They are linked to form the substituted piperazine ring. In other embodiments, R 10 and R 11 It is linked to form 1-(piperazin-1-yl)ethyl ketone. In other embodiments, R 10 and R 11 They are linked to form 1-(methylsulfonyl)piperazine or 4-(methylsulfonyl)piperazine. In some embodiments, substitutions include: F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight-chain or branched alkyl groups (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight-chain or branched C(O)-alkyl groups (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl groups (e.g., SO2-CH3), C(O)-NH-alkyl groups, C1-C5 straight-chain or branched alkyl-OH groups (e.g., C(CH3)2CH2-OH, CH2CH2-OH), 3-8 membered heterocycles (e.g., piperidine), substituted or unsubstituted C1-C5 straight-chain or branched alkoxy groups, N(R)2, N(R 10 (R) 11), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, (benzyloxy)phenyl or any combination thereof; each represents a separate embodiment according to the invention.

[0073] In some implementations, R of formula IV 12 It is a substituted or unsubstituted C1-C5 straight-chain alkyl group. In some embodiments, R 12 It is an unsubstituted C1-C5 branched alkyl group. In some embodiments, R 12 It is a substituted C1-C5 branched alkyl group. In some embodiments, R 12 It is a substituted C1-C5 branched alkyl group. In some embodiments, R 12 It is an unsubstituted C1-C5 branched alkyl group. In some embodiments, R 12 It is methyl. In some embodiments, R 12 It is an ethyl group. In some embodiments, the alkyl group may be substituted with at least one substituent selected from: F, Cl, Br, I, OH, CF3, CN, NO2, OH, C1-C5 straight-chain or branched alkoxy groups, cyclic alkoxy groups, amides (i.e., C(O)-NH-alkyl or NH-C(O)-alkyl), C(O)N(R) 10 (R) 11 ), amines (i.e., NH(R) 10 ), N(R 10 (R) 11 (NH2), aryl, phenyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycles, which may be saturated, unsaturated, aromatic, single, fused, bridged or spiro; each represents a separate embodiment according to the invention.

[0074] In some embodiments, the G=X of the compound of formula I is C=O.

[0075] In some embodiments, the G'=X' of the compound of formula IV is C=O. In some embodiments, G'=X' is S(O)2. In some embodiments, G'=X' is S(O).

[0076] In some embodiments, Q1 of the compound of formula I is S.

[0077] In some implementations, R of formulas I-V 30It is a substituted or unsubstituted C1-C5 straight-chain or branched alkyl group. In some embodiments, the alkyl group may be further substituted with at least one of the following: F, Cl, Br, I, OH, CF3, CN, NO2, C1-C5 straight-chain or branched alkoxy (e.g., OCH3), C2-C5 straight-chain or branched alkynyl (e.g., CCH), C1-C5 straight-chain or branched thioalkoxy (e.g., SCH3), C1-C5 straight-chain or branched alkylsulfinyl (e.g., S(O)CH3), C1-C5 straight-chain or branched alkylsulfonyl (e.g., S(O)2-CH3), NH2, C1-C5 straight-chain or branched N(H)(alkyl) (e.g., N(H)(CH3)) and C1-C5 straight-chain or branched N(alkyl)2; each representing a separate embodiment according to the invention. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is C(H)(OH)(CH3). In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is methyl. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is ethyl. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-CH2-O-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-O-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-S-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-CH2-S-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-S(O)-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-CH2-S(O)-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-S(O)2-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-NH-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-CH2-NH-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-CCH. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-CHF2. In some embodiments, R 30It is a C2-C5 straight-chain or branched substituted or unsubstituted alkynyl group. In some embodiments, the C2-C5 straight-chain or branched substituted or unsubstituted alkynyl group is CCH. In some embodiments, R 30 It is a C1-C5 straight-chain or branched alkoxy group. In some embodiments, the C1-C5 straight-chain or branched alkoxy group is O-CH3. In some embodiments, R... 30 It is a C1-C5 straight-chain or branched thioalkoxy group. In some embodiments, the C1-C5 straight-chain or branched thioalkoxy group is S-CH3. In some embodiments, R... 30 It is a C1-C5 straight-chain, branched, or cyclic haloalkyl group. In some embodiments, the C1-C5 straight-chain, branched, or cyclic haloalkyl group is CHF2. In some embodiments, R... 30 It is a substituted or unsubstituted 3-8 membered heterocycle. In some embodiments, the substituted or unsubstituted 3-8 membered heterocycle is tetrahydro- 2H -Pyran. In some implementations, R 30 It is N(R) 10 (R) 11 In some implementations, N(R) 10 (R) 11 ) is N(H)(CH3). In some implementations, R 30 It is S(O)R. In some embodiments, S(O)R is S(O)-CH3. In some embodiments, R 30 It is SO2R. In some implementations, SO2R is SO2-CH3.

[0078] In some embodiments, at least one of X2, X3, X4, and X5 in Formulas II-III is N. In some embodiments, at least two of X2, X3, X4, and X5 are N. In some embodiments, both X2 and X3 in Formulas II-III are N.

[0079] In some embodiments, X1 of compounds of formulas II-III is N. In other embodiments, X1 is C.

[0080] In some embodiments, X2 of compounds of formulas II-V is N. In other embodiments, X2 is C.

[0081] In some embodiments, X3 of compounds of formulas II-III is N. In other embodiments, X3 is C.

[0082] In some embodiments, both X2 and X3 of the compounds of formulas II-III are N.

[0083] In some embodiments, X4 of compounds of formulas II-III is N. In other embodiments, X4 is C.

[0084] In some embodiments, X5 of the compounds of formulas II-III is N. In other embodiments, X5 is C.

[0085] It should be understood that H atoms are added where necessary to complete the valence of the unsubstituted carbon atoms X1-X5 in any of Formulas II-V.

[0086] It should be understood that if any of X1-X5 is N, then none of R1-R4 can be attached to it.

[0087] In some embodiments, X6 of the compound of formula III is NC(O)-R 10 In other embodiments, X6 is NC(O)-CH3. In other embodiments, X6 is NR. In other embodiments, R is a C1-C5 substituted or unsubstituted SO2-alkyl group. In other embodiments, R is SO2-CH3. In other embodiments, X6 is NS(O)2-R. 10 In other embodiments, X6 is N-SO2-CH3.

[0088] In some embodiments, the X of compounds of formula IV, formula IV(a) and / or formula IV(b) 10 It is O. In some implementations, X 10 It is S. In some implementations, X 10 It is NH. In some implementations, X 10 It is N(H)C(O).

[0089] In various embodiments, the present invention relates to the compounds, pharmaceutical compositions and / or methods of use presented in Table 1, each representing a separate embodiment of the invention: Table 1: .

[0090] It should be well understood that in the structures provided in this invention in which carbon atoms have fewer than four bonds, H atoms are present to complete the valence of carbon. It should be well understood that in the structures provided in this invention in which nitrogen atoms have fewer than three bonds, H atoms are present to complete the valence of nitrogen.

[0091] In some embodiments, the present invention relates to the compounds, pharmaceutical compositions and / or methods of use listed above, wherein the compounds are pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N - Oxides, prodrugs, isotope variants (deuterated analogs), PROTACs, pharmaceutical products, or any combination thereof. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is a collagen I, II, II, IV, or V translation inhibitor; each represents a separate embodiment according to the invention. In some embodiments, the compound is selective for collagen I, II, II, IV, or V; each represents a separate embodiment according to the invention. In some embodiments, the compound is selective for collagen I. In some embodiments, the compound is selective for collagen IA. In some embodiments, the compound is selective for collagen IA1.

[0092] Other embodiments of the present invention In various embodiments, ring A of Formula I is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetraazinyl, thiazolyl, isothiazinyl, oxazinyl, isoxazinyl, imidazole, 1-methylimidazolium, isoquinoline, pyrazinyl, pyrroleyl, furanyl, thiophene-yl, isoquinoline, indoleyl, 1H-indole, isoindoleyl, naphthyl, anthraceneyl, benzimidazolyl, indazoleyl, 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-1,3-benzothiazolyl, quinazolinyl, quinoxalinyl, terpinenyl, phthalazinyl, quinolinyl, isoquinolinyl, 2,3-dihydroindenyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxacycloheptenene, benzo[d][1,3]m-dioxacyclopentene, acridinel, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzofuran-2(3H)-one, benzothiophene, benzooxadiazole, benzo[c][1,2,5]oxadiazole, benzo[ cThiopheneyl, benzodioxolyl, benzo[d][1,3]-dioxolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiazolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazo[4,5-d]pyrimidine Pyridine, [1,3]thiazo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thienozo[3,2-d]pyrimidin-4(3H)-one, 4-oxo-4H-thienozo[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]pyridine -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 Pyridine, thieno[3,2-c]pyridine; each representing a separate embodiment according to the invention; or A is a C3-C8 cycloalkyl (e.g., cyclohexyl, cyclopentyl, bicyclo[1.1.1]pentyl, cyclobutyl) or a 3-8 membered heterocycle, said 3-8 membered heterocycle including but not limited to: tetrahydropyran, piperidine, 1-methylpiperidine, tetrahydrothiophene 1,1-dioxide, pyrrolidone-2-one, piperazine, 1-(piperidin-1-yl)acetone or morpholine; each representing a separate embodiment according to the invention. In some embodiments, A is phenyl. In some embodiments, A is pyridyl. In some embodiments, A is 3-pyridyl.

[0093] In various embodiments, ring B of Formula I is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, tetraazinyl, thiazolyl, isothiazinyl, oxazinyl, isoxazinyl, imidazole, 1-methylimidazolium, isoquinoline, pyrazinyl, pyrroleyl, furanyl, thiophene-yl, isoquinoline, indoleyl, 1H-indole, isoyindoleyl, 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-dioxacyclopentene, indazole, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indole-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzoisoxazolyl, benzothiazolyl, 1,3-benzothiazol, 4,5,6,7-tetrahydro-1,3-benzothiazol, quinazolinyl, quinoxalinyl, terpineyl, phthalazinyl, quinolinyl, isoquinolinyl, acridineyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzothiophenyl, benzoxadiazole, benzo[c][1,2,5]oxadiazoleyl, benzo[ cThiopheneyl, benzo[2,1-b][1,3]thiazolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiazolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopentazo[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 Pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thienozo[3,2-d]pyrimidin-4(3H)-one, 4-oxo-4H-thienozo[3,2-d][1,3]thiazine, imidazo[1,2-a]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2- a] Pyrazine, imidazo[1,2-a]pyrimidine, pyrido[2,3-b]pyrazine or pyrido[2,3-b]pyrazine-3(4H)-one, 4H-thieno[3,2-b]pyrrole, 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]pyrrole Pyrimidine, oxazolo[5,4-b]pyridine, thiazo[5,4-b]pyridine, thieno[3,2-c]pyridine, C3-C8 cycloalkyl or 3-8 membered heterocycles, wherein the 3-8 membered heterocycles include, but are not limited to: tetrahydropyran, piperidine, 1-methylpiperidine, tetrahydrothiophene 1,1-dioxide, 1-(piperidin-1-yl)acetone, bicyclo[1.1.1]pentyl, cyclobutyl, cyclohexyl or morpholine; each representing a separate embodiment according to the invention. In some embodiments, B is pyridyl. In some embodiments, B is 2-pyridyl.

[0094] In various embodiments, R1 of Formulas I-III and / or R2 of Formula I are each independently H. In some embodiments, R1 is not H. In some embodiments, R1 is Cl. In some embodiments, R1 is F. In some embodiments, R1 is R8-OH. In some embodiments, R1 is CH2OH. In some embodiments, R1 is -R8-OR 10 In some implementations, R 10 It is tetrahydro- 2H -Pyran. In some implementations, R1 is -R8-OR 10 , where R 10 It is tetrahydro- 2H -Pyran. In some embodiments, R1 is CH2-O-CH2-CH2-O-CH3.

[0095] In various embodiments, R1 of Formulas I-III and / or R2 of Formula I are each independently F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2OH), R8-SH, -R8-OR 10 (e.g., CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3, CH2-O-CH3), -O-R8-OR 10 (e.g., O-CH2-CH2-O-CH3), -R8-O-R6-R 30 (For example, CH2O-tetrahydro-) 2H -Pyran, CH2O-CH2-CCH, CH2O-CH2CH2O-CH3, CH2O-CH2CH2NH-CH3, CH2O-CH2CH2S-CH3, CH2O-CH2CH2S(O)CH3, CH2O-CH2CH2SO2-CH3, CH2O-CH2CF2H, CH2-O-CH2-CH2-O-CH3, CH2O-CH2-C(H)(OH)-CH3), R8-(C3-C8 cycloalkyl), R8-(3-8 membered heterocyclic), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, R8-N(R 10 (R) 11 (e.g., CH2-NH-CH3, CH2-NH-C(O)CH3, CH2-N(CH3)2), R9-R8-N(R 10 (R) 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R (e.g., NHCO-Ph, NHCO-CH3), NHC(O)-R 10 (For example, 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), C2-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) in the alkoxy group is replaced by an oxygen atom, C1-C5 straight-chain or branched The possible meanings are: 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 3-8 membered heterocycles (e.g., aziridine, pyridine), substituted or unsubstituted aryl (e.g., phenyl), or substituted or unsubstituted benzyl; each possibility represents a separate embodiment according to the invention. In some embodiments, R1 and / or R2 may be further substituted with at least one substituent selected from the following: F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight-chain or branched alkyl groups (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight-chain or branched C(O)-alkyl groups (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl groups (e.g., SO2-CH3), C(O)-NH-alkyl groups, C1-C5 straight-chain or branched alkyl-OH groups (e.g., C(CH3)2CH2-OH, CH2CH2-OH), 3-8 membered heterocycles (e.g., piperidine), substituted or unsubstituted C1-C5 straight-chain or branched alkoxy groups, N(R)2, N(R 10 (R) 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl and (benzyloxy)phenyl; each possibility represents a separate embodiment according to the invention.

[0096] In some embodiments, R2 in Formula I is H. In some embodiments, R2 is Cl. In some embodiments, R2 is F. In some embodiments, R2 is R8-OH. In some embodiments, R2 is CH2OH. In some embodiments, R2 is -R8-OR. 10 In some implementations, R2 is CH2-O-CH2-CH2-O-CH3. In some implementations, R2 is CH2-O-CH3. In some implementations, R2 is -O-R8-OR. 10 In some implementations, R2 is O-CH2-CH2-O-CH3. In some implementations, R2 is CN. In some implementations, R2 is R8-N(R 10 (R) 11In some embodiments, R2 is CH2-NH-CH3. In some embodiments, R2 is CH2-NH-C(O)CH3. In some embodiments, R2 is CH2-N(CH3)2. In some embodiments, R2 is 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 t-Bu. In other embodiments, R2 is isobutyl. In other embodiments, R2 is pentyl. In other embodiments, R2 is propyl. In other embodiments, R2 is benzyl. In other embodiments, R2 is in the ortho position. In other embodiments, R2 is o-methyl. 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 a substituted or unsubstituted aryl group. In other embodiments, R2 is phenyl. 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 according to the invention.

[0097] In some embodiments, R1 and R2 of Formula I 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 1,4-dioxane. In some embodiments, R1 and R2 are linked together to form a 2,3-dihydro-1,4-dioxacyclohexene ring. In some embodiments, R1 and R2 are linked together to form a furan-2(3H)-ketone 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.

[0098] In various embodiments, R3 of Formulas I-II and / or R4 of Formula I are each independently H. In various embodiments, R3 of Formulas I-II and / or R4 of Formula I are each independently F, Cl, Br, I, OH, SH, R8-OH, R8-SH, -R8-OR 10 R8-(C3-C8 cycloalkyl), R8-(3-8 membered heterocyclic), CF3, CD3, OCD3, CN, NO2, -CH2CN, -R8CN, NH2, NHR, N(R)2, N(R) 10 (R) 11 (e.g., morpholine, piperazine, 1-(piperazin-1-yl)ketene, 1-(methanesulfonyl)piperazine, or 4-(methanesulfonyl)piperazine), R8-N(R 10 (R) 11 ), R9-R8-N(R 10 (R) 11 ), B(OH)2, -OC(O)CF3, -OCH2Ph, NHC(O)-R 10 NHCO-N(R) 10 (R) 11 ), COOH, -C(O)Ph, C(O)OR 10 R8-C(O)-R 10 C(O)H, C(O)-R 10 C1-C5 straight-chain or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(O)NH(CH3)2O-CH3, C(O)N(R) 10 (R) 11 ), C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH3)2, C(O)-piperazine, SO2R, SO2N(R 10 (R) 11 ), CH(CF3)(NH-R 10C1-C5 straight-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl), C2-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, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(acetone) Piperidine-4-oxy), optionally wherein at least one methylene group (CH2) in the alkoxy group 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 single, spirocyclic, fused or bridged C3-C 10 Heterocyclic compounds (e.g., piperazine, 1-(2-methoxyethyl)piperazine, 1-methylpiperazine or 4-methylpiperazine, 1-(methylsulfonyl)piperazine or 4-(methylsulfonyl)piperazine, 1-(methylsulfonyl)piperidine or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ketene, 1-(piperazin-1-yl)ethyl ketene, 2-(dimethylamino)-1-(piperazin-1-yl)ethyl ketene, 2-(dimethylamino)-1-(piperazin-1-yl)acetone, 2-hydroxy-1-(piperazin-1-yl)ketene, N 1-Methylpiperazine-1-carboxamide, piperidine-4-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H-thiaran 1,1-dioxide, tetrahydro- 2H-Pyran, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]hept-2-yl)ethenone, 2-methoxy-1-(2,6-diazaspiro[3.3]hept-2-yl)ethenone, 2,8-diazaspiro[4.5]dec-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g., phenyl) or substituted or unsubstituted benzyl; each possibility represents a separate embodiment of the invention. In some embodiments, R3 and / or R4 may be further substituted with at least one substituent selected from the following: F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight-chain or branched alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight-chain or branched C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight-chain or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), 3-8 membered heterocycles (e.g., piperidine), substituted or unsubstituted C1-C5 straight-chain or branched alkoxy, N(R)2, N(R 10 (R) 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl and (benzyloxy)phenyl; each possibility represents a separate embodiment of the invention.

[0099] In some embodiments, R3 in Formulas I-III is H. In other embodiments, R3 is F. In other embodiments, R3 is Cl. In other embodiments, R3 is Br. In other embodiments, R3 is I. In other embodiments, R3 is N(R 10 (R) 11 In other implementations, R3 is N(R 10 (R) 11 ), where N(R) 10 (R) 11 The heterocycle is a substituted or unsubstituted 3-8 membered heterocycle. In other embodiments, the heterocycle is a substituted piperazine. In other embodiments, the heterocycle is 1-(piperazin-1-yl)ethyl ketone. In other embodiments, the heterocycle is morpholine, alkyl-substituted morpholine, pyrrolidine, pyrrolidone, piperazine, alkyl-substituted piperazine (e.g., 1-(2-methoxyethyl)piperazine), amide-substituted piperazine (e.g., 1-(methylsulfonyl)piperazine or 4-(methylsulfonyl)piperazine), N1-methylpiperazine-1-carboxamide or 1-(piperazin-1-yl)ethyl ketone), sulfonyl-substituted piperazines (e.g., 1-(methylsulfonyl)piperazine or 4-(methylsulfonyl)piperazine), octahydropyrrolo[1,2-α]pyrazine, hydroxy-substituted piperidines, sulfonyl-substituted piperidines (e.g., 1-(methylsulfonyl)piperidine or 4-(methylsulfonyl)piperidine), 2-methoxy-1-(piperazin-1-yl)ethenone, tetrahydro- 2H -Pyran, tetrahydro-2H-thiaran 1,1-dioxide, 6-methyl-2,6-diazaspiro[3.3]heptane; each is a separate embodiment according to the invention. In other embodiments, R3 is morpholine. In other embodiments, R3 is piperazine. In other embodiments, R3 is a substituted or unsubstituted C3-C8 cycloalkyl group. In other embodiments, R3 is a substituted or unsubstituted single, spirocyclic, fused or bridged C3-C 10 Heterocyclic. In other embodiments, R3 is 1-(piperazin-1-yl)ethyl ketone. In other embodiments, R3 is 1-(methanesulfonyl)piperazine or 4-(methanesulfonyl)piperazine. In some embodiments, R3 is morpholine, 3-methylmorpholine, 3-hydroxypiperidine, pyrrolidine, pyrrolidone, octahydropyrrolo[1,2-α]pyrazine or 6-methyl-2,6-diazaspiro[3,3]heptane; each representing a separate embodiment according to the invention. In other embodiments, R3 may be further substituted with at least one substituent selected from the following: F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight-chain or branched alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight-chain or branched C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight-chain or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), 3-8 membered heterocycles (e.g., piperidine), substituted or unsubstituted C1-C5 straight-chain or branched alkoxy, N(R)2, N(R 10 (R) 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl and (benzyloxy)phenyl.

[0100] In some embodiments, R4 of Formula I 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.

[0101] In some embodiments, R3 and R4 of the compound of formula I 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. In some embodiments, R3 and R4 are linked together to form a [1,3]-meta-dioxane ring. In some embodiments, R3 and R4 are linked together to form a dihydrofuran-2(3H)-ketone ring. In some embodiments, R3 and R4 are linked together to form a furan-2(3H)-ketone 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 linked together to form a pyrazole ring. In some embodiments, R3 and R4 are linked together to form a cyclohexene ring. In some embodiments, R3 and R4 are linked together to form a cyclopentene ring. In some embodiments, R4 and R3 are linked together to form a dioxane-heptene ring.

[0102] In some implementations, R5 in Formula I is H. In some implementations, R5 is R. 20 In some embodiments, R5 is a C1-C5 straight-chain or branched, substituted or unsubstituted alkyl group. In some embodiments, R5 is methyl. In some embodiments, R5 is ethyl. In some embodiments, R5 is C(O)-R 10 In some embodiments, R5 is SO2R. In some embodiments, R5 of the compound of formula I is R. 20 ,F,Cl,Br,I,OH,SH,R8-OH,R8-SH,-R8-OR 10 R8-(C3-C8 cycloalkyl), R8-(3-8 membered 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 The following are possible representations of the following compounds: C1-C5 straight-chain or branched substituted or unsubstituted alkyl groups (e.g., methyl, ethyl); C2-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 group (CH2) in 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 3-8 membered heterocycles; substituted or unsubstituted aryl groups; substituted or unsubstituted benzyl groups; each representing a separate embodiment of the invention. In some embodiments, R5 may be further substituted with at least one substituent selected from the following: F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight-chain or branched alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight-chain or branched C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight-chain or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), 3-8 membered heterocycles (e.g., piperidine), substituted or unsubstituted C1-C5 straight-chain or branched alkoxy, N(R)2, N(R 10 (R) 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl and (benzyloxy)phenyl; each possibility represents a separate embodiment of the invention.

[0103] In many embodiments, n is 1 for the compound of formula I. 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 1 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.

[0104] In many embodiments, m of the compound of formula I is 0. In some embodiments, m is 0 or 1. In some embodiments, m is between 1 and 3. In some embodiments, m is between 1 and 4. In some embodiments, m is between 0 and 2. In some embodiments, m is between 0 and 3. In some embodiments, m is between 0 and 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0105] In various embodiments, l in the compound of formula I is 0. In some embodiments, l is 0 or 1. In some embodiments, l is between 1 and 3. In some embodiments, l is between 1 and 4. In some embodiments, l is 1 or 2. In some embodiments, l is between 0 and 3. In some embodiments, l is between 0 and 4. In some embodiments, l is 1. In some embodiments, l is 2. In some embodiments, l is 3. In some embodiments, l is 4.

[0106] In many embodiments, k is 0 for the compound of formula I. 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.

[0107] It should be understood that for heterocyclic and / or heteroaromatic rings A or B, n, m, l, and / or k are limited to the number of positions that can be substituted, i.e., the number of CH groups 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.

[0108] In many embodiments, R6 is absent in compounds of formulas I-III. In many embodiments, R6 is CH2. In some embodiments, R6 is CH2CH2. In some embodiments, R6 is CH2CH2CH2. In some embodiments, R6 is CH2CH2CH2CH2.

[0109] In various embodiments, w is 0 for compounds of formulas I-V. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4. In some embodiments, w is 5. In some embodiments, w is between 0 and 3. In some embodiments, w is between 0 and 2. In some embodiments, w is between 1 and 2. In some embodiments, w is between 0 and 4. In other embodiments, w is between 1 and 3. In other embodiments, w is 0 or 1.

[0110] In many embodiments, R8 of the compounds of formulas I-III is CH2. In some embodiments, R8 is CH2CH2. In some embodiments, R8 is CH2CH2CH2. In some embodiments, R8 is CH2CH2CH2CH2.

[0111] In many embodiments, the p-value of compounds of formulas I-V is 1. In some embodiments, p-value is 2. In some embodiments, p-value is 3. In some embodiments, p-value is 4. In some embodiments, p-value is 5. In some embodiments, p-value is between 1 and 3. In other embodiments, p-value is 1 or 2. In some embodiments, p-value is between 1 and 5. In some embodiments, p-value is between 1 and 10.

[0112] In some embodiments, R9 of compounds of formulas I-III is C C. In some implementations, R9 is C CC C. In some implementations, R9 is CH=CH. In some implementations, R9 is CH=CH-CH=CH.

[0113] In some embodiments, q is 2 for compounds of formulas I-III. 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.

[0114] In various embodiments, the R of compounds of formulas I-V 10 It is H. In some implementations, R 10 It is OH. In some implementations, R 10It 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 implementations, R 10 It is isopropyl. In some implementations, R 10 It is butyl. In some implementations, R 10 It is isobutyl. In some implementations, R 10 It is tert-butyl. In some implementations, R 10 It is cyclopropyl. In some implementations, R 10 It is pentyl. In some implementations, R 10 It is isopentyl. In some implementations, R 10 It is neopentyl. In some implementations, R 10 It is benzyl. In some embodiments, R 10 It is CH2-CH2-O-CH3. In some implementations, R 10 It is a substituted or unsubstituted 3-8 membered heterocyclic ring. In some embodiments, R 10 It is tetrahydro- 2H -Pyran. In some implementations, R 10 It is 1-(methylsulfonyl)piperidine. In some embodiments, R 10 It is 1-(methylsulfonyl)piperazine. In some embodiments, R 10 It is morpholine. In some implementations, R 10 It is thiomorpholine 1,1-dioxide. In some embodiments, R 10 It is methylpyrrolidine. In some embodiments, R 10 It is methylpiperidine. In some embodiments, R 10 It is a C(O)-alkyl group. In some embodiments, R 10 It is an S(O)2-alkyl group. In some embodiments, R 10It may be further substituted with at least one of the following substituents: F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight-chain or branched alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight-chain or branched C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight-chain or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), 3-8 membered heterocycles (e.g., piperidine), substituted or unsubstituted C1-C5 straight-chain or branched alkoxy, N(R)2, N(R 10 (R) 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl and (benzyloxy)phenyl; each possibility represents a separate embodiment of the invention.

[0115] In various embodiments, the R of compounds of formulas I-V 11 It is H. In some implementations, R 11 It is OH. In some implementations, 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 implementations, R 11 It is isopropyl. In some implementations, R 11 It is butyl. In some implementations, R 11 It is isobutyl. In some implementations, R 11 It is tert-butyl. In some implementations, R 11 It is cyclopropyl. In some implementations, R 11 It is pentyl. In some implementations, R 11 It is isopentyl. In some implementations, R 11 It is neopentyl. In some implementations, R 11 It is benzyl. In some embodiments, R 11 It is CH2-CH2-O-CH3. In some implementations, R 11 It is a substituted or unsubstituted 3-8 membered heterocyclic ring. In some embodiments, R 11 It is 1-(methylsulfonyl)piperidine. In some embodiments, R 11 It is 1-(methylsulfonyl)piperazine. In some embodiments, R 11 It is tetrahydro- 2H-Pyran. In some implementations, R 11 It is morpholine. In some implementations, R 11 It is thiomorpholine 1,1-dioxide. In some embodiments, R 11 It is methylpyrrolidine. In some embodiments, R 11 It is methylpiperidine. In some embodiments, R 11 It is a C(O)-alkyl group. In some embodiments, R 11 It is an S(O)2-alkyl group. In some embodiments, R 11 It may be further substituted with at least one of the following substituents: F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight-chain or branched alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight-chain or branched C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight-chain or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), 3-8 membered heterocycles (e.g., piperidine), substituted or unsubstituted C1-C5 straight-chain or branched alkoxy, N(R)2, N(R 10 (R) 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl and (benzyloxy)phenyl; each possibility represents a separate embodiment of the invention.

[0116] In some implementations, R of formulas I-V 10 and R 11 They are linked to form substituted or unsubstituted 3-8 membered heterocycles. In other embodiments, R 10 and R 11 It is linked to form a morpholine ring. In other embodiments, R 10 and R 11 They are linked to form a piperazine ring. In other embodiments, R 10 and R 11 They are linked to form the substituted piperazine ring. In other embodiments, R 10 and R 11 It is linked to form 1-(piperazin-1-yl)ethenone. In other embodiments, R 10 and R 11 They are linked to form 1-(methylsulfonyl)piperazine or 4-(methylsulfonyl)piperazine. In other embodiments, R 10 and R 11 They are linked to form a piperidine ring. In other embodiments, R 10and R 11 They are linked to form an unsubstituted pyrrolidine ring. In other embodiments, R 10 and R 11 It is linked to form a 1-methylpyrrolidone-2-one ring. In other embodiments, R 10 and R 11 It is linked to form an oxetane. In other embodiments, R 10 and R 11 It is linked to form a nitrogen-containing heterocyclic butane. In other embodiments, R 10 and R 11 It is linked to form 1-methylazacyclobutane. In some embodiments, R 10 and / or R 11 It may be further substituted with at least one of the following substituents: F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight-chain or branched alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight-chain or branched C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight-chain or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), 3-8 membered heterocycles (e.g., piperidine), substituted or unsubstituted C1-C5 straight-chain or branched alkoxy, N(R)2, N(R 10 (R) 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl and (benzyloxy)phenyl; each possibility represents a separate embodiment of the invention.

[0117] In some implementations, R of formula IV 12 It is H. In some implementations, R 12 It is a substituted or unsubstituted C1-C5 straight-chain or branched alkyl group. In some embodiments, R 12 It is a C1-C5 straight-chain alkyl group. In some embodiments, R 12 It is a C1-C5 branched alkyl group. In some embodiments, R 12 It is methyl. In some embodiments, R 12 It is ethyl. In some embodiments, R 12 It is propyl. In some implementations, R 12 It is isopropyl. In some implementations, R 12 It is butyl. In some implementations, R 12 It is isobutyl. In some implementations, R 12It is tert-butyl. In some implementations, R 12 It is cyclopropyl. In some implementations, R 12 It is pentyl. In some implementations, R 12 It is isopentyl. In some implementations, R 12 It is neopentyl. In some implementations, R 12 It is CH2-CH2-O-CH3. In some implementations, R 12 It may be further substituted by at least one of the following substituents: F, Cl, Br, I, OH, CF3, CN, NO2, OH, C1-C5 straight-chain or branched alkoxy, cyclic alkoxy, amide (i.e., C(O)-NH-alkyl or NH-C(O)-alkyl), C(O)N(R 10 (R) 11 ), amines (i.e., NH(R) 10 ), N(R 10 (R) 11 (NH2), aryl, phenyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycles, which may be saturated, unsaturated, aromatic, single, fused, bridged, or spirocyclic; each represents a separate embodiment according to the invention. In some embodiments, R 12 It has not been replaced.

[0118] In some implementations, R of formulas I-V 30It is a substituted or unsubstituted C1-C5 straight-chain or branched alkyl group. In some embodiments, the alkyl group may be further substituted with at least one of the following: F, Cl, Br, I, OH, CF3, CN, NO2, C1-C5 straight-chain or branched alkoxy (e.g., OCH3), C2-C5 straight-chain or branched alkynyl (e.g., CCH), C1-C5 straight-chain or branched thioalkoxy (e.g., SCH3), C1-C5 straight-chain or branched alkylsulfinyl (e.g., S(O)CH3), C1-C5 straight-chain or branched alkylsulfonyl (e.g., S(O)2-CH3), NH2, C1-C5 straight-chain or branched N(H)(alkyl) (e.g., N(H)(CH3)) and C1-C5 straight-chain or branched N(alkyl)2; each representing a separate embodiment according to the invention. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is C(H)(OH)(CH3). In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is methyl. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is ethyl. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-CH2-O-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-O-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-S-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-CH2-S-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-S(O)-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-CH2-S(O)-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-S(O)2-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-NH-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-CH2-NH-CH3. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-CCH. In some embodiments, the substituted or unsubstituted C1-C5 straight-chain or branched alkyl group is CH2-CHF2. In some embodiments, R 30It is a C2-C5 straight-chain or branched substituted or unsubstituted alkynyl group. In some embodiments, the C2-C5 straight-chain or branched substituted or unsubstituted alkynyl group is CCH. In some embodiments, R 30 It is a C1-C5 straight-chain or branched alkoxy group. In some embodiments, the C1-C5 straight-chain or branched alkoxy group is O-CH3. In some embodiments, R... 30 It is a C1-C5 straight-chain or branched thioalkoxy group. In some embodiments, the C1-C5 straight-chain or branched thioalkoxy group is S-CH3. In some embodiments, R... 30 It is a C1-C5 straight-chain, branched, or cyclic haloalkyl group. In some embodiments, it is a C1-C5 straight-chain, branched, or cyclic haloalkyl group CHF2. In some embodiments, R 30 It is a substituted or unsubstituted 3-8 membered heterocycle. In some embodiments, the substituted or unsubstituted 3-8 membered heterocycle is tetrahydro- 2H -Pyran. In some implementations, R 30 It is N(R) 10 (R) 11 In some implementations, N(R) 10 (R) 11 ) is N(H)(CH3). In some implementations, R 30 It is S(O)R. In some embodiments, S(O)R is S(O)-CH3. In some embodiments, R 30 It is SO2R. In some implementations, SO2R is SO2-CH3.

[0119] In some embodiments, R in formulas I-V 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 NH2. In other embodiments, R is NH(R) 10 In other embodiments, R is NH(CH3). In other embodiments, R is N(R) 10 (R) 11 In other implementations, R is R 20In 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 substituted alkyl group. In other embodiments, R is CH2CH2OH. In other embodiments, R is CH2CH2OCH3. In other embodiments, R is R8-R 10 In other embodiments, R is CH2-OH. In other embodiments, R is CH2CH2-OH. In other embodiments, R is C(O)-R. 10 In other embodiments, R is C(O)-methylpyrrolidine. In other embodiments, R is C(O)-methylpiperidine. In other embodiments, R is C(O)-CH3. In other embodiments, R is -R8-OR. 10 In other embodiments, R is CH2-CH2-O-CH3. In other embodiments, R is a C1-C5 substituted or unsubstituted C(O)-alkyl group. In other embodiments, R is C(O)-CH2CH2-OCH3. In other embodiments, R is C(O)-CH3. In other embodiments, R is C(O)-CH2-N(CH3)2. In other embodiments, R is C(O)-CH2-CH2-N(CH3)2. In other embodiments, R is C(O)-CH2-OH. In other embodiments, R is C(O)-R8-R 10 In other embodiments, R is C(O)-CH2CH2-OH. In other embodiments, R is a C(O)-substituted or unsubstituted 3-8-membered heterocycle. In other embodiments, R is C(O)-methylpyrrolidine. In other embodiments, R is C(O)-methylpiperidine. In other embodiments, R is SO2-alkyl. In other embodiments, R is SO2-CH3. In other embodiments, R is a C1-C5 substituted or unsubstituted C(O)-NH-alkyl. In other embodiments, R is C(O)-NH-CH3. In other embodiments, R is a C1-C5 straight-chain or branched C(O)-O-alkyl. In other embodiments, R is C(O)-O-tBu. In other embodiments, R is a C1-C5 straight-chain or branched alkoxy. In other embodiments, R is -R8-OR. 10In other embodiments, R is CH2-CH2-O-CH3. In other embodiments, R is a C1-C5 straight-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 some embodiments, R may be further substituted with at least one substituent selected from the following: F, Cl, Br, I, OH, SH, CF3, CN, NO2, substituted or unsubstituted C1-C5 straight-chain or branched alkyl (e.g., methyl, methoxyethyl), substituted or unsubstituted C1-C5 straight-chain or branched C(O)-alkyl (e.g., C(O)-CH3, C(O)-CH2-O-CH3), SO2-alkyl (e.g., SO2-CH3), C(O)-NH-alkyl, C1-C5 straight-chain or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), 3-8 membered heterocycles (e.g., piperidine), substituted or unsubstituted C1-C5 straight-chain or branched alkoxy, N(R)2 ... 10 (R) 11 ), aryl, phenyl, heteroaryl, C3-C8 cycloalkyl, halophenyl, and (benzyloxy)phenyl; each possibility represents a separate embodiment of the invention. In some embodiments, two geminal R-substituted compounds are linked together to form a 3-6 member substituted or unsubstituted aliphatic carbocyclic ring (e.g., cyclopropyl, cyclopentene) or aromatic carbocyclic ring (e.g., benzene) or heterocyclic ring (e.g., thiophene, furan, pyrrole, pyrazole); each represents a separate embodiment of the invention.

[0120] It should be understood that H atoms are added where necessary to complete the valence of the unsubstituted carbon atoms X1-X5 in any of Formulas II-V.

[0121] In some embodiments, X6 of the compound of formula III is O. In other embodiments, X6 is CH2. In other embodiments, X6 is CHR. In other embodiments, X6 is CH(OH). In other embodiments, X6 is CH(NH2). In other embodiments, X6 is CH(NH(CH3)). In other embodiments, X6 is C(R) 10 (R) 11 In other embodiments, X6 is C(H)CH2CH2-OH. In other embodiments, X6 is C(H)CH2-OH. In other embodiments, X6 is 1-methylpyrrolidone-2-one. In other embodiments, X6 is oxetane. In other embodiments, X6 is NH. In other embodiments, X6 is NR. In other embodiments, X6 is N-CH3. In other embodiments, X6 is N-SO2-CH3. In other embodiments, X6 is NS(O)2-R. 10 In other implementations, X6 is NR 20 In other embodiments, X6 is NC(O)O-tBu. In other embodiments, X6 is NC(O)-CH2CH2-OCH3. In other embodiments, X6 is N-CH2CH2-OCH3. In other embodiments, X6 is NC(O)-CH3. In other embodiments, X6 is a C1-C5 substituted or unsubstituted NC(O)-NH-alkyl. In other embodiments, X6 is NC(O)-NH-CH3. In other embodiments, X6 is NC(O)-CH2-N(CH3)2. In other embodiments, X6 is NC(O)-CH2-CH2-N(CH3)2. In other embodiments, X6 is NC(O)-CH2CH2-OH. In other embodiments, X6 is NC(O)-CH2-OH. In other embodiments, X6 is NC(O)-R 10 In other embodiments, X6 is 1-methylazacyclobutane. In other embodiments, X6 is NC(O)-1-methyl-2-pyrrolidine. In other embodiments, X6 is NC(O)-1-methyl-3-pyrrolidine. In other embodiments, X6 is NC(O)-1-methyl-3-piperidine. In other embodiments, X6 is NC(O)-1-methyl-4-piperidine. In other embodiments, X6 is NR. 20 .

[0122] In some implementations, at least one of X1-X2 in Formulas II-III is N.

[0123] In some embodiments, at least one of X3-X5 in Formulas II-III is N. In some embodiments, at least two of X3-X5 are N. In some embodiments, X3 is N.

[0124] In some embodiments, Q1 in Formula I is S. In other embodiments, Q1 is O. In still other embodiments, Q1 is NH.

[0125] In some embodiments, G=X in Formula I is C=O. In other embodiments, G=X is C=S. In other embodiments, G=X is S=O. In other embodiments, G=X is SO2.

[0126] In some embodiments, the G'=X' of the compound of formula IV is C=O. In some embodiments, G'=X' is S(O)2. In some embodiments, G'=X' is S(O).

[0127] 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, isothiazinyl, oxazinyl, isoxazinyl, imidazolyl, 1-methylimidazolium, 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, indole, 1H-indole, isoyindole, anthraceneyl, benzimidazole 2,3-Dihydro-1H-benzo[d]imidazolyl, indazole, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indol-3-one, purine, benzoxazolyl, 1,3-benzoxazolyl, benzoisoxazolyl, benzothiazolyl, 1,3-benzothiazol, 4,5,6,7-tetrahydro-1,3-benzothiazol, quinoline Azoline, quinoxalinyl, 1,2,3,4-tetrahydroquinoxalin, 1-(pyridin-1(2H)-yl)acetone, cenolinyl, phthalazinyl, quinolinyl, isoquinolinyl, acridineyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzofuran-2(3H)-one, benzothiophene, benzoxadiazole, benzo[c][1,2,5]oxadiazoleyl, benzo[ cThiopheneyl, benzo[2,1-b][1,3]thiazolyl, thiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxazolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopentazo[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazolyl Azo[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-imidazo[4,5-b]pyridine Pyridine, 1H-imidazo[4,5-c]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrido[2,3-b]pyrazine, pyrido[2,3-b]pyrazine-3(4H)-one, 4H-thiazoline Pheno[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.

[0128] 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 many embodiments, the alkyl group includes C1-C5 carbon atoms. In some embodiments, the alkyl group includes C1-C6 carbon atoms. In some embodiments, the alkyl group includes C1-C8 carbon atoms. In some embodiments, the alkyl group includes 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. 20Carbon. In some embodiments, the branched alkyl group is an alkyl group substituted with an alkyl side chain of 1 to 5 carbons. In many 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, alkylamide, dialkylamide, 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.

[0129] The alkyl group can be the only substituent, or it can be part of a larger substituent, such as alkoxy, alkoxyalkyl, haloalkyl, arylalkyl, alkylamino, dialkylamino, alkylamide, alkylurea, etc. Preferred alkyl groups are methyl, ethyl, and propyl, and therefore include halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, halopropyl, dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl, arylethyl, arylpropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylamide, acetamino, propylamide, halomethylamide, haloethylamide, halopropylamide, methyl-urea, ethyl-urea, propyl-urea, 2-CH2-C6H4-Cl, 3-CH2-C6H4-Cl or 4-CH2-C6H4-Cl, C(OH)(CH3)(Ph), etc.

[0130] As used herein, the term "aryl" refers to any aromatic ring that is directly bonded to another group and may be substituted or unsubstituted. An aryl group may be the only substituent, or it may be part of a larger substituent, 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, imidazole, thiophene-, pyrroleyl, indolyl, phenylmethyl, phenylethyl, phenylamino, phenylamide, 3-methyl-4H-1,2,4-triazolyl, 5-methyl-1,2,4-oxadiazolyl, etc. Substitutions include, but are not limited to: F, Cl, Br, I, C1-C5 straight-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.

[0131] As used herein, the term "alkoxy" refers to an ether group substituted with an alkyl group as defined above. Alkoxy groups include both straight-chain and branched-chain alkoxy groups. Non-limiting examples of alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, and tert-butoxy.

[0132] As used herein, the term "aminoalkyl" refers to an amine group substituted with an alkyl group as defined above. Aminoalkyl means monoalkylamine, dialkylamine, or trialkylamine. Non-limiting examples of aminoalkyl groups are -N(Me)2, -NHMe, and -NH3.

[0133] In some embodiments, a "haloalkyl" group 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 carrying at least one fluorine atom. Non-limiting examples of haloalkyl groups are CF3, CF2CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2, and CF(CH3)-CH(CH3)2.

[0134] In some embodiments, a "halophenyl" group 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 4-chlorophenyl.

[0135] In some embodiments, "alkoxyalkyl" group refers to an alkyl group as defined above that has been substituted with an alkoxy group as defined above, such as an alkyl group substituted with 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.

[0136] In various embodiments, a "cycloalkyl" or "carbocyclic" group refers to a ring structure containing a carbon atom as a ring atom, which can be saturated or unsaturated, substituted or unsubstituted, single or fused. In some embodiments, the cycloalkyl group is a 3-10 membered ring. In some embodiments, the cycloalkyl group is a 3-12 membered ring. In some embodiments, the cycloalkyl group is a 6-membered ring. In some embodiments, the cycloalkyl group is a 5-7 membered ring. In some embodiments, the cycloalkyl group is a 3-8 membered ring. In some embodiments, the cycloalkyl group may be unsubstituted or substituted with: halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amide, alkylamide, dialkylamide, cyano, nitro, CO2H, amino, alkylamide, dialkylamide, 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 3-8 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.

[0137] 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 the 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 the ring in addition to a carbon atom. In some embodiments, the heterocycle or heteroaromatic ring is a 3-10 membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3-12 membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 6-membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 5-7 membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3-8 membered ring. In some embodiments, the heterocyclic group or heteroaromatic ring may be unsubstituted or substituted with: halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amide, alkylamide, dialkylamide, cyano, nitro, CO2H, amino, alkylamide, dialkylamide, 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, benzodioxole, benzofuran-2(3H)-one, benzo[d][1,3]-dioxole, indole, oxazole, isoxazole, imidazole and 1-methylimidazolium, furan, triazole, pyrimidine, pyrazine, oxetane (1-oxetane 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.

[0138] In various embodiments, the present invention provides compounds or isomers thereof, metabolites, pharmaceutically acceptable salts, pharmaceutical products, tautomers, hydrates, etc. N-Oxides, reverse amide analogs, prodrugs, isotope variants (deuterated analogs), PROTACs, polymorphs, or crystals or combinations thereof. In many 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. In some embodiments, the present invention provides reverse amide analogs 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 isotopic 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, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, tautomers, hydrates, etc., comprising the compounds of the present invention. N - A combination of oxides, reverse amide analogs, prodrugs, isotope variants (deuterated analogs), PROTACs, polymorphs, or crystals.

[0139] In various embodiments, the term "isomer" includes, but is not limited to, stereoisomers and analogs, structural isomers and analogs, conformational isomers and analogs, etc. In some embodiments, the isomer is an optical isomer. In some embodiments, the isomer is a stereoisomer.

[0140] 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, the compounds used in the methods of the present invention may be present in or racemic form and may be separated in or racemic form. Therefore, the compounds according to the present invention can be used as optically active isomers (enantiomers or diastereomers, including but not limited to: ( R Isomers, ( S Isomers (R)(R) Isomers (R)(S) Isomers (S)(S) Isomers (S)(R) Isomers (R)(R)(R) Isomers (R)(R)(S) Isomers (R)(S)(R) Isomers (S)(R)(R) Isomers (R)(S) (S) Isomers (S)(R)(S) Isomers (S)(S)(R) Isomers or (S)(S)(S) The compounds may exist as isomers; as racemic mixtures; or as mixtures enriched with enantiomers. Some compounds may also exhibit polymorphism. It should be understood that the present invention covers any racemic form, optically active form, polymorphic form, or stereoisomer form or mixture thereof, whichever has properties suitable for treating the various conditions described herein.

[0141] How to prepare the optically active form is well known in the art (e.g., by resolving the racemic form via recrystallization, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

[0142] The compounds of the present invention may also exist in the form of racemic mixtures comprising 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 stereoisomers are at least about 95% pure, more preferably at least about 98% pure, and most preferably at least about 99% pure. In many embodiments, the compounds according to the present invention comprise substantially pure stereoisomers. In some embodiments, the substantially pure stereoisomers are at least 70%; 75%; 80%; 85%; 90%; 93%; 95%; 97%; 98%; 99%; and 99.5% pure; each representing a separate embodiment according to the present invention.

[0143] In various embodiments, the compound comprises an enantiomer with a purity of >80%; >85%; >90%; >91%; >92%; >93%; >94%; >95%; >96%; >97%; >98%; >99%; >99.5% excess. ee) A single stereoisomer; each representing a separate embodiment according to the invention. In various embodiments, the compound comprises an enantiomer ratio of >80%; >85%; >90%; >91%; >92%; >93%; >94%; >95%; >96%; >97%; >98%; >99%; >99.5% ( er)The compound comprises a single stereoisomer; each representing a separate embodiment according to the invention. In various embodiments, the compound comprises a single stereoisomer with a purity greater than 80%; 85%; 90%; 91%; 92%; 93%; 94%; 95%; 96%; 97%; 98%; 99%; 99.5%; each representing a separate embodiment according to the invention.

[0144] In many embodiments, the compound is a substantially pure single enantiomer. In many embodiments, the compound comprises a mixture of enantiomers. In many embodiments, the compound is a racemic mixture.

[0145] In various embodiments, the compound has two chiral centers. In various embodiments, the compound comprises a mixture of stereoisomers. In various embodiments, the compound comprises a mixture of two, three, or four stereoisomers; each representing a separate embodiment of the invention. In various embodiments, the compound is a single stereoisomer. In various embodiments, the compound is a substantially pure single stereoisomer. In various embodiments, the substantially pure stereoisomer has a purity of at least 80%, 85%, 90%, 95%, 97%, 98%, or 99%; each representing a separate embodiment of the invention. In various embodiments, the compound is substantially pure... RR Stereoisomers. In many embodiments, the compound is substantially pure. SS Stereoisomers. In many embodiments, the compound is substantially pure. RS Stereoisomers. In many embodiments, the compound is substantially pure. SR Stereoisomer.

[0146] The compounds of the present invention may also be in the form of hydrates, which means that the compounds also include stoichiometric or nonstoichiometric amounts of water bonded by noncovalent intermolecular forces.

[0147] As used herein, a "reverse amide analog" refers to a compound in which the carbonyl group (C=O) and the amine group (-NH or -NR) in the parent amide functional group (-C(=O)-NR-) are in reverse positions. Specifically, reverse amide analogs comprise a structure of the form -NR-C(=O)-, wherein the nitrogen atom is directly bonded to the carbon atom of the carbonyl group. In some embodiments, the reverse amide analog is not composed of a cyclic amide or not of a cyclic amine.

[0148] As used herein, when some chemical functional group (e.g., alkyl or aryl) is referred to as “substituted,” it is possible to define one or more substitutions herein. In some embodiments, the term "substituted" according to the invention refers to, but is not limited to, at least one group selected from: F, Cl, Br, I, OH, CF3, CN, NO2, C1-C5 straight-chain or branched alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl), C1-C5 straight-chain or branched haloalkyl groups, OH, C1-C5 straight-chain or branched alkoxy groups (e.g., OCH3), cyclic alkoxy groups (e.g., oxetane), C1-C5 straight-chain or branched thioalkoxy groups (e.g., SCH3), C1-C5 straight-chain or branched alkylsulfinyl groups (e.g., S(O)CH3), C1-C5 straight-chain or branched alkylsulfonyl groups (e.g., S(O)2-CH3), R8-OH (e.g., CH2-OH), OMe, amides (i.e., C(O)-NH-alkyl or NH-C(O)-alkyl), C(O)N(R) 10 (R) 11 ), R8-C(O)N(R 10 (R) 11 ), NH(R 10 ), N(R 10 (R) 11), NH2, C1-C5 straight-chain or branched N(H)(alkyl) (e.g., N(H)(CH3)), C1-C5 straight-chain or branched N(alkyl)2, aryl, phenyl, heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycles, which may be saturated, unsaturated, aromatic, single, fused, bridged or spiro (e.g., pyran, oxetane, piperidine, pyrazole, methyl-pyrazole, triazole, imidazole); each represents a separate embodiment according to the invention. In some embodiments, the term "substituted" according to the invention refers to at least one group selected from the group consisting of: F, Cl, Br, I, OH, CF3, CN, NO2, C1-C5 straight-chain or branched alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl), C1-C5 straight-chain or branched alkoxy groups (e.g., OCH3), C2-C5 straight-chain or branched alkynyl groups (e.g., CCH), C1-C5 straight-chain or branched thioalkoxy groups (e.g., SCH3), C1-C5 straight-chain or branched alkylsulfinyl groups (e.g., S(O)CH3), C1-C5 straight-chain or branched alkylsulfonyl groups (e.g., S(O)2-CH3), NH2, and C1-C5 straight-chain or branched N(H) (alkyl) groups. (e.g., N(H)(CH3)) and C1-C5 straight-chain or branched N(alkyl)2; each representing a separate embodiment according to the invention. In some embodiments, the substitution includes at least one group selected from: F, Cl, Br, I, OH, CF3, CN, NO2, C1-C5 straight-chain or branched alkoxy (e.g., OCH3), C2-C5 straight-chain or branched alkynyl (e.g., CCH), C1-C5 straight-chain or branched thioalkoxy (e.g., SCH3), C1-C5 straight-chain or branched alkylsulfinyl (e.g., S(O)CH3), C1-C5 straight-chain or branched alkylsulfonyl (e.g., S(O)2-CH3), C1-C5 straight-chain or branched N(H)(alkyl) (e.g., N(H)(CH3)) and C1-C5 straight-chain or branched N(alkyl)2; each representing a separate embodiment according to the invention.

[0149] The compounds of the present invention may exist in one or more of the possible tautomers, and depending on the circumstances, it is possible to separate some or all of the tautomers into separate and distinct entities. It should be understood that all possible tautomers are covered herein, including all additional enol and ketone tautomers and / or isomers. For example, but not limited to, the following tautomers are included: Tautomerization of the imidazole ring: , Tautomerization of the pyrazolone ring: .

[0150] This invention includes "pharmaceutically acceptable salts" of the compounds of this invention, which can be produced by reacting the compounds of this invention with an acid or a 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, and 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, and similar inorganic acids, and such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic 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, etc. N - Acetylcysteine ​​and similar organic acids. Other salts are known to those skilled in the art and can be readily adapted for use according to the present invention.

[0151] Suitable pharmaceutically acceptable salts of the amines of the compounds of the present invention can be prepared from inorganic or organic acids. In various embodiments, examples of inorganic salts of the amines are hydrogen sulfates, borates, bromides, chlorides, hemisulfates, hydrobroms, hydrochlorides, 2-hydroxyethyl sulfonates (hydroxyethane sulfonates), iodates, iodides, hydroxyethyl sulfonates, nitrates, persulfates, phosphates, sulfates, aminosulfonates, sulfanamides, sulfonic acids (alkyl sulfonates, aryl sulfonates, halogenated alkyl sulfonates, halogenated aryl sulfonates), sulfonates, and thiocyanates.

[0152] In various embodiments, examples of organic salts of amines can be selected from organic acids of the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes, including acetates, arginine salts, aspartate salts, ascorbic acid salts, adipic acid salts, anthranilates, alginates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, hydrogen sulfates, butyrates, bicarbonates, hydrogen tartrates, citrates, camphorates, camphor sulfonates, cyclohexylaminosulfonate, cyclopentane propionate, and calcium edetate. edetate), dextrorotatory camphor sulfonate, camsylate, carbonate, clavulanate, cinnamate, dicarboxylate, digluconate, dodecyl sulfonate, dihydrochloride, decanoate, heptanoate, ethanesulfonate, edetate, ethanedisulfonate, propionate, estolate, esylate, fumarate, formate, fluoride, galacturonate, gluconate, glutamate, glycolate, glucorate, glucoheptanoate, glycerophosphate, gluceptate, glycoacetaminophenarsenate llylarsanilate), glutamate, glutamate, heptamate, hexanoate, hydroxymaleate, hydroxycarboxylic acid, hexylresorcinol salt, hydroxybenzoate, hydroxynaphthylcarboxate, hydrofluoric acid salt, lactate, lactobionate, laurate, malate, maleate, methylenebis(beta-oxynaphthoate)), malonate, mandelate, mesylate, methanesulfonate, methyl bromide, methyl nitrate, methanesulfonate, monopotassium maleate, mucate, monocarboxylate, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, napsylate N-Methylglucosamine, oxalate, caprylate, oleate, dihydroxynaphthyl acidate, phenylacetate, picrate, phenylbenzoate, pivalate, propionate, phthalate, phenylacetate, pectate, phenylpropionate, palmitate, pantothenate, polygalactosate, pyruvate, quinic acid salt, salicylate, succinate, stearate, sulfanilate, basic acetate, tartrate, theophylline acetate, p-toluenesulfonate (toluenesulfonate), trifluoroacetate, terephthalate, tannate, teoclate, trihaloacetate, triethyliodide, tricarboxylate, undecanoate, and valerate.

[0153] 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).

[0154] 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 (-Benzylphenethylamine), 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, tromethamine, and urea.

[0155] In various embodiments, the salt can be formed by conventional means, 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, wherein the solvent is removed in a vacuum or by freeze-drying or by exchanging the ions of the existing salt for another ion or a suitable ion exchange resin.

[0156] Pharmaceutical Composition Another aspect of the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to an aspect of the invention. The pharmaceutical composition may comprise one or more of the compounds identified above in the 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 excipient, carrier, excipient, or stabilizer, and may be in solid or liquid form, such as tablets, capsules, powders, solutions, suspensions, or emulsions.

[0157] Typically, the composition will comprise from about 0.01% to 99%, preferably from about 20% to 75%, of the active compound, as well as excipients, carriers, and / or excipients. Although individual needs may vary, the determination of the optimal range of effective amounts for each component is within the scope of the art. Typical doses include from about 0.01 mg / kg body weight to about 100 mg / kg body weight. Preferred doses include from about 0.1 mg / kg body weight to about 100 mg / kg body weight. Most preferred doses include from about 1 mg / kg body weight to about 100 mg / kg body weight. Those skilled in the art can also readily determine the therapeutic regimen for administering the compounds of the present invention. That is, the frequency and dosage of administration can be determined through routine optimization, preferably while minimizing any side effects.

[0158] Solid dosage forms can be of conventional types. Solid forms can be capsules and similar forms, such as common gelatin types containing the compounds of the present invention and carriers such as lubricants and inert fillers such as lactose, sucrose, or corn starch. In some embodiments, these compounds are formulated into tablets together with a conventional tablet base such as lactose, sucrose, or corn starch, 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.

[0159] Tablets, capsules, and the like 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 alginate; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose, or saccharin. When the dosage unit is in capsule form, in addition to the materials of the types described above, the capsule may also contain a liquid carrier such as fatty oil.

[0160] Many other materials can be used as coatings or to modify the physical form of the dosage unit. For example, tablets can be coated with shellac, sugar, or both. In addition to the active ingredient, syrups can contain sucrose as a sweetener, methylparaben and propylparaben as preservatives, dyes, and flavorings such as cherry or orange flavorings.

[0161] For oral therapeutic administration, these active compounds can be combined with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and articles 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.

[0162] The active compounds of the present invention can be administered orally, for example, with an inert diluent or with an assimilated edible carrier, or they can be encapsulated in hard or soft capsules, or they can be compressed into tablets, or they can be directly incorporated into edible foods.

[0163] Suitable drug forms for injection include sterile aqueous solutions or dispersions, as well as sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be a fluid sufficient to be injectable. It should be stable under manufacturing and storage conditions and should be preserved against contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0164] The compounds or pharmaceutical compositions of the present invention can also be administered in injectable doses in solutions or suspensions of these materials in physiologically acceptable diluents having pharmaceutical excipients, carriers, or excipients. Such excipients, carriers, and / or excipients include, but are not limited to, sterile liquids, such as water and oils, with or without the addition of surfactants and other pharmaceutically and physiologically acceptable components. Exemplary oils are petroleum, animal, plant, or synthetic oils, such as peanut oil, soybean oil, or mineral oil. Typically, water, saline, aqueous solutions of dextran and related sugar solutions, as well as glycols such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.

[0165] These active compounds can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with surfactants such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oils. Exemplary oils are petroleum, animal, vegetable, or synthetic oils, such as peanut oil, soybean oil, or mineral oil. Typically, water, brine, aqueous solutions of dextrose and related sugar solutions, as well as glycols such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under normal storage and use conditions, these products contain preservatives to prevent microbial growth.

[0166] For use as an aerosol, the compounds of the present invention in solution or suspension can be packaged together with a suitable propellant, such as a hydrocarbon propellant with conventional adjuvants, like propane, butane, or isobutane, in a pressurized aerosol container. The materials of the present invention can also be administered in a non-pressurized form, such as in a sprayer or atomizer.

[0167] In various embodiments, the compounds of the present invention are administered in combination with agents for treating fibrosis. In some embodiments, the agent for treating pulmonary fibrosis is at least one selected from 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.

[0168] When the compounds of the present invention are administered, they can be administered systemically, or alternatively, they can be administered directly to specific sites where fibrosis exists. Therefore, administration can be accomplished in any manner that effectively delivers the compound or pharmaceutical composition to the 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 via application to mucous membranes (such as the mucous membranes of the nose, throat, and bronchi).

[0169] biological activity In various embodiments, the present invention provides compounds and compositions for use in any of the methods of the invention, including any 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 desired response in a subject, as will be understood by those skilled in the art. In some embodiments, the composition may also comprise additional active ingredients whose activity is useful for the specific application of the application of the compounds of the present invention.

[0170] This invention relates to the treatment, inhibition, and reduction of fibrosis, including pulmonary fibrosis and liver fibrosis. More specifically, embodiments of the invention provide compositions and methods for treating and inhibiting fibrotic disorders, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), and liver fibrosis conditions associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), employing the use of compounds according to the invention or pharmaceutically acceptable salts thereof. In another embodiment, a human subject has pulmonary fibrosis. In another embodiment, a human subject has idiopathic pulmonary fibrosis (IPF). In another embodiment, a human subject has non-alcoholic fatty liver disease (NAFLD). In another embodiment, a human subject has non-alcoholic steatohepatitis (NASH). In another embodiment, a human subject does not have non-alcoholic steatohepatitis (NASH).

[0171] In many conditions, the formation of fibrotic tissue is characterized by the deposition of abnormally large amounts of collagen. Collagen synthesis is also associated with many other pathological conditions. For example, clinical conditions and disorders associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, and autoimmune disorders, are identified by the excessive production of connective tissue, leading to the disruption of normal tissue structure and function. These diseases are best explained by interference with 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.

[0172] Excessive collagen accumulation is a major pathological feature in a variety of clinical conditions characterized by tissue fibrosis. These conditions include localized processes such as pulmonary fibrosis and cirrhosis, or more generalized processes such as progressive systemic sclerosis. Collagen deposition is characteristic of various forms of dermal 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 means to reduce excessive collagen accumulation in disease.

[0173] Therefore, in various embodiments, the present invention relates to methods 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 a subject suffering from fibrosis, provided that the subject's fibrosis is effectively treated, inhibited, reduced in severity, reduced in the risk of developing fibrosis in the subject, or suppressed in the subject's 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 disorders, or any combination thereof; each representing a separate embodiment according to the invention. In another embodiment, a human subject suffers from pulmonary fibrosis. In another embodiment, a human subject suffers from idiopathic pulmonary fibrosis (IPF). In some embodiments, fibrosis is pulmonary fibrosis. In some embodiments, the subject has cirrhosis of the liver. In some embodiments, fibrosis is liver fibrosis, pulmonary fibrosis, or dermal fibrosis. In some embodiments, dermal fibrosis is scleroderma. In some embodiments, dermal fibrosis is the result of localized or generalized scleroderma, keloids, hypertrophic scars, familial skin collagenoma, collagen-type connective tissue nevi, or any combination thereof; each represents a separate embodiment according to the invention. In some embodiments, fibrosis is caused by tissue damage, inflammation, oxidative stress, or any combination thereof; each represents a separate embodiment according to the invention. In some embodiments, fibrosis is gingival fibromatosis. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is selective for collagen I. In some embodiments, the compound is selective for collagen IA. 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. In some embodiments, the compound is selective for collagen IA1. 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. In some embodiments, the compound is compound 100.

[0174] Human fibrotic diseases constitute a major health problem worldwide due to the large number of individuals affected, the incomplete understanding of the pathogenesis of the fibrotic process, the significant heterogeneity of its etiology and clinical presentation, the lack of appropriate and well-validated biomarkers, and, most importantly, the current lack of effective disease-modifying treatments. Fibrotic disorders encompass a broad spectrum of clinical entities and many organ-specific disorders, including systemic fibrotic diseases such as systemic sclerosis (SSc), scleroderma-related graft-versus-host disease, and renal systemic fibrosis, and 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 several cases, these diseases share a common characteristic: the uncontrolled and gradual accumulation of fibrotic tissue in the affected organs, leading to dysfunction and eventual failure. Although the etiological mechanisms leading to the development of fibrotic diseases and the clinical manifestations of fibrotic diseases are significantly heterogeneous, many studies have identified activated myofibroblasts as a common cellular element that ultimately leads to the replacement of normal tissue with nonfunctional fibrotic tissue.

[0175] 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, comprising administering a compound according to the invention to a subject suffering from systemic fibrosis, provided that the subject's systemic fibrosis is effectively treated, inhibited, reduced, reduced, or suppressed. In some embodiments, the systemic fibrosis is systemic sclerosis. In some embodiments, the systemic fibrosis is multifocal fibrosis (IgG4-associated fibrosis). In some embodiments, the systemic fibrosis is renal systemic fibrosis. In some embodiments, the systemic fibrosis is scleroderma graft-versus-host disease.

[0176] 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, comprising administering a compound according to the invention to a subject suffering from organ-specific fibrosis, provided that the subject's organ-specific fibrosis is effectively treated, inhibited, reduced, reduced, or suppressed.

[0177] In some implementations, organ-specific fibrotic disease is pulmonary fibrosis. In some implementations, organ-specific fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0178] In some embodiments, the 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.

[0179] In some embodiments, the 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.

[0180] 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, comprising administering a compound of the invention to a subject suffering from cardiac fibrosis, provided that the subject's cardiac fibrosis is effectively treated, inhibited, reduced, reduced, or suppressed. 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 compound 100.

[0181] In some embodiments, the 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 chemotherapeutic agent-induced pulmonary fibrosis.

[0182] In some embodiments, the organ-specific fibrotic disease is hepatic and portal vein fibrosis. In some embodiments, hepatic and portal vein fibrosis is alcoholic and non-alcoholic liver fibrosis. In some embodiments, hepatic and portal vein fibrosis is hepatitis C-induced liver fibrosis. In some embodiments, hepatic and portal vein fibrosis is primary biliary cirrhosis. In some embodiments, hepatic and portal vein fibrosis is parasite-induced liver fibrosis (schistosomiasis).

[0183] In some embodiments, organ-specific fibrosis is radiation-induced fibrosis (multiple 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.

[0184] In some embodiments, the organ-specific fibrotic disease is diffuse fasciitis. In some embodiments, diffuse fasciitis is localized scleroderma or keloid scarring. In some embodiments, diffuse fasciitis is palmar aponeurosis contracture. 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.

[0185] In some implementations, organ-specific fibrosis is a result of wound healing. In other implementations, organ-specific fibrosis is a result of scar formation.

[0186] Liver fibrosis, also referred to herein as hepatic fibrosis, can be caused by a variety of types of chronic liver injury, particularly those involving inflammatory components. Self-limiting acute liver injury (e.g., acute hepatitis A), even when fulminant, does not necessarily distort 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.

[0187] 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 a subject suffering from liver fibrosis, provided that the subject's liver fibrosis is effectively treated, inhibited, reduced, reduced, or suppressed. 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: alcoholism, malnutrition, hemochromatosis, exposure to toxins, poisons, or drugs; each representing a separate embodiment of the invention. In some embodiments, the subject suffers from cirrhosis. 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 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 implementations, the compound is compound 100.

[0188] Fibrosis itself is not necessarily asymptomatic; however, it can lead to the development of portal hypertension or cirrhosis, in which scarring distorts blood flow through the liver, and in which scarring causes destruction of normal liver structure and impaired liver function. The extent of each of these conditions determines the clinical presentation of liver fibrosis disorders. For example, congenital liver fibrosis affects the portal vein branches, which largely preserves the parenchyma. The result is portal hypertension with preserved hepatocellular function.

[0189] 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, comprising administering a compound of the invention to a subject suffering from liver fibrosis, provided that the subject's liver fibrosis is effectively treated, inhibited, reduced, reduced, or suppressed. In some embodiments, liver fibrosis is: portal hypertension, cirrhosis, congenital liver fibrosis, or any combination thereof; each represents 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. In some embodiments, the compound is compound 100.

[0190] 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, comprising administering a compound of the invention to a subject suffering from portal hypertension, provided that the subject's portal hypertension is effectively treated, inhibited, reduced, reduced, or suppressed. 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 compound 100.

[0191] 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 inhibiting cirrhosis in a subject, the method comprising administering a compound of the invention to a subject suffering from cirrhosis, provided that the subject's cirrhosis is effectively treated, inhibited, reduced in severity, reduced in the risk of developing cirrhosis, or inhibited. 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. In some embodiments, the compound is compound 100.

[0192] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity, reducing the risk of developing, or suppressing human alcohol poisoning in a subject, comprising administering a compound of the invention to a subject suffering from alcohol poisoning, provided that the alcohol poisoning is effectively treated, inhibited, reduced, reduced, or suppressed. 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 compound 100.

[0193] Nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) share similar pathogenesis and histopathology, but differ in etiology and epidemiology. NASH and ASH represent advanced stages of nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is characterized by excessive fat accumulation (steatodegeneration) in the liver, without any other obvious cause of chronic liver disease (viral, autoimmune, genetic, etc.), and with alcohol consumption ≤20-30 g / day. Conversely, AFLD is defined as the presence of steatosis and alcohol consumption >20-30 g / day.

[0194] In various embodiments, the present invention relates to a method for treating, suppressing, reducing the severity of, or inhibiting nonalcoholic steatohepatitis (NASH) in a subject, comprising administering a compound of the invention to a subject suffering from NASH, under conditions that effectively treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit NASH 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. In some embodiments, the compound is compound 100.

[0195] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of developing, or suppressing alcoholic steatohepatitis (ASH) in a subject, comprising administering a compound of the invention to a subject suffering from ASH, under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing, or suppress ASH 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. In some embodiments, the compound is compound 100.

[0196] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing, or suppressing non-alcoholic fatty liver disease (NAFLD) in a subject, including administering a compound of the invention to a subject suffering from NAFLD, under conditions that effectively treat, inhibit, reduce, reduce the risk of developing, or suppress NAFLD 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. In some embodiments, the compound is compound 100.

[0197] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of developing, or suppressing alcoholic fatty liver disease (AFLD) in a subject, comprising administering a compound of the invention to a subject suffering from AFLD, under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing, or suppress AFLD 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. In some embodiments, the compound is compound 100.

[0198] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, 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 a subject suffering from pulmonary fibrosis, provided that the subject's pulmonary fibrosis is effectively treated, inhibited, reduced, reduced, or suppressed. 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 compound 100.

[0199] Idiopathic pulmonary fibrosis (IPF) is an age-related, intractable lung disease with historically limited treatment options. The recent approval of pirfenidone and nintedanib by the United States Food and Drug Administration (FDA) in 2014 heralds a new era in its management. Both drugs demonstrated efficacy in Phase III clinical trials by slowing the rate of IPF progression; however, neither drug completely halted disease progression. Advances in understanding 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 in multiple stages of clinical development.

[0200] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, or reducing the risk of developing idiopathic pulmonary fibrosis (IPF) in a subject, or suppressing IPF in a subject, comprising administering a compound of the invention to a subject suffering from IPF, under conditions that effectively treat, inhibit, reduce the severity of, reduce the risk of developing, or suppress IPF 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. In some embodiments, the compound is compound 100. In some embodiments, the compound is administered in combination with an agent for treating IPF. In some embodiments, the compound is applied in combination with pirfenidone, nintedanib, or a combination thereof: each representing a separate embodiment according to the invention.

[0201] In various embodiments, the present invention relates to a method for treating, inhibiting, reducing the severity of, reducing the risk of developing dermal fibrosis in a subject, or suppressing dermal fibrosis in a subject, comprising administering a compound of the invention to a subject suffering from dermal fibrosis, provided that the dermal fibrosis in the subject is effectively treated, inhibited, reduced, reduced, or suppressed. In some embodiments, dermal fibrosis is scleroderma. In some embodiments, dermal fibrosis is the result of localized or generalized scleroderma, keloids, hypertrophic scars, familial skin collagenoma, collagenous connective tissue nevi, or any combination thereof; each represents 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. In some embodiments, the compound is compound 100.

[0202] 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 a subject suffering from scleroderma, provided that the subject's scleroderma is effectively treated, inhibited, reduced, reduced, or suppressed. 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 compound 100.

[0203] 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 of 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 a collagen I, II, II, IV, or V translation inhibitor; each represents a separate embodiment of the invention. In some embodiments, the compound is selective for collagen I, II, II, IV, or V; each represents a separate embodiment of the invention. In some embodiments, the compound is selective for collagen I. In some embodiments, the compound is selective for collagen IA. In some embodiments, the compound is selective for collagen IA1. In some embodiments, the compound is selective for collagen IA1. 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 compound 100.

[0204] 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 disorder in a subject, or inhibiting an autoimmune disease or disorder in a subject, the method comprising administering a compound of the invention to a subject suffering from an autoimmune disease or disorder, provided that the subject's autoimmune disease or disorder is effectively treated, suppressed, reduced in severity, reduced in the risk of developing, or 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 of the invention. In some embodiments, the compound is compound 100.

[0205] As used herein, subject or patient refers to any mammalian patient, including but not limited to humans and other primates, dogs, cats, horses, cattle, sheep, pigs, rats, mice, and other rodents. In many embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, although the methods described herein may be used to treat either males or females.

[0206] The following embodiments are presented to illustrate preferred embodiments of the invention more fully. However, they should not in any way be construed as limiting the broad scope of the invention.

[0207] Example General Principles The cellular efficacy of all compounds in inhibiting the translation of collagen 1 (COL1) protein was analyzed using a phenotypic screening platform.

[0208] Example 1 Synthetic details of compounds 100-118 (Scheme 1-Scheme 20) General methods 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 (0.25 mm thick). Recordings were made on a Bruker Avance 400MHz or Avance III 400MHz spectrometer. 1 H-NMR and 19F-NMR spectra. Residual solvent was used as an internal standard, and chemical shifts are expressed in ppm. The splitting mode was specified as s (single peak) d (double peak) dd (The twin peaks of the twin peaks) t (Triple Peak) dt (The twin peaks of the triple peak) q (Quadruple peak), m (multiple peak) and br s (Broad single peak). intermediate preparation 5-Fluoro- N -(4-(2-(((tetrahydro- 2H Synthesis of pyridine amide (-pyran-4-yl)oxy)methyl)pyridin-3-yl)thiazo-2-yl)pyridine amide Option 1. 5-Fluoro-N-(4-(2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)pyridin-3-yl)thiazolyl-2- pyridine amide Synthesis (3-bromopyridin-2-yl)methylmethanesulfonate Synthesis At 0 °C for 10 min, methanesulfonic anhydride (100.00 g, 0.57 mol) was added dropwise to a stirred solution of (3-bromopyridin-2-yl)methanol (100.00 g, 0.53 mol) and DIPEA (100.00 g, 0.77 mol) in DCM (1000 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for an additional 1 h. After the reaction was complete, the resulting mixture was quenched with a saturated aqueous solution of NaHCO3 (1000 mL). The resulting mixture was extracted with CH2Cl2 (3 × 2000 mL). The combined organic layers were washed with brine (1 × 2000 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 120.00 g of crude (3-bromopyridin-2-yl)methylmethanesulfonate as a purple solid.

[0209] Yield 120.00 g. m / z: [ESI] + 266, 268 (M + H) + .

[0210] 3-Bromo-2-(((Tetrahydro- 2H -pyran-4-yl)oxy)methyl)pyridine Synthesis NaH (30.00 g, 0.75 mmol, 60%) was added dropwise to a stirred solution of oxacyclohexane-4-ol (69.00 g, 0.68 mol) in 1000 mL of THF at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at 0 °C under a nitrogen atmosphere for another 0.5 h. Then, (3-bromopyridin-2-yl)methyl methanesulfonate (120.00 g, crude) was added dropwise in 500 mL of THF at 0 °C over 15 min. The resulting mixture was allowed to be stirred at room temperature for another 1 h. After the reaction was complete, the reaction was quenched at 0 °C with 2000 mL of saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 2000 mL). The combined organic layers were washed with brine (1 × 2000 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 85.00 g of crude 3-bromo-2-[(oxacyclohexane-4-yloxy)methyl]pyridine as a brown oil.

[0211] Yield 85.00 g. m / z: [ESI] + 272,274 (M + H) + .

[0212] 3-(1-ethoxyvinyl)-2-(((tetrahydro- 2H -pyran-4-yl)oxy)methyl)pyridine Synthesis Pd(PPh3)2Cl2 (20.00 g, 0.03 mol) was added in portions to a stirred solution of 3-bromo-2-[(oxecyclohexane-4-yloxy)methyl]pyridine (85.00 g, crude) and tributyl(1-ethoxyvinyl)stanane (140.00 g, 0.38 mol) in dioxane (1000 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for an additional 2 h. After the reaction was complete, the mixture was allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was used directly in the next step without further purification.

[0213] Use directly. m / z: [ESI + 264 (M + H) + .

[0214] Synthesis of 2-bromo-1-(2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)pyridin-3-yl)acet-1-one NBS (55.00 g, 0.31 mol) was added in portions over 5 min at 0 °C to a stirred solution of 3-(1-ethoxyvinyl)-2-[(oxacyclohexane-4-yloxy)methyl]pyridine (the crude product from the previous step) in dioxane (1000 mL) and water (20 mL). The resulting mixture was allowed to be stirred at room temperature under nitrogen atmosphere for an additional 30 min. After the reaction was complete, the reaction mixture was washed with brine (3 × 800 mL) and the organic layer was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide 2-bromo-1-(2-(((tetrahydro- 2H Crude product of pyran-4-yl)oxy)methyl)pyridin-3-yl)ethyl-1-one.

[0215] m / z: [ESI] + 332 (M + H + 18) + .

[0216] 4-(2-(((tetrahydro- 2H -pyran-4-yl)oxy)methyl)pyridin-3-yl)thiazolyl-2-amine Synthesis Thiourea (20.00 g, 0.26 mol) was added in portions to a stirred solution of 2-bromo-1-{2-[(oxecyclohexane-4-yloxy)methyl]pyridin-3-yl} ethyl ketone (the crude product from the previous step) in dioxane (600 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 h. After the reaction was complete, the mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (1000 mL) and alkalized to pH 9 with saturated NaOH (aqueous solution). The resulting mixture was extracted with EtOAc (5 × 2000 mL). The combined organic layers were washed with brine (1 × 2000 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide 60 g of crude 4-{2-[(oxacyclohexane-4-yloxy)methyl]pyridin-3-yl}-1,3-thiazolyl-2-amine as a yellow solid.

[0217] Yield: 60.00 g (70% purity). m / z: [ESI] + 292 (M + H) + .

[0218] 5-Fluoro- N -(4-(2-(((tetrahydro- 2H Synthesis of pyridine amide (-pyran-4-yl)oxy)methyl)pyridin-3-yl)thiazo-2-yl)pyridine amide T3P (250.00 g, 0.39 mol, 50%) was added dropwise to a stirred solution of 4-{2-[(oxacyclohexane-4-yloxy)methyl]pyridin-3-yl}-1,3-thiazolyl-2-amine (60.00 g, crude) and 5-fluoropyridin-2-carboxylic acid (30.00 g, 0.21 mol) in EtOAc (500 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 h. After the reaction was complete, the mixture was allowed to cool to room temperature. The resulting mixture was quenched with saturated NaHCO3 (aqueous solution) (1000 mL). The resulting mixture was extracted with EtOAc (5 × 2000 mL). The combined organic layers were washed with brine (1 × 2000 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1%–50% ethyl acetate in petroleum ether and concentrated under reduced pressure to provide 28.00 g of 5-fluoro-N-(4-{2-[(oxacyclohexane-4-yloxy)methyl]pyridin-3-yl}-1,3-thiazo-2-yl)pyridin-2-carboxamide as a yellow solid.

[0219] Yield 28.00 g (13% after six steps). 1 H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 2.8 Hz, 1H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H), 8.29 (dd, J = 8.8, 4.4 Hz, 1H), 8.12 -7.99 (m, 2H), 7.65 (s, 1H), 7.47 (dd, J = 8.0, 4.8 Hz, 1H), 4.79 (s, 2H), 4.03 (q, J = 7.2 Hz, 1H), 3.73 (dt, J = 11.6, 4.2 Hz, 2H), 3.32 (s, 2H), 1.99(s, 2H), 1.78 (dd, J = 13.0, 3.4 Hz, 2H). m / z:[ESI + 415 (M + H) + .

[0220] Final compound 5-(4-acetylpiperazin-1-yl)- N-(4-(2-(((tetrahydro- 2H Synthesis of pyran-4-yl)oxy)methyl)pyridin-3-yl)thiazo-2-yl)pyridineamide (compound 100) Option 2. 5-(4-acetylpiperazin-1-yl)-N-(4-(2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl) Pyridine-3-yl)thiazolyl)pyridineamide Synthesis of (Compound 100) At room temperature under a nitrogen atmosphere, to 5-fluoro- N -(4-{2-[(oxacyclohexane-4-yloxy)methyl]pyridin-3-yl}-1,3-thiazo-2-yl)pyridine-2-carboxamide (28.00 g, 0.08 mol) was added in portions to a stirred solution in DMSO (150 mL) with 1-(piperazin-1-yl)acetone (28.00 g, 0.22 mol). The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 1 h. After the reaction was complete, the mixture was allowed to cool to room temperature. 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: 30% B – 50% B over 20 min; detector: 254 nm. The fraction containing the desired product was collected and concentrated under reduced pressure. The residue was washed with EtOH (3 × 100 mL). The resulting solid was collected and dried under vacuum to provide 19.93 g of 5-(4-acetylpiperazin-1-yl)-N-(4-{2-[(oxacyclohexane-4-yloxy)methyl]pyridin-3-yl}-1,3-thiazo-2-yl)pyridin-2-carboxamide as an off-white solid.

[0221] Yield: 19.93 g (56%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.62 (s, 1H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H), 8.41 (d, J = 2.8 Hz, 1H), 8.09 (dd, J = 7.8, 1.6 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.60 (s, 1H), 7.48 (ddd, J = 14.0, 8.4, 3.6Hz, 2H), 4.78 (s, 2H), 3.73 (dt,J = 11.8, 4.2 Hz, 2H), 3.66 - 3.55 (m, 5H), 3.47 (dt, J = 26.8, 5.6 Hz, 4H), 3.33 - 3.22 (m, 2H), 2.06 (s, 3H), 1.85 -1.74 (m, 2H), 1.37 - 1.34 (m, 2H). m / z:[ESI + 523 (M + H) + , (C 26 H 30 N6O4S). Option 3. 5-(4-formylpiperazin-1-yl)-N-(4-(2-((prop-2-yn-1-yloxy)methyl)phenyl)thia Synthesis of (2-yl)pyridine amide (compound 101) Synthesis of 2-(((2-bromobenzyl)oxy)methyl)-1,3-dioxane NaH (4.28 g, 106.932 mmol, 60%) was added fractionally to a stirred solution of 2-bromobenzyl alcohol (10.00 g, 53.466 mmol) in DMF (25 mL, 323.039 mmol) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 30 min. At 0 °C, 2-(bromomethyl)-1,3-dioxane (13.39 g, 80.199 mmol) was added to the mixture. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 days. The reaction was quenched at 0 °C with saturated NH4Cl (aqueous solution). The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (3 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography: column: silica-CS column 330 g; mobile phase A: PE, mobile phase B: EA; flow rate: 100 mL / min; gradient: 0% B to 25% B over 40 min; 254 nm / 280 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to provide 2-{[(2-bromophenyl)methoxy]methyl}-1,3-dioxane as a yellow solid.

[0222] Yield: 6.00 g (41%). 1 H NMR (400 MHz, CDCl3) δ 7.60 - 7.51 (m, 2H), 7.37 -7.31 (m, 1H), 7.20 -7.14 (m, 1H), 5.16 (t,J = 4.0 Hz, 1H), 4.70 (s, 2H), 4.07 - 4.02 (m, 2H), 3.96 - 3.92 (m, 2H), 3.67 (d, J = 4.0 Hz, 2H). m / z: [ESI + ]273 (M + H) + .

[0223] Synthesis of 2-(((2-(1-ethoxyvinyl)benzyl)oxy)methyl)-1,3-dioxane Pd(PPh3)2Cl2 (1.28 g, 1.831 mmol) was added to a stirred solution of 2-{[(2-bromophenyl)methoxy]methyl}-1,3-dioxane (5.00 g, 18.307 mmol) and tributyl(1-ethoxyvinyl)stanane (7.93 g, 21.968 mmol) in 1,4-dioxane (50 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography: column: silica-CS column 330 g; mobile phase A: PE, mobile phase B: EA; flow rate: 100 mL / min; gradient: 0% B to 25% B over 40 min; 254 nm / 280 nm. The fraction containing the desired product was collected and concentrated under reduced pressure to provide 2-({[2-(1-ethoxyvinyl)phenyl]methoxy}methyl)-1,3-dioxane as a pale yellow solid.

[0224] Yield: 4.30 g (88%). 1 H NMR (400 MHz, CDCl3) δ 7.78 - 7.73 (m, 2H), 7.56 -7.52 (m, 1H), 7.39 - 7.33 (m, 1H), 5.13 (t, J = 4.0 Hz, 1H), 4.73 (s, 2H), 4.34 - 4.32 (m, 1H), 4.27 - 4.25 (m, 1H), 4.03 (q, J = 7.2 Hz, 2H), 3.95 -3.87 (m, 4H), 3.57 (d, J = 4.0 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). m / z: [ESI + 265 (M + H) + .

[0225] Synthesis of 1-(2-(((1,3-dioxacyclopentan-2-yl)methoxy)methyl)phenyl)-2-bromoethyl-1-one NBS (3.48 g, 19.545 mmol) was added to a stirred solution of 2-({[2-(1-ethoxyvinyl)phenyl]methoxy}methyl)-1,3-dioxacyclopentane (4.30 g, 16.288 mmol) in THF (150 mL) and H₂O (9 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (150 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide 2-bromo-1-{2-[(1,3-dioxacyclopentan-2-ylmethoxy)methyl]phenyl}ethyl ketone as a brown oil.

[0226] Yield: 3.99 g (78%). 1 H NMR (400 MHz, CDCl3) δ 7.74 - 7.65 (m, 2H), 7.61 -7.45 (m, 2H), 5.15 (t, J = 4.0 Hz, 1H), 4.87 (s, 2H), 4.50 (s, 2H), 4.08 -3.97 (m, 2H), 3.96 - 3.88 (m, 2H), 3.65 (d, J = 4.0 Hz, 2H). m / z: [ESI + 315 (M+H) + .

[0227] Synthesis of 4-(2-(((1,3-dioxacyclopentan-2-yl)methoxy)methyl)phenyl)thiazol-2-amine Thiourea (944 mg, 12.220 mmol) was added to a stirred solution of 2-bromo-1-{2-[(1,3-dioxolane-2-ylmethoxy)methyl]phenyl}acetone (3.99 g, 12.420 mmol) in EtOH (600 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 30 min. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography: column: silica-CS column 330 g; mobile phase A: PE, mobile phase B: EA; flow rate: 100 mL / min; gradient: 0% B to 25% B over 40 min; 254 nm / 280 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to provide 4-{2-[(1,3-dioxolane-2-ylmethoxy)methyl]phenyl}-1,3-thiazolyl-2-amine as a pale yellow solid.

[0228] Yield: 1.20 g (32%). 1 H NMR (400 MHz, DMSO- d 6) δ 7.63 - 7.58 (m, 1H), 7.50- 7.45 (m, 1H), 7.35 - 7.30 (m, 2H), 6.99 (s, 2H), 6.74 (s, 1H), 5.00 (t, J =4.0 Hz, 1H), 4.66 (s, 2H), 3.93 - 3.87 (m, 2H), 3.86 - 3.77 (m, 2H), 3.49 (d, J = 4.0 Hz, 2H). m / z: [ESI + 293 (M + H) + .

[0229] N-(4-(2-(((1,3-dioxacyclopentan-2-yl)methoxy)methyl)phenyl)thiazo-2-yl)-5-fluoropyridine Synthesis of amides T3P (3265 mg, 10.261 mmol) and TEA (1038 mg, 10.258 mmol) were added to a stirred solution of 4-{2-[(1,3-dioxolane-2-ylmethoxy)methyl]phenyl}-1,3-thiazolyl-2-amine (1.00 g, 3.421 mmol) and 5-fluoropyridine-2-carboxylic acid (579 mg, 4.103 mmol) in EA (10 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (10 mL) and 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: C18 column, 120 g; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 80 mL / min; gradient: 30% B to 50% B over 20 min; detector: UV 254 nm / 220 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to provide a brown solid. N -(4-{2-[(1,3-dioxacyclopentan-2-ylmethoxy)methyl]phenyl}-1,3-thiazolyl)-5-fluoropyridine-2-carboxamide.

[0230] Yield: 1.02 g (71%). 1 H NMR (400 MHz, CDCl3) δ 8.55 - 8.51 (m, 1H), 8.40 -8.36 (m, 1H), 7.73 - 7.63 (m, 2H), 7.58 - 7.54 (m, 1H), 7.44 - 7.38 (m, 2H), 7.37 (s, 1H), 5.12 (t, J = 4.0 Hz, 1H), 4.74 (s, 2H), 4.04 - 4.00 (m, 2H), 3.95 - 3.91 (m, 2H), 3.62 (d, J = 4.0 Hz, 2H). m / z: [ESI + 416 (M+H) + .

[0231] N-(4-(2-(((1,3-dioxacyclopentan-2-yl)methoxy)methyl)phenyl)thiazo-2-yl)-5-(4-ethyl) Synthesis of acylpiperazine-1-yl)pyridine amide At room temperature under a nitrogen atmosphere, to N-(4-{2-[(1,3-dioxacyclopentan-2-ylmethoxy)methyl]phenyl}-1,3-thiazo-2-yl)-5-fluoropyridine-2-carboxamide (2.00 g, 4.814 mmol) and 1-(piperazin-1-yl)acetone (1.23 g, 9.628 mmol) were added to a stirred solution of DMSO (20 mL) with TEA (974 mg, 9.625 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. The mixture was allowed to cool to room temperature. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C18 column 330 g; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 100 mL / min; gradient: 30% B to 50% B over 20 min; 254 nm / 220 nm. The fraction containing the desired product was collected and concentrated under reduced pressure to provide 5-(4-acetylpiperazin-1-yl)- as a brown solid. N -(4-{2-[(1,3-dioxacyclopentan-2-ylmethoxy)methyl]phenyl}-1,3-thiazolyl)pyridine-2-carboxamide.

[0232] Yield 400 mg (54%). ¹H-NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 8.17 (d, 1H). J =8.8 Hz, 1H), 7.73 - 7.68 (m, 1H), 7.58 - 7.53 (m, 1H), 7.40 - 7.36 (m, 2H),7.29 (s, 1H), 7.27 (d, J = 8.8 Hz, 1H), 5.11 (t, J = 4.0 Hz, 1H), 4.74 (s,2H), 4.01 - 3.98 (m, 2H), 3.93 - 3.90 (m, 2H), 3.86 - 3.82 (m, 2H), 3.72 -3.67 (m, 2H), 3.60 (d, J = 4.0 Hz, 2H), 3.46 - 3.42 (m, 4H), 2.17 (s, 3H). m / z:[ESI + 390 (M + H) + .

[0233] 5-(4-acetylpiperazin-1-yl)-N-(4-(2-((2,2-dihydroxyethoxy)methyl)phenyl)thiazolyl-2-yl) Synthesis of pyridine amide At room temperature under a nitrogen atmosphere, the 5-(4-acetylpiperazin-1-yl)-N -(4-{2-[(1,3-dioxacyclopentan-2-ylmethoxy)methyl]phenyl}-1,3-thiazo-2-yl)pyridine-2-carboxamide (400 mg, 0.764 mmol) was added to a stirred solution in THF (4 mL, 3.056 mmol) with HCl (4.00 mL, 12.002 mmol). The resulting mixture was stirred at 40 °C under a nitrogen atmosphere for 3 h. The mixture was allowed to cool to room temperature. The mixture was alkalized to pH = 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography: column: 80 g silica-CS column; mobile phase A: PE, mobile phase B: EA; flow rate: 40 mL / min; gradient: 35% B to 55% B over 20 min; 254 nm / 280 nm, to provide 5-(4-acetylpiperazin-1-yl)- as a grayish-white solid. N -(4-{2-[(2,2-dihydroxyethoxy)methyl]phenyl}-1,3-thiazolyl)pyridine-2-carboxamide.

[0234] Yield: 210 mg (55%). 1 H NMR (400 MHz, DMSO- d 6) δ 9.75 (s, 1H), 8.43 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.76 - 7.66 (m, 1H), 7.61 - 7.48 (m, 2H), 7.45- 7.33 (m, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.20 (s, 1H), 4.66 (s, 2H), 3.69 -3.57 (m, 4H), 3.56 - 3.48 (m, 2H), 3.48 - 3.42 (m, 2H), 3.26 (s, 2H), 2.07(s, 3H). m / z:[ESI + 498 (M + H) + .

[0235] 5-(4-formylpiperazin-1-yl)-N-(4-(2-((prop-2-yn-1-yloxy)methyl)phenyl)thiazolyl-2-yl) Synthesis of pyridine amide (compound 101) At room temperature under a nitrogen atmosphere, the 5-(4-acetylpiperazin-1-yl)- N K₂CO₃ (173 mg, 1.252 mmol) was added to a stirred solution of 4-{2-[(2-oxoethoxy)methyl]phenyl}-1,3-thiazolyl-2-yl)pyridine-2-carboxamide (200 mg, 0.417 mmol) and its Saiferth-Gilbert homologue (240 mg, 1.249 mmol) in MeOH (5 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. The resulting mixture was then concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 42% B to 52% B over 8 min; wavelength: 254 nm) to provide 5-(4-acetylpiperazin-1-yl)- as a grayish-white solid. N -(4-{2-[(prop-2-yn-1-yloxy)methyl]phenyl}-1,3-thiazolyl-2-yl)pyridine-2-carboxamide.

[0236] Yield 30 mg (15%). 1 H NMR (400 MHz, DMSO- d 6) δ 8.44 (s, 1H), 8.03 (d, J =8.8 Hz, 1H), 7.73 - 7.66 (m, 1H), 7.55 - 7.48 (m, 2H), 7.45 - 7.37 (m, 1H),7.40 (d, J = 8.8 Hz, 1H), 7.37 (s, 1H), 4.75 (s, 2H), 4.22 (d, J = 2.4 Hz,2H), 3.63 -3.60 (m, 4H), 3.54 - 3.50 (m, 2H), 3.47 - 3.42 (m, 2H), 3.33 (t, J = 2.4 Hz, 1H), 2.07 (s, 3H). m / z:[ESI + 476 (M + H) + .

[0237] Experimental Procedure (Compound 118) Option 4. 5-(4-(methylsulfonyl)piperazin-1-yl)-N-(4-(2-((prop-2-yn-1-yloxy)methyl)benzene) Synthesis of 2-(2-)thiazolyl)pyridine amide (compound 118) N-(4-(2-(((1,3-dioxacyclopentan-2-yl)methoxy)methyl)phenyl)thiazo-2-yl)-5-(4-(methyl) Synthesis of (sulfonyl)piperazine-1-yl)pyridine amide At room temperature, towards N -(4-(2-(((1,3-dioxacyclopentan-2-yl)methoxy)methyl)phenyl)thiazo-2-yl)-5-fluoropyridineamide (750 mg, 1.805 mmol) was added in portions to a stirred solution in DMSO (5 mL) with 1-(methanesulfonyl)piperazine (900 mg, 5.480 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was poured into 30 mL of water. The precipitated solid was collected by filtration and washed with water (3 × 10 mL). This produced a yellow solid. N -(4-(2-(((1,3-dioxacyclopentan-2-yl)methoxy)methyl)phenyl)thiazo-2-yl)-5-(4-(methylsulfonyl)piperazin-1-yl)pyridineamide.

[0238] Yield: 500 mg (49%). 1 HNMR (400 MHz, CDCl3) δ 11.21 (s, 1H), 8.32 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.80 - 7.68 (m, 1H), 7.58 - 7.54 (m, 1H), 7.48 -7.36 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.28 (s, 1H), 5.12 (t, J = 4.0 Hz,1H), 4.74 (s, 2H), 4.08 - 3.84 (m, 4H), 3.62 (d, J = 4.0 Hz, 2H), 3.56 - 3.52 (m, 4H), 3.47 - 3.43 (m, 4H), 2.88 (s, 3H). m / z:[ESI + 560 (M + H) + .

[0239] 5-(4-(methylsulfonyl)piperazin-1-yl)-N-(4-(2-((2-oxoethoxy)methyl)phenyl)thiazole-2- Synthesis of pyridine amide At room temperature, to N-(4-(2-(((1,3-dioxacyclopentan-2-yl)methoxy)methyl)phenyl)thiazo-2-yl)-5-(4-(methanesulfonyl)piperazin-1-yl)pyridine amide (500 mg, 0.893 mmol) was added dropwise to a stirred mixture in THF (10 mL) with HCl (6 M) (10 mL). The resulting mixture was stirred at 40 °C under a nitrogen atmosphere for 16 h. The mixture was allowed to cool to room temperature. The mixture was alkalized to pH = 10 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 5-(4-(methanesulfonyl)piperazin-1-yl)- as a yellow solid. N -(4-(2-((2-oxoethoxy)methyl)phenyl)thiazolyl-2-yl)pyridineamide.

[0240] Yield 250 mg (54%). 1 HNMR (400 MHz, CDCl3) δ 11.03 (s, 1H), 9.75 (s, 1H), 8.32 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.77 - 7.65 (m, 1H), 7.63 - 7.53 (m,1H), 7.47 - 7.39 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.22 (s, 1H), 4.84 (s,2H), 4.16 (s, 2H), 3.56 - 3.52 (m, 4H), 3.48 - 3.44 (m, 4H), 2.86 (s, 3H). m / z:[ESI + 560 (M + H) + .

[0241] 5-(4-(methylsulfonyl)piperazin-1-yl)-N-(4-(2-((prop-2-yn-1-yloxy)methyl)phenyl)thia Synthesis of (2-yl)pyridine amide (compound 118) At room temperature, towards 5-(4-methanesulfonylpiperazin-1-yl)- NK₂CO₃ (200 mg, 1.447 mmol) was added in portions to a stirred solution of 4-{2-[(2-oxoethoxy)methyl]phenyl}-1,3-thiazolyl-2-yl)pyridine-2-carboxamide (250 mg, 0.485 mmol) and its Saiferth-Gilbert homologue (300 mg, 1.562 mmol) in MeOH (10 mL). The resulting mixture was stirred at 40 °C under a nitrogen atmosphere for 16 h. The mixture was allowed to cool to room temperature. The mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: Xselect CSH C18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 52% B to 62% B over 10 min; wavelength: 254 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to provide 5-(4-methanesulfonylpiperazin-1-yl)- as a white solid. N -(4-{2-[(prop-2-yn-1-yloxy)methyl]phenyl}-1,3-thiazolyl-2-yl)pyridine-2-carboxamide.

[0242] Yield 40 mg (16%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.52 (s, 1H), 8.47 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.76 - 7.64 (m, 1H), 7.58 - 7.49 (m, 2H), 7.45- 7.32 (m, 2H), 7.30 (d, J = 8.8 Hz, 1H), 4.75 (s, 2H), 4.22 (d, J = 2.4 Hz,2H), 3.61 - 3.57 (m, 4H), 3.45 (t, J = 2.4 Hz, 1H), 3.30 - 3.26 (m, 4H), 2.95 (s, 3H). m / z:[ESI + 512 (M + H) + .

[0243] Experimental Procedure (Compound 102) Option 5. 5-(4-acetylpiperazin-1-yl)-N-(4-(2-((2-methoxyethoxy)methyl)phenyl)thiazole- 2-yl)pyridine amide Synthesis of (Compound 102) Synthesis of 1-bromo-2-((2-methoxyethoxy)methyl)benzene NaH (1.05 g, 60%) was added dropwise to a stirred solution of 2-methoxyethanol (1.00 g, 13.141 mmol) in DMF (10 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 30 min. 1-Bromo-2-(bromomethyl)benzene (4.93 g, 19.725 mmol) was added dropwise to the mixture at 0 °C over 5 min. The resulting mixture was stirred at room temperature for another 16 h. The reaction was quenched at room temperature with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography: column: silica-CS column 80 g; mobile phase A: PE, mobile phase B: EA; flow rate: 60 mL / min; gradient: 0% B to 25% B over 20 min; 254 nm / 280 nm, to provide 1-bromo-2-[(2-methoxyethoxy)methyl]benzene as a white oil.

[0244] Yield: 1.20 g (37%). 1 H NMR (400 MHz, CDCl3) δ 7.55 - 7.49 (m, 2H), 7.33 -7.30 (m, 1H), 7.17 - 7.10 (m, 1H), 4.64 (s, 2H), 3.71 (t, J = 6.0 Hz, 2H), 3.62 (t, J = 6.0 Hz, 2H), 3.42 (s, 3H). m / z:[ESI + 245 (M + H) + .

[0245] Synthesis of 1-(1-ethoxyvinyl)-2-((2-methoxyethoxy)methyl)benzene Pd(PPh3)2Cl2 (340 mg, 0.490 mmol) was added to a stirred solution of 1-bromo-2-[(2-methoxyethoxy)methyl]benzene (1.20 g, 4.896 mmol) and tributyl(1-ethoxyvinyl)stanane (2.12 g, 5.875 mmol) in 1,4-dioxane (15 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The mixture was alkalized to pH = 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0246] 1 H NMR (400 MHz, CDCl3) δ 7.58 - 7.45 (m, 2H), 7.39 - 7.32 (m, 2H), 4.69 (s, 2H), 4.32 (d, J = 2.0 Hz, 1H), 4.26 (d, J = 2.0 Hz, 1H), 3.90 (q, J = 7.2 Hz, 2H), 3.63 (t, J = 6.0 Hz, 2H), 3.60 (t, J = 6.0 Hz, 2H), 3.42 (s,3H), 1.13 (t, J = 7.2 Hz, 3H). m / z: [ESI + 237 (M + H) + .

[0247] Synthesis of 2-bromo-1-(2-((2-methoxyethoxy)methyl)phenyl)ethyl-1-one NBS (644 mg, 3.618 mmol) was added in portions to a stirred solution of 1-(1-ethoxyvinyl)-2-[(2-methoxyethoxy)methyl]benzene (950 mg, 4.020 mmol) in THF (10 mL) and H₂O (0.5 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. The mixture was then concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0248] 1H NMR (400 MHz, CDCl3) δ 7.69 - 7.64 (m, 2H), 7.59 - 7.51 (m, 2H), 4.82 (s, 2H), 4.50 (s, 2H), 3.69 (t, J = 6.0 Hz, 2H), 3.61 (t, J = 6.0 Hz, 2H), 3.42 (s, 3H). m / z:[ESI + 287 (M + H) + .

[0249] Synthesis of 4-(2-((2-methoxyethoxy)methyl)phenyl)thiazole-2-amine Thiourea (254 mg, 3.337 mmol) was added to a stirred solution of 2-bromo-1-{2-[(2-methoxyethoxy)methyl]phenyl}ethyl ketone (800 mg, 2.786 mmol) in EtOH (10 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography: column: silica-CS column 80 g; mobile phase A: PE, mobile phase B: EA; flow rate: 60 mL / min; gradient: 30% B to 45% B over 20 min; 254 nm / 280 nm, to provide 4-{2-[(2-methoxyethoxy)methyl]phenyl}-1,3-thiazol-2-amine as a yellow oil.

[0250] Yield: 526 mg (71%). 1 H NMR (400 MHz, CDCl3) δ 7.66 - 7.62 (m, 1H), 7.53 -7.49 (m, 1H), 7.37 - 7.32 (m, 2H), 6.80 (s, 1H), 5.40 (s, 2H), 4.66 (s, 2H), 3.66 (d, J = 6.0 Hz, 2H), 3.58 (d, J = 6.0 Hz, 2H), 3.40 (s, 3H). m / z:[ESI + 265 (M + H) + .

[0251] Synthesis of 5-fluoro-N-(4-(2-((2-methoxyethoxy)methyl)phenyl)thiazo-2-yl)pyridine amide T3P (722 mg, 2.269 mmol) was added to a stirred solution of 4-{2-[(2-methoxyethoxy)methyl]phenyl}-1,3-thiazolyl-2-amine (200 mg, 0.757 mmol) and 5-fluoropyridine-2-carboxylic acid (128 mg, 0.907 mmol) in EA (5 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0252] 1 H NMR (400 MHz, CDCl3) δ 8.52 - 8.50 (m, 1H), 8.37 - 8.33 (m, 1H), 7.72 - 7.68 (m, 1H), 7.67 - 7.60 (m, 1H), 7.55 - 7.52 (m, 1H), 7.37 - 7.35(m, 3H), 4.67 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.57 (t, J = 6.0 Hz, 2H), 3.38 (s, 3H). m / z:[ESI + 388 (M + H) + .

[0253] 5-(4-acetylpiperazin-1-yl)-N-(4-(2-((2-methoxyethoxy)methyl)phenyl)thiazolyl-2-yl)pyridine Synthesis of pyridine amide (compound 102) At room temperature under a nitrogen atmosphere, to 5-fluoro- NTEA (118 mg, 1.166 mmol) was added to a stirred solution of 4-{2-[(2-methoxyethoxy)methyl]phenyl}-1,3-thiazolyl-2-yl)pyridine-2-carboxamide (150 mg, 0.387 mmol) and 1-(piperazin-1-yl)acetone (100 mg, 0.780 mmol) in DMSO (3 mL). The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 50% B over 10 min; wavelength: 254 nm) to provide 5-(4-acetylpiperazin-1-yl)- N -(4-{2-[(2-methoxyethoxy)methyl]phenyl}-1,3-thiazolyl)pyridine-2-carboxamide.

[0254] Yield 15 mg (8%). 1 H NMR (400 MHz, DMSO- d 6) δ 8.43 (s, 1H), 8.03 (d, J =8.8 Hz, 1H), 7.74 - 7.67 (m, 1H), 7.58 - 7.48 (m, 2H), 7.46 (s, 1H), 7.44 -7.35 (m, 2H), 4.67 (s, 2H), 3.66 - 3.57 (m, 5H), 3.54 - 3.47 (m, 3H), 3.47 -3.43 (m, 2H), 3.35 - 3.30 (m, 5H), 2.07 (s, 3H). m / z:[ESI + 496 (M + H) + .

[0255] Experimental Procedure (Compound 103) Option 6. 5-(4-acetylpiperazin-1-yl)-N-(4-(2-((2-(methylamino)ethoxy)methyl)phenyl) Synthesis of thiazolyl-2-yl)pyridine amide (compound 103) Synthesis of tert-butyl (2-((2-bromobenzyl)oxy)ethyl(methyl)carbamate At 0°C under a nitrogen atmosphere, to N -(2-hydroxyethyl)- N1-Brominated tert-butyl methylcarbamate (1.40 g, 8.002 mmol) was added in portions to a stirred mixture in DMF (20 mL) with NaH (0.19 g, 8.002 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. 1-Bromo-2-(bromomethyl)benzene (2.00 g, 8.002 mmol) was added in portions to the mixture at room temperature over 5 min. The resulting mixture was stirred at room temperature for another 1 h. The reaction was quenched at 0 °C with saturated NH4Cl (aqueous solution). The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (3 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography: column: 80 g silica-CS column; mobile phase A: DCM, mobile phase B: MeOH; flow rate: 60 mL / min; gradient: 0% B to 10% B over 20 min; 254 nm / 280 nm, to provide a pale yellow oil. N -{2-[(2-bromophenyl)methoxy]ethyl}- N 1-Tert-butyl methylcarbamate.

[0256] Yield (1.50 g 55%). 1 H NMR (400 MHz, CDCl3) δ 8.59 - 8.57 (m, 1H), 8.38 -8.36 (m, 1H), 7.79 - 7.56 (m, 2H), 5.32 (s, 2H), 4.73 (t, J = 6.0 Hz, 2H), 3.63 (t, J = 6.0 Hz, 2H), 3.20 (s, 3H), 1.42 (s, 9H).

[0257] Synthesis of tert-butyl (2-((2-(1-ethoxyvinyl)benzyl)oxy)ethyl)(methyl)carbamate At room temperature under a nitrogen atmosphere, to N -{2-[(2-bromophenyl)methoxy]ethyl}- NPd(PPh3)2Cl2 (0.31 g, 0.436 mmol) was added in portions to a stirred mixture of tert-butyl methylcarbamate (1.50 g, 4.357 mmol) and tributyl(1-ethoxyvinyl)stanane (1.89 g, 5.228 mmol) in dioxane (20 mL). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded a black oil. N -(2-{[2-(1-ethoxyvinyl)phenyl]methoxy}ethyl)- N 1-Tert-butyl methylcarbamate.

[0258] Yield (800 mg, 55%). 1 H NMR (400 MHz, CDCl3) δ 8.59 - 8.57 (m, 1H), 8.38 -8.35 (m, 1H), 7.79 - 7.56 (m, 2H), 5.32 (d, J = 2.0 Hz, 1H), 5.30 (d, J = 2.0Hz, 1H), 4.73 (s, 2H), 3.90 (q, J = 7.2 Hz, 2H), 3.63 (t, J = 6.0 Hz, 2H), 3.60 (t, J = 6.0 Hz, 2H), 3.22 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H).

[0259] Synthesis of tert-butyl (2-((2-(2-bromoacetyl)benzyl)oxy)ethyl)(methyl)carbamate At room temperature under a nitrogen atmosphere, to N -(2-{[2-(1-ethoxyvinyl)phenyl]methoxy}ethyl)- NNBS (637 mg, 3.579 mmol) was added in portions to a stirred mixture of tert-butyl methylcarbamate (800 mg, 2.385 mmol) in THF (10 mL) and H₂O (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (200 mL). The combined organic phases were washed with brine (2 × 100 mL) and dried over Na₂SO₄. The filtrate was concentrated under reduced pressure. The crude product (800 mg) was used directly in the next step without further purification.

[0260] Synthesis of tert-butyl (2-((2-(2-aminothiazo-4-yl)benzyl)oxy)ethyl)(methyl)carbamate Thiourea (158 mg, 4.156 mmol) was added to a stirred solution of (2-((2-(2-bromoacetyl)benzyl)oxy)ethyl)(methyl)carbamate (800 mg, 2.076 mmol) in EtOH (10 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography: column: silica-CS column 80 g; mobile phase A: PE, mobile phase B: EA; flow rate: 60 mL / min; gradient: 30% B to 45% B over 20 min; 254 nm / 280 nm, to provide (2-((2-(2-aminothiazol-4-yl)benzyl)oxy)ethyl)(methyl)carbamate as a yellow oil.

[0261] Yield (400 mg, 53%). 1 H NMR (400 MHz, CDCl3) δ 8.58-8.56 (m, 1H), 8.41-8.37 (m, 1H), 7.80-7.66 (m, 2H), 7.48 (s, 1H), 7.02 (s, 2H), 4.68 (s, 2H), 4.15 (t, J = 7.2 Hz, 2H), 3.65 (t, J = 7.2 Hz, 2H), 2.92 (s, 3H), 1.46 (s, 9H).

[0262] (2-((2-(2-(5-Fluoropyridinylamino)thiazolyl-4-yl)benzyl)oxy)ethyl)(methyl)tert-butyl carbamate Ester Synthesis At room temperature under a nitrogen atmosphere, to N -(2-{[2-(2-amino-1,3-thiazo-4-yl)phenyl]methoxy}ethyl)-N TEA (167 mg, 1.650 mmol) was added dropwise to a stirred mixture of tert-butyl methylcarbamate (200 mg, 0.550 mmol), 5-fluoropyridine-2-carboxylic acid (93 mg, 0.659 mmol), and T3P (525 mg, 1.650 mmol) in EA (5 mL). The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1% to 70% ethyl acetate in petroleum ether to provide a pale yellow oil. N -[2-({2-[2-(5-fluoropyridin-2-acylamino)-1,3-thiazolyl]phenyl}methoxy)ethyl]- N 1-Tert-butyl methylcarbamate.

[0263] Yield (200 mg, 75%). 1 H NMR(400 MHz, CDCl3) δ 8.36 (s, 1H), 8.20-8.16 (m,1H), 7.77-7.73 (m, 2H), 7.58-7.53 (m, 3H), 7.46-7.42 (m, 2H), 4.66 (s, 2H), 3.71 (t, J = 7.2 Hz, 2H), 3.46 (t, J = 7.2 Hz, 2H), 2.92 (s, 3H), 1.46 (s, 9H).

[0264] (2-((2-(2-(5-(4-acetylpiperazin-1-yl)pyridinylamino)thiazolyl-4-yl)benzyl)oxy)ethyl) Synthesis of tert-butyl (methyl)carbamate At room temperature under a nitrogen atmosphere, to N -[2-({2-[2-(5-fluoropyridin-2-acylamino)-1,3-thiazolyl]phenyl}methoxy)ethyl]- N1-(piperazin-1-yl)acetone (263 mg, 2.052 mmol) was added in portions to a stirred mixture of tert-butyl methylcarbamate (200 mg, 0.411 mmol) in DMSO (3 mL). The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The mixture was purified by reversed-phase rapid chromatography under the following conditions: column: Spherical C18, 20–40 μm, 120 g; mobile phase A: water (with 10 mM NH4HCO3); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 60% B to 80% B over 20 min; detector: 254 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to provide a pale yellow solid. N -{2-[(2-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-acylamino]-1,3-thiazolyl-4-yl}phenyl)methoxy]ethyl}- N 1-Tert-butyl methylcarbamate.

[0265] Yield (150 mg, 61%). 1 H NMR(400 MHz, CDCl3) δ 8.36 (s, 1H), 8.20-8.16 (m,1H), 7.77-7.73 (m, 2H), 7.54 (s, 1H), 7.47-7.44 (m, 2H), 4.66 (s, 2H), 3.71(t, J = 7.2 Hz, 2H), 3.55-3.50 (m, 4H), 3.46 (t, J = 7.2 Hz, 2H), 3.42-3.38(m, 4H), 2.92 (s, 3H), 2.13 (s, 3H), 1.46 (s, 9H).

[0266] 5-(4-acetylpiperazin-1-yl)-N-(4-(2-((2-(methylamino)ethoxy)methyl)phenyl)thiazole-2- Synthesis of pyridine amide (compound 103) Will N -{2-[(2-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-acylamino]-1,3-thiazolyl-4-yl}phenyl)methoxy]ethyl}- NA mixture of tert-butyl methylcarbamate (150 mg, 0.252 mmol) and HCl (gas) in 1,4-dioxane (2 mL, 8.000 mmol) in DCM (4 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (3 mL). The mixture was purified by reversed-phase rapid chromatography under the following conditions: column: Spherical C18, 20–40 μm, 120 g; mobile phase A: water (with 10 mM NH4HCO3); mobile phase B: ACN; flow rate: 80 mL / min; gradient: 40% B to 60% B over 20 min; detector: 254 nm. Fractions containing the desired product were collected and concentrated under reduced pressure to provide 5-(4-acetylpiperazin-1-yl)- N -(4-(2-((2-(methylamino)ethoxy)methyl)phenyl)thiazolyl-2-yl)pyridineamide.

[0267] Yield: 39 mg (31%). 1 H NMR (400 MHz, DMSO- d 6) δ 8.43 (s, 1H), 8.05-8.02(m, 1H), 7.74-7.65 (m, 1H), 7.53-7.52 (m, 2H), 7.49-7.29 (m, 3H), 4.62 (s,2H), 3.71 (t, J = 7.2 Hz, 2H), 3.70-3.55 (m, 4H), 3.49-3.45 (m, 4H), 2.67 (t, J = 7.2 Hz, 2H), 2.30 (s, 3H), 2.07 (s, 3H).

[0268] Experimental Procedure ( Compound 104 ) Scheme 7. 5-(4-acetylpiperazin-1-yl)- N -(4-(2-((2-(methylthio)ethoxy)methyl)phenyl)thiazo-2-yl)pyridineamide Compound 104 ) Synthesis Synthesis of (2-((2-bromobenzyl)oxy)ethyl)(methyl)thion At 0 °C, NaH (0.96 g, 40.01 mmol) was added to a solution of 2-(methylthio)ethane-1-ol (5.53 g, 60.01 mmol) in DMF (50 mL). The mixture was stirred for 15 min. 1-Bromo-2-(bromomethyl)benzene (5.00 g, 20.01 mmol) was added, and the mixture was allowed to heat to rt and stirred for 2 h. The reaction was quenched at 0 °C with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (10 / 1) and concentrated under reduced pressure to provide (2-((2-bromobenzyl)oxy)ethyl)(methyl)thione as a colorless oil.

[0269] Yield: 2.00 g (38%). 1 H NMR (400 MHz, CDCl3) δ 7.56-7.54 (m, 2H), 7.34(td, J = 7.6, 1.2 Hz, 1H), 7.17 (td, J = 7.6, 1.2 Hz, 1H), 4.64 (s, 2H), 3.78(t, J = 6.8 Hz, 2H), 2.79 (t, J = 6.8 Hz, 2H), 2.19 (s, 3H). m / z:[ESI + 261,263 (M + H) + .

[0270] Synthesis of (2-((2-(1-ethoxyvinyl)benzyl)oxy)ethyl)(methyl)thion Pd(PPh3)2Cl2 (0.54 g, 0.76 mmol) was added to a stirred mixture of (2-((2-bromobenzyl)oxy)ethyl)(methyl)thion (2.00 g, 7.65 mmol) and tributyl(1-ethoxyvinyl)stanane (4.15 g, 11.48 mmol) in dioxane (20 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The mixture was alkalized to pH 9 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide (2-((2-(1-ethoxyvinyl)benzyl)oxy)ethyl)(methyl)thion as a yellow oil.

[0271] Yield: 1.30 g (67%). 1 H NMR (400 MHz, CDCl3) δ 7.63-7.59 (m, 2H), 7.42-7.40 (m, 1H), 7.21-7.19 (m, 1H), 3.81 (s, 2H), 2.81-2.79 (m, 2H), 2.62 (q, J = 8.0, 2H), 2.18 (t, J = 6.8 Hz, 2H), 1.68 (t, J = 6.8 Hz, 2H), 1.33 (s, 3H), 0.95 (t, J = 7.2 Hz, 3H). m / z: [ESI + 253 (M + H) + .

[0272] Synthesis of 2-bromo-1-(2-((2-(methylthio)ethoxy)methyl)phenyl)ethyl-1-one A mixture of (2-((2-(1-ethoxyvinyl)benzyl)oxy)ethyl(methyl)thione (300 mg, 1.18 mmol) and NBS (190 mg, 1.06 mmol) in THF (3 mL) and H₂O (0.15 mL) was stirred at room temperature under a nitrogen atmosphere for 30 min. The desired product was detectable by LCMS. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide 2-bromo-1-(2-((2-(methylthio)ethoxy)methyl)phenyl)ethyl-1-one as a yellow oil.

[0273] Yield: 120 mg (33%). 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 6.4 Hz, 1H), 7.61 (t, J = 6.8 Hz, 1H), 7.44 (d, J = 6.4 Hz, 1H), 7.34 (t, J = 6.8 Hz, 1H), 4.67 (s, 2H), 3.67 (s, 2H), 2.58 (t, J = 8.0 Hz, 2H), 2.18 (t, J = 8.0 Hz, 2H), 1.69 (s, 3H). m / z:[ESI + 314, 303 (M + H) + .

[0274] Synthesis of 4-(2-((2-(methylthio)ethoxy)methyl)phenyl)thiazole-2-amine A mixture of 2-bromo-1-(2-((2-(methylthio)ethoxy)methyl)phenyl)ethyl-1-one (120 mg, 0.396 mmol) and thiourea (36 mg, 0.473 mmol) in EtOH (2 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1 / 2) and concentrated under reduced pressure to provide 4-(2-((2-(methylthio)ethoxy)methyl)phenyl)thiazol-2-amine as a yellow oil.

[0275] Yield: 90 mg (81%). 1H NMR (400 MHz, DMSO- d 6) δ 7.47-7.66 (m, 4H), 7.06(s, 1H), 7.04 (s, 2H), 4.70 (s, 2H), 3.72 (t, J = 6.8 Hz, 2H), 2.75 (t, J =6.8 Hz, 2H), 2.16 (s, 3H). m / z:[ESI + 281 (M+H) + .

[0276] 5-Fluoro- N Synthesis of 4-(2-((2-(methylthio)ethoxy)methyl)phenyl)thiazo-2-yl)pyridine amide At room temperature, T3P (1021 mg, 3.209 mmol) and TEA (0.5 mL) were added to a stirred solution of 4-(2-((2-(methylthio)ethoxy)methyl)phenylthiazol-2-amine (300 mg, 1.070 mmol) and 5-fluoropyridine-2-carboxylic acid (543 mg, 3.848 mmol) in EtOAc (3 mL). The resulting mixture was stirred at 70 °C for 2 h. The mixture was allowed to cool to room temperature. The desired product could be detected by LCMS. The mixture was alkalized to pH 9 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1 / 1) and concentrated under reduced pressure to provide 5-fluoro- as a pale yellow solid. N -(4-(2-((2-(methylthio)ethoxy)methyl)phenyl)thiazo-2-yl)pyridineamide.

[0277] Yield: 90 mg (21%). 1 H NMR (400 MHz, CDCl3) δ 11.27 (s, 1H), 8.55 (d, J =2.8 Hz, 1H), 8.39 (dd, J = 8.4, 4.4 Hz, 1H), 7.77-7.70 (m, 1H), 7.60-7.38 (m,4H), 7.34 (s, 1H), 4.70 (s, 2H), 3.72 (t, J= 6.8 Hz, 2H), 2.75 (t, J = 6.8Hz, 2H), 2.16 (s, 3H). m / z:[ESI + 404 (M+H) + .

[0278] Final compound 5-(4-acetylpiperazin-1-yl)- N -(4-(2-((2-(methylthio)ethoxy)methyl)phenyl)thiazo-2-yl)pyridineamide Compound 104 ) Synthesis 5-fluoro- N A solution of 4-(2-((2-(methylthio)ethoxy)methyl)phenyl)thiazolyl-2-yl)pyridineamide (90 mg, 0.223 mmol) and 1-(piperazin-1-yl)ethyl-1-one (86 mg, 0.671 mmol) in DMSO (1 mL) was stirred at 120 °C for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (90 mg) was purified by preparative HPLC under the following conditions (column: XBridge preparative phenyl OBD column, 19). 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 47% B to 52% B, 52% B over 8 min; Wavelength: 254 nm; RT1 (min): 7.5; Runs: 0) and concentrated under reduced pressure to provide 5-(4-acetylpiperazin-1-yl)- as a yellow semi-solid. N -[4-(2-{[2-(methylthioalkyl)ethoxy]methyl}phenyl)-1,3-thiazolyl]pyridine-2-carboxamide.

[0279] Yield: 60 mg (53%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.45 (s, 1H), 8.42 (d, J = 2.8 Hz, 1H), 8.03 (d, J= 8.8 Hz, 1H), 7.73-7.64 (m, 1H), 7.57-7.55 (m,1H), 7.52-7.50 (m, 1H), 7.46 (s, 1H), 7.43-7.34 (m, 2H), 4.69 (s, 2H), 3.66-3.62 (m, 6H), 3.51 (d, J = 5.8 Hz, 2H), 3.44 (t, J = 5.2 Hz, 2H), 2.67 (t, J = 6.0 Hz, 2H), 2.06 (s, 3H), 2.04 (s, 3H). m / z: [ESI + 512 (M + H) + .(C 25 H 29 N5O3S2).

[0280] Experimental Procedure ( Compound 105 ) Scheme 8. 5-(4-acetylpiperazin-1-yl)- N -(4-(2-((2-(methylsulfonyl)ethoxy)methyl)phenyl)thiazo-2-yl)pyridineamide Compound 105 Synthesis of Synthesis of 1-bromo-2-((2-(methylsulfonyl)ethoxy)methyl)benzene At 0 °C, NaH (0.38 g, 16.04 mmol) was added to a solution of 2-(methanesulfonyl)ethane-1-ol (1.49 g, 12.01 mmol) in DMF (20 mL). The mixture was stirred for 15 min. 1-Bromo-2-(bromomethyl)benzene (2.00 g, 8.02 mmol) was added, and the mixture was allowed to heat to rt and stirred for 1 h. The mixture was alkalized to pH 8 with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1 / 1) to provide 1-bromo-2-((2-(methanesulfonyl)ethoxy)methyl)benzene as a white oil.

[0281] Yield: 1.40 g (60%). 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 8.0, 1.2 Hz, 1H), 7.43 (dd, J = 7.6, 1.6 Hz, 1H), 7.35 (td, J = 7.6, 1.2 Hz, 1H), 7.21(td, J = 7.6, 1.6 Hz, 1H), 4.66 (s, 2H), 4.06 (t, J = 6.0 Hz, 2H), 3.30 (t, J = 6.0 Hz, 2H), 3.03 (s, 3H). m / z:[ESI + 293, 295 (M + H) + .

[0282] Synthesis of 1-(1-ethoxyvinyl)-2-((2-(methylsulfonyl)ethoxy)methyl)benzene Pd(PPh3)2Cl2 (0.34 g, 0.478 mmol) was added to a stirred mixture of 1-bromo-2-((2-(methanesulfonyl)ethoxy)methyl)benzene (1.40 g, 4.77 mmol) and tributyl(1-ethoxyvinyl)stanane (2.59 g, 7.16 mmol) in dioxane (20 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The mixture was alkalized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (1 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure to provide 1-(1-ethoxyvinyl)-2-((2-(methylsulfonyl)ethoxy)methyl)benzene as a black oil.

[0283] Yield: 1.10 g (81%). 1 H NMR (400 MHz, CDCl3) δ 7.74-7.30 (m, 4H), 4.69 (s,2H), 4.25-4.23 (m, 2H), 3.99-3.93 (m, 4H), 3.01 (t, J = 4.4 Hz, 2H), 3.03 (s,3H), 1.39 (t, J = 2.0 Hz, 3H). m / z: [ESI+ 285 (M + H) + .

[0284] Synthesis of 2-bromo-1-(2-((2-(methylsulfonyl)ethoxy)methyl)phenyl)ethyl-1-one A mixture of 1-(1-ethoxyvinyl)-2-((2-(methanesulfonyl)ethoxy)methyl)benzene (1.10 g, 3.86 mmol) and NBS (0.76 g, 4.25 mmol) in THF (15 mL) and H₂O (3 mL) was stirred at room temperature for 30 min. The desired product was detectable by LCMS. The resulting mixture was extracted with EtOAc (1 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide 2-bromo-1-(2-((2-(methanesulfonyl)ethoxy)methyl)phenyl)ethyl-1-one as a black oil.

[0285] Yield: 900 mg (69%). 1 H NMR (400 MHz, CDCl3) δ 7.79-7.32 (m, 4H), 4.66 (s,2H), 4.14 (s, 2H), 3.46 (t, J = 7.2 Hz, 2H), 2.88 (t, J = 7.2 Hz, 2H), 2.80(s, 3H). m / z:[ESI + 335, 337 (M + H) + .

[0286] Synthesis of 4-(2-((2-(methylsulfonyl)ethoxy)methyl)phenyl)thiazole-2-amine A solution of 2-bromo-1-(2-((2-(methanesulfonyl)ethoxy)methyl)phenyl)ethyl-1-one (900 mg, 2.685 mmol) and thiourea (245 mg, 3.219 mmol) in EtOH (10 mL) was stirred at 80 °C for 2 h. The mixture was allowed to cool to room temperature. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1 / 2) and concentrated under reduced pressure to provide 4-(2-((2-(methanesulfonyl)ethoxy)methyl)phenyl)thiazol-2-amine as a yellow solid.

[0287] Yield: 700 mg (83%). 1H NMR (400 MHz, CDCl3) δ 7.60-7.31 (m, 4H), 6.59 (s,1H), 4.62 (s, 2H), 4.04-3.91 (m, 2H), 3.30-3.23 (m, 2H), 3.03 (s, 3H). m / z:[ESI + 313 (M + H) + .

[0288] 5-Fluoro- N Synthesis of 4-(2-((2-(methylsulfonyl)ethoxy)methyl)phenyl)thiazo-2-yl)pyridine amide At room temperature, T3P (2139 mg, 6.723 mmol) and DIEA (1 mL) were added to a stirred mixture of 4-(2-((2-(methanesulfonyl)ethoxy)methyl)phenyl)thiazol-2-amine (700 mg, 2.241 mmol) and 5-fluoropyridine-2-carboxylic acid (379 mg, 2.686 mmol) in EtOAc (10 mL). The resulting mixture was stirred at 70 °C for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1 / 1) and concentrated under reduced pressure to provide 5-fluoro- N -(4-(2-((2-(methylsulfonyl)ethoxy)methyl)phenyl)thiazo-2-yl)pyridineamide.

[0289] Yield: 300 mg (31%). 1 H NMR (300 MHz, CDCl3) δ 11.21 (s, 1H), 8.60-8.53(m, 1H), 8.39-8.34 (m, 1H), 7.73-7.60 (m, 2H), 7.58-7.47 (m, 1H), 7.47-7.36(m, 2H), 7.16 (s, 1H), 4.75 (s, 2H), 3.99 (t, J = 5.2 Hz, 2H), 3.27 (t, J =5.2 Hz, 2H), 3.03 (s, 3H). m / z:[ESI + 436 (M + H) + .

[0290] Final compound 5-(4-acetylpiperazin-1-yl)- N-(4-(2-((2-(methylsulfonyl)ethoxy)methyl)phenyl)thiazo-2-yl)pyridineamide Compound 105 Synthesis of 5-fluoro- N A solution of 4-(2-((2-(methanesulfonyl)ethoxy)methyl)phenyl)thiazolyl-2-yl)pyridine amide (90 mg, 0.21 mmol) and 1-(piperazin-1-yl)acetone (79 mg, 0.61 mmol) in DMSO (1 mL) was stirred at 120 °C for 2 h. The mixture was allowed to cool to 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, 120 g; mobile phase A: water (with 10 mM NH4HCO3); mobile phase B; flow rate: 80 mL / min; gradient: 40% B to 60% B over 20 min; detector, UV 254 nm. The fraction containing the desired product was collected at 54% B and concentrated under reduced pressure to provide 5-(4-acetylpiperazin-1-yl)- N -(4-(2-((2-(methylsulfonyl)ethoxy)methyl)phenyl)thiazo-2-yl)pyridineamide.

[0291] Yield: 68 mg (61%). 1 H NMR (400 MHz, DMSO) δ 11.64 (s, 1H), 8.43 (d, J =2.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.73-7.67 (m, 1H), 7.61-7.48 (m, 2H), 7.44 (s, 1H), 7.43- 7.32 (m, 2H), 4.75 (s, 2H), 3.86 (t, J = 5.6 Hz, 2H), 3.73-3.58 (m, 4H), 3.57- 3.49 (m, 2H), 3.49-3.39 (m, 4H), 2.95 (s, 3H), 2.07(s, 3H). m / z:[ESI + 544 (M + H) + , (C 25 H 29 N5O5S2).

[0292] Experimental Procedure ( Compound 108 ) Scheme 9. 5-(4-acetylpiperazin-1-yl)- N -(4-(2-((2-methoxyethoxy)methyl)pyridin-3-yl)thiazo-2-yl)pyridineamide (Compound 108) Synthesis of Synthesis of 3-bromo-2-((2-methoxyethoxy)methyl)pyridine Sodium hydride (0.32 g, 7.97 mmol) was added dropwise to a stirred solution of 2-methoxyethyl-1-ol (0.45 g, 5.98 mmol) in DMF (15 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. 3-Bromo-2-(bromomethyl)pyridine (1.00 g, 3.99 mmol) in DMF (5 mL) was added dropwise to the mixture at 0 °C over 1 min. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched at room temperature with saturated NH4Cl (aqueous solution) (50 mL). The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 30% to 50% ethyl acetate in petroleum ether and concentrated under reduced pressure to provide 3-bromo-2-[(2-methoxyethoxy)methyl]pyridine as a yellow oil.

[0293] Yield: 0.27 g (27%). 1 H NMR (300 MHz, CDCl3) δ 8.62 (dd, J = 4.8, 1.6 Hz, 1H), 7.95 (dd, J = 8.0, 1.6 Hz, 1H), 7.20 (dd, J = 8.0, 4.8 Hz, 1H), 4.87 (s,2H), 3.86-3.77 (m, 2H), 3.70-3.61 (m, 2H), 3.41 (s, 3H). m / z:[ESI + 246, 248 (M + H) + .

[0294] Synthesis of 3-(1-ethoxyvinyl)-2-((2-methoxyethoxy)methyl)pyridine At room temperature, bis(triphenylphosphine)palladium dichloride (77 mg, 0.11 mmol) was added in portions to a stirred solution of 2-bromo-3-[(2-methoxyethoxy)methyl]pyridine (0.27 g, 1.10 mmol) and tributyl(1-ethoxyvinyl)stanane (594 mg, 1.65 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at 100 °C for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (1 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide 3-(1-ethoxyvinyl)-2-((2-methoxyethoxy)methyl)pyridine as a brown oil. The crude product mixture was used directly in the next step without further purification.

[0295] Yield: 0.25 g (96%). 1 H NMR (300 MHz, CDCl3) δ 7.74-7.44 (m, 3H), 4.79 (s,2H), 4.42-4.40 (m, 2H), 3.93 (q, J = 7.0 Hz, 2H), 3.71 (dd, J = 6.0, 3.6 Hz,2H), 3.65-3.61 (m, 4H), 3.39 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H). m / z: [ESI + 238(M + H) + .

[0296] Synthesis of 2-bromo-1-(2-((2-methoxyethoxy)methyl)pyridin-3-yl)acet-1-one 3-(1-ethoxyvinyl)-2-((2-methoxyethoxy)methyl)pyridine (270 mg, 1.14 mmol) and N A mixture of 2-bromosuccinimide (243 mg, 1.37 mmol) in THF (20 mL) and H₂O (1 mL) was stirred at room temperature for 1 h. The resulting mixture was extracted with EtOAc (1 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide 2-bromo-1-(2-((2-methoxyethoxy)methyl)pyridin-3-yl)ethyl-1-one as a brown oil.

[0297] Yield: 0.30 g (92%). m / z: [ESI] + 288, 290 (M + H) + .

[0298] Synthesis of 4-(2-((2-methoxyethoxy)methyl)pyridin-3-yl)thiazolyl-2-amine Thiourea (0.53 g, 6.94 mmol) was added to a stirred mixture of 2-bromo-1-(2-((2-methoxyethoxy)methyl)pyridin-3-yl)ethyl-1-one (1 g, 3.47 mmol) in C2H5OH (10 mL) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (1 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by 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: 30% B to 50% B over 20 min; detector: 254 nm. Fractions containing the desired product were collected at 40% B and concentrated under reduced pressure to provide 4-(2-((2-methoxyethoxy)methyl)pyridin-3-yl)thiazolyl-2-amine as a yellow oil.

[0299] Yield: 84 mg (9%). 1 H NMR (300 MHz, CDCl3) δ 8.65-8.60 (m, 1H), 7.85-7.34(m, 3H), 4.90 (s, 2H), 3.68 (dd, J = 5.6, 3.2 Hz, 2H), 3.57 (dd, J = 5.6, 3.2Hz, 2H), 2.61 (s, 3H). m / z:[ESI + 266 (M + H) + .

[0300] 5-Fluoro- N Synthesis of 4-(2-((2-methoxyethoxy)methyl)pyridin-3-yl)thiazo-2-yl)pyridine amide At room temperature, triethylamine (291 mg, 2.88 mmol) and tripropyl-1,3,5,2λ 5,4λ 5,6λ 5-trioxatriphosphazenethanide-2,4,6-trione (1827 mg, 2.87 mmol) were added to a stirred solution of 4-(2-((2-methoxyethoxy)methyl)pyridin-3-yl)thiazolyl-2-amine (254 mg, 0.96 mmol) and 5-fluoropyridinecarboxylic acid (270 mg, 1.91 mmol) in ethyl acetate (2 mL). The resulting mixture was stirred at 120 °C for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (1 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by 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: 30% B – 60% B over 20 min; detector: 254 nm. Fractions containing the desired product were collected at 40% B and concentrated under reduced pressure to provide 5-fluoro- N -(4-(2-((2-methoxyethoxy)methyl)pyridin-3-yl)thiazolyl-2-yl)pyridineamide.

[0301] Yield: 50 mg (13%). 1 H NMR (300 MHz, CDCl3) δ 8.56-8.32 (m, 2H), 7.96 (s,1H), 7.69-7.61 (m, 4H), 4.44 (s, 2H), 3.70-3.62 (m, 4H), 3.41 (s, 3H). m / z:[ESI + 389 (M + H) + .

[0302] Final compound 5-(4-acetylpiperazin-1-yl)- N -(4-(2-((2-methoxyethoxy)methyl)pyridin-3-yl)thiazo-2-yl)pyridineamide (Compound 108) Synthesis of At room temperature, to 5-fluoro- N1-(piperazin-1-yl)acetone (83 mg, 0.65 mmol) was added to a stirred solution of 4-(2-((2-methoxyethoxy)methyl)pyridin-3-yl)thiazolyl-2-yl)pyridineamide (50 mg, 0.13 mmol) in methanesulfinylmethane (3 mL). The resulting mixture was stirred at 120 °C for 2 h. The mixture was allowed to cool to room temperature. The reaction solution was purified by preparative HPLC under the following conditions (column: XSelect CSH Prep C18 OBD column, 19...). 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 33% B to 38% B, 38% B over 8 min; Wavelength: 254 nm; RT1 (min): 9; Runs: 0) and concentrated under reduced pressure to provide 5-(4-acetylpiperazin-1-yl)- as a white solid. N -(4-(2-((2-methoxyethoxy)methyl)pyridin-3-yl)thiazolyl-2-yl)pyridineamide.

[0303] Yield: 30 mg (47%). 1 1H NMR (400 MHz, DMSO- d 6) δ 11.69 (s, 1H), 8.56 (dd, J = 4.8, 1.6 Hz, 1H), 8.43 (d, J = 2.8 Hz, 1H), 8.15 (dd, J = 8.0, 1.6 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.66 (s, 1H), 7.54-7.45 (m, 2H), 4.72 (s, 2H), 3.66-3.59 (m, 6H), 3.51 (t, J = 5.2 Hz, 2H), 3.48-3.42 (m, 4H), 3.23 (s, 3H), 2.07 (s, 3H). m / z:[ESI + 497 (M + H) + .(C 24 H 28 N6O4S).

[0304] Experimental Procedure ( Compound 116 ) Scheme 10. 5-(4-acetylpiperazin-1-yl)-N-(4-(2-((2-(methylamino)ethoxy)methyl)pyridin-3-yl)thiazolyl)pyridineamide (Compound 116) Synthesis Synthesis of tert-butyl (2-((3-bromopyridin-2-yl)methoxy)ethyl)(methyl)carbamate A solution of (3-bromopyridin-2-yl)methanol (1.50 g, 7.97 mmol) in DMF (20 mL) was treated with NaH (0.50 g, 20.82 mmol) at 0 °C for 30 min, followed by fractional addition at 0 °C. N -[2-(methanesulfonyloxy)ethyl]- N 2-((3-bromopyridin-2-yl)methoxy)ethyl(methyl)carbamate tert-butyl ester (3.05 g, 12.04 mmol). The reaction was stirred at room temperature for 16 h. The resulting mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (3 × 40 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1 / 1) and concentrated under reduced pressure to provide (2-((3-bromopyridin-2-yl)methoxy)ethyl(methyl)carbamate tert-butyl ester) as a brown oil.

[0305] Yield: 1.20 g (44%). 1 H NMR (300 MHz, CDCl3) δ 8.57 (d, J = 4.4, 1H), 7.89(d, J = 4.4 Hz, 1H), 7.15 (t, J = 4.8 Hz, 1H), 4.78 (s, 2H), 3.57 (t, J = 8.4Hz, 2H), 3.49 (s, 3H), 3.44 (t, J = 8.4 Hz, 2H), 1.49 (s, 9H). m / z:[ESI + 345(M + H) + .

[0306] Synthesis of tert-butyl (2-((3-(1-ethoxyvinyl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate A mixture of (2-((3-bromopyridin-2-yl)methoxy)ethyl)(methyl)carbamate tert-butyl ester (500 mg, 1.448 mmol), tributyl(1-ethoxyvinyl)stanane (790 mg, 2.187 mmol), and bis(triphenylphosphine)palladium dichloride (150 mg, 0.214 mmol) in 1,4-dioxane (6 mL) was stirred at 120 °C for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (3 × 40 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide (2-((3-(1-ethoxyvinyl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate tert-butyl ester as a brown oil.

[0307] Yield: 400 mg (82%). 1 H NMR (300 MHz, CDCl3) δ 8.59 (d, J = 4.8 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 4.74 (s, 2H), 4.72-4.70(m, 2H), 3.94 (q, J = 7.2 Hz, 2H), 3.78 (t, J = 8.4 Hz, 2H), 2.91 (s, 3H), 2.78 (t, J = 8.4 Hz, 2H), 1.45 (s, 9H), 1.17 (t, J = 4.8 Hz, 3H). m / z: [ESI + 337 (M + H) + .

[0308] Synthesis of tert-butyl (2-((3-(2-bromoacetyl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate A mixture of (2-((3-(1-ethoxyvinyl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate tert-butyl ester (400 mg, 1.189 mmol), NBS (260 mg, 1.461 mmol), and H₂O (0.20 mL) in THF (4 mL) was stirred at room temperature for 2 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide (2-((3-(2-bromoacetyl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate tert-butyl ester as a brown oil.

[0309] Yield: 350 mg (76%). 1 H NMR (300 MHz, CDCl3) δ 8.59 (d, J = 4.8 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 3.46 (s, 2H), 3.01 (s, 2H), 2.79-2.70 (m, 4H), 1.68 (s, 3H), 1.41 (s, 9H). m / z:[ESI + 387 (M + H) + .

[0310] Synthesis of tert-butyl (2-((3-(2-aminothiazolyl-4-yl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate A mixture of (2-((3-(2-bromoacetyl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate tert-butyl ester (350 mg, 0.904 mmol) and thiourea (350 mg, 4.598 mmol) in EtOH (4 mL) was stirred at 80 °C for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN (10 mmol / L NH4HCO3) in water, in a 40% to 60% gradient over 10 min; detector, UV 254 nm. It was then concentrated under reduced pressure to provide (2-((3-(2-aminothiazol-4-yl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate tert-butyl ester as a brown oil.

[0311] Yield 200 mg (61%).1 H NMR (300 MHz, CDCl3) δ 8.59 (d, J = 4.8 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.06 (s, 1H), 6.95 (s, 2H), 4.76 (s, 2H), 3.73-3.45 (m, 4H), 2.89 (s, 3H), 1.45 (s, 9H). m / z:[ESI + 365 (M + H) + .

[0312] Synthesis of tert-butyl (2-((3-(2-(5-fluoropyridinylamino)thiazolyl-4-yl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate A mixture of (2-((3-(2-aminothiazolyl-4-yl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate tert-butyl ester (200 mg, 0.549 mmol), T3P (450 mg, 1.414 mmol), triethylamine (0.3 mL), and 5-fluoropyridinecarboxylic acid (700 mg, 4.961 mmol) in EtOAc (3 mL) was stirred at 70 °C for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN (10 mmol / L NH4HCO3) in water, in a 50% to 60% gradient over 10 min; detector, UV 254 nm. The filtrate was concentrated under reduced pressure to provide (2-((3-(2-(5-fluoropyridinylamino)thiazolyl-4-yl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate tert-butyl ester as a brown oil.

[0313] Yield: 120 mg (45%). 1 H NMR (300 MHz, CDCl3) δ 11.06 (s, 1H), 8.69-8.55 (m, 4H), 8.40 (t, J = 8.8 Hz, 1H), 8.30 (s, 1H), 7.68 (t, J = 8.8 Hz, 1H), 4.89 (s, 2H), 3.78-3.49 (m, 4H), 2.90 (s, 3H), 1.45 (s, 9H). m / z:[ESI +488 (M+H) + .

[0314] Synthesis of tert-butyl (2-((3-(2-(5-(4-acetylpiperazin-1-yl)pyridinylamino)thiazolyl-4-yl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate A solution of (2-((3-(2-(5-fluoropyridinylamino)thiazolyl-4-yl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate tert-butyl ester (120 mg, 0.246 mmol) and 1-(piperazin-1-yl)ethyl-1-one (160 mg, 1.248 mmol) in DMSO (2 mL) was stirred at 120 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN (10 mmol / L NH4HCO3) in water, in a 50% to 60% gradient over 10 min; UV 254 nm. The resulting mixture was concentrated under reduced pressure to provide (2-((3-(2-(5-(4-acetylpiperazin-1-yl)pyridinamido)thiazolyl-4-yl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate tert-butyl ester as a brown oil.

[0315] Yield: 80 mg (55%). 1 H NMR (300 MHz, CDCl3) δ 11.05 (s, 1H), 8.75 (s, 1H), 8.30 (d, J = 2.8 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.60-7.57 (m, 2H), 7.32(d, J = 2.8 Hz, 1H), 4.89 (s, 2H), 3.86-3.82 (m, 4H), 3.72 (t, J = 6.0 Hz,2H), 3.49 (s, 3H), 3.46 (t, J = 6.0 Hz, 2H), 2.92-2.99 (m, 4H), 2.20 (s, 3H), 1.62 (s, 9H). m / z:[ESI + 596 (M + H) + .

[0316] Final compound 5-(4-acetylpiperazin-1-yl)-N-(4-(2-((2-(methylamino)ethoxy)methyl)pyridin-3-yl)thiazolyl)pyridineamide (Compound 116) Synthesis A solution of 2-((3-(2-(5-(4-acetylpiperazin-1-yl)pyridinylamino)thiazolyl-4-yl)pyridin-2-yl)methoxy)ethyl)(methyl)carbamate tert-butyl (80 mg, 0.134 mmol) in 1,4-dioxane (3 mL, 98.738 mmol) and HCl (gas) in 1,4-dioxane (3 mL) was stirred at room temperature for 1 h. The mixture was alkalized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by preparative HPLC under the following conditions (column: XBridge preparative OBD C18 column, 30...). 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 27% B, 27% B over 10 min; Wavelength: 254 nm; RT1 (min): 10; Runs: 0) and concentrated under reduced pressure to provide 5-(4-acetylpiperazin-1-yl)-N-(4-(2-((2-(methylamino)ethoxy)methyl)pyridin-3-yl)thiazolyl-2-yl)pyridine amide as a white solid.

[0317] Yield 20 mg (30%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.05 (s, 1H), 8.55-8.51(m, 1H), 8.42-8.39 (m, 2H), 8.11-8.02 (m, 1H), 7.60 (s, 1H), 7.48-742 (m,2H), 4.67 (s, 1H), 3.50 (s, 2H), 3.43-3.31 (m, 6H), 3.06 (s, 3H), 2.70-2.58(m, 4H), 2.28 (t, J = 5.2 Hz, 2H), 2.06 (s, 3H). m / z: [ESI + 496 (M + H) + .(C 22 H 29 N7O).

[0318] Experimental Procedure (Compound 112) Option 11. 5-(4-acetylpiperazin-1-yl)-N-(4-(2-((2-(methylthio)ethoxy)methyl)pyridine-3- Synthesis of (2-yl)thiazolyl)pyridine amide (compound 112) Synthesis of 3-bromo-2-((2-(methylthio)ethoxy)methyl)pyridine At 0 °C, NaH (0.38 g, 15.942 mmol) was added to a solution of 2-(methylthio)ethanol (1.10 g, 11.957 mmol) in DMF (20 mL). The mixture was stirred for 15 min. 3-Bromo-2-(bromomethyl)pyridine (2.00 g, 7.971 mmol) was added, and the mixture was allowed to heat to RT and stirred for 1 h. The mixture was alkalized to pH 8 with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1 / 1) to provide 3-bromo-2-((2-(methylthio)ethoxy)methyl)pyridine as a yellow oil.

[0319] Yield: 1.00 g (48%). 1 H NMR (400 MHz, chloroform-) d ) δ 8.58 (dd, J = 4.8, 1.6Hz, 1H), 7.90 (dd, J = 8.0, 1.6 Hz, 1H), 7.15 (dd, J = 8.0, 4.8 Hz, 1H), 4.81(s, 2H), 3.80 (t, J = 7.2 Hz, 2H), 2.79 (d, J = 7.2 Hz, 2H), 2.16 (s, 3H). m / z:[ESI + 262, 264 (M+H) + .

[0320] (4-(2-((2-(methylthio)ethoxy)methyl)pyridin-3-yl)thiazo-2-yl)tert-butyl carbamate become At room temperature under a nitrogen atmosphere, 3-bromo-2-((2-(methylthio)ethoxy)methyl)pyridine (400 mg, 1.526 mmol) and N[4-(tributylmtinyl)-1,3-thiazolyl-2-yl]tert-butyl carbamate (1120 mg, 2.289 mmol) was added in portions to a stirred solution in DMF (5 mL) with ZnCl2 (208 mg, 1.526 mmol) and di-tert-butyl({dichloro[di-tert-butyl(phenyl)-λ5-phosphino]palladium})phenyl-λ5-phosphonane (95 mg, 0.152 mmol). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, Spherical C18, 20–40 μm, 330; mobile phase A: water (with 10 mM NH4HCO3); mobile phase B: (ACN); flow rate: 80 mL / min; gradient: 45% B–65% B over 20 min; detector, UV 254 nm. Fractions containing the desired product were collected at 54% B and concentrated under reduced pressure to provide tert-butyl (4-(2-((2-(methylthio)ethoxy)methyl)pyridin-3-yl)thiazolyl)carbamate as a yellow solid.

[0321] Yield: 260 mg (45%). 1 H NMR (400 MHz, chloroform-) d ) δ 8.62 (dd, J = 4.8, 1.6Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.39 (dd, J = 8.0, 4.8 Hz,1H), 4.80 (s, 2H), 3.81 ( t , J = 6.4 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.14(s, 3H), 1.56(s, 9H). m / z:[ESI + 382,384 (M+H) + .

[0322] Synthesis of 4-(2-((2-(methylthio)ethoxy)methyl)pyridin-3-yl)thiazolyl-2-amine hydrochloride At room temperature, 4 M HCl in 1,4-dioxane (3 mL) was added dropwise to a solution of (260 mg, 0.682 mmol) of 4-(2-(2-(methylthio)ethoxy)methyl)pyridin-3-yl)thiazolyl-2-yl)carbamate (260 mg, 0.682 mmol) in 1,4-dioxane (3 mL, 98.738 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under vacuum to provide 4-(2-(2-(2-(methylthio)ethoxy)methyl)pyridin-3-yl)thiazolyl-2-amine hydrochloride as a grayish-white solid.

[0323] Yield: 180 mg (94%). 1 H NMR (400 MHz, methanol-) d 4) δ 8.88 (d, J = 5.6 Hz, 1H), 8.73 (dd, J = 8.0, 1.6 Hz, 1H), 8.12 (dd, J = 8.0, 5.6 Hz, 1H), 7.16 (s, 3H), 5.13 (s, 2H), 3.94 (t, J = 6.4 Hz, 2H), 2.85 (t, J = 6.4 Hz, 2H), 2.15 (s, 3H). m / z:[ESI + 282 (M+H) + .

[0324] Synthesis of 4-fluoro-N-(4-(2-((2-(methylthio)ethoxy)methyl)pyridin-3-yl)thiazo-2-yl)benzamide become At room temperature, T3P (271 mg, 0.852 mmol) and DIEA (110 mg, 0.851 mmol) were added dropwise to a stirred solution of 4-(2-((2-(methylthio)ethoxy)methyl)pyridin-3-yl)thiazolyl-2-amine hydrochloride (106 mg, 0.334 mmol) and 5-fluoropyridin-2-carboxylic acid (80 mg, 0.567 mmol) in EtOAc (1 mL). The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, Spherical C18, 20–40 μm, 330; mobile phase A: water (with 10 mM NH4HCO3); mobile phase B: (ACN); flow rate: 80 mL / min; gradient: 45% B–65% B over 20 min; detector, UV 254 nm. Fractions containing the desired product were collected at 54% B and concentrated under reduced pressure to provide 4-fluoro- N -(4-(2-((2-(methylthio)ethoxy)methyl)pyridin-3-yl)thiazo-2-yl)benzamide.

[0325] Yield: 80 mg (52%). 1 H NMR (400 MHz, chloroform-) d ) δ 11.05 (s, 1H), 8.66 (dd, J = 4.8, 2.8 Hz, 1H), 8.55 (d, J = 2.8 Hz, 1H), 8.40 (dd, J = 8.0, 4.8 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.72 - 7.63 (m, 2H), 7.50 - 7.42 (m, 1H), 4.88 (s,2H), 3.85 (t, J = 6.4 Hz, 2H), 2.78 (t, J = 6.4 Hz, 2H), 2.15 (s, 3H). m / z:[ESI + 404 (M+H) + .

[0326] Final compound 5-(4-acetylpiperazin-1-yl)-N-(4-(2-((2-(methylthio)ethoxy)methyl)pyridin-3-yl)thiazole- Synthesis of 2-yl)pyridine amide (compound 112) 4-fluoro- N A solution of 4-(2-((2-(methylthio)ethoxy)methyl)pyridin-3-yl)thiazolyl-2-yl)benzamide (80 mg, 0.198 mmol) and 1-(piperazin-1-yl)acetone (76 mg, 0.593 mmol) in DMSO (1 mL) was stirred at 120 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC under the following conditions (column: XBridge preparative OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 52% B to 62% B, 62% B over 10 min; wavelength: 254 nm; RT1 (min): 10; runs: 0) to provide 5-(4-acetylpiperazin-1-yl)- as a white solid. N -(4-(2-((2-(methylthio)ethoxy)methyl)pyridin-3-yl)thiazo-2-yl)pyridineamide.

[0327] Yield: 36 mg (36%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.68 (s, 1H), 8.56 (dd, J = 4.8, 1.6 Hz, 1H), 8.43 (d, J = 4.8 Hz, 1H), 8.14 (dd, J = 8.0, 1.6 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.49 - 7.43 (m, 2H), 4.77 (s, 2H), 3.69 - 3.59 (m, 6H), 3.52 (d, J = 6.0 Hz, 2H), 3.45 (d, J = 6.0 Hz, 2H), 2.61(t, J = 6.0 Hz, 3H), 2.10 - 2.05 (m, 5H). m / z:[ESI + 513 (M+H) + , (C 24 H 28 N6O3S2).

[0328] Experimental Procedure (Compound 113) Scheme 12. 5-Fluoro- N -(4-(2-((2-(methylsulfonyl)ethoxy)methyl)pyridin-3-yl)thiazo-2-yl)pyridineamide (Compound 113) Synthesis Synthesis of 3-bromo-2-((2-(methylsulfonyl)ethoxy)methyl)pyridine 3-bromo-2-((2-(methylthio)ethoxy)methyl)pyridine (500 mg, 1.907 mmol) and m A solution of CPBA (987 mg, 5.720 mmol) in DCM (5 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, Spherical C18, 20–40 μm, 330; 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 nm. The fraction containing the desired product was collected at 54% B and concentrated under reduced pressure to provide 3-bromo-2-((2-(methanesulfonyl)ethoxy)methyl)pyridine as a yellow solid.

[0329] Yield: 300 mg (53%). 1 H NMR (400 MHz, chloroform-) d ) δ 8.57 (dd, J = 4.8, 1.6Hz, 1H), 7.91 (dd, J = 8.0, 1.6 Hz, 1H), 7.19 (dd, J = 8.0, 4.8 Hz, 1H), 4.83(s, 2H), 4.11 - 4.04 (m, 2H), 3.30 (t, J = 6.0 Hz, 2H), 3.08 (s, 3H). m / z:[ESI + 294, 296 (M+H) + .

[0330] Synthesis of 3-(1-ethoxyvinyl)-2-((2-(methylsulfonyl)ethoxy)methyl)pyridine Pd(PPh3)2Cl2 (72 mg, 0.103 mmol) was added in portions to a stirred mixture of 3-bromo-2-((2-(methanesulfonyl)ethoxy)methyl)pyridine (300 mg, 1.020 mmol) and tributyl(1-ethoxyvinyl)stanane (552 mg, 1.528 mmol) in dioxane (3 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The mixture was alkalized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure to provide 3-(1-ethoxyvinyl)-2-((2-(methanesulfonyl)ethoxy)methyl)pyridine as a black oil.

[0331] Yield: 260 mg (89%). 1 H NMR (400 MHz, chloroform-) d ) δ 8.62 (dd, J = 4.8, 1.6Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.39 (dd, J = 8.0, 4.8 Hz,1H), 4.80 (s, 2H), 3.81 (t, J = 6.4 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.14(s, 3H), 1.56(s, 9H). m / z:[ESI + 286 (M+H) + .

[0332] Synthesis of 2-bromo-1-(2-((2-(methanesulfonyl)ethoxy)methyl)pyridin-3-yl)acet-1-one A solution of 3-(1-ethoxyvinyl)-2-((2-(methanesulfonyl)ethoxy)methyl)pyridine (300 mg, 1.051 mmol) and NBS (281 mg, 1.579 mmol) in THF (3 mL) and H₂O (0.15 mL) was stirred at room temperature under a nitrogen atmosphere for 30 min. The desired product was detectable by LCMS. The resulting mixture was concentrated under vacuum to provide 2-bromo-1-(2-((2-(methanesulfonyl)ethoxy)methyl)pyridin-3-yl)ethyl-1-one (200 mg, 56.59%) as a black oil.

[0333] Yield: 200 mg (57%). 1 H NMR (300 MHz, chloroform-) d ) δ 7.76 - 7.63 (m, 1H), 7.63- 7.35 (m, 2H), 5.11 - 3.69 (m, 1H), 2.78 (s, 3H), 1.82 - 1.79 (m, 4H), 1.73- 1.70 (m, 2H). m / z:[ESI + 336 (M+H) + .

[0334] Synthesis of 4-(2-((2-(methanesulfonyl)ethoxy)methyl)pyridin-3-yl)thiazolyl-2-amine A solution of 2-bromo-1-(2-((2-(methanesulfonyl)ethoxy)methyl)pyridin-3-yl)ethyl-1-one (200 mg, 0.595 mmol) and thiourea (91 mg, 1.195 mmol) in EtOH (2 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, Spherical C18, 20–40 μm, 330; mobile phase A: water (with 10 mM NH4HCO3); mobile phase B: (ACN); flow rate: 80 mL / min; gradient: 45% B–65% B over 20 min; detector, UV 254 nm. The fraction containing the desired product was collected at 54% B and concentrated under reduced pressure to provide 4-(2-((2-(methanesulfonyl)ethoxy)methyl)pyridin-3-yl)thiazolyl-2-amine as a yellow solid.

[0335] Yield 150 mg (80%). 1 H NMR (400 MHz, chloroform-) d ) δ 8.64 - 8.62 (m, 1H), 7.95- 7.90 (m, 1H), 7.39 - 7.29 (m, 1H), 6.72 (s, 1H), 5.41 (s, 2H), 4.77 (s,2H), 4.12 - 4.04 (m, 2H), 3.07 (s, 3H). m / z:[ESI + 313(M+H) + .

[0336] 5-Fluoro-N-(4-(2-((2-(methanesulfonyl)ethoxy)methyl)pyridin-3-yl)thiazo-2-yl)pyridineamide Synthesis T3P (457 mg, 1.436 mmol) and DIEA (186 mg, 1.439 mmol) were added dropwise to a stirred solution of 4-(2-((2-(methanesulfonyl)ethoxy)methyl)pyridin-3-yl)thiazolyl-2-amine (150 mg, 0.479 mmol) and 5-fluoropyridin-2-carboxylic acid (135 mg, 0.957 mmol) in EtOAc (2 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, Spherical C18, 20–40 μm, 330; mobile phase A: water (with 10 mM NH4HCO3); mobile phase B: (ACN); flow rate: 80 mL / min; gradient: 45% B–65% B over 20 min; detector, UV 254 nm. Fractions containing the desired product were collected at 54% B and concentrated under reduced pressure to provide 5-fluoro- N -(4-(2-((2-(methylsulfonyl)ethoxy)methyl)pyridin-3-yl)thiazolyl-2-yl)pyridineamide.

[0337] Yield 100 mg (48%). 1 H NMR (400 MHz, chloroform-) d ) δ 8.70 - 8.66 (m, 1H), 8.59- 8.55 (m, 1H), 8.33 - 8.28 (m, 1H), 8.06 - 8.03 (m, 1H), 7.69 - 7.66 (m,1H), 7.42 - 7.38 (m, 1H), 7.31 - 7.28 (m, 1H), 4.87 (s, 2H), 4.09 (t, J = 5.6Hz, 2H), 3.31 (t, J = 5.6 Hz, 2H), 3.02 (s, 3H). m / z:[ESI + 437(M+H) + .

[0338] Final compound 5-Fluoro- N -(4-(2-((2-(methylsulfonyl)ethoxy)methyl)pyridin-3-yl)thiazo-2-yl)pyridineamide (Compound 113) Synthesis 5-fluoro- N A solution of 4-{2-[(2-methanesulfonylethoxy)methyl]pyridin-3-yl}-1,3-thiazolyl-2-yl)pyridin-2-carboxamide (100 mg, 0.229 mmol) and 1-(piperazin-1-yl)acetone (88 mg, 0.687 mmol) in DMSO (1 mL) was stirred at 120 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: XBridge preparative OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 52% B to 62% B, 62% B over 10 min; wavelength: 254 nm; RT1 (min): 10; runs: 0) to provide 5-(4-acetylpiperazin-1-yl)- as a white solid. N -(4-(2-((2-(methylsulfonyl)ethoxy)methyl)pyridin-3-yl)thiazolyl-2-yl)pyridineamide.

[0339] Yield: 30 mg (24%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.73 (br s, 1H), 8.60 -8.56 (m, 1H), 8.45 - 8.42 (m, 1H), 8.15 - 8.12 (m, 1H), 8.05 - 8.01 (m, 1H),7.60 (s, 1H), 7.53 - 7.45 (m, 2H), 4.82 (s, 2H), 3.87 (t, J = 5.6 Hz, 2H),3.71 - 3.54 (m, 4H), 3.54 - 3.48 (m, 2H), 3.48 - 3.40 (m, 2H), 3.37 (t, J =5.6 Hz, 2H), 2.91 (s, 3H), 2.06 (s, 3H). m / z:[ESI + 545 (M+H) + , (C 24 H 28 N6O5S2).

[0340] Experimental Procedure (Compound 106) Option 13. 5-(4-acetylpiperazin-1-yl)-N-(4-{2-[(oxacyclohexane-4-yloxy)methyl]benzene Synthesis of 1,3-thiazolyl-2-yl)pyridine-2-carboxamide (compound 106) Synthesis of 4-((2-bromobenzyl)oxy)tetrahydro-2H-pyran At 0 °C, NaH (0.64 g, 16.004 mmol) was added dropwise to a stirred solution of oxadiazon-4-ol (1.23 g, 12.003 mmol) in DMF (20 mL). The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 30 min. At 0 °C, 1-bromo-2-(bromomethyl)benzene (2.00 g, 8.002 mmol) in DMF (20 mL) was added dropwise over 2 min. The resulting mixture was stirred at room temperature for another 1 h. The reaction was quenched at 0 °C with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (1 × 150 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1%–30% ethyl acetate in petroleum ether and concentrated under reduced pressure to provide 4-[(2-bromophenyl)methoxy]oxacyclohexane (1.60 g, 73%) as a pale yellow oil. Yield: 1.60 g (60%). 1 H NMR (300 MHz, CDCl3) δ 7.60 - 7.52 (m, 2H), 7.45 - 7.31 (m, 1H), 7.25 - 7.12 (m, 1H), 4.64 (s, 2H), 4.07 - 3.93 (m, 2H), 3.74 - 3.62 (m, 1H), 3.55 - 3.44 (m, 2H), 2.10 - 1.92 (m, 2H), 1.85 - 1.64 (m, 2H). No MS signal.

[0341] Synthesis of 4-((2-(1-ethoxyvinyl)benzyl)oxy)tetrahydro-2H-pyran At room temperature, Pd(PPh3)2Cl2 (0.41 g, 0.590 mmol) was added in portions to a stirred solution of 4-[(2-bromophenyl)methoxy]oxetine (1.60 g, 5.901 mmol) and tributyl(1-ethoxyvinyl)stanane (3.20 g, 8.851 mmol) in dioxane (30 mL). The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 4-{[2-(1-ethoxyvinyl)phenyl]methoxy}oxetine (1.50 g, 96%) as a brown oil.

[0342] Yield: 1.50 g (97%). 1 H NMR (400 MHz, CDCl3) δ 7.52 - 7.45 (m, 1H), 7.40 -7.32 (m, 2H), 7.28 - 7.24 (m, 1H), 4.67 (s, 2H), 4.32 (d, J = 2.0 Hz, 1H), 4.26 (d, J = 2.0 Hz, 1H), 4.03 - 3.95 (m, 2H), 3.91 (q, J = 7.2 Hz, 2H), 3.64- 3.54 (m, 1H), 3.53 - 3.41 (m, 2H), 2.01 - 1.88 (m, 2H), 1.75 - 1.65 (m,2H), 1.13 (t, J = 7.2 Hz, 3H).

[0343] m / z: [ESI] + 263 (M+H) + .

[0344] Synthesis of 2-bromo-1-(2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl)ethyl-1-one NBS (1.19 g, 6.709 mmol) was added in portions to a stirred solution of 4-{[2-(1-ethoxyvinyl)phenyl]methoxy}oxetine (1.60 g, 6.099 mmol) in THF (30 mL) and water (2 mL) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (1 × 150 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide 2-bromo-1-{2-[(oxetine-4-yloxy)methyl]phenyl}acetone (1.60 g, 83%) as a brown oil.

[0345] Yield: 1.60 g (83%). 1 H NMR (300 MHz, CDCl3) δ 7.61 - 7.49 (m, 2H), 7.49 -7.33 (m, 2H), 4.82 (s, 2H), 4.50 (s, 2H), 4.00 - 3.94 (m, 2H), 3.69 - 3.56(m, 1H), 3.54 - 3.43 (m, 2H), 2.06 - 1.85 (m, 2H), 1.62 - 1.57 (m, 2H). m / z:[ESI + 313, 315 (M+H) + .

[0346] Synthesis of 4-(2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl)thiazol-2-amine At room temperature, thiourea (0.55 g, 7.183 mmol) was added in portions to a stirred solution of 2-bromo-1-{2-[(oxecyclohexane-4-yloxy)methyl]phenyl}acetone (1.50 g, 4.789 mmol) in EtOH (30 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with saturated NaHCO3 (50 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1%–70% ethyl acetate in petroleum ether and concentrated under reduced pressure to provide 4-{2-[(oxacyclohexane-4-yloxy)methyl]phenyl}-1,3-thiazol-2-amine (1.00 g, 72%) as a pale yellow solid.

[0347] Yield: 1.00 g (72%). 1 H NMR (400 MHz, CDCl3) δ 7.61 - 7.53 (m, 1H), 7.54 -7.45 (m, 1H), 7.33 - 7.29 (m, 2H), 6.99 (br s, 2H), 6.70 (s, 1H), 4.67 (s,2H), 3.89 - 3.71 (m, 2H), 3.66 - 3.47 (m, 1H), 3.39 - 3.32 (m, 2H), 1.96 -1.79 (m, 2H), 1.55 - 1.35 (m, 2H).

[0348] m / z: [ESI] + 291 (M+H) + .

[0349] 5-Fluoro-N-(4-(2-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl)thiazo-2-yl)pyridineamide synthesis At room temperature, T3P (3.29 g, 5.166 mmol) was added dropwise to a stirred solution of 4-{2-[(oxacyclohexane-4-yloxy)methyl]phenyl}-1,3-thiazolyl-2-amine (500 mg, 1.722 mmol), TEA (500 mg, 4.941 mmol), and 5-fluoropyridine-2-carboxylic acid (480 mg, 3.402 mmol) in EtOAc (15 mL). The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1%–70% ethyl acetate in petroleum ether and concentrated under reduced pressure to provide 5-fluoro- as a pale yellow oil. N -(4-{2-[(oxacyclohexane-4-yloxy)methyl]phenyl}-1,3-thiazolyl)pyridine-2-carboxamide (600 mg, 84%).

[0350] 1 H NMR (400 MHz, DMSO- d 6 ) δ12.20 (br s, 1H), 8.87 - 8.74 (m, 1H),8.39 - 8.25 (m, 1H), 8.13 - 7.99 (m, 1H), 7.74 - 7.62 (m, 1H), 7.62 - 7.53(m, 1H), 7.53 - 7.45 (m, 1H), 7.45 - 7.33 (m, 2H), 4.74 (s, 2H), 3.84 - 3.69(m, 2H), 3.69 - 3.49 (m, 1H), 3.32 - 3.31 (m, 2H), 1.94 - 1.62 (m, 2H), 1.61- 1.19 (m, 2H).

[0351] m / z: [ESI] + 414 (M+H) + .

[0352] Final compound 5-(4-acetylpiperazin-1-yl)-N-(4-{2-[(oxacyclohexane-4-yloxy)methyl]phenyl}-1,3-thiazolinone Synthesis of (2-azolyl)pyridine-2-carboxamide (compound 106) At room temperature, to 5-fluoro- N 1-(piperazin-1-yl)acetone (450 mg, 3.511 mmol) was added dropwise to a stirred solution of 4-{2-[(oxacyclohexane-4-yloxy)methyl]phenyl}-1,3-thiazolyl-2-yl)pyridine-2-carboxamide (300 mg, 0.726 mmol) in DMSO (10 mL). The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The reaction solution 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: 50 mL / min; gradient: 20% B – 40% B over 20 min; detector: 254 nm. The fraction containing the desired product was collected at 30% B and concentrated under reduced pressure to provide 5-(4-acetylpiperazin-1-yl)- as a pale yellow solid. N -(4-{2-[(oxacyclohexane-4-yloxy)methyl]phenyl}-1,3-thiazolyl)pyridine-2-carboxamide (200 mg, 53%).

[0353] Yield 200 mg (53%). 1 H NMR (400 MHz, DMSO- d6 ) δ 11.62 (br s, 1H), 8.42 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.67 - 7.62 (m, 1H), 7.60 -7.53 (m, 1H), 7.50 (dd, J = 2.8, 8.8 Hz, 1H), 7.41 (s, 1H), 7.40 - 7.34 (m,2H), 4.71 (s, 2H), 3.91 - 3.70 (m, 2H), 3.69 - 3.52 (m, 5H), 3.54 - 3.48 (m,2H), 3.47 - 3.35 (m, 2H), 3.35 - 3.24 (m, 2H), 2.06 (s, 3H), 1.94 - 1.72 (m,2H), 1.51 - 1.36 (m, 2H).

[0354] m / z: [ESI] + 522 (M+H) + , (C 27 H 31 N5O4S).

[0355] Experimental procedure (compound 107) Scheme 14. 5-(4-acetylpiperazin-1-yl)- N -(4-(2-((2,2-difluoroethoxy)methyl)phenyl)thiazo-2-yl)pyridineamide (Compound 107) Synthesis Synthesis of 1-bromo-2-[(2,2-difluoroethoxy)methyl]benzene NaH (0.29 g, 12.003 mmol) was added in portions to a stirred mixture of 2,2-difluoroethanol (1.31 g, 16.004 mmol) in DMF (20 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. 1-Bromo-2-(bromomethyl)benzene (2.00 g, 8.002 mmol) was added in portions to the mixture at room temperature over 5 min. The resulting mixture was stirred at room temperature for another 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched at 0 °C with saturated NH4Cl (aqueous solution). The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1%–30% methanol in dichloromethane to provide 1.20 g of 1-bromo-2-[(2,2-difluoroethoxy)methyl]benzene as a pale yellow oil.

[0356] Yield: 1.20 g (60%). 1 H NMR (300 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 5.97 (tt, J = 55.6, 4.0 Hz, 1H), 4.72 (s, 2H), 3.90 - 3.77 (m, 2H). m / z:[ESI + 251, 253 (M + H) + .

[0357] Synthesis of 1-((2,2-difluoroethoxy)methyl)-2-(1-ethoxyvinyl)benzene Pd(PPh3)2Cl2 (0.67 g, 0.955 mmol) was added in portions to a stirred mixture of 1-bromo-2-[(2,2-difluoroethoxy)methyl]benzene (1.20 g, 4.780 mmol) and tributyl(1-ethoxyvinyl)stanane (2.07 g, 5.736 mmol) in dioxane (10 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with water (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 850 mg of 1-((2,2-difluoroethoxy)methyl)-2-(1-ethoxyvinyl)benzene as a pale yellow oil.

[0358] Yield: 850 mg (73%). 1 H NMR (300 MHz, CDCl3) δ 7.76 - 7.63 (m, 1H), 7.61 -7.35 (m, 2H), 7.34 - 7.25 (m, 1H), 5.97 (tt, J = 55.6, 4.0 Hz, 1H), 4.72 (s,2H), 4.30 - 4.18 (m, 2H), 3.90 - 3.77 (m, 2H), 3.51 - 3.17 (m, 2H), 1.28 -1.18 (m, 3H). m / z:[ESI + 243 (M + H) + .

[0359] Synthesis of 2-bromo-1-(2-((2,2-difluoroethoxy)methyl)phenyl)ethyl-1-one A mixture of 1-[(2,2-difluoroethoxy)methyl]-2-(1-ethoxyvinyl)benzene (850 mg, 3.509 mmol) and NBS (937 mg, 5.264 mmol) in THF (20 mL) and H₂O (1 mL) was stirred at room temperature under a nitrogen atmosphere for 30 min. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with water (3 × 300 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide 800 mg of 2-bromo-1-(2-((2,2-difluoroethoxy)methyl)phenyl)ethyl-1-one as a yellow oil.

[0360] Yield: 1.00 g (98%). 1 H NMR (300 MHz, CDCl3) δ 7.78 - 7.65 (m, 1H), 7.64 -7.36 (m, 3H), 5.96 (tt, J = 55.6, 4.0 Hz, 1H), 5.02 - 4.61 (m, 2H), 4.48 (s,2H), 3.99 - 3.61 (m, 2H). m / z:[ESI + 293, 295 (M + H) + .

[0361] Synthesis of 4-(2-((2,2-difluoroethoxy)methyl)phenyl)thiazole-2-amine A mixture of 2-bromo-1-(2-((2,2-difluoroethoxy)methyl)phenyl)ethyl-1-one (1.00 g, 3.412 mmol) and thiourea (0.39 g, 5.118 mmol) in EtOH (10 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with water (300 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1%–30% methanol in dichloromethane to provide 800 mg of 4-(2-((2,2-difluoroethoxy)methyl)phenyl)thiazol-2-amine as a yellow oil.

[0362] Yield: 800 mg (87%). m / z: [ESI] + 271 (M + H) + .

[0363] N Synthesis of -(4-(2-((2,2-difluoroethoxy)methyl)phenyl)thiazolyl)-5-fluoropyridine amide Under a nitrogen atmosphere at room temperature, 5-fluoropyridine-2-carboxylic acid (313 mg, 2.218 mmol) and TEA (337 mg, 3.330 mmol) were added in portions to a stirred mixture of 4-(2-((2,2-difluoroethoxy)methyl)phenyl)thiazol-2-amine (300 mg, 1.110 mmol) and T3P (1.06 g, 3.328 mmol) in ethyl acetate (5 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with water (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting in dichloromethane with 1%–70% methanol to provide 300 mg as a pale yellow oil. N -(4-(2-((2,2-difluoroethoxy)methyl)phenyl)thiazolyl-2-yl)-5-fluoropyridineamide.

[0364] Yield: 300 mg (69%). 1 H NMR (400 MHz, CDCl3) δ 11.39 (s, 1H), 8.57 (d, J =2.8 Hz, 1H), 8.39 (dd, J = 8.8, 4.4 Hz, 1H), 7.76 - 7.61 (m, 2H), 7.60 - 7.50(m, 1H), 7.55 - 7.38 (m, 2H), 7.27 (s, 1H), 5.96 (tt, J = 55.6, 4.0 Hz, 1H), 4.79 (s, 2H), 3.78 - 3.72 (m, 2H). m / z:[ESI + 394 (M + H) + .

[0365] Final compound 5-(4-acetylpiperazin-1-yl)- N -(4-(2-((2,2-difluoroethoxy)methyl)phenyl)thiazo-2-yl)pyridineamide (Compound 107) Synthesis Will N A mixture of 4-(2-((2,2-difluoroethoxy)methyl)phenyl)thiazolyl-2-yl)-5-fluoropyridine amide (300 mg, 0.763 mmol) and 1-(piperazin-1-yl)acetone (391 mg, 3.051 mmol) in DMSO (3 mL) was stirred at 120 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The mixture was purified by reversed-phase rapid chromatography under the following conditions: column: Spherical C18, 20–40 μm, 120 g; mobile phase A: water (with 10 mM NH4HCO3); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 50% B – 70% B over 20 min; detector: 254 nm. The fraction containing the desired product was collected at 60% B and concentrated under reduced pressure to provide 130 mg of 5-(4-acetylpiperazine-1-yl)- as a white solid. N -(4-(2-((2,2-difluoroethoxy)methyl)phenyl)thiazolyl-2-yl)pyridineamide.

[0366] Yield: 130 mg (34%). 1 H NMR (400 MHz, DMSO) δ 8.43 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.79 - 7.63 (m, 1H), 7.57 - 7.50 (m, 2H), 7.46 -7.35 (m, 3H), 6.24 - 6.18 (m, 1H), 4.83 (s, 2H), 3.81 - 3.76 (m, 2H), 3.63(dd, J = 6.8, 3.8 Hz, 4H), 3.50 - 3.46 (m, 4H), 2.07 (s, 3H). m / z:[ESI + 502(M + H) + .

[0367] Experimental Procedure (Compound 109) Option 15. S )-5-(4-acetylpiperazin-1-yl)- N -(4-(2-((2-hydroxypropoxy)methyl)phenyl)thiazo-2-yl)pyridineamide (Compound 109) Synthesis (2 S Synthesis of 1-[(2-bromophenyl)methoxy]prop-2-ol NaH (0.72 g, 30.008 mmol) was added in portions to a stirred mixture of 1-bromo-2-(bromomethyl)benzene (5.00 g, 20.005 mmol) in DMF (50 mL) at 0 °C under a nitrogen atmosphere. NaH was added in portions over 2 min at room temperature. S 1,2-Propanediol (3.04 g, 40.010 mmol). The resulting mixture was stirred at room temperature for another 1 h. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (4 × 100 mL). The combined organic layers were washed with water (4 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 2.30 g of a pale yellow oil (2... S )-1-[(2-bromophenyl)methoxy]prop-2-ol.

[0368] Yield: 2.30 g (47%). 1 H NMR (300 MHz, CDCl3) δ 7.58 (dd, J = 8.0, 1.2 Hz,1H), 7.54 - 7.43 (m, 1H), 7.40 - 7.30 (m, 1H), 7.25 - 7.13 (m, 1H), 4.65 (d, J = 1.6 Hz, 2H), 4.25 - 3.99 (m, 1H), 3.58 (dd, J = 9.6, 3.2 Hz, 1H), 3.40(dd, J = 9.6, 8.0 Hz, 1H). m / z:[ESI + 245, 247 (M + H) + .

[0369] ( SSynthesis of 1-((2-(1-ethoxyvinyl)benzyl)oxy)prop-2-ol At room temperature under a nitrogen atmosphere, towards (2 S Pd(PPh3)2Cl2 (0.57 g, 0.816 mmol) was added in portions to a stirred mixture of 1-[(2-bromophenyl)methoxy]prop-2-ol (1.00 g, 4.080 mmol) and tributyl(1-ethoxyvinyl)stanane (1.77 g, 4.896 mmol) in dioxane (10 mL). The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with water (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 800 mg of a pale yellow oil. S )-1-((2-(1-ethoxyvinyl)benzyl)oxy)prop-2-ol.

[0370] Yield: 800 mg (83%). 1 H NMR (400 MHz, CDCl3) δ 7.54 - 7.21 (m, 4H), 4.76 -4.72 (m, 2 H), 4.32 - 4.28 (m, 2H), 3.99 - 3.60 (m, 5 H), 1.37 - 1.29 (m, 3H), 0.95 - 0.85 (m, 3 H). m / z:[ESI + 237 (M + H) + .

[0371] ( S Synthesis of 2-bromo-1-(2-((2-hydroxypropoxy)methyl)phenyl)ethyl-1-one Will( SA mixture of 1-((2-(1-ethoxyvinyl)benzyl)oxy)prop-2-ol (700 mg, 2.962 mmol) and NBS (791 mg, 4.444 mmol) in THF (7 mL) and H2O (1 mL) was stirred at room temperature under nitrogen atmosphere for 30 min. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with water (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 700 mg of a pale yellow oil. S )-2-bromo-1-(2-((2-hydroxypropoxy)methyl)phenyl)ethyl-1-one.

[0372] Yield: 700 mg (82%). 1 H NMR (400 MHz, CDCl3) δ 7.81 - 7.64 (m, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.56 - 7.32 (m, 2H), 4.91 (s, 2H), 4.75 - 4.49 (m, 2H), 3.94 - 3.64 (m, 3H), 0.95 - 0.85 (m, 3H). m / z:[ESI + 287 (M + H) + .

[0373] ( S Synthesis of 1-((2-(2-aminothiazol-4-yl)benzyl)oxy)prop-2-ol Will( S A mixture of 2-bromo-1-(2-((2-hydroxypropoxy)methyl)phenyl)ethyl-1-one (700 mg, 2.438 mmol) and thiourea (278 mg, 3.652 mmol) in EtOH (10 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with water (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1%–30% methanol in dichloromethane to provide 500 mg of the product as a yellow oil. S)-1-((2-(2-aminothiazo-4-yl)benzyl)oxy)prop-2-ol.

[0374] Yield: 500 mg (78%). 1 H NMR (400 MHz, CDCl3) δ 7.79 - 7.68 (m, 2H), 7.45 -7.32 (m, 3H), 4.53 (s, 2H), 4.10 - 3.95 (m, 1H), 3.79 - 3.39 (m, 1H), 3.45 -2.98 (m, 1H), 1.22 - 1.06 (m, 3H). m / z:[ESI + 265 (M + H) + .

[0375] ( S Synthesis of 4-(2-((2-((tert-butyldiphenylsilyl)oxy)propoxy)methyl)phenyl)thiazol-2-amine At room temperature under a nitrogen atmosphere, towards ( S )-1-((2-(2-aminothiazol-4-yl)benzyl)oxy)prop-2-ol (500 mg, 1.892 mmol) and 1 H -Imidazole (193 mg, 2.835 mmol) was added in portions to a stirred mixture in a DCM (8 mL) with TBDPS-Cl (780 mg, 2.838 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. AcOH (2 mL) was added in portions over 2 min at room temperature. The resulting mixture was stirred at room temperature for another 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1%-70% ethyl acetate in petroleum ether to provide 800 mg as a yellow oil. S )-4-(2-((2-((tert-butyldiphenylsilyl)oxy)propoxy)methyl)phenyl)thiazol-2-amine.

[0376] Yield 800 mg (84%). m / z: [ESI] + 503 (M + H) + .

[0377] (S )- N Synthesis of -(4-(2-((2-((tert-butyldiphenylsilyl)oxy)propoxy)methyl)phenyl)thiazo-2-yl)-5-fluoropyridine amide At room temperature under a nitrogen atmosphere, towards ( S 5-Fluoropyridine-2-carboxylic acid (336 mg, 2.381 mmol) and TEA (362 mg, 3.577 mmol) were added in portions to a stirred mixture of 4-(2-((2-((tert-butyldiphenylsilyl)oxy)propoxy)methyl)phenyl)thiazol-2-amine (600 mg, 1.193 mmol) and T3P (1.14 g, 3.580 mmol) in EtOH (10 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The residue was purified by silica gel column chromatography eluting with 1%–6% methanol in dichloromethane to provide 440 mg as a yellow oil. S )- N -(4-(2-((2-((tert-butyldiphenylsilyl)oxy)propoxy)methyl)phenyl)thiazolyl)-5-fluoropyridineamide.

[0378] Yield 440 mg (59%). m / z: [ESI] + 626 (M + H) + .

[0379] Final compound ( S )-5-(4-acetylpiperazin-1-yl)- N -(4-(2-((2-hydroxypropoxy)methyl)phenyl)thiazo-2-yl)pyridineamide (Compound 109) Synthesis Will( S )- NA mixture of 4-(2-((2-((tert-butyldiphenylsilyl)oxy)propoxy)methyl)phenyl)thiazo-2-yl)-5-fluoropyridine amide (440 mg, 0.703 mmol) and 1-(piperazin-1-yl)acetone (360 mg, 2.809 mmol) in DMSO (7 mL) was stirred at 120 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The mixture was allowed to cool to room temperature. The mixture 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 nm. The fraction containing the desired product was collected using 30% B and concentrated under reduced pressure to provide 10 mg as a white solid. S )-5-(4-acetylpiperazin-1-yl)- N -(4-(2-((2-hydroxypropoxy)methyl)phenyl)thiazolyl-2-yl)pyridineamide.

[0380] Yield 500 mg (78%). Yield 10 mg (3%). 1 H NMR (400 MHz, DMSO) δ 11.59 (s,1H), 8.43 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.85 - 7.62 (m, 1H), 7.69 - 7.45 (m, 2H), 7.45 - 7.25 (m, 2H), 4.65 (dd, J = 8.4, 4.0 Hz, 3H),3.81 - 3.76 (m, 1H), 3.70 - 3.45 (m, 5H), 3.44 (s, 5H), 2.07(s, 3H), 1.04 (d, J = 6.4 Hz, 3H). m / z: [ESI + 496 (M + H) + .

[0381] Experimental Procedure (Compound 110) Option 16. R )-5-(4-acetylpiperazin-1-yl)- N-(4-(2-((2-hydroxypropoxy)methyl)phenyl)thiazo-2-yl)pyridineamide (Compound 110) Synthesis ( R Synthesis of 1-((2-bromobenzyl)oxy)prop-2-ol Will R A solution of 1,2-propanediol (3.04 g, 40.010 mmol) in DMF (50 mL) was treated with NaH (0.72 g, 30.008 mmol) at 0 °C under a nitrogen atmosphere for 30 min, followed by dropwise addition of 1-bromo-2-(bromomethyl)benzene (5.00 g, 20.005 mmol) at room temperature. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (300 mL). The combined organic layers were washed with brine (3 × 100 mL) and drie...

Claims

1. A compound, represented by the structure of formula IV(a): in X2 is C or N; X 10 is O, NH, N(H)C(O); w is between 0 and 3 (e.g., 0, 1, 2); p is between 1 and 3 (e.g., 1); R 30 It is a substituted C1-C5 straight-chain or branched alkyl group (e.g., C(H)(OH)(CH3)), a C2-C5 straight-chain or branched substituted or unsubstituted alkynyl group (e.g., CCH), a C1-C5 straight-chain or branched alkoxy group (e.g., O-CH3), a C1-C5 straight-chain or branched thioalkoxy group (e.g., S-CH3), a C1-C5 straight-chain, branched or cyclic haloalkyl group (e.g., CHF2), or a substituted or unsubstituted 3-8 membered heterocycle (e.g., tetrahydro- 2H -pyran), N(R) 10 (R) 11 (e.g., N(H)(CH3)), S(O)R (e.g., S(O)-CH3), SO2R (e.g., SO2-CH3), or C(O)R; R 10 and R 11 Each is independently H, OH, a substituted or unsubstituted C1-C5 straight-chain or branched alkyl group, a C1-C5 straight-chain or branched alkoxy group, or a substituted or unsubstituted 3-8 membered heterocycle (e.g., tetrahydro- 2H -pyran); Or R 10 and R 11 They are linked to form substituted or unsubstituted 3-8 membered heterocycles; R is an H or a C1-C5 alkyl group, either substituted or unsubstituted; For example, this article focuses on R and R. 10 R 11 and R 30 As used, the term 'substituted' refers to a substitution selected from the group consisting of: F, Cl, Br, I, OH, CF3, CN, NO2, C1-C5 straight-chain or branched alkoxy (e.g., OCH3), C2-C5 straight-chain or branched alkynyl (e.g., CCH), C1-C5 straight-chain or branched thioalkoxy (e.g., SCH3), C1-C5 straight-chain or branched alkylsulfinyl (e.g., S(O)CH3), C1-C5 straight-chain or branched alkylsulfonyl (e.g., S(O)2-CH3), NH2, C1-C5 straight-chain or branched N(H)(alkyl) (e.g., N(H)(CH3)) and C1-C5 straight-chain or branched N(alkyl)2; Or its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N -Oxides, isotopic variants (e.g., deuterated analogs), reverse amides, or any combination thereof.

2. The compound according to claim 1, represented by any of the following structures: 。 3. A compound, represented by the structure of compound 100: ， Or its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N -Oxides, isotopic variants (e.g., deuterated analogs), reverse amides, or any combination thereof.

4. A compound, represented by the structure of compound 118: ， Or its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N -Oxides, isotopic variants (e.g., deuterated analogs), reverse amides, or any combination thereof.

5. The compound according to any one of claims 1-4, wherein the compound is a collagen translation inhibitor.

6. A pharmaceutical composition comprising the compound according to any one of claims 1-4 and a pharmaceutically acceptable carrier.

7. The compound according to any one of claims 1-5 or the pharmaceutical composition according to claim 6, for use in treating fibrosis in a subject, inhibiting fibrosis in a subject, reducing the severity of fibrosis in a subject, reducing the risk of a subject developing fibrosis, or inhibiting fibrosis in a subject.

8. The compound according to claim 7, wherein the fibrosis is a systemic fibrotic disease.

9. The compound of claim 8, wherein the systemic fibrotic disease is systemic sclerosis, multifocal fibrosis (IgG4-associated fibrosis), renal systemic fibrosis, scleroderma graft-versus-host disease, or any combination thereof.

10. The compound of claim 7, wherein the fibrosis is an organ-specific fibrotic disease.

11. The compound of claim 10, wherein the organ-specific fibrotic disease is pulmonary fibrosis, cardiac fibrosis, renal fibrosis, lung 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.

12. The compound of claim 11, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

13. The compound of claim 11, wherein the cardiac fibrosis is hypertension-related cardiac fibrosis, post-myocardial infarction, Chagas disease-induced myocardial fibrosis, or any combination thereof.

14. The compound of claim 11, wherein the renal fibrosis is diabetic and hypertensive nephropathy, urinary tract obstruction-induced renal fibrosis, inflammatory / autoimmune-induced renal fibrosis, aristolochic acid nephropathy, polycystic kidney disease, or any combination thereof.

15. The compound of claim 11, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, silica-induced pneumoconiosis (silicosis), asbestos-induced pulmonary fibrosis (asbestosis), chemotherapeutic agent-induced pulmonary fibrosis, or any combination thereof.

16. The method of claim 11, wherein the liver 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.

17. The compound of claim 11, wherein the diffuse fasciitis is localized scleroderma, keloid, palmar aponeurosis contracture, Peroni's disease, myelofibrosis, oral submucosal fibrosis, or any combination thereof.

18. The compound of claim 7, wherein the fibrosis is primary fibrosis or secondary fibrosis.

19. The compound of claim 7, wherein the fibrosis is the result of systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, autoimmune disorders, tissue damage, inflammation, oxidative stress, or any combination thereof.

20. The compound of claim 7, wherein the fibrosis is liver fibrosis, pulmonary fibrosis, or dermal fibrosis.

21. The compound according to any one of claims 7 or 16, wherein the subject suffers from cirrhosis.

22. The compound of claim 20, wherein the dermal fibrosis is scleroderma.

23. The compound of claim 20, wherein the dermal fibrosis is the result of localized or generalized morphine scleroderma, keloids, hypertrophic scars, familial skin collagenomas, collagen-type connective tissue nevi, or any combination thereof.

24. The compound of claim 20, wherein the liver fibrosis is a result of liver scarring or chronic liver injury.

25. The compound of claim 24, wherein the chronic liver injury is caused by: alcohol poisoning, malnutrition, hemochromatosis, or exposure to toxins, poisons, or drugs.

26. The compound according to any one of claims 1-5 or the pharmaceutical composition according to claim 6, for use in treating a subject with pulmonary fibrosis, inhibiting pulmonary fibrosis in a subject, reducing the severity of pulmonary fibrosis in a subject, reducing the risk of a subject developing pulmonary fibrosis, or inhibiting pulmonary fibrosis in a subject.

27. The compound of claim 26, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

28. The compound according to any one of claims 1-5 or the pharmaceutical composition according to claim 6, for use in treating a subject with idiopathic pulmonary fibrosis (IPF), inhibiting a subject with idiopathic pulmonary fibrosis (IPF), reducing the severity of a subject with idiopathic pulmonary fibrosis (IPF), reducing the risk of a subject developing idiopathic pulmonary fibrosis (IPF), or inhibiting a subject with idiopathic pulmonary fibrosis (IPF).

29. The compound according to any one of claims 1-5 or the pharmaceutical composition according to claim 6, for use in treating a subject with liver fibrosis disorder, inhibiting a subject with liver fibrosis disorder, reducing the severity of a subject with liver fibrosis disorder, reducing the risk of a subject developing liver fibrosis disorder, or suppressing a subject with liver fibrosis disorder.

30. The compound of claim 29, wherein the liver fibrosis disorder is portal hypertension, cirrhosis, congenital liver fibrosis, or any combination thereof.

31. The compound according to any one of claims 1-5 or the pharmaceutical composition according to claim 6, for use in 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.

32. The compound of claim 31, wherein the cirrhosis is the result of hepatitis or alcohol poisoning.

33. The compound according to any one of claims 1-5 or the pharmaceutical composition according to claim 6, for use in treating alcoholic steatohepatitis (ASH) in a subject, inhibiting alcoholic steatohepatitis (ASH) in a subject, reducing the severity of alcoholic steatohepatitis (ASH) in a subject, reducing the risk of a subject developing alcoholic steatohepatitis (ASH), or inhibiting alcoholic steatohepatitis (ASH) in a subject.

34. The compound according to any one of claims 1-5 or the pharmaceutical composition according to claim 6, for use in treating a subject with non-alcoholic steatohepatitis (NASH), inhibiting a subject's non-alcoholic steatohepatitis (NASH), reducing the severity of a subject's non-alcoholic steatohepatitis (NASH), reducing the risk of a subject developing non-alcoholic steatohepatitis (NASH), or inhibiting a subject's non-alcoholic steatohepatitis (NASH).

35. The compound according to any one of claims 1-5 or the pharmaceutical composition according to claim 6, for use in treating, inhibiting, reducing the severity of alcoholic fatty liver disease (AFLD) in a subject, reducing the risk of developing AFLD in a subject, or inhibiting AFLD in a subject.

36. The compound according to any one of claims 1-5 or the pharmaceutical composition according to claim 6, for use in treating a subject with non-alcoholic fatty liver disease (NAFLD), inhibiting a subject's non-alcoholic fatty liver disease (NAFLD), reducing the severity of a subject's non-alcoholic fatty liver disease (NAFLD), reducing the risk of a subject developing non-alcoholic fatty liver disease (NAFLD), or inhibiting a subject's non-alcoholic fatty liver disease (NAFLD).

37. The compound according to any one of claims 1-5 or the pharmaceutical composition according to claim 6, for use in treating, inhibiting, reducing the severity of an autoimmune disease or disorder in a subject, reducing the risk of the subject developing an autoimmune disease or disorder, or suppressing an autoimmune disease or disorder in a subject.

Images