Collagen 1 translation inhibitors and methods of use thereof

Abstract

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

Description

Technical field

[0001] The present invention provides novel collagen 1 translation inhibitors, compositions containing the same, methods for producing them, and fibrosis (including pulmonary fibrosis, liver fibrosis, renal fibrosis, cardiac fibrosis, and dermal fibrosis). , IPF (idiopathic pulmonary fibrosis), wound healing, cicatricial fibromatosis, gingival fibromatosis, systemic sclerosis, alcoholic steatohepatitis, and non-alcoholic steatohepatitis (NASH) regarding the use of [Background technology]

[0002] The formation of fibrous connective tissue is part of the normal healing process after tissue damage due to injury or inflammation. During this healing process, activated immune cells, including macrophages, stimulate the proliferation and activation of fibroblasts, thereby depositing connective tissue. Abnormal or excessive production of connective tissue, however, can lead to the accumulation of fibrous material that interferes with the normal functioning of the tissue. Fibrogrowth can continue and invade healthy surrounding tissue even after the original injury has healed. Such abnormal formation of excess connective tissue occurs in a reparative or reactive process and is called fibrosis.

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

[0004] Physiologically, fibrosis deposits connective tissue and obliterates the structure and function of the underlying organs and tissues. Fibrosis, defined by the pathological accumulation of extracellular matrix (ECM) proteins, leads to scarring and thickening of the affected tissue and interferes with normal organ function. In a variety of conditions, the formation of fibrous tissue is characterized by the deposition of abnormally large amounts of collagen. Collagen synthesis is also implicated in a variety of other pathological conditions. Clinical conditions and diseases associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, and autoimmune diseases, are associated with normal histology. and by overproduction of connective tissue leading to disruption of function. These diseases can best be interpreted in terms of perturbations of cellular function, the major symptom of which is excessive synthesis and deposition of collagen. Given the role of collagen in fibrosis, attempts have been made to develop drugs that inhibit collagen accumulation.

[0005] Excessive accumulation of collagen is a major pathological feature in various clinical conditions characterized by tissue fibrosis. These clinical conditions include local processes such as pulmonary fibrosis and cirrhosis, or systemic processes such as progressive systemic sclerosis. In addition to scleroderma, collagen deposition is associated with various forms of dermal fibrosis, including focal or generalized scleroderma, keloids, hypertrophic scars, familial cutaneous collagenoma, and collagenous connective tissue nevus. It is a feature. Recent advances in understanding the normal biochemistry of collagen have made it possible to define specific levels of collagen biosynthesis and degradation at which pharmacological intervention would lead to reduced collagen deposition within tissues. Such compounds may provide a novel means to reduce collagen over-accumulation in disease.

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

[0007] Although fibrosis itself is not necessarily symptomatic, it can lead to the development of cirrhosis, and scarring can lead to portal hypertension, which distorts blood flow through the liver, and to disruption of normal liver architecture and liver dysfunction. There is The degree of each of these pathologies determines the clinical manifestations of liver fibrotic disorders. For example, in congenital liver fibrosis, the portal vein branches are affected and the parenchyma is rarely affected. The result is portal hypertension with preservation of hepatocyte function.

[0008] treatment

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

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

[0011] Many patients do not respond to available therapies for fibrosis, and long-term treatment is limited by toxicity and side effects. As such, there remains a need to develop therapies aimed at reducing fibrosis. The development of safe and effective therapies for established cirrhosis and portal hypertension and to attenuate fibrosis would be of great benefit.

[0012] Attempts to treat idiopathic pulmonary fibrosis (IPF) with concomitant use of anti-inflammatory drugs (prednisone, azathioprine, N-acetyl-L-cysteine ​​(NAC)) failed to improve prognosis and rather increased mortality. rice field. In 2014, pirfenidone, a drug with poorly understood mechanisms, and tyrosine kinase inhibitor Two drugs, nintedanib, have been approved for the treatment of IPF. However, it is currently unclear whether these agents improve symptoms such as dyspnea and cough, or whether their beneficial effects on functional decline lead to increased survival.

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

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

[0015] The present invention further provides compounds represented by the structures of Formulas I-VIII defined herein below and the structures listed in Table 1, or pharmaceutically acceptable salts, optical isomers, tautomers thereof , hydrates, N-oxides, reverse amide analogs, prodrugs, isotopic variants (e.g., deuterated analogs), PROTACs, pharmaceuticals, or any combination thereof and a pharmaceutically acceptable carrier. and a pharmaceutical composition.

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

[0017] The invention further provides a method for treating, inhibiting, reducing the severity of, reducing the risk of developing, or inhibiting pulmonary fibrosis in a subject, comprising: Compounds represented by the structures of Formulas I-VIII defined herein below and the structures listed in Table 1 are used to treat, inhibit, reduce the severity of, reduce the risk of developing, or inhibit pulmonary fibrosis in said subject. Methods are provided that include administering under effective conditions. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

[0018] The invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting idiopathic pulmonary fibrosis (IPF) in a subject, comprising: Compounds represented by the structures of Formulas I-VIII defined herein below and the structures listed in Table 1 for the treatment of idiopathic pulmonary fibrosis (IPF) in said subject, Methods are provided comprising administering under conditions effective to suppress, reduce severity, reduce risk of developing, or inhibit.

[0019] The invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting liver fibrosis in a subject, comprising: Compounds represented by the structures of Formulas I-VIII defined below in this document and the structures listed in Table 1 are used to treat, inhibit, reduce the severity of, reduce the risk of developing, or inhibit liver fibrosis in said subject. Methods are provided that include administering under effective conditions. In some embodiments, the liver fibrosis is portal hypertension, liver cirrhosis, congenital liver fibrosis, or any combination thereof.

[0020] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting cirrhosis in a subject, comprising: Administering a compound represented by the defined structures of Formulas I-VIII and the structures listed in Table 1 under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of developing, or inhibit cirrhosis in said subject. A method is provided that includes the step of: In some embodiments, cirrhosis is the result of hepatitis or alcoholism.

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

[0022] The invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting non-alcoholic steatohepatitis (NASH) in a subject, comprising: Compounds represented by the structures of Formulas I-VIII defined herein below and the structures listed in Table 1 are administered to a subject suffering from non-alcoholic steatohepatitis (NASH) in said subject. Methods are provided comprising administering under conditions effective to treat, suppress, reduce severity, reduce risk of developing, or inhibit.

[0023] The invention further provides a method for treating, inhibiting, reducing the severity of, reducing the risk of developing, or inhibiting alcoholic fatty liver disease (AFLD) in a subject, comprising: Compounds represented by the structures of Formulas I-VIII defined herein below and the structures listed in Table 1 are administered to a subject suffering from Alcoholic Fatty Liver Disease (AFLD) in said subject. administering under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of developing, or inhibit

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

[0025] The invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting an autoimmune disease or disorder in a subject, comprising: Thus, compounds represented by the structures of Formulas I-VIII defined herein below and the structures listed in Table 1 are used to treat, inhibit, reduce the severity of, or risk developing an autoimmune disease or disorder in said subject. administering under conditions effective to reduce or inhibit

[0026] The invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting an autoimmune disease or disorder in a subject, comprising: Thus, compounds represented by the structures of Formulas I-VIII defined herein below and the structures listed in Table 1 are used to treat, inhibit, reduce the severity of, or risk developing an autoimmune disease or disorder in said subject. administering under conditions effective to reduce or inhibit [Brief description of the drawing]

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

[0028]

Figure 1

Figure 2

[0029] In various embodiments, the present invention provides compounds represented by Formula I below, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N-oxides, reverse amides thereof. Analogs, prodrugs, isotopic variants (eg, deuterated analogs), PROTACs, pharmaceuticals, or any combination thereof are provided.

[0030] [formation]

[0031] During the ceremony, Ring A and Ring B are independently of each other single or fused aromatic or heteroaromatic ring systems (e.g. Ring A: phenyl, thiophene, imidazole, pyrazole, pyrimidine, 2-, 3- or 4-pyridine, benzimidazole, indole, benzothiazole, benzoxazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine, pyridazine, pyrazine; B ring: phenyl, pyrimidine, 2-, 3- or 4-pyridine, pyridazine, pyrazine, thiophene, thiazole, pyrrole, imidazole, indazole), single or condensed C 3 -C 10 Cycloalkyl (e.g. A ring: pyrrolidin-2-one; B ring: bicyclo[1.1.1]pentyl, cyclobutyl, cyclohexyl, cyclopentyl), or single or fused C 3 -C 10 is a heterocycle (e.g. morpholine, piperidine, piperazine, tetrahydro-2H-pyran, azetidine, pyrrolidin-2-one); R. 1 and R 2 are, independently of each other, H, F, Cl, Br, I, OH, SH, R 8 -OH (e.g. CH 2 OH), R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 3 ), -O-R 8 -O-R 10 (e.g. O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , R 8 -N(R 10 )(R 11 ) (e.g. CH 2 -NH-CH 3 , CH 2 -NH-C(O)CH 3 , CH 2 -N(CH 3 ) 2 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R (e.g., NHCO-Ph, NHCO-CH 3 ), NHC(O)-R 10 (e.g., NHC(O)CH 3 ), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g. C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO 2 R, SO 2 N(R 10 )(R 11 ), NHSOs 2 (R 10 ) (for example, NHSO 2 CH 3 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 linear or branched or cyclic alkoxy (e.g. methoxy) (optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocycle (e.g. azetidine, pyridine), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; or R 2 and R 1 are bonded to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., 1,4-dioxane, 2,3-dihydro -1,4-dioxin, dioxol, dioxolpyridine); R. 3 and R 4 are, independently of each other, H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , N(R 10 )(R 11 ) (e.g. morpholine, piperazine), R8 -N(R 10 )(R 11 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R 10 , NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g., C(O)NH(CH 3 ) 2 O-CH 3 ), C(O)N(R 10 )(R 11 ) (e.g. C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH 3 ) 2 , C(O)-piperazine), SO 2 R, SO 2 N(R 10 )(R 11 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 straight or branched chain or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone)piperidin-4-oxy) ( Optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted, single, spirocyclic, fused or bridged C 3 -C 10 heterocycles (e.g. piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy -1-(piperazin-1-yl)ethenone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1- (piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)ethenone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methyl Morpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl- 2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2, 6-diazaspiro[3.3]heptan-2-yl)ethenone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; or R 3 and R 4 are attached to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole); R. 5 is H, R 20 , F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 , R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , R 8 -N(R 10 )(R 11 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R 10 , NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR, C(O)N(R 10 )(R 11 ), SO 2 R, SO 2 N(R 10 )(R 11 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 linear or branched or cyclic alkoxy (e.g. methoxy) (optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocycle (e.g. azetidine, pyridine), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; Q. 1 is NH, S, or O; G=X is C=O, C=S, S=O, or SO 2 is; R is H, OH, F, Cl, Br, I, CN, CF 3 , NO 2 , NH 2 , NH(R 10 )(e.g. NH(CH 3 )), N(R 10 )(R 11 ), R 20 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 ), R 8 -R 10 (e.g. CH 2 -OH, CH 2 CH 2 -OH), C(O)-R 10 (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH 3 ), C 1 -C 5 substituted or unsubstituted C(O)-alkyl (e.g. C(O)-CH 2 CH 2 -OCH 3 , C(O)-CH 3 , C(O)-CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -OH), C(O)-R 8 -R10 (e.g. C(O)-CH 2 CH 2 -OH), C(O) substituted or unsubstituted C 3 -C 8 heterocycles (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine), C 1 -C 5 Substituted or unsubstituted SO for 2 -alkyl (e.g. SO 2 -CH 3 ), C 1 -C 5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH 3 ), C 1 -C 5 linear or branched C(O)-O-alkyl (e.g. C(O)-O-tBu), C 1 -C 5 straight or branched alkoxy, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain haloalkyl (e.g. CF 3 , CF 2 CH 3 , CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )-CH(CH 3 ) 2 ), R 8 -aryl (e.g., CH 2 -Ph), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted heteroaryl (e.g. pyridine (2-, 3- or 4-pyridine)); or two geminal R substituents joined together to form a 3- to 6-membered substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene), or heterocyclic ring (e.g. thiophene, furan, pyrrole, pyrazole); R. 8 is [CH 2 ]p, where p is between 1 and 10 (eg, 2); R. 9 is [CH]q, [C]q, q is 2-10; R. 10 and R 11 are independently of each other H, OH, substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain alkoxy (e.g., O-CH 3 ), substituted or unsubstituted C 3 -C 8 heterocycles (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 - is an alkyl; or R 10 and R 11 are combined with each other to form a substituted or unsubstituted C 3 -C 8 forming heterocycles (e.g. morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R. 20 is represented by the following structure;

[0032] [formation]

[0033] Substituents include F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are each independently an integer from 1 to 3 (eg, 1 or 2); m and k are independently integers from 0 to 3 (eg, 0).

[0034] In various embodiments, the present invention provides compounds represented by Formula II below, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N-oxides, reverse amides thereof. Analogs, prodrugs, isotopic variants (eg, deuterated analogs), PROTACs, pharmaceuticals, or any combination thereof are provided.

[0035] [formation]

[0036] During the ceremony, Ring A is a single or fused aromatic or heteroaromatic ring system (e.g. phenyl, thiophene, imidazole, pyrazole, pyrimidine, 2-, 3- or 4-pyridine, benzimidazole, indole, benzothiazole , benzoxazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine, pyridazine, pyrazine), single or condensed C 3 -C 10 cycloalkyl (e.g. pyrrolidin-2-one) or single or fused C 3 -C 10 is a heterocycle (e.g. morpholine, piperidine, piperazine, tetrahydro-2H-pyran, azetidine, pyrrolidin-2-one); R. 1 and R 2 are, independently of each other, H, F, Cl, Br, I, OH, SH, R 8 -OH (e.g. CH 2 OH), R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 3 ), -O-R 8 -O-R 10 (e.g. O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , R 8 -N(R 10 )(R 11 ) (e.g. CH 2 -NH-CH 3 , CH 2 -NH-C(O)CH 3 , CH 2 -N(CH 3 ) 2 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R (e.g., NHCO-Ph, NHCO-CH 3 ), NHC(O)-R 10 (e.g., NHC(O)CH 3 ), NHCO-N(R 10 )(R11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO 2 R, SO 2 N(R 10 )(R 11 ), NHSOs 2 (R 10 ) (for example, NHSO 2 CH 3 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 linear or branched or cyclic alkoxy (e.g. methoxy) (optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocycle (e.g. azetidine, pyridine), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; or R 2 and R 1 are bonded to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., 1,4-dioxane, 2,3-dihydro -1,4-dioxin, dioxol, dioxolpyridine); R. 3 and R 4 are, independently of each other, H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , N(R 10 )(R 11 ) (e.g. morpholine, piperazine), R 8 -N(R 10 )(R 11 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R 10 , NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g., C(O)NH(CH 3 ) 2 O-CH 3 ), C(O)N(R 10 )(R 11 ) (e.g. C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH 3 ) 2 , C(O)-piperazine), SO 2 R, SO 2 N(R 10 )(R 11 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 straight or branched chain or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone)piperidin-4-oxy) ( Optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted, single, spirocyclic, fused or bridged C 3 -C 10 heterocycles (e.g. piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy -1-(piperazin-1-yl)ethenone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1- (piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)ethenone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methyl Morpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl- 2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2, 6-diazaspiro[3.3]heptan-2-yl)ethenone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; or R 3 and R 4 are attached to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole); X 3 , X 4 , and X 5 are, independently of each other, C or N; R is H, OH, F, Cl, Br, I, CN, CF 3 , NO 2 , NH 2 , NH(R 10 )(e.g. NH(CH 3 )), N(R 10 )(R 11 ), R 20 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 ), R 8 -R 10 (e.g. CH 2 -OH, CH 2 CH 2 -OH), C(O)-R 10 (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH 3 ), C 1 -C 5 substituted or unsubstituted C(O)-alkyl (e.g. C(O)-CH 2 CH 2 -OCH 3, C(O)-CH 3 , C(O)-CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -OH), C(O)-R 8 -R 10 (e.g. C(O)-CH 2 CH 2 -OH), C(O) substituted or unsubstituted C 3 -C 8 heterocycles (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine), C 1 -C 5 Substituted or unsubstituted SO for 2 -alkyl (e.g. SO 2 -CH 3 ), C 1 -C 5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH 3 ), C 1 -C 5 linear or branched C(O)-O-alkyl (e.g. C(O)-O-tBu), C 1 -C 5 straight or branched alkoxy, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain haloalkyl (e.g. CF 3 , CF 2 CH 3 , CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )-CH(CH 3 ) 2 ), R 8 -aryl (e.g., CH 2 -Ph), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted heteroaryl (e.g. pyridine (2-, 3- or 4-pyridine)); or two geminal R substituents joined together to form a 3- to 6-membered substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene), or heterocyclic ring (e.g. thiophene, furan, pyrrole, pyrazole); R. 8 is [CH 2 ]p, where p is between 1 and 10 (eg, 2); R. 9 is [CH]q, [C]q, q is 2-10; R. 10 and R 11 are independently of each other H, OH, substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain alkoxy (e.g., O-CH 3 ), substituted or unsubstituted C 3 -C 8 heterocycles (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 - is an alkyl; or R 10 and R 11 are combined with each other to form a substituted or unsubstituted C 3 -C 8 forming heterocycles (e.g. morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R. 20 is represented by the following structure;

[0037] [formation]

[0038] Substituents include F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 including cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are each independently an integer from 1 to 3 (eg, 1 or 2); m and k are independently integers from 0 to 3 (eg, 0).

[0039] In various embodiments, the present invention provides compounds represented by Formula III below, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N-oxides, reverse amides thereof. Analogs, prodrugs, isotopic variants (eg, deuterated analogs), PROTACs, pharmaceuticals, or any combination thereof are provided.

[0040] [formation]

[0041] During the ceremony, R. 1 and R 2 are, independently of each other, H, F, Cl, Br, I, OH, SH, R 8 -OH (e.g. CH 2 OH), R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 3 ), -O-R 8 -O-R 10 (e.g. O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , R 8 -N(R 10 )(R 11 ) (e.g. CH 2 -NH-CH 3 , CH 2 -NH-C(O)CH 3 , CH 2 -N(CH 3 ) 2 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R (e.g., NHCO-Ph, NHCO-CH 3 ), NHC(O)-R 10 (e.g., NHC(O)CH 3 ), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO 2 R, SO 2 N(R 10 )(R 11 ), NHSOs 2 (R 10 ) (for example, NHSO 2 CH 3 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 linear or branched or cyclic alkoxy (e.g. methoxy) (optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocycle (e.g. azetidine, pyridine), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; or R 2 and R 1 are bonded to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., 1,4-dioxane, 2,3-dihydro -1,4-dioxin, dioxol, dioxolpyridine); R. 3 and R 4 are, independently of each other, H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , N(R 10 )(R 11 ) (e.g. morpholine, piperazine), R 8 -N(R 10 )(R 11 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R 10 , NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g., C(O)NH(CH 3 ) 2 O-CH 3 ), C(O)N(R 10 )(R 11 ) (e.g. C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH 3 ) 2 , C(O)-piperazine), SO 2 R, SO 2 N(R 10 )(R 11 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 straight or branched chain or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone)piperidin-4-oxy) ( Optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted, single, spirocyclic, fused or bridged C 3 -C 10 heterocycles (e.g. piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy -1-(piperazin-1-yl)ethenone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1- (piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)ethenone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methyl Morpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl- 2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2, 6-diazaspiro[3.3]heptan-2-yl)ethenone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; or R 3 and R 4 are attached to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole); X 1 , X 2 , X 3 , X 4 , and X 5 are, independently of each other, C or N; R is H, OH, F, Cl, Br, I, CN, CF 3 , NO 2 , NH 2 , NH(R 10 )(e.g. NH(CH 3 )), N(R 10 )(R 11 ), R 20 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 ), R 8 -R 10 (e.g. CH 2 -OH, CH 2 CH 2 -OH), C(O)-R 10 (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH 3 ), C 1 -C 5 substituted or unsubstituted C(O)-alkyl (e.g. C(O)-CH 2 CH 2 -OCH 3 , C(O)-CH 3 , C(O)-CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -CH2 -N(CH 3 ) 2 , C(O)-CH 2 -OH), C(O)-R 8 -R 10 (e.g. C(O)-CH 2 CH 2 -OH), C(O) substituted or unsubstituted C 3 -C 8 heterocycles (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine), C 1 -C 5 Substituted or unsubstituted SO for 2 -alkyl (e.g. SO 2 -CH 3 ), C 1 -C 5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH 3 ), C 1 -C 5 linear or branched C(O)-O-alkyl (e.g. C(O)-O-tBu), C 1 -C 5 straight or branched alkoxy, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain haloalkyl (e.g. CF 3 , CF 2 CH 3 , CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )-CH(CH 3 ) 2 ), R 8 -aryl (e.g., CH 2 -Ph), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted heteroaryl (e.g. pyridine (2-, 3- or 4-pyridine)); or two geminal R substituents joined together to form a 3- to 6-membered substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene), or heterocyclic ring (e.g. thiophene, furan, pyrrole, pyrazole); R. 8 is [CH 2 ]p, where p is between 1 and 10 (eg, 2); R. 9 is [CH]q, [C]q, q is 2-10; R. 10 and R 11 are independently of each other H, OH, substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain alkoxy (e.g., O-CH 3 ), substituted or unsubstituted C 3 -C 8 heterocycles (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 - is an alkyl; or R 10 and R 11 are combined with each other to form a substituted or unsubstituted C 3 -C 8 forming heterocycles (e.g. morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R. 20 is represented by the following structure;

[0042] [formation]

[0043] Substituents include F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 including cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are each independently an integer from 1 to 3 (eg, 1 or 2); m and k are independently integers from 0 to 3 (eg, 0).

[0044] In various embodiments, the present invention provides compounds represented by Formula IV below, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N-oxides, reverse amides thereof. Analogs, prodrugs, isotopic variants (eg, deuterated analogs), PROTACs, pharmaceuticals, or any combination thereof are provided.

[0045] [formation]

[0046] During the ceremony, R. 1 is H, F, Cl, Br, I, OH, SH, R 8 -OH (e.g. CH 2 OH), R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 3 ), -O-R 8 -O-R 10 (e.g. O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , R 8 -N(R 10 )(R 11 ) (e.g. CH 2 -NH-CH 3 , CH 2 -NH-C(O)CH 3 , CH 2 -N(CH 3 ) 2 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R (e.g., NHCO-Ph, NHCO-CH 3 ), NHC(O)-R 10 (e.g., NHC(O)CH 3 ), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO 2 R, SO 2N(R 10 )(R 11 ), NHSOs 2 (R 10 ) (for example, NHSO 2 CH 3 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 linear or branched or cyclic alkoxy (e.g. methoxy) (optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocycle (e.g. azetidine, pyridine), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; R. 3 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , N(R 10 )(R 11 ) (e.g. morpholine, piperazine), R 8 -N(R 10 )(R 11 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R 10 , NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g., C(O)NH(CH 3 ) 2 O-CH 3 ), C(O)N(R 10 )(R 11 ) (e.g. C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH 3 ) 2 , C(O)-piperazine), SO 2 R, SO 2 N(R 10 )(R 11 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 straight or branched chain or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone)piperidin-4-oxy) ( Optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted, single, spirocyclic, fused or bridged C 3 -C 10 heterocycles (e.g. piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy -1-(piperazin-1-yl)ethenone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1- (piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)ethenone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methyl Morpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl- 2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2, 6-diazaspiro[3.3]heptan-2-yl)ethenone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; or R 3 and R 4 are attached to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic (e.g., cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furan, pyrrole, pyrazole); X 1 , X 2 , X 3 , X 4 , and X 5 are, independently of each other, C or N; R is H, OH, F, Cl, Br, I, CN, CF 3 , NO 2 , NH 2 , NH(R 10 )(e.g. NH(CH 3 )), N(R 10 )(R 11 ), R 20 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 ), R 8 -R 10 (e.g. CH 2 -OH, CH 2 CH 2 -OH), C(O)-R 10 (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH 3 ), C 1 -C 5 substituted or unsubstituted C(O)-alkyl (e.g. C(O)-CH 2 CH 2 -OCH 3 , C(O)-CH 3 , C(O)-CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -OH), C(O)-R 8 -R 10 (e.g. C(O)-CH 2 CH 2 -OH), C(O) substituted or unsubstituted C 3 -C 8 heterocycles (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine), C 1 -C 5 Substituted or unsubstituted SO for 2 -alkyl (e.g. SO 2 -CH 3 ), C1 -C 5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH 3 ), C 1 -C 5 linear or branched C(O)-O-alkyl (e.g. C(O)-O-tBu), C 1 -C 5 straight or branched alkoxy, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain haloalkyl (e.g. CF 3 , CF 2 CH 3 , CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )-CH(CH 3 ) 2 ), R 8 -aryl (e.g., CH 2 -Ph), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted heteroaryl (e.g. pyridine (2-, 3- or 4-pyridine)); or two geminal R substituents joined together to form a 3- to 6-membered substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene), or heterocyclic ring (e.g. thiophene, furan, pyrrole, pyrazole); R. 8 is [CH 2 ]p, where p is between 1 and 10 (eg, 2); R. 9 is [CH]q, [C]q, q is 2-10; R. 10 and R 11 are independently of each other H, OH, substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain alkoxy (e.g., O-CH 3 ), substituted or unsubstituted C 3 -C 8 heterocycles (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 - is an alkyl; or R 10 and R 11 are combined with each other to form a substituted or unsubstituted C 3 -C 8 forming heterocycles (e.g. morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R. 20 is represented by the following structure;

[0047] [formation]

[0048] Substituents include F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are each independently an integer from 1 to 3 (eg, 1 or 2); m and k are independently integers from 0 to 3 (eg, 0).

[0049] In various embodiments, the present invention provides compounds represented by Formula V below, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N-oxides, reverse amides thereof. Analogs, prodrugs, isotopic variants (eg, deuterated analogs), PROTACs, pharmaceuticals, or any combination thereof are provided.

[0050] [formation]

[0051] During the ceremony, R. 1 is H, F, Cl, Br, I, OH, SH, R 8 -OH (e.g. CH 2 OH), R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 3 ), -O-R 8 -O-R 10 (e.g. O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , R 8 -N(R 10 )(R 11 ) (e.g. CH 2 -NH-CH 3 , CH 2 -NH-C(O)CH 3 , CH 2 -N(CH 3 ) 2 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R (e.g., NHCO-Ph, NHCO-CH 3 ), NHC(O)-R 10 (e.g., NHC(O)CH 3 ), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g. C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO 2 R, SO 2 N(R 10 )(R 11 ), NHSOs 2 (R 10 ) (for example, NHSO 2 CH 3 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF2 ), C 1 -C 5 linear or branched or cyclic alkoxy (e.g. methoxy) (optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocycle (e.g. azetidine, pyridine), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; R. 3 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , N(R 10 )(R 11 ) (e.g. morpholine, piperazine), R 8 -N(R 10 )(R 11 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R 10 , NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g., C(O)NH(CH 3 ) 2 O-CH 3 ), C(O)N(R 10 )(R 11 ) (e.g. C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH 3 ) 2 , C(O)-piperazine), SO 2 R, SO 2 N(R 10 )(R 11 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 straight or branched chain or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone)piperidin-4-oxy) ( Optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted, single, spirocyclic, fused or bridged C 3 -C 10 heterocycles (e.g. piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy -1-(piperazin-1-yl)ethenone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1- (piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)ethenone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methyl Morpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl- 2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2, 6-diazaspiro[3.3]heptan-2-yl)ethenone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; X 1 , X 2 , X 3 , X 4 , and X 5 are, independently of each other, C or N; R is H, OH, F, Cl, Br, I, CN, CF 3 , NO 2 , NH 2 , NH(R 10 )(e.g. NH(CH 3 )), N(R 10 )(R 11 ), R 20 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 ), R 8 -R 10 (e.g. CH 2 -OH, CH 2 CH 2 -OH), C(O)-R 10 (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH 3 ), C 1 -C 5 substituted or unsubstituted C(O)-alkyl (e.g. C(O)-CH 2 CH 2 -OCH 3 , C(O)-CH 3 , C(O)-CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -OH), C(O)-R 8 -R 10 (e.g. C(O)-CH 2 CH 2 -OH), C(O) substituted or unsubstituted C 3 -C 8 heterocycles (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine), C 1 -C 5 Substituted or unsubstituted SO for 2 -alkyl (e.g. SO 2 -CH 3 ), C 1 -C 5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH 3 ), C 1 -C 5 linear or branched C(O)-O-alkyl (e.g. C(O)-O-tBu), C 1 -C 5 straight or branched alkoxy, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain haloalkyl (e.g. CF 3 , CF 2 CH 3 , CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )-CH(CH 3 ) 2 ), R 8 -aryl (e.g., CH 2 -Ph), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted heteroaryl (e.g. pyridine (2-, 3- or 4-pyridine)); or two geminal R substituents joined together to form a 3- to 6-membered substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene), or heterocyclic ring (e.g. thiophene, furan, pyrrole, pyrazole); R. 8 is [CH 2 ]p, where p is between 1 and 10 (eg, 2); R. 9 is [CH]q, [C]q, q is 2-10; R. 10 and R 11 are independently of each other H, OH, substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain alkoxy (e.g., O-CH 3 ), substituted or unsubstituted C 3 -C 8 heterocycles (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 - is an alkyl; or R 10 and R 11 are combined with each other to form a substituted or unsubstituted C 3 -C 8 forming heterocycles (e.g. morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R. 20 is represented by the following structure;

[0052] [formation]

[0053] Substituents include F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 including cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are each independently an integer from 1 to 3 (eg, 1 or 2); m and k are independently integers from 0 to 3 (eg, 0).

[0054] In various embodiments, the present invention provides compounds represented by Formula VI below, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N-oxides, reverse amides thereof. Analogs, prodrugs, isotopic variants (eg, deuterated analogs), PROTACs, pharmaceuticals, or any combination thereof are provided.

[0055] [formation]

[0056] During the ceremony, R. 1 and R 2 are, independently of each other, H, F, Cl, Br, I, OH, SH, R 8 -OH (e.g. CH 2 OH), R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 3 ), -O-R 8 -O-R 10 (e.g. O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , R 8 -N(R 10 )(R 11 ) (e.g. CH 2 -NH-CH 3 , CH 2 -NH-C(O)CH 3 , CH 2 -N(CH 3 ) 2 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R (e.g., NHCO-Ph, NHCO-CH 3 ), NHC(O)-R 10 (e.g., NHC(O)CH 3 ), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO 2 R, SO 2 N(R 10 )(R 11 ), NHSOs 2 (R 10 ) (for example, NHSO 2 CH 3 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 linear or branched or cyclic alkoxy (e.g. methoxy) (optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocycle (e.g. azetidine, pyridine), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; or R 2 and R 1 are bonded to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., 1,4-dioxane, 2,3-dihydro -1,4-dioxin, dioxol, dioxolpyridine); R. 4 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , N(R 10 )(R 11 ) (e.g. morpholine, piperazine), R 8 -N(R 10 )(R 11 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R 10 , NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g., C(O)NH(CH 3 ) 2 O-CH 3 ), C(O)N(R 10 )(R 11 ) (e.g. C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH 3 ) 2 , C(O)-piperazine), SO 2 R, SO 2 N(R 10 )(R 11 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 straight or branched chain or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone)piperidin-4-oxy) ( Optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted, single, spirocyclic, fused or bridged C 3 -C 10 heterocycles (e.g. piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy -1-(piperazin-1-yl)ethenone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1- (piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)ethenone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methyl Morpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl- 2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2, 6-diazaspiro[3.3]heptan-2-yl)ethenone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; X 1 , X 2 , X 3 , X 4 , and X 5 are, independently of each other, C or N; X 6 is O, CH 2 , CHR (e.g., CH(OH), CH(NH 2 ), CH(NH(CH 3 ))), C(R 10 )(R 11 ) (e.g., C(H)CH 2 CH 2 -OH, C(H)CH 2 -OH, 1-methylazetidine), NH, N-R (e.g. N-CH 3 , N-SO 2 -CH 3 , N-R 20 , N-CH 2 CH 2 -OCH 3 , ) or N-C(O)-R 10 (e.g., N-C(O)O-tBu, N-C(O)-CH 2 CH 2 -OCH 3 , N-C(O)-CH 3 , N-C(O)-CH 2 -N(CH 3 ) 2 , N-C(O)-CH 2 -CH 2 -N(CH 3 ) 2 , N-C(O)-CH 2 -OH, N-C(O)-CH 2 CH 2 -OH, N-C(O)-NH-CH 3 , N-C(O)-1-methyl-2-pyrrolidine, N-C(O)-1-methyl-3-pyrrolidine, N-C(O)-1-methyl-3-piperidine, N-C(O)-1-methyl-4 -piperidine); R is H, OH, F, Cl, Br, I, CN, CF 3 , NO 2 , NH 2 , NH(R 10 )(e.g. NH(CH 3 )), N(R 10 )(R 11 ), R 20 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 ), R 8 -R 10 (e.g. CH 2 -OH, CH 2 CH 2 -OH), C(O)-R 10 (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH 3 ), C 1 -C 5 substituted or unsubstituted C(O)-alkyl (e.g. C(O)-CH 2 CH 2 -OCH 3 , C(O)-CH 3 , C(O)-CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -OH), C(O)-R 8 -R 10 (e.g. C(O)-CH 2 CH 2 -OH), C(O) substituted or unsubstituted C 3 -C 8 heterocycles (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine), C 1 -C 5 Substituted or unsubstituted SO for 2 -alkyl (e.g. SO 2 -CH3 ), C 1 -C 5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH 3 ), C 1 -C 5 linear or branched C(O)-O-alkyl (e.g. C(O)-O-tBu), C 1 -C 5 straight or branched alkoxy, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain haloalkyl (e.g. CF 3 , CF 2 CH 3 , CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )-CH(CH 3 ) 2 ), R 8 -aryl (e.g., CH 2 -Ph), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted heteroaryl (e.g. pyridine (2-, 3- or 4-pyridine)); or two geminal R substituents joined together to form a 3- to 6-membered substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene), or heterocyclic ring (e.g. thiophene, furan, pyrrole, pyrazole); R. 8 is [CH 2 ]p, where p is between 1 and 10 (eg, 2); R. 9 is [CH]q, [C]q, q is 2-10; R. 10 and R 11 are independently of each other H, OH, substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain alkoxy (e.g., O-CH 3 ), substituted or unsubstituted C 3 -C 8 heterocycles (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 - is an alkyl; or R 10 and R 11 are combined with each other to form a substituted or unsubstituted C 3 -C 8 forming heterocycles (e.g. morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R. 20 is represented by the following structure;

[0057] [formation]

[0058] Substituents include F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are each independently an integer from 1 to 3 (eg, 1 or 2); m and k are independently integers from 0 to 2 (eg, 0).

[0059] In various embodiments, the present invention provides compounds represented by Formula VII below, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N-oxides, reverse amides thereof. Analogs, prodrugs, isotopic variants (eg, deuterated analogs), PROTACs, pharmaceuticals, or any combination thereof are provided.

[0060] [formation]

[0061] During the ceremony, Ring A is a single or fused aromatic or heteroaromatic ring system (e.g. phenyl, thiophene, imidazole, pyrazole, pyrimidine, 2-, 3- or 4-pyridine, benzimidazole, indole, benzothiazole , benzoxazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine, pyridazine, pyrazine), single or condensed C 3 -C 10 cycloalkyl (e.g. pyrrolidin-2-one) or single or fused C 3 -C 10 is a heterocycle (e.g. morpholine, piperidine, piperazine, tetrahydro-2H-pyran, azetidine, pyrrolidin-2-one); R. 1 and R 2 are, independently of each other, H, F, Cl, Br, I, OH, SH, R 8 -OH (e.g. CH 2 OH), R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 3 ), -O-R 8 -O-R 10 (e.g. O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , R 8 -N(R 10 )(R 11 ) (e.g. CH 2 -NH-CH 3 , CH 2 -NH-C(O)CH 3 , CH 2 -N(CH 3 ) 2 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R (e.g., NHCO-Ph, NHCO-CH 3 ), NHC(O)-R 10 (e.g., NHC(O)CH 3 ), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R11 ), SO 2 R, SO 2 N(R 10 )(R 11 ), NHSOs 2 (R 10 ) (for example, NHSO 2 CH 3 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 linear or branched or cyclic alkoxy (e.g. methoxy) (optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocycle (e.g. azetidine, pyridine), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; or R 2 and R 1 are bonded to each other to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., 1,4-dioxane, 2,3-dihydro -1,4-dioxin, dioxol, dioxolpyridine); R. 4 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , N(R 10 )(R 11 ) (e.g. morpholine, piperazine), R 8 -N(R 10 )(R 11 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R 10 , NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g., C(O)NH(CH 3 ) 2 O-CH 3 ), C(O)N(R 10 )(R 11 ) (e.g. C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH 3 ) 2 , C(O)-piperazine), SO 2 R, SO 2 N(R 10 )(R 11 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 straight or branched chain or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone)piperidin-4-oxy) ( Optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted, single, spirocyclic, fused or bridged C 3 -C 10 heterocycles (e.g. piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy -1-(piperazin-1-yl)ethenone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1- (piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)ethenone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methyl Morpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl- 2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2, 6-diazaspiro[3.3]heptan-2-yl)ethenone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; X 3 , X 4 , and X 5 are, independently of each other, C or N; X 6 is O, CH 2 , CHR (e.g., CH(OH), CH(NH 2 ), CH(NH(CH 3 ))), C(R 10 )(R 11 ) (e.g., C(H)CH 2 CH 2 -OH, C(H)CH 2 -OH, 1-methylazetidine), NH, N-R (e.g. N-CH 3 , N-SO 2 -CH 3 , N-R 20 , N-CH 2 CH 2 -OCH 3 , ) or N-C(O)-R 10 (e.g., N-C(O)O-tBu, N-C(O)-CH 2 CH 2 -OCH 3 , N-C(O)-CH 3 , N-C(O)-CH 2 -N(CH 3 ) 2 , N-C(O)-CH 2 -CH 2 -N(CH 3 ) 2 , N-C(O)-CH 2 -OH, N-C(O)-CH 2 CH 2 -OH, N-C(O)-NH-CH 3 , N-C(O)-1-methyl-2-pyrrolidine, N-C(O)-1-methyl-3-pyrrolidine, N-C(O)-1-methyl-3-piperidine, N-C(O)-1-methyl-4 -piperidine); R is H, OH, F, Cl, Br, I, CN, CF 3 , NO 2 , NH 2 , NH(R 10 )(e.g. NH(CH 3 )), N(R 10 )(R 11 ), R 20 , C 1 -C 5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 ), R 8 -R 10 (e.g. CH 2 -OH, CH 2 CH 2 -OH), C(O)-R 10 (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH 3 ), C 1 -C 5 substituted or unsubstituted C(O)-alkyl (e.g. C(O)-CH 2 CH 2 -OCH 3 , C(O)-CH 3 , C(O)-CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -OH), C(O)-R 8 -R 10 (e.g. C(O)-CH 2 CH 2 -OH), C(O) substituted or unsubstituted C 3 -C 8 heterocycles (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine), C 1 -C 5 Substituted or unsubstituted SO for 2 -alkyl (e.g. SO 2 -CH 3 ), C 1 -C 5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH 3 ), C 1 -C 5 linear or branched C(O)-O-alkyl (e.g. C(O)-O-tBu), C 1 -C 5 straight or branched alkoxy, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain haloalkyl (e.g. CF 3 , CF 2 CH 3 , CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )-CH(CH 3 ) 2 ), R 8 -aryl (e.g., CH 2 -Ph), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted heteroaryl (e.g. pyridine (2-, 3- or 4-pyridine)); or two geminal R substituents joined together to form a 3- to 6-membered substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene), or heterocyclic ring (e.g. thiophene, furan, pyrrole, pyrazole); R. 8 is [CH 2 ]p, where p is between 1 and 10 (eg, 2); R. 9 is [CH]q, [C]q, q is 2-10; R. 10 and R 11 are independently of each other H, OH, substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain alkoxy (e.g., O-CH 3 ), substituted or unsubstituted C 3 -C 8 heterocycles (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 - is an alkyl; or R 10 and R 11 are combined with each other to form a substituted or unsubstituted C 3 -C 8 forming heterocycles (e.g. morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R. 20 is represented by the following structure;

[0062] [formation]

[0063] Substituents include F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 including cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are each independently an integer from 1 to 3 (eg, 1 or 2); m and k are independently integers from 0 to 2 (eg, 0).

[0064] In various embodiments, the present invention provides compounds represented by Formula VIII below, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, N-oxides, reverse amides thereof. Analogs, prodrugs, isotopic variants (eg, deuterated analogs), PROTACs, pharmaceuticals, or any combination thereof are provided.

[0065] [formation]

[0066] During the ceremony, R. 1 is H, F, Cl, Br, I, OH, SH, R 8 -OH (e.g. CH 2 OH), R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 3 ), -O-R 8 -O-R 10 (e.g. O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , R 8 -N(R 10 )(R 11 ) (e.g. CH 2 -NH-CH 3 , CH 2 -NH-C(O)CH 3 , CH 2 -N(CH 3 ) 2 ), R 9 -R 8-N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R (e.g., NHCO-Ph, NHCO-CH 3 ), NHC(O)-R 10 (e.g., NHC(O)CH 3 ), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g., C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO 2 R, SO 2 N(R 10 )(R 11 ), NHSOs 2 (R 10 ) (for example, NHSO 2 CH 3 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 linear or branched or cyclic alkoxy (e.g. methoxy) (optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocycle (e.g. azetidine, pyridine), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; X 1 , X 2 , X 3 , X 4 , and X 5 are, independently of each other, C or N; X 6 is O, CH 2 , CHR (e.g., CH(OH), CH(NH 2 ), CH(NH(CH 3 ))), C(R 10 )(R 11 ) (e.g., C(H)CH 2 CH 2 -OH, C(H)CH 2 -OH, 1-methylazetidine), NH, N-R (e.g. N-CH 3 , N-SO 2 -CH 3 , N-R 20 , N-CH 2 CH 2 -OCH 3 , ) or N-C(O)-R 10 (e.g., N-C(O)O-tBu, N-C(O)-CH 2 CH 2 -OCH 3 , N-C(O)-CH 3 , N-C(O)-CH 2 -N(CH 3 ) 2 , N-C(O)-CH 2 -CH 2 -N(CH 3 ) 2 , N-C(O)-CH 2 -OH, N-C(O)-CH 2 CH 2 -OH, N-C(O)-NH-CH 3 , N-C(O)-1-methyl-2-pyrrolidine, N-C(O)-1-methyl-3-pyrrolidine, N-C(O)-1-methyl-3-piperidine, N-C(O)-1-methyl-4 -piperidine); R is H, OH, F, Cl, Br, I, CN, CF 3 , NO 2 , NH 2 , NH(R 10 )(e.g. NH(CH 3 )), N(R 10 )(R 11 ), R 20 , C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 ), R 8 -R 10 (e.g. CH 2 -OH, CH 2 CH 2 -OH), C(O)-R 10 (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine, C(O)-CH 3 ), C 1 -C 5 substituted or unsubstituted C(O)-alkyl (e.g. C(O)-CH 2 CH 2 -OCH 3 , C(O)-CH 3 , C(O)-CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -CH 2 -N(CH 3 ) 2 , C(O)-CH 2 -OH), C(O)-R 8 -R 10 (e.g. C(O)-CH 2 CH 2 -OH), C(O) substituted or unsubstituted C 3 -C 8 heterocycles (e.g. C(O)-methylpyrrolidine, C(O)-methylpiperidine), C 1 -C 5 Substituted or unsubstituted SO for 2 -alkyl (e.g. SO 2 -CH 3 ), C 1 -C 5 substituted or unsubstituted C(O)-NH-alkyl (e.g., C(O)-NH-CH 3 ), C 1 -C 5 linear or branched C(O)-O-alkyl (e.g. C(O)-O-tBu), C 1 -C 5 straight or branched alkoxy, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain haloalkyl (e.g. CF 3 , CF 2 CH 3 , CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )-CH(CH 3 ) 2 ), R 8 -aryl (e.g., CH 2 -Ph), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted heteroaryl (e.g. pyridine (2-, 3- or 4-pyridine)); or two geminal R substituents joined together to form a 3- to 6-membered substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene), or heterocyclic ring (e.g. thiophene, furan, pyrrole, pyrazole); R. 8 is [CH 2 ]p, where p is between 1 and 10 (eg, 2); R. 9 is [CH]q, [C]q, q is 2-10; R. 10 and R 11 are independently of each other H, OH, substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 straight or branched chain alkoxy (e.g., O-CH 3 ), substituted or unsubstituted C 3 -C 8heterocycles (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 - is an alkyl; or R 10 and R 11 are combined with each other to form a substituted or unsubstituted C 3 -C 8 forming heterocycles (e.g. morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, 1-methylazetidine); R. 20 is represented by the following structure;

[0067] [formation]

[0068] Substituents include F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 including cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; n and l are each independently an integer from 1 to 3 (eg, 1 or 2); m and k are independently integers from 0 to 3 (eg, 0).

[0069] In some embodiments, R 1 and R 3 is not H. In some embodiments, R 1 and R 3 are not H.

[0070] In some embodiments, R 1 is Cl. In some embodiments, R 1 is in the ortho position.

[0071] In some embodiments, R 3 is a substituted or unsubstituted, single, spirocyclic, fused or bridged C 3 -C 10 It is a heterocycle. In some embodiments, R 3 is morpholine, 3-methylmorpholine, 3-hydroxypiperidine, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, or 6-methyl-2,6-diazaspiro[3.3]heptane; Represents a separate embodiment of the present invention. In some embodiments, R 3 is N(R 10 )(R 11 ). In some embodiments, R 1 is Cl and R 3 is N(R 10 )(R 11 ). In some embodiments, N(R 10 )(R 11 ) is a substituted or unsubstituted C 3 -C 8 It is a heterocycle. In some embodiments, N(R 10 )(R 11 ) is a substituted or unsubstituted 6-membered heterocyclic ring. In some embodiments, N(R 10 )(R 11 ) includes morpholine, alkyl-substituted morpholine, pyrrolidine, pyrrolidinone, piperazine, alkyl-substituted piperazine (e.g. 1-(2-methoxyethyl)piperazine), amide-substituted piperazine (e.g. N-methylpiperazine-1-carboxamide), sulfonyl-substituted piperazines (e.g. 1- or 4-(methylsulfonyl)piperazine), octahydropyrrolo[1,2-α]pyrazines, hydroxy-substituted piperidines, sulfonyl-substituted piperidines (e.g. 1- or 4-(methylsulfonyl)piperidine), 2-methoxy-1-(piperazin-1-yl)ethenone, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, 6-methyl-2,6-diazaspiro[3.3]heptane; , represent separate embodiments of the present invention.

[0072] In some embodiments, R 3 is a heterocycle, then R 1 is not H. In some embodiments, R 3 is a heterocycle, then R 1 is Cl.

[0073] In some embodiments, X of Formulas II-VIII 3 , X 4 , and X 5 is N. In some embodiments, X 3 , X 4 , and X 5 are N.

[0074] In some embodiments, A in Formulas I, II, and / or VII is phenyl. In another embodiment, A is pyridinyl. In another embodiment, A is 2-pyridinyl. In another embodiment, A is 3-pyridinyl. In another embodiment, A is 4-pyridinyl. In another embodiment, A is pyrimidine. In another embodiment, A is pyridazine. In another embodiment, A is pyrazine. In other embodiments, A is pyrazole. In another embodiment, A is naphthyl. In another embodiment, A is benzothiazolyl. In another embodiment, A is benzimidazolyl. In another embodiment, A is quinolinyl. In another embodiment, A is isoquinolinyl. In another embodiment, A is indolyl. In other embodiments, A is benzoxazole. In another embodiment, A is imidazopyridine. In another embodiment, A is pyrazolopyridine. In another embodiment, A is pyrrolopyridine. In another embodiment, A is tetrahydronaphthyl. In other embodiments, A is indenyl. In other embodiments, A is benzofuran-2(3H)-one. In another embodiment, A is benzo[d][1,3]dioxole. In another embodiment, A is tetrahydrothiophene 1,1-dioxide. In other embodiments, A is thiazole. In another embodiment, A is piperidine. In another embodiment A is tetrahydro-2H-pyran. In another embodiment, A is pyrrolidin-2-one. In another embodiment A is morpholine. In another embodiment, A is piperazine. In another embodiment, A is azetidine. In another embodiment, A is 1-methylpiperidine. In other embodiments, A is imidazole. In another embodiment, A is 1-methylimidazole. In another embodiment, A is thiophene. In another embodiment, A is isoquinoline. In other embodiments, A is 1,3-dihydroisobenzofuran. In another embodiment, A is benzofuran. In other embodiments, A is a single or fused C 3 -C 10 It is a cycloalkyl ring. In another embodiment, A is bicyclo[1.1.1]pentyl. In another embodiment, A is cyclobutyl. In another embodiment, A is cyclohexyl.

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

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

[0077] In some embodiments, X in compounds of Formulas III-VIII 2 is N. In other embodiments, X 2 is C.

[0078] In some embodiments, X in compounds of Formulas II-VIII 3 is N. In other embodiments, X 3 is C.

[0079] In some embodiments, X in compounds of Formulas II-VIII 4 is N. In other embodiments, X 4 is C.

[0080] In some embodiments, X in compounds of Formulas II-VIII 5 is N. In other embodiments, X 5 is C.

[0081] In some embodiments, X of compounds of Formulas VI-VIII 6 is O. In other embodiments, X 6 is CHR. In other embodiments, X 6 is CH(OH). In other embodiments, X 6 is CH 2 is. In other embodiments, X 6 is CHR. In other embodiments, X 6 is CH(NH 2 ). In other embodiments, X 6 is CH(NH(CH 3 )). In other embodiments, X 6 is C(H)CH 2 -OH. In other embodiments, X 6 is 1-methylazetidine. In other embodiments, X 6 is N-R 20 is. In other embodiments, X 6 is C(R 10 )(R 11 ). In other embodiments, X 6 is 1-methylpyrrolidin-2-one. In other embodiments, X 6 is an oxetane. In other embodiments, X 6 is C(H)CH 2 CH 2 -OH. In other embodiments, X 6 is C(H)CH 2 -OH. In other embodiments, X 6 is 1-methylazetidine. In other embodiments, X 6 is NH. In other embodiments, X 6 is N-R. In other embodiments, X 6 is N-CH 3 is. In other embodiments, X 6 is N-SO 2 -CH 3 is. In other embodiments, X 6 is N-R 20 is. In other embodiments, X 6 is N-CH 2 CH 2 -OCH 3 is. In other embodiments, X 6 is N-C(O)O-tBu. In other embodiments, X 6 is N-C(O)-CH 2 CH 2 -OCH 3 is. In other embodiments, X 6 is N-CH 2 CH 2 -OCH 3 is. In other embodiments, X 6 is N-C(O)-R 10 is. In other embodiments, X 6 is N-C(O)-CH 3 is. In other embodiments, X 6 is C 1 -C 5 is a substituted or unsubstituted N-C(O)-NH-alkyl. In other embodiments, X 6 is N-C(O)-NH-CH 3 is. In other embodiments, X 6 is NC(O)-CH 2 -N(CH 3 ) 2 is. In other embodiments, X 6 is N-C(O)-CH 2 -CH 2 -N(CH 3 ) 2 is. In other embodiments, X 6 is N-C(O)-CH 2 -OH. In other embodiments, X 6 is N-C(O)-CH 2 CH 2 -OH. In other embodiments, X 6 is N-C(O)-NH-CH 3 is. In other embodiments, X 6 is N-C(O)-1-methyl-2-pyrrolidine. In other embodiments, X 6 is N-C(O)-1-methyl-3-pyrrolidine. In other embodiments, X 6 is N-C(O)-1-methyl-3-piperidine. In other embodiments, X 6 is N-C(O)-1-methyl-4-piperidine. In other embodiments, X 6 is N-C(O)-1-methyl-3-piperidine.

[0082] X 1 -X 5 is N, then R 1 -R 4 It is understood that any of the

[0083] In some embodiments, R of Formulas I-VIII 1 is H. In some embodiments, R 1 is not H. In some embodiments, R 1 is Cl. In some embodiments, R 1 is F. In some embodiments, R 1 is R 8 -OH. In some embodiments, R 1 is CH 2 is OH. In some embodiments, R 1 is -R 8 -O-R 10 is. In some embodiments, R 1 is CH 2 -O-CH 2 -CH 2 -O-CH 3 is. In some embodiments, R 1 is CH 2 -O-CH 3 is. In some embodiments, R 1 is -O-R 8 -O-R 10 is. In some embodiments, R 1 is O-CH 2 -CH 2 -O-CH 3 is. In some embodiments, R1 is CN. In some embodiments, R 1 is R 8 -N(R 10 )(R 11 ). In some embodiments, R 1 is CH 2 -NH-CH 3 is. In some embodiments, R 1 is CH 2 -NH-C(O)CH 3 is. In some embodiments, R 1 is CH 2 -N(CH 3 ) 2 is. In some embodiments, R 1 is alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is C 1 -C 5 linear, branched, or cyclic haloalkyl, C 1 -C 5 is linear, branched, or cyclic alkoxy. In some embodiments, R 1 is methoxy. In some embodiments, R 1 is a substituted or unsubstituted C 3 -C 8 It is a heterocycle. In some embodiments, R 1 is azetidine. In some embodiments, R 1 is the CF 3 is. In some embodiments, R 1 is CHF 2 is. In some embodiments, R 1 is C 1 -C 5 is straight or branched chain, substituted or unsubstituted alkyl. In other embodiments, R 1 is methyl. In other embodiments, R 1 is ethyl. In other embodiments, R 1 is isopropyl. In other embodiments, R 1 is t-Bu. In other embodiments, R 1 is isobutyl. In other embodiments, R 1 is a pentyl. In other embodiments, R 1 is propyl. In other embodiments, R 1 is benzyl. In other embodiments, R 1 is in the ortho position. In other embodiments, R 1 is ortho-methyl.

[0084] In some embodiments, R of Formulas I-III, VI, and / or VII 2 is H. In some embodiments, R 2 is Cl. In some embodiments, R 2 is F. In some embodiments, R 2 is R 8 -OH. In some embodiments, R 2 is CH 2 is OH. In some embodiments, R 2 is -R 8 -O-R 10 is. In some embodiments, R 2 is CH 2 -O-CH 2 -CH 2 -O-CH 3 is. In some embodiments, R 2 is CH 2 -O-CH 3 is. In some embodiments, R 2 is -O-R 8 -O-R 10 is. In some embodiments, R 2 is O-CH 2 -CH 2 -O-CH 3 is. In some embodiments, R 2 is CN. In some embodiments, R 2 is R 8 -N(R 10 )(R 11 ). In some embodiments, R 2 is CH 2 -NH-CH 3 is. In some embodiments, R 2 is CH 2 -NH-C(O)CH 3 is. In some embodiments, R 2 is CH 2 -N(CH 3 ) 2 is. In some embodiments, R 2 is C 1 -C 5 is straight or branched chain, substituted or unsubstituted alkyl. In other embodiments, R 2 is methyl. In other embodiments, R 2 is ethyl. In other embodiments, R 2 is isopropyl. In other embodiments, R 2 is t-Bu. In other embodiments, R 2 is isobutyl. In other embodiments, R 2 is a pentyl. In other embodiments, R 2 is propyl. In other embodiments, R 2 is benzyl. In other embodiments, R 2 is in the ortho position. In other embodiments, R 2 is ortho-methyl. In other embodiments, R 2 is C 1 -C 5 is linear, branched, or cyclic alkoxy. In other embodiments, R 2 is methoxy. In other embodiments, R 2 is ethoxy. In other embodiments, R 2 is propoxy. In other embodiments, R 2 is isopropoxy. In other embodiments, R 2 is a substituted or unsubstituted aryl. In other embodiments, R 2 is phenyl. In other embodiments, the substituents include C 1 -C 5 straight or branched chain alkyl (e.g., methyl), aryl, phenyl, heteroaryl (e.g., imidazole), and / or C 3 -C 8 Cycloalkyls are included; each represents a separate embodiment of the invention.

[0085] In some embodiments, R of Formulas I-III, VI, and / or VII 1 and R 2 are attached to each other to form a pyrrole ring. In some embodiments, R 1 and R 2 are attached to each other to form a 1,4-dioxane ring. In some embodiments, R 1 and R 2 combine with each other to form a 2,3-dihydro-1,4-dioxin ring. In some embodiments, R 1 and R 2 combine with each other to form a benzene ring. In some embodiments, R 1 and R 2 are attached to each other to form a pyridine ring. In some embodiments, R 1 and R 2 are attached to each other to form a furanone ring (eg furan-2(3H)-one).

[0086] In some embodiments, R of Formulas IV 3 is H. In other embodiments, R 3 is F. In other embodiments, R 3 is Cl. In other embodiments, R 3 is BR. In other embodiments, R 3 is I. In other embodiments, R 3 is N(R 10 )(R 11 ). In other embodiments, R 3 is morpholine. In other embodiments, R 3 is piperazine. In other embodiments, R 3 is C(O)-R 10 is. In other embodiments, R 3 is C(O)NHR. In other embodiments, R 3 is C(O)NH(CH 3 ) 2 O-CH 3 is. In other embodiments, R 3 is C(O)N(R 10 )(R 11 ). In other embodiments, R 3 is C(O)-piperidine. In other embodiments, R 3 is C(O)-pyrrolidine. In other embodiments, R 3 is C(O)N(CH 3 ) 2 is. In other embodiments, R 3 is SO 2 is R. In other embodiments, R 3 is C 1 -C 5 is straight or branched chain, substituted or unsubstituted alkyl. In other embodiments, R 3 is methyl. In other embodiments, R 3 is ethyl. In other embodiments, R 3 is C 1 -C 5 is a straight, branched, or cyclic haloalkyl. In other embodiments, R 3 is CHF 2is. In other embodiments, R 3 is C 1 -C 5 is linear, branched, or cyclic alkoxy. In other embodiments, R 3 is methoxy. In other embodiments, R 3 is 1-(methylsulfonyl)piperidin-4-oxy. In other embodiments, R 3 is 1-(methyl)piperidin-4-oxy. In other embodiments, R 3 is 1-(ethanone)piperidine-4-oxy. In other embodiments, R 3 is a substituted or unsubstituted C 3 -C 8 is cycloalkyl. In other embodiments, R 3 is a substituted or unsubstituted single, spirocyclic, fused, or bridged C 3 -C 10 It is a heterocycle. In other embodiments, R 3 is piperazine. In other embodiments, R 3 is 1-(2-methoxyethyl)piperazine. In other embodiments, R 3 is 1- or 4-(methylsulfonyl)piperidine. In other embodiments, R 3 is 2-methoxy-1-(piperazin-1-yl)ethenone. In other embodiments, R 3 is morpholine. In other embodiments, R 3 is 3-methylmorpholine. In other embodiments, R 3 is 3-hydroxypiperidine. In other embodiments, R 3 is pyrrolidine. In other embodiments, R 3 is pyrrolidinone. In other embodiments, R 3 is octahydropyrrolo[1,2-α]pyrazine. In other embodiments, R 3 is 6-methyl-2,6-diazaspiro[3.3]heptane. In other embodiments, R 3 is tetrahydro-2H-thiopyran 1,1-dioxide. In other embodiments, R 3 is 1- or 4-methylpiperazine. In other embodiments, R 3 is 1- or 4-(methylsulfonyl)piperazine. In other embodiments, R 3 is 1-(piperazin-1-yl)ethanone. In other embodiments, R 3 is 2-(dimethylamino)-1-(piperazin-1-yl)ethanone. In other embodiments, R 3 is 2-(dimethylamino)-1-(piperazin-1-yl)propanone. In other embodiments, R 3 is 2-hydroxy-1-(piperazin-1-yl)ethenone. In other embodiments, R 3 is N-methylpiperazine-1-carboxamide. In other embodiments, R 3 is piperidin-4-ol. In other embodiments, R 3 is piperidin-3-ol. In other embodiments, R 3 is tetrahydro-2H-pyran. In other embodiments, R 3 is 2-oxa-7-azaspiro[3.5]nonane. In other embodiments, R 3 is 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone. In other embodiments, R 3 is 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone. In other embodiments, R 3 is 2,8-diazaspiro[4.5]decan-1-one. In other embodiments, R 3 is 2-methyl-2,8-diazaspiro[4.5]decan-1-one. In other embodiments, R 3 is 2-oxa-7-azaspiro[3.5]nonane. In other embodiments, R 3 is tetrahydro-2H-thiopyran 1,1-dioxide. In other embodiments, R 3 is pyrrolidine. In other embodiments, R 3 is (1-methylpiperidin-3-yl)(piperazin-1-yl)methanone. In other embodiments, R 3 is also F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 It may be substituted with at least one substituent selected from cycloalkyl, halophenyl and (benzyloxy)phenyl.

[0087] In some embodiments, R of Formulas I-III and / or VI-VII 4 is H. In other embodiments, R 4 is C 1 -C 5 is straight or branched chain, substituted or unsubstituted alkyl. In other embodiments, R 4 is methyl. In other embodiments, R 4 is ethyl.

[0088] In some embodiments, R of Formulas I-III 3 and R 4 are joined together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic ring. In some embodiments, R 3 and R 4 combine with each other to form cyclopentene. In some embodiments, R 3 and R 4 are joined together to form an aromatic carbocycle. In some embodiments, R 3 and R 4 combine with each other to form benzene. In some embodiments, R 3 and R 4 are joined together to form an aromatic heterocycle. In some embodiments, R 3 and R 4 combine with each other to form thiophenes. In some embodiments, R 3 and R 4 combine with each other to form furans. In some embodiments, R 3 and R 4 combine with each other to form pyrrole. In some embodiments, R 3 and R 4 are attached to each other to form a pyrazole ring ([1,3]dioxole ring). In some embodiments, R 3 and R 4 are attached to each other to form a furanone ring (eg furan-2(3H)-one). In some embodiments, R 3 and R 4 combine with each other to form a cyclopentene ring. In some embodiments, R 3 and R 4 are attached to each other to form an imidazole ring.

[0089] In some embodiments, R of Formula I 5 is H. In some embodiments, R 5 is R 20 is. In some embodiments, R 5 is C 1 -C 5 is straight or branched chain, substituted or unsubstituted alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is C(O)-R 10 is. In some embodiments, R 5 is SO 2 is R.

[0090] In some embodiments, R in formulas I-VIII is H. In other embodiments, R is OH. In other embodiments, R is NH 2 is. In other embodiments, R is NH(R 10 ). In other embodiments, R is NH(CH 3 ). In other embodiments, R is 20 is. In other embodiments, R is C 1 -C 5 is straight or branched chain, substituted or unsubstituted alkyl. In other embodiments, R is substituted alkyl. In another embodiment, R is methyl. In another embodiment, R is ethyl. In other embodiments, R is CH 2 CH 2OCH 3 is. In other embodiments, R is CH 2 CH 2 is OH. In other embodiments, R is 8 -R 10 is. In other embodiments, R is CH 2 -OH. In other embodiments, R is CH 2 CH 2 -OH. In other embodiments, R is C(O)-R 10 is. In another embodiment, R is C(O)-methylpyrrolidine. In another embodiment, R is C(O)-methylpiperidine. In another embodiment, R is C(O)-CH 3 is. In other embodiments, R is C 1 -C 5 is substituted or unsubstituted C(O)-alkyl. In another embodiment, R is C(O)-CH 2 CH 2 -OCH 3 is. In another embodiment, R is C(O)-CH 3 is. In other embodiments, R is C(O)-R 8 -R 10 is. In another embodiment, R is C(O)-CH 2 CH 2 -OH. In other embodiments, R is C(O)-substituted or unsubstituted C 3 -C 8 It is a heterocycle. In another embodiment, R is C(O)-methylpyrrolidine. In another embodiment, R is C(O)-methylpiperidine. In other embodiments, R is C 1 -C 5 Substituted or unsubstituted SO for 2 - is alkyl. In other embodiments, R is SO 2 -CH 3 is. In other embodiments, R is -R 8 -O-R 10 is. In other embodiments, R is CH 2 -CH 2 -O-CH 3 is. In another embodiment, R is C(O)-CH 2 -N(CH 3 ) 2 is. In another embodiment, R is C(O)-CH 2 -CH 2 -N(CH 3 ) 2 is. In another embodiment, R is C(O)-CH 2 -OH. In other embodiments, R is C 1 -C 5 is substituted or unsubstituted C(O)-NH-alkyl. In another embodiment, R is C(O)-NH-CH 3 is. In other embodiments, R is C 1 -C 5 is straight or branched C(O)-O-alkyl. In another embodiment, R is C(O)-O-tBu. In other embodiments, R is further F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 It may be substituted with at least one substituent selected from cycloalkyl, halophenyl and (benzyloxy)phenyl; each represents a separate embodiment of the invention. In some embodiments, two geminal R substitutions are joined together to form a 3- to 6-membered substituted or unsubstituted, aliphatic (eg, cyclopropyl, cyclopentene) or aromatic, carbocyclic (eg, benzene) ring. or form a heterocyclic (eg, thiophene, furan, pyrrole, pyrazole) ring.

[0091] In some embodiments, R of Formulas I-VIII 8 is CH 2 is. In other embodiments, R 8 is CH 2 CH 2 is. In other embodiments, R 8 is CH 2 CH 2 CH 2 is.

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

[0093] In some embodiments, R of Formulas I-VIII 9 is C≡C.

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

[0095] In some embodiments, R of Formulas I-VIII 10 is a substituted or unsubstituted C 1 -C 5 is a straight or branched alkyl of In other embodiments, R 10 is H. In other embodiments, R 10 is CH 3 is. In other embodiments, R 10 is CH 2 CH 3 is. In other embodiments, R 10 is CH 2 CH 2 CH 3 is. In other embodiments, R 10 is CH 2 -CH 2 -O-CH 3 is. In other embodiments, R 10 is OH. In other embodiments, R 10 is a substituted or unsubstituted C 3 -C 8 It is a heterocycle. In other embodiments, R 10 is 1-(methylsulfonyl)piperidine. In other embodiments, R 10 is 1-(methylsulfonyl)piperazine. In other embodiments, R 10 is tetrahydro-2H-pyran. In other embodiments, R 10 is morpholine. In other embodiments, R 10 is thiomorpholine 1,1-dioxide. In other embodiments, R 10 is methyl-pyrrolidine. In other embodiments, R 10 is methyl-piperidine.

[0096] In some embodiments, R of Formulas I-VIII 11 is C 1 -C 5 is a straight or branched alkyl of In other embodiments, R 11 is H. In other embodiments, R 11 is CH 3 is.

[0097] In some embodiments, R of Formulas I-VIII 10 and R 11 are combined with each other to form a substituted or unsubstituted C 3 -C 8 Forms a heterocycle. In other embodiments, R 10 and R 11 are attached to each other to form a morpholine ring. In other embodiments, R 10 and R 11 are attached to each other to form an unsubstituted piperazine ring. In other embodiments, R 10 and R 11 are attached to each other to form a substituted piperazine ring. In other embodiments, R 10 and R 11 are attached to each other to form an unsubstituted piperidine ring. In other embodiments, R 10 and R 11 are attached to each other to form an unsubstituted pyrrolidine ring. In other embodiments, R 10 and R 11 are attached to each other to form a substituted piperidine ring. In other embodiments, R 10 and R 11 are attached to each other to form a 1-methylpyrrolidin-2-one ring. In other embodiments, R 10 and R 11 are attached to each other to form an oxetane ring. In other embodiments, R 10 and R 11 are attached to each other to form an azetidine ring. In other embodiments, R 10 and R 11combine with each other to form 1-methylazetidine. In some embodiments, the substituents include F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 Included are cycloalkyl, halophenyl, (benzyloxy)phenyl, or any combination thereof; each represents a separate embodiment of this invention.

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

[0099] In some embodiments, m in formulas I-III and / or VI-VII is zero. In some embodiments, m is 1. In some embodiments, m is two.

[0100] In some embodiments, k in Formulas I-III and / or VI-VII is zero. In other embodiments, k is one. In other embodiments, k is two.

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

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

[0103] In some embodiments, G=X 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 SO 2 is.

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

[0105] [Table 1-1]

[0106] [Table 1-2]

[0107] [Table 1-3]

[0108] [Table 1-4]

[0109] [Table 1-5]

[0110] [Table 1-6]

[0111] [Table 1-7]

[0112] [Table 1-8]

[0113] [Table 1-9]

[0114] [Table 1-10]

[0115] [Table 1-11]

[0116] [Table 1-12]

[0117] [Table 1-13]

[0118] [Table 1-14]

[0119] [Table 1-15]

[0120] [Table 1-16]

[0121] [Table 1-17]

[0122] [Table 1-18]

[0123] [Table 1-19]

[0124] [Table 1-20]

[0125] [Table 1-21]

[0126] [Table 1-22]

[0127] [Table 1-23]

[0128] [Table 1-24]

[0129] [Table 1-25]

[0130] [Table 1-26]

[0131] [Table 1-27]

[0132] [Table 1-28]

[0133] [Table 1-29]

[0134] [Table 1-30]

[0135] [Table 1-31]

[0136] [Table 1-32]

[0137] [Table 1-33]

[0138] [Table 1-34]

[0139] [Table 1-35]

[0140] [Table 1-36]

[0141] It is well understood that in structures presented in this invention, where the number of carbon atom bonds is less than 4, H atoms are present to complete the carbon valences. It is well understood that in the structures presented in this invention, when the nitrogen atom has less than 3 bonds, an H atom is present to complete the valence of the nitrogen.

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

[0143] In various embodiments, the A ring of formulas I, II, and / or VII is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole , isoquinoline, pyrazolyl, pyrrolyl, furanyl, thiophen-yl, isoquinolinyl, indolyl, 1H-indole, isoindolyl, naphthyl, anthracenyl, benzimidazolyl, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H- indole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4,5,6,7-tetrahydro -1,3-benzothiazole, quinazolinyl, quinoxalinyl, cinnolinyl, phytazolinyl, quinolinyl, isoquinolinyl, 2,3-dihydroindenyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4] Dioxepin, benzo[d][1,3]dioxole, acridinyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzofuran-2(3H)-one, benzothiophenyl, benzoxadiazole, benzo[c][1 ,2,5]oxadiazolyl, benzo[c]thiophenyl, benzodioxolyl, benzodioxolyl[d][1,3]dioxole, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxa Diaziolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2- a]pyridine, 7-oxo-6H,7H-[1,3]thiazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2, 1-b][1,3]thiazole, thieno[3,2-d]pyrimidin-4(3H)-one, 4-oxo-4H-thieno[3,2-d][1,3]thiazine, imidazo pyridine, imidazo[1,2-a]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-imidazo[4,5-c]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazolo pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrido[2,3- b]pyrazine, pyrido[2,3-b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, pyrrolopyridine, 1H-pyrrolo[3 ,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, or thieno[3,2-c]pyridine each representing a separate embodiment of the present invention. Alternatively, the A ring of Formulas I, II, and / or VII is C 3 -C 8 cycloalkyl (e.g., cyclohexyl, cyclopentyl, bicyclo[1.1.1]pentyl, or cyclobutyl), or C 3 -C 8 heterocycles (such as, but not limited to, tetrahydropyran, piperidine, 1-methylpiperidine, tetrahydrothiophene 1,1-dioxide, pyrrolidin-2-one, piperazine, 1-(piperidin-1-yl)ethanone, or morpholine ); each represents a separate embodiment of the present invention. In some embodiments, A is phenyl. In some embodiments, A is C 3 -C 8 It is a heterocycle. In some embodiments A is tetrahydro-2H-pyran. In another embodiment, A is azetidine. In another embodiment, A is piperidine.

[0144] In various embodiments, the B ring of formula I is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, isoquinoline, pyrazolyl, pyrrolyl, furanyl, thiophen-yl, isoquinolinyl, indolyl, 1H-indole, isoindolyl, naphthyl, anthracenyl, benzimidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[ b][1,4]dioxepin, benzofuran-2(3H)-one, benzo[d][1,3]dioxole, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indole , 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4,5,6,7-tetrahydro- 1,3-benzothiazole, quinazolinyl, quinoxalinyl, cinnolinyl, phytazolinyl, quinolinyl, isoquinolinyl, acridinyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzothiophenyl, benzoxadiazole, benzo[c][1,2, 5]oxadiazolyl, benzo[c]thiophenyl, benzodioxolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, oxadiazolyl, imidazo[2,1-b][1,3] Thiazole, 4H,5H,6H-Cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3] Thiazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2- d]pyrimidin-4(3H)-one, 4-oxo-4H-thieno[3,2-d][1,3]thiazine, imidazo[1,2-a]pyridine, 1H-imidazo[4,5- b]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[ 1,2-a]pyrimidine, pyrido[2,3-b]pyrazine, pyrido[2,3-b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxaline-2 (1H)-one, 1,2,3,4-tetrahydroquinoxaline, 1-(pyridin-1(2H)-yl)ethanone, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[3,2 -b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thieno[3,2-c]pyridine, C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocycles (for example, but not limited to, tetrahydropyran, piperidine, 1-methylpiperidine, tetrahydrothiophene 1,1-dioxide, 1-(piperidin-1-yl)ethanone, bicyclo[1.1.1]pentyl, cyclobutyl, cyclohexyl, or morpholine); each represents a separate embodiment of the present invention. In some embodiments, B is C 3 -C 8It is a heterocycle. In some embodiments, B is piperidine. In some embodiments, B is piperazine. In some embodiments, B is pyrrolidin-2-one. In some embodiments, B is tetrahydro-2H-pyran. In some embodiments, B is azetidine. In some embodiments, B is pyrimidine. In some embodiments, B is phenyl. In some embodiments, B is pyridinyl. In some embodiments, B is 2-pyridinyl. In some embodiments, B is thiophenyl.

[0145] In various embodiments, compounds of Formulas I-VIII are R 15 is replaced by In various embodiments, compounds of Formulas I-III, VI, and / or VII are represented by R 2 is replaced by In various embodiments, compounds of Formulas IV are represented by R 3 is replaced by In various embodiments, compounds of Formulas I-III and / or VI-VII are R 4 is replaced by A single substituent can be present in the ortho, meta or para position.

[0146] In various embodiments, R of Formulas I-VIII 1 , and / or R of Formulas I-III 2 are H independently of each other.

[0147] In various embodiments, R of Formulas I-VIII 1 , and R of Formulas I-III, VI, and / or VII 2 are, independently of each other, H, F, Cl, Br, I, OH, SH, R 8 -OH (e.g. CH 2 OH), R 8 -SH, -R 8 -O-R 10 (e.g. CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 3 ), -O-R 8 -O-R 10 (e.g. O-CH 2 -CH 2 -O-CH 3 ), R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , R 8 -N(R 10 )(R 11 ) (e.g. CH 2 -NH-CH 3 , CH 2 -NH-C(O)CH 3 , CH 2 -N(CH 3 ) 2 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R (e.g., NHCO-Ph, NHCO-CH 3 ), NHC(O)-R 10 (e.g., NHC(O)CH 3 ), NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR (e.g. C(O)NH-Ph), C(O)N(R 10 )(R 11 ), SO 2 R, SO 2 N(R 10 )(R 11 ), NHSOs 2 (R 10 ) (for example, NHSO 2 CH 3 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 linear or branched or cyclic alkoxy (e.g. methoxy) (optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocycle (eg, azetidine, pyridine), substituted or unsubstituted aryl (eg, phenyl), or substituted or unsubstituted benzyl; each represents a separate embodiment of the invention. In some embodiments, R 1 and / or R 2 is F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 It may be substituted with at least one substituent selected from cycloalkyl, halophenyl and (benzyloxy)phenyl; each represents a separate embodiment of the invention.

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

[0149] In various embodiments, R of Formulas IV 3 , and R of formulas I-III and VII-IX 4 are, independently of each other, H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 , R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , N(R 10 )(R 11 ) (e.g. morpholine, piperazine), R 8 -N(R 10 )(R 11 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R 10 , NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR, C(O)NH(CH 3 ) 2 O-CH 3 , C(O)N(R 10 )(R 11 ), C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH 3 ) 2 , C(O)-piperazine, SO 2 R, SO 2 N(R 10 )(R 11 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl, CHF 2 , C 1 -C 5 straight or branched chain or cyclic alkoxy (e.g., methoxy, 1-(methylsulfonyl)piperidin-4-oxy, 1-(methyl)piperidin-4-oxy, 1-(ethanone)piperidin-4-oxy) ( Optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted, single, spirocyclic, fused or bridged C 3 -C 10 heterocycles (e.g. piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy -1-(piperazin-1-yl)ethenone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1- (piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)ethenone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methyl Morpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl- 2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2, 6-diazaspiro[3.3]heptan-2-yl)ethenone, 2,8-diazaspiro[4.5]decan-1-one, 2-oxa-7-azaspiro[3.5]nonane), substituted or unsubstituted aryl (e.g. phenyl), or substituted or unsubstituted benzyl; each represents a separate embodiment of the present invention. In some embodiments, R 3 and / or R 4 is F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 It may be substituted with at least one substituent selected from cycloalkyl, halophenyl and (benzyloxy)phenyl; each represents a separate embodiment of the invention.

[0150] In some embodiments, R 3 and R 4 are joined together to form a 5- or 6-membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring. In some embodiments, R 3 and R 4 are joined together to form a 5- or 6-membered carbocyclic ring. In some embodiments, R 3 and R 4 are joined together to form a 5- or 6-membered heterocyclic ring. In some embodiments, R 3 and R 4 are attached to each other to form a [1,3]dioxole ring. In some embodiments, R 3 and R 4 are attached to each other to form a dihydrofuran-2(3H)-one ring. In some embodiments, R 3 and R 4 are attached to each other to form a furan-2(3H)-one ring. In some embodiments, R 3 and R 4 combine with each other to form a benzene ring. In some embodiments, R 3 and R 4 combine with each other to form an imidazole. In some embodiments, R 3 and R 4 are attached to each other to form a pyridine ring. In some embodiments, R 3 and R 4 are attached to each other to form a thiophene ring. In some embodiments, R 3 and R 4 combine with each other to form a furan ring. In some embodiments, R 3 and R 4 are attached to each other to form a pyrrole ring. In some embodiments, R 3 and R 4 are attached to each other to form a pyrazole ring. In some embodiments, R 3 and R 4 combine with each other to form a cyclohexene ring. In some embodiments, R 3 and R 4 combine with each other to form a cyclopentene ring. In some embodiments, R 4 and R3 are attached to each other to form a dioxepin ring.

[0151] In some embodiments, R of Formula I 5 is H, R 20 , F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 , R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocycle), CF 3 , CDs 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , R 8 -N(R 10 )(R 11 ), R 9 -R 8 -N(R 10 )(R 11 ), B(OH) 2 , -OC(O)CF 3 , -OCH 2 Ph, NHC(O)-R 10 , NHCO-N(R 10 )(R 11 ), COOH, -C(O)Ph, C(O)O-R 10 , R 8 -C(O)-R 10 , C(O)H, C(O)-R 10 , C 1 -C 5 straight or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR, C(O)N(R 10 )(R 11 ), SO 2 R, SO 2 N(R 10 )(R 11 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 linear or branched, substituted or unsubstituted alkenyl, C 1 -C 5 straight, branched or cyclic haloalkyl (e.g. CHF 2 ), C 1 -C 5 linear or branched or cyclic alkoxy (e.g. methoxy) (optionally at least one methylene group in the alkoxy (CH 2 ) replaced by an oxygen atom), C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 straight or branched chain haloalkoxy, C 1 -C 5 straight or branched chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g. cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocycle, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl; each represents a separate embodiment of the present invention. In some embodiments, R 5 is F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 It may be substituted with at least one substituent selected from cycloalkyl, halophenyl and (benzyloxy)phenyl; each represents a separate embodiment of the invention.

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

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

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

[0155] In various embodiments, k is 0 for compounds of Formulas I-III and / or VI-VII. In some embodiments, k is 0 or 1. In some embodiments, k is 1-3. In some embodiments, k is 1-4. In some embodiments, k is 0-2. In some embodiments, k is 0-3. In some embodiments, k is 0-4. In some embodiments, k is one. In some embodiments, k is two. In some embodiments, k is three. In some embodiments, k is four.

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

[0157] In various embodiments, R of compounds of Formulas I-VIII 8 is CH 2 is. In some embodiments, R 8 is CH 2 CH 2 is. In some embodiments, R 8 is CH 2 CH 2 CH 2 is. In some embodiments, R 8 is CH 2 CH 2 CH 2 CH 2 is.

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

[0159] In some embodiments, R 9 is C≡C. In some embodiments, R 9is C≡C-C≡C. In some embodiments, R 9 is CH=CH. In some embodiments, R 9 is CH=CH-CH=CH.

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

[0161] In various embodiments, R of compounds of Formulas I-VIII 10 is H. In some embodiments, R 10 is a substituted or unsubstituted C 1 -C 5 A straight or branched chain alkyl. In some embodiments, R 10 is methyl. In some embodiments, R 10 is ethyl. In some embodiments, R 10 is propyl. In some embodiments, R 10 is isopropyl. In some embodiments, R 10 is butyl. In some embodiments, R 10 is isobutyl. In some embodiments, R 10 is t-butyl. In some embodiments, R 10 is cyclopropyl. In some embodiments, R 10 is a pentyl. In some embodiments, R 10 is isopentyl. In some embodiments, R 10 is neopentyl. In some embodiments, R 10 is benzyl. In some embodiments, R 10 is CH 2 -CH 2 -O-CH 3 is. In some embodiments, R 10 is a substituted or unsubstituted C 3 -C 8 It is a heterocycle. In some embodiments, R 10 is 1-(methylsulfonyl)piperidine. In some embodiments, R 10 is 1-(methylsulfonyl)piperazine. In some embodiments, R 10 is tetrahydro-2H-pyran. In some embodiments, R 10 is morpholine. In some embodiments, R 10 is thiomorpholine 1,1-dioxide. In some embodiments, R 10 is methyl-pyrrolidine. In some embodiments, R 10 is methyl-piperidine. In some embodiments, R 10 is C(O)-alkyl. In some embodiments, R 10 is S(O) 2 - is alkyl. In other embodiments, R 10 is also F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 It may be substituted with at least one substituent selected from cycloalkyl, halophenyl and (benzyloxy)phenyl; each represents a separate embodiment of the invention.

[0162] In various embodiments, R of compounds of Formulas I-VIII 11 is H. In some embodiments, R 11 is C 1 -C 5 A straight or branched chain alkyl. In some embodiments, R 11 is methyl. In some embodiments, R 11 is ethyl. In some embodiments, R 11 is propyl. In some embodiments, R 11 is isopropyl. In some embodiments, R 11 is butyl. In some embodiments, R 11 is isobutyl. In some embodiments, R 11 is t-butyl. In some embodiments, R 11 is cyclopropyl. In some embodiments, R 11 is a pentyl. In some embodiments, R 11 is isopentyl. In some embodiments, R 11 is neopentyl. In some embodiments, R 11 is benzyl. In some embodiments, R 11 is CH 2 -CH 2 -O-CH 3 is. In some embodiments, R 11 is a substituted or unsubstituted C 3 -C 8 It is a heterocycle. In some embodiments, R 11 is 1-(methylsulfonyl)piperidine. In some embodiments, R 11 is 1-(methylsulfonyl)piperazine. In some embodiments, R 11 is tetrahydro-2H-pyran. In some embodiments, R 11 is morpholine. In some embodiments, R 11 is thiomorpholine 1,1-dioxide. In some embodiments, R 11 is methyl-pyrrolidine. In some embodiments, R 11 is methyl-piperidine. In some embodiments, R 11 is C(O)-alkyl. In some embodiments, R 11 is S(O) 2 - is alkyl. In other embodiments, R 11 is also F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 It may be substituted with at least one substituent selected from cycloalkyl, halophenyl and (benzyloxy)phenyl; each represents a separate embodiment of the invention.

[0163] In some embodiments, R of Formulas I-VIII 10 and R 11 are combined with each other to form a substituted or unsubstituted C 3 -C 8 Forms a heterocycle. In other embodiments, R 10 and R 11 are attached to each other to form a morpholine ring. In other embodiments, R 10 and R 11 are attached to each other to form a piperazine ring. In other embodiments, R 10 and R 11 are attached to each other to form a substituted piperazine ring. In other embodiments, R 10 and R 11 are attached to each other to form a piperidine ring. In other embodiments, R 10 and R11 are attached to each other to form an unsubstituted pyrrolidine ring. In other embodiments, R 10 and R 11 are attached to each other to form a 1-methylpyrrolidin-2-one ring. In other embodiments, R 10 and R 11 combine with each other to form an oxetane. In other embodiments, R 10 and R 11 combine with each other to form azetidine. In other embodiments, R 10 and R 11 combine with each other to form 1-methylazetidine. In other embodiments, R 10 and / or R 11 is also F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8 It may be substituted with at least one substituent selected from cycloalkyl, halophenyl and (benzyloxy)phenyl; each represents a separate embodiment of the invention.

[0164] In some embodiments, R in Formulas I-VIII is H. In other embodiments, R is OH. In other embodiments, R is F. In other embodiments, R is Cl. In other embodiments, R is Br. In other embodiments, R is I. In another embodiment, R is CN. In other embodiments, R is CF 3 is. In other embodiments, R is NO 2 is. In other embodiments, R is NH 2 is. In other embodiments, R is NH(R 10 ). In other embodiments, R is NH(CH 3 ). In other embodiments, R is N(R 10 )(R 11 ). In other embodiments, R is 20 is. In other embodiments, R is C 1 -C 5 is straight or branched, substituted or unsubstituted alkyl. In another embodiment, R is methyl. In another embodiment, R is ethyl. In other embodiments, R is substituted alkyl. In other embodiments, R is CH 2 CH 2 is OH. In other embodiments, R is CH 2 CH 2 OCH 3 is. In other embodiments, R is 8 -R 10 is. In other embodiments, R is CH 2 -OH. In other embodiments, R is CH 2 CH 2 -OH. In other embodiments, R is C(O)-R 10 is. In another embodiment, R is C(O)-methylpyrrolidine. In another embodiment, R is C(O)-methylpiperidine. In another embodiment, R is C(O)-CH 3 is. In other embodiments, R is -R 8 -O-R 10 is. In other embodiments, R is CH 2 -CH 2 -O-CH 3 is. In other embodiments, R is C 1 -C 5 is substituted or unsubstituted C(O)-alkyl. In another embodiment, R is C(O)-CH 2 CH 2 -OCH 3 is. In another embodiment, R is C(O)-CH 3 is. In another embodiment, R is C(O)-CH 2 -N(CH 3 ) 2 is. In another embodiment, R is C(O)-CH 2 -CH 2 -N(CH 3 ) 2 is. In another embodiment, R is C(O)-CH 2 -OH. In other embodiments, R is C(O)-R 8 -R 10 is. In another embodiment, R is C(O)-CH 2 CH 2 -OH. In other embodiments, R is C(O)-substituted or unsubstituted C 3 -C 8 It is a heterocycle. In another embodiment, R is C(O)-methylpyrrolidine. In another embodiment, R is C(O)-methylpiperidine. In other embodiments, R is SO 2 - is alkyl. In other embodiments, R is SO 2 -CH 3 is. In other embodiments, R is C 1 -C 5 is substituted or unsubstituted C(O)-NH-alkyl. In another embodiment, R is C(O)-NH-CH 3 is. In other embodiments, R is C 1 -C 5 is straight or branched C(O)-O-alkyl. In another embodiment, R is C(O)-O-tBu. In other embodiments, R is C 1 -C 5 is straight or branched chain alkoxy. In other embodiments, R is -R 8 -O-R 10 is. In other embodiments, R is CH 2 -CH 2 -O-CH 3 is. In other embodiments, R is C 1 -C 5 is a straight or branched chain haloalkyl. In other embodiments, R is CF 3 is. In other embodiments, R is CF 2 CH 3 is. In other embodiments, R is CH 2 CF 3 is. In other embodiments, R is CF 2 CH 2 CH 3 is. In other embodiments, R is CH 2 CH 2 CF 3 is. In other embodiments, R is CF 2 CH(CH 3 ) 2 is. In other embodiments, R is CF(CH 3 )-CH(CH 3 ) 2 is. In other embodiments, R is 8 - is aryl. In other embodiments, R is CH 2 -Ph. In other embodiments, R is substituted or unsubstituted aryl. In another embodiment, R is phenyl. In other embodiments, R is substituted or unsubstituted heteroaryl. In another embodiment, R is pyridine. In other embodiments, R is 2, 3 or 4-pyridine. In other embodiments, R 3 is also F, Cl, Br, I, OH, SH, CF 3 , CN, NO 2 , substituted or unsubstituted C 1 -C 5 straight or branched chain alkyl (e.g. methyl, methoxyethyl), substituted or unsubstituted C 1 -C 5 straight or branched chain C(O)-alkyl (e.g. C(O)-CH 3 , C(O)-CH 2 -O-CH 3 ), SO 2 -alkyl (e.g. SO 2 -CH 3 ), C(O)-NH-alkyl, C 1 -C 5 straight- or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocycle (e.g. piperidine), substituted or unsubstituted C 1 -C 5 straight or branched alkoxy, N(R) 2 , N(R 10 )(R 11 ), aryl, phenyl, heteroaryl, C 3 -C 8It may be substituted with at least one substituent selected from cycloalkyl, halophenyl and (benzyloxy)phenyl; each represents a separate embodiment of the invention. In some embodiments, two geminal R substitutions are joined together to form a 3- to 6-membered substituted or unsubstituted, aliphatic (eg, cyclopropyl, cyclopentene) or aromatic, carbocyclic (eg, benzene) ring. or form a heterocyclic (eg, thiophene, furan, pyrrole, pyrazole) ring.

[0165] In some embodiments, X in compounds of Formulas III-VIII 1 is N. In other embodiments, X 1 is C.

[0166] In some embodiments, X in compounds of Formulas III-VIII 2 is N. In other embodiments, X 2 is C.

[0167] In some embodiments, X in compounds of Formulas II-VIII 3 is N. In other embodiments, X 3 is C.

[0168] In some embodiments, X in compounds of Formulas II-VIII 4 is C. In other embodiments, X 4 is N.

[0169] In some embodiments, X in compounds of Formulas II-VIII 5 is C. In other embodiments, X 5 is N.

[0170] X of any one of formulas II-VIII 1 -X 5 It is understood that an H atom is added as necessary to complete the valence of the unsubstituted carbon atom of .

[0171] In some embodiments, X in compounds of Formulas VI-VIII 6 is O. In other embodiments, X 6 is CH 2 is. In other embodiments, X 6 is CHR. In other embodiments, X 6 is CH(OH). In other embodiments, X 6 is CH(NH 2 ). In other embodiments, X 6 is CH(NH(CH 3 )). In other embodiments, X 6 is C(R 10 )(R 11 ). In other embodiments, X 6 is C(H)CH 2 CH 2 -OH. In other embodiments, X 6 is C(H)CH 2 -OH. In other embodiments, X 6 is 1-methylpyrrolidin-2-one. In other embodiments, X 6 is an oxetane. In other embodiments, X 6 is NH. In other embodiments, X 6 is N-R. In other embodiments, X 6 is N-CH 3 is. In other embodiments, X 6 is N-SO 2 -CH 3 is. In other embodiments, X 6 is N-R 20 is. In other embodiments, X 6 is N-C(O)O-tBu. In other embodiments, X 6 is N-C(O)-CH 2 CH 2 -OCH 3 is. In other embodiments, X 6 is N-CH 2 CH 2 -OCH 3 is. In other embodiments, X 6 is N-C(O)-CH 3 is. In other embodiments, X 6 is C1-C5 substituted or unsubstituted N-C(O)-NH-alkyl. In other embodiments, X 6 is N-C(O)-NH-CH 3 is. In other embodiments, X 6 is N-C(O)-CH 2 -N(CH 3 ) 2 is. In other embodiments, X 6 is N-C(O)-CH 2 -CH 2 -N(CH 3 ) 2 is. In other embodiments, X 6 is N-C(O)-CH 2 CH 2 -OH. In other embodiments, X 6 is N-C(O)-CH 2 -OH. In other embodiments, X 6 is N-C(O)-R 10 is. In other embodiments, X 6 is 1-methylazetidine. In other embodiments, X 6 is N-C(O)-1-methyl-2-pyrrolidine. In other embodiments, X 6 is N-C(O)-1-methyl-3-pyrrolidine. In other embodiments, X 6 is N-C(O)-1-methyl-3-piperidine. In other embodiments, X 6 is N-C(O)-1-methyl-4-piperidine. In other embodiments, X 6 is N-R 20 is.

[0172] In some embodiments, X 1 -X 2 is N.

[0173] In some embodiments, X 3 -X 5 is N. In some embodiments, X 3 -X 5 are N.

[0174] In some embodiments, Q in formula I 1 is S. In another embodiment, Q 1 is O. In other embodiments, Q1 is NH.

[0175] In some embodiments, G=X in Formula I is C=O. In another embodiment G=X is C=S. In another embodiment G=X is S=O. In other embodiments, G=X is SO 2 is.

[0176] As used herein, "monocyclic or fused ring aromatic or heteroaromatic ring system" includes, but is not limited to, phenyl, naphthyl, pyridinyl, (2-, 3-, and 4-pyridinyl), quinolinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazole, pyrazolyl, pyrrolyl, furanyl, thiophen-yl, quinolinyl, isoquinolinyl, 2,3 -dihydroindenyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepin, benzodioxolyl, benzo[d][1,3]dioxole, tetrahydronaphthyl, indolyl, 1H-indole, isoindolyl, anthracenyl, benzimidazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indole -3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4,5,6,7-tetrahydro-1,3- benzothiazole, quinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxaline, 1-(pyridin-1(2H)-yl)ethanone, cinnolinyl, phthalazinyl, quinolinyl, isoquinolinyl, acridinyl, benzofuranyl, 1-benzofuran, isobenzo furanyl, benzofuran-2(3H)-one, benzothiophenyl, benzoxadiazole, benzo[c][1,2,5]oxadiazolyl, benzo[c]thiophenyl, benzodioxolyl, thiadiazolyl, [1, 3]oxazolo[4,5-b]pyridine, oxadiazolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H ,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H, 7H-[1,3]thiazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4 -b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2-d]pyrimidin-4(3H)-one, 4-oxo-4H-thieno[3 ,2-d][1,3]thiazine, imidazo[1,2-a]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-imidazo[4,5-c]pyridine, 3H-imidazo[ 4,5-c]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrido[2,3-b]pyrazine, pyrido[2,3-b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxaline-2(1H)-one, 1H- pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thieno[3,2-c] pyridine, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole and the like.

[0177] As used herein, unless otherwise specified, the term "alkyl" can be a straight or branched chain alkyl group containing up to about 30 carbons. In various embodiments, alkyl is C 1 -C 5 Contains carbon. In some embodiments, alkyl is C 1 -C 6 Contains carbon. In some embodiments, alkyl is C 1 -C 8 Contains carbon. In some embodiments, alkyl is C 1 -C 10 Contains carbon. In some embodiments, alkyl is C 1 -C 12 Contains carbon. In some embodiments, alkyl is C 1 -C 20 Contains carbon. In some embodiments, a branched alkyl is an alkyl substituted with a 1-5 carbon alkyl side chain. In various embodiments, alkyl groups can be unsubstituted. In some embodiments, alkyl groups are halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO 2 H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C 1 -C 5 straight or branched chain haloalkoxy, CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, -CH 2 CN, NH 2 , NH-alkyl, N(alkyl) 2 , -OC(O)CF 3 , -OCH 2 Ph, -NHCO-alkyl, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH 2 , or any combination thereof.

[0178] Alkyl groups can be sole substituents or can be part of larger substituents such as alkoxy, alkoxyalkyl, haloalkyl, arylalkyl, alkylamino, dialkylamino, alkylamido, alkylurea, and the like. . Preferred alkyl groups are methyl, ethyl and propyl, thus halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, halopropyl, dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl, arylethyl, arylpropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylamide, acetamide, propylamide, halomethylamide, haloethylamide, halopropylamide, methyl-urea, ethyl-urea, propyl-urea, 2, 3,4-CH 2 -C 6 H. 4 -Cl, C(OH)(CH 3 )(Ph).

[0179] As used herein, the term "aryl" refers to any aromatic ring that is directly attached to another group and can be either substituted or unsubstituted. An aryl group can be the only substituent group or can be part of a larger substituent group such as arylalkyl, arylamino, arylamide, and the like. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, xylyl, furanyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiophen-yl, pyrrolyl, Indolyl, phenylmethyl, phenylethyl, phenylamino, phenylamido, 3-methyl-4H-1,2,4-triazolyl, 5-methyl-1,2,4-oxadiazolyl. Substituents include but are not limited to F, Cl, Br, I, C 1 -C 5 straight or branched chain alkyl, C 1 -C 5 straight or branched chain haloalkyl, C 1 -C 5 straight or branched alkoxy, C 1 -C 5 straight or branched chain haloalkoxy, CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , -CH 2 CN, NH 2 , NH-alkyl, N(alkyl) 2 , hydroxyl, -OC(O)CF 3 , -OCH 2 Ph, -NHCO-alkyl, COOH, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH 2 , or combinations thereof.

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

[0181] As used herein, the term "aminoalkyl" refers to an amine group substituted with an alkyl group as defined above. Aminoalkyl refers to monoalkylamines, dialkylamines, or trialkylamines. Non-limiting examples of aminoalkyl groups include -N(Me) 2 , -NHMe, -NH 3 is mentioned.

[0182] A "haloalkyl" group, in some embodiments, refers to an alkyl group, as defined above, substituted by one or more halogen atoms, eg, F, Cl, Br or I. The term "haloalkyl" includes, but is not limited to, fluoroalkyl, ie, alkyl groups having at least one fluorine atom. Non-limiting examples of haloalkyl groups include CF 3 , CF 2 CF 3 , CF 2 CH 3 , CH 2 CF 3 , CF 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CF 2 CH(CH 3 ) 2 , CF(CH 3 )-CH(CH 3 ) 2is mentioned.

[0183] A “halophenyl” group refers to a phenyl substituent substituted by one or more halogen atoms, eg, F, Cl, Br, or I, in some embodiments. In one embodiment, halophenyl is 4-chlorophenyl.

[0184] An "alkoxyalkyl" group, in some embodiments, refers to an alkyl group as defined above substituted with an alkoxy group as defined above, e.g., by methoxy, ethoxy, propoxy, i-propoxy, t-butoxy, etc. . Non-limiting examples of alkoxyalkyl groups include -CH 2 -O-CH 3 , -CH 2 -O-CH(CH 3 ) 2 , -CH 2 -O-C(CH 3 ) 3 , -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -O-CH(CH 3 ) 2 , -CH 2 -CH 2 -O-C(CH 3 ) 3 is mentioned.

[0185] A “cycloalkyl” or “carbocyclic” group, in various embodiments, refers to a ring structure containing carbon atoms as ring atoms, and is either saturated or unsaturated, substituted or unsubstituted, monocyclic or fused. In some embodiments, the cycloalkyl is a 3-10 membered ring. In some embodiments, cycloalkyl is a 3-12 membered ring. In some embodiments, cycloalkyl is a 6-membered ring. In some embodiments, cycloalkyl is a 5-7 membered ring. In some embodiments, cycloalkyl is a 3-8 membered ring. In some embodiments, cycloalkyl groups can be unsubstituted or halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO 2 H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C 1 -C 5 straight or branched chain haloalkoxy, CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, -CH 2 CN, NH 2 , NH-alkyl, N(alkyl) 2 , -OC(O)CF 3 , -OCH 2 Ph, -NHCO-alkyl, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH 2 , or any combination thereof. In some embodiments, a cycloalkyl ring may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring. In some embodiments, cycloalkyl rings are saturated rings. In some embodiments, cycloalkyl rings are unsaturated rings. Non-limiting examples of cycloalkyl groups include cyclohexyl, cyclohexenyl, cyclopropyl, cyclopropenyl, cyclopentyl, cyclopentenyl, cyclobutyl, cyclobutenyl, cyclooctyl, cyclooctadienyl (COD), cyclooctaene (COE), etc. is mentioned.

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

[0187] In various embodiments, the invention provides compounds of the invention, or isomers, metabolites, pharmaceutically acceptable salts, pharmaceuticals, tautomers, hydrates, N-oxides, reverse amide analogs thereof. , prodrugs, isotopic variants (eg, deuterated analogs), PROTACs, polymorphs, crystals, or any combination thereof. In some embodiments, this invention provides isomers of compounds of this invention. In some embodiments, the invention provides metabolites of compounds of the invention. In some embodiments, the invention provides pharmaceutically acceptable salts of compounds of the invention. In some embodiments, the invention provides medicaments of the compounds of the invention. In some embodiments, the invention provides tautomers of compounds of the invention. In some embodiments, the invention provides hydrates of compounds of the invention. In some embodiments, the invention provides N-oxides of compounds of the invention. In some embodiments, the invention provides reverse amide analogs of compounds of the invention. In some embodiments, the invention provides prodrugs of compounds of the invention. In some embodiments, the invention provides isotopic variants (eg, but not limited to, deuterated analogs) of compounds of the invention. In some embodiments, the present invention provides PROTACs (proteolysis-induced chimeras) of compounds of the present invention. In some embodiments, the invention provides polymorphs of the compounds of the invention. In some embodiments, the invention provides crystals of compounds of the invention. In some embodiments, the present invention provides compounds of the invention described herein, or isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical agents, tautomers of compounds of the invention. , hydrates, N-oxides, reverse amide analogs, prodrugs, isotopic variants (e.g., deuterated analogs), PROTACs, polymorphs, crystals, or any combination thereof. do.

[0188] In various embodiments, the term "isomer" includes, but is not limited to, stereoisomers or analogs thereof, optical isomers or analogs thereof, structural isomers or analogs thereof, conformational isomers or analogs thereof. In some embodiments, isomers are optical isomers. In some embodiments, isomers are stereoisomers.

[0189] In various embodiments, the invention encompasses the use of various optical isomers of the compounds of the invention. It will be appreciated by those skilled in the art that the compounds of the invention may contain at least one chiral center. Accordingly, the compounds used in the methods of the present invention may exist in, and be isolated in, optically active or racemic forms. Accordingly, the compounds of the present invention can be divided into optically active isomers (enantiomers or diastereomers, including but not limited to (R), (S), (R)(R), as racemic mixtures or as enantiomerically enriched mixtures). (R)(S), (S)(R), (R)(R)(R), (R)(R)(S), (R)(S)(R), (S)(R) (R), (R)(S)(S), (S)(R)(S), (S)(S)(R), or (S)(S)(S) isomers) may Some compounds may also exhibit polymorphism. The present invention encompasses any racemic, optically active, polymorphic, or stereoisomeric forms, or combinations thereof, that are useful in treating the various diseases (conditions) described herein. It should be understood that it has useful properties for

[0190] Methods for making optically active forms (e.g., resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separations using chiral stationary phases) are well known in the art. It is

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

[0192] The compounds of the present invention may also take the form of hydrates, in which the compounds further incorporate stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces. means to contain

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

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

[0195] [formation]

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

[0197] Suitable pharmaceutically acceptable salts of amines of the compounds of the invention can be made from inorganic or organic acids. In various embodiments, examples of inorganic salts of amines include hydrogen sulfate, borate, bromide, chloride, hemisulfate, hydrobromide, hydrochloride, 2-hydroxyethylsulfonate. (hydroxyethanesulfonate), iodate, iodide, isothionate, nitrate, persulfate, phosphate, sulfate, sulfamate, sulfanilate, sulfonic acid (alkylsulfonate, arylsulfone) acid salts, halogen-substituted alkylsulfonates, halogen-substituted arylsulfonates), sulfonates, and thiocyanates.

[0198] In various embodiments, examples of organic salts of amines can be selected from the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxyl, and sulfone classes of organic acids, such as Examples include acetates, arginine, aspartates, ascorbates, adipates, anthranilates, algenates, alkanecarboxylates, substituted alkanecarboxylates, alginates, benzenesulfonates, benzoic acid salt, bisulfate, butyrate, bicarbonate, bitartrate, citrate, camphorate, camphorsulfonate, cyclohexylsulfamate, cyclopentanepropionate, calcium edetate, camsylate, Carbonate, clavulanate, cinnamate, dicarboxylate, digluconate, dodecylsulfonate, dihydrochloride, decanoate, enanthate, ethanesulfonate, edetate, edisylate , estolate, esylate, fumarate, formate, fluoride, galacturonate, gluconate, glutamate, glycolate, glucolate, glucoheptanoate, glycerophosphate, gluceptate, Glycolyl Arsanilate, Glutarate, Glutamate, Heptanoate, Hexanoate, Hydroxymaleate, Hydroxycarboxylic Acid, Hexyl Resorcinate, Hydroxybenzoate, Hydroxynaphthoate, Hydrofluoric Acid Salt, Lactate, Lactobionate, Laurate, Malate, Maleate, Methylenebis(beta-oxynaphthoate), Malonate, Mandelate, Mesylate, Methanesulfonate, Methyl Bromide , methyl nitrate, methanesulfonate, monopotassium maleate, mucinate, monocarboxylate, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, napsylate, N-methylglucamine , oxalate, octanoate, oleate, pamoate, phenylacetate, picrate, phenylbenzoate, pivalate, propionate, phthalate, phenylacetate, pectate, Phenylpropionate, Palmitate, Pantothenate, Polygalacturonate, Pyruvate, Quinate, Salicylate, Succinate, Stearate, Sulfanilate, Basic Acetate, Tartrate, Theophylline Acetates, p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates, triethiodes, tricarboxylates, undecanoates, and valerates are mentioned.

[0199] Examples of inorganic salts of carboxylic acids or hydroxyls, in various embodiments, include alkali metals, including ammonium, lithium, sodium, potassium, and cesium; alkaline earth metals, including calcium, magnesium, and aluminum; ammonium class.

[0200] In some embodiments, examples of organic salts of carboxylic acids or hydroxyls are arginine, organic amines (aliphatic organic amines, cycloaliphatic organic amines, aromatic organic amines, benzathine, t-butylamine, betaamine (N-benzyl phenethylamine), dicyclohexylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, hydrabamine, imidazole, lysine, methylamine, megramine, N-methyl-D-glucamine, N,N´-dibenzylethylenediamine, nicotinamide, organic amines, ornithine, pyridine, picoline, piperazine, procaine, tris(hydroxymethyl)methylamine, triethylamine, triethanolamine, trimethylamine, tromethamine), and urea.

[0201] In various embodiments, the salt is prepared by conventional means, e.g., in a solvent or medium in which the salt is insoluble, or in a solvent such as water, to dissolve the product in free base or free acid form with one or more equivalents of a suitable acid. or by reacting with a base, which is removed under vacuum or by lyophilization, or by exchanging the ions of an existing salt with another ion or a suitable ion exchange resin.

[0202] Pharmaceutical composition

[0203] Another aspect of the invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound according to aspects of the invention. The pharmaceutical compositions of the invention may contain one or more compounds of the invention as described above. Generally, the pharmaceutical compositions of the invention can comprise a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to any suitable adjuvant, carrier, excipient or stabilizer, solid or liquid such as tablets, capsules, powders, solutions, suspensions or emulsions. can take the form of

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

[0205] A solid form dosage form can be, for example, a capsule, such as the usual gelatin type, containing a compound of the invention and carriers such as lubricants and inert fillers (eg, lactose, sucrose, or corn starch). In some embodiments, these compounds are added to a conventional tablet base such as lactose, sucrose, or cornstarch, a binder such as acacia, cornstarch, or gelatin, a disintegrant such as cornstarch, potato starch, or alginic acid, and It is combined with a lubricant such as, stearic acid or magnesium stearate and tableted.

[0206] In addition, tablets and capsules contain binders such as gum tragacanth, acacia, cornstarch, or gelatin, excipients such as dicalcium phosphate, disintegrants such as cornstarch, potato starch, and alginic acid, and lubricants such as magnesium stearate. , and sweetening agents such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

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

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

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

[0210] Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It should also be stable under the conditions of manufacture and storage and preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium including, for example, water, ethanol, polyols (eg, glycerol, propylene glycol, and liquid polyethylene glycols), suitable mixtures thereof, or vegetable oils.

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

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

[0213] For use as an aerosol, the compounds of the invention in solution or suspension are placed into a pressurized aerosol container with a suitable propellant, for example a conventional adjuvant and a hydrocarbon propellant such as propane, butane, or isobutane. can be packaged. The materials of the invention can also be administered in non-pressurized forms such as nebulizers and atomizers.

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

[0215] When administering the compounds of the invention, the compounds of the invention may be administered systemically or may be administered directly to the specific site where the cancer or precancerous cells reside. Thus, administration can be accomplished by any method effective to deliver a compound or pharmaceutical composition of the invention to cancer or precancerous cells. Exemplary modes of administration of a compound or composition of the invention include, but are not limited to, oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, intracavity, bladder. Administration or application includes intra-, intra-ocular, intra-arterial, intra-lesional, or to mucous membranes such as the nose, throat, and bronchi.

[0216] biological activity

[0217] In various embodiments, the invention provides compounds and compositions, including any of the embodiments described herein, for use in any of the methods of the invention. In various embodiments, use of the compounds of the invention or compositions comprising them has utility in inhibiting, suppressing, enhancing, or stimulating a desired response in a subject, as will be appreciated by those skilled in the art. Will. In some embodiments, compositions of the invention may further comprise additional active ingredients that have useful activity in the particular use for which the compound of the invention is administered.

[0218] The present invention relates to the treatment, inhibition and alleviation of fibrosis, including lung and liver fibrosis. More specifically, embodiments of the present invention employ the use of a compound according to the present invention or a pharmaceutically acceptable salt thereof to treat fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), or Compositions and methods useful for treating and inhibiting liver fibrosis associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are provided.

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

[0220] In a variety of conditions, the formation of fibrous tissue is characterized by the deposition of abnormally large amounts of collagen. Collagen synthesis is also implicated in a variety of other pathological conditions. Clinical conditions and diseases associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, and autoimmune diseases, are associated with normal histology. and by overproduction of connective tissue leading to disruption of function. These diseases can best be interpreted in terms of perturbations of cellular function, the major symptom of which is excessive synthesis and deposition of collagen. Given the role of collagen in fibrosis, attempts have been made to develop drugs that inhibit collagen accumulation.

[0221] Excessive accumulation of collagen is a major pathological feature in various clinical conditions characterized by tissue fibrosis. These clinical conditions include local processes such as pulmonary fibrosis and cirrhosis, or systemic processes such as progressive systemic sclerosis. In addition to scleroderma, collagen deposition is associated with various forms of dermal fibrosis, including focal or generalized scleroderma, keloids, hypertrophic scars, familial cutaneous collagenoma, and collagenous connective tissue nevus. It is a feature. Recent advances in understanding the normal biochemistry of collagen have made it possible to define specific levels of collagen biosynthesis and degradation at which pharmacological intervention would lead to reduced collagen deposition within tissues. Such compounds may provide a novel means to reduce collagen over-accumulation in disease.

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

[0223] Human fibrosis is characterized by a high prevalence, incomplete knowledge of the etiology of the fibrotic process, significant heterogeneity in etiology and clinical manifestations, and lack of adequate and well-validated biomarkers. This, and most importantly, the current lack of effective disease-modifying therapeutics presents a major global health problem. Fibrosis encompasses a wide range of clinical manifestations, including systemic fibrosis such as systemic sclerosis (SSc), scleroderma graft-versus-host disease, and nephrogenic systemic fibrosis. , and various organ-specific diseases such as radiation-induced fibrosis, cardiac fibrosis, pulmonary fibrosis, liver fibrosis, and renal fibrosis. Although the causative mechanisms of these diseases are highly diverse and, in some cases, still unexplained, these diseases are characterized by the uncontrolled and progressive accumulation of fibrotic tissue in the affected organs and their have the common feature of causing organ dysfunction and, ultimately, dysfunction. Despite the significant heterogeneity in the etiological mechanisms involved in the development of fibrosis and its clinical manifestations, many studies have investigated the differentiation of activated myofibroblasts into normal and non-functional fibrotic tissue. identified as the common cellular element ultimately responsible for replacement.

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

[0225] In various embodiments, the present invention provides a method for treating, inhibiting, reducing the severity of, reducing the risk of developing, or inhibiting organ-specific fibrosis in a subject, wherein a compound of the present invention is administered to an organ-specific administering to a subject suffering from organ-specific fibrosis under conditions effective to treat, inhibit, reduce the severity of, reduce the risk of developing, or inhibit organ-specific fibrosis in the subject Regarding.

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

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

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

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

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

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

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

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

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

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

[0236] Accordingly, in various embodiments, the invention provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting liver fibrosis in a subject, wherein the compounds of the invention are administering to a subject suffering from a disease under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit liver fibrosis in the subject. In some embodiments, liver fibrosis is the result of liver scarring. In some embodiments, liver fibrosis is the result of chronic liver injury. In some embodiments, chronic liver injury results from chronic alcoholism, malnutrition, hemochromatosis, or exposure to poisons, toxins, or drugs; each represents a separate embodiment of the invention. show. In some embodiments, the subject has cirrhosis. In some embodiments, the compounds of the invention are collagen I translation inhibitors. In some embodiments, the compounds of the invention are any of the compounds listed in Table 1; each compound represents a separate embodiment of the invention.

[0237] Although fibrosis itself is not necessarily symptomatic, it can lead to the development of cirrhosis, and scarring can lead to portal hypertension, which distorts blood flow through the liver, and to disruption of normal liver architecture and liver dysfunction. There is The degree of each of these pathologies determines the clinical manifestations of liver fibrotic disorders. For example, in congenital liver fibrosis, the portal vein branches are affected and the parenchyma is rarely affected. The result is portal hypertension with preservation of hepatocyte function.

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

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

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

[0241] In various embodiments, the invention provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholism in a subject, wherein a compound of the invention is administered to administering to an afflicted subject under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit alcoholism in the subject. In some embodiments, the compounds of the invention are collagen I translation inhibitors. In some embodiments, the compounds of the invention are any of the compounds listed in Table 1; each compound represents a separate embodiment of the invention.

[0242] Nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) have similar pathogenesis and histopathology, but different etiology and epidemiology. NASH and ASH are advanced stages of nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is defined as excess fat accumulation in the liver (steatosis), no other definite cause of chronic liver disease (viral, autoimmune, hereditary, etc.), and an alcohol intake of 20-30 g / day. Characterized by: In contrast, AFLD is defined as the presence of adiposity and alcohol consumption greater than 20-30 g / day.

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

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

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

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

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

[0248] Idiopathic pulmonary fibrosis (IPF) is an age-related refractory lung disease with historically limited treatment options. The 2014 US Food and Drug Administration (FDA) approval of two drugs, pirfenidone and nintedanib, heralded a new era in IPF treatment. Both agents have demonstrated efficacy in phase III clinical trials by slowing the rate of progression of IPF. However, both drugs appear unable to completely arrest disease progression. Advances in understanding the pathobiology of IPF have led to an unprecedented expansion of the number of potential therapeutic targets. Drugs targeting some of these are under investigation in various stages of clinical development.

[0249] In various embodiments, the invention provides a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting idiopathic pulmonary fibrosis (IPF) in a subject, comprising: , to a subject suffering from idiopathic pulmonary fibrosis (IPF), a It relates to a method comprising administering under conditions. In some embodiments, the compounds of the invention are collagen I translation inhibitors. In some embodiments, the compounds of the invention are any of the compounds listed in Table 1; each compound represents a separate embodiment of the invention. In some embodiments, the compounds of the invention are administered in combination with agents that treat IPF. In some embodiments, the compound is administered in combination with pirfenidone, nintedanib, or a combination thereof; each representing a separate embodiment of the invention.

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

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

[0252] In various embodiments, the invention provides a method of inhibiting collagen I (ColI) overproduction in a subject, comprising administering a compound of the invention to a subject suffering from collagen I (ColI) overproduction in said subject. administering under conditions effective to inhibit collagen I (ColI) overproduction in a subject. In some embodiments, the compounds of the invention are collagen I translation inhibitors. In some embodiments, the compounds of the invention are collagen I translation inhibitors, collagen II translation inhibitors, collagen III translation inhibitors, collagen IV translation inhibitors, or collagen V translation inhibitors; Represents a separate embodiment of the present invention. In some embodiments, the compounds of the invention are selective for collagen I. In some embodiments, the compounds of the invention are selective for collagen IA. In some embodiments, the compounds of the invention are selective for collagen IA1. In some embodiments, the compounds of the invention are any of the compounds listed in Table 1; each compound represents a separate embodiment of the invention.

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

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

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

[0256] Example

[0257] overview

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

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

[0260] General method

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

[0262] Abbreviations AcOH: acetic acid amphos : bis(di-tert-butyl(4-dimethylaminophenyl))phosphine Boc: tert-butyloxycarbonyl BuLi : n-butyllithium t-BuLi : tert-butyllithium CDI: 1,1´-carbonyldiimidazole DBU : 1,8-diazabicyclo[5.4.0]undec-7-ene dppb : 1,4-bis(diphenylphosphino)butane dppf : 1,1´-bis(diphenylphosphino)ferrocene DCM: Dichloromethane DCE: 1,2-dichloroethane DEAD : diethyl azodicarboxylate DIAD: diisopropyl azodicarboxylate DIBAL-H : Diisobutylaluminum hydride DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMA: dimethylacetamide DMAP: 4-(dimethylamino)pyridine DME: 1,2-dimethoxyethane DMSO: dimethylsulfonamide EDC.HCl: N-(3-dimethylaminopropyl)-N´-ethylcarbodiimide hydrochloride HATU: [0-(7-Azabenzotriazol-1-yl)-N,N,N´,N´-tetramethyluronium-hexafluorophosphato] HPLC : high performance liquid chromatography MsCl: methanesulfonyl chloride NBS: N-bromosuccinimide NMP: N-methyl-2-pyrrolidone rt : room temperature SEM: 2-(trimethylsilyl)ethoxymethyl T3P : Propylphosphonic anhydride TBAF : Tetrabutylammonium fluoride TBDMS : tert-butyldimethylsilyl TBDPS : tert-butyldiphenylsilyl TCFH: N,N,N´,N´-tetramethylchloroformamidinium hexafluorophosphate THF: Tetrahydrofuran TMS-OTf : trimethylsilyltrifluoromethanesulfonate

[0263] General Synthetic Methods for Compounds of the Invention

[0264] RHS-qualified

[0265] A two-step synthetic sequence to the RHS-modified analogs of compound 300 (see Table 1 for structures) is shown in Scheme 1. Scheme 1.4 - Synthesis of aryl-modified analogs 5

[0266] [formation]

[0267] The first step of the synthesis involves the amide coupling reaction of 4-bromothiazol-2-amine 1 and 4-methoxybenzoic acid 2 at elevated temperature in the presence of propylphosphonic anhydride (T3P) to give intermediate 3. got The second and final step involved a Suzuki coupling with intermediate 3 under microwave conditions at 120°C. Catalysis of [1,1´-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in a mixed solvent of dioxane and water using a variety of different arylboronic acids or pinacol esters 4 with sodium carbonate as the base. provided the final compound (4-aryl modified analog 5) as.

[0268] Synthesis of the 4-aryl modified analogues of 6-methylnicotinamide shown in Scheme 2 was performed using a synthetic sequence similar to Scheme 1. Scheme 2. Synthesis of 4-aryl modified analogs of 6-methylnicotinamide 8

[0269] [formation]

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

[0271] [formation]

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

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

[0274] [formation]

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

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

[0277] [formation]

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

[0279] LHS modification

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

[0281] [formation]

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

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

[0284] [formation]

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

[0286] Piperazine sulfonamide analogues were accessed by the synthetic route shown in Scheme 8. Scheme 8. Synthesis of piperazine sulfonamide analog 34

[0287] [formation]

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

[0289] The syntheses of two non-commercially available morpholinocarboxylic acids are summarized in Scheme 9. Scheme 9. Synthesis of two non-commercially available morpholinocarboxylic acids

[0290] [formation]

[0291] Aromatic substitution of the commercially available chloropyrazine, pyridazine esters 35, and 39 with morpholine 36 using microwaves at 100° C. afforded access to morpholino ester intermediates 37 and 40, respectively. These intermediates 37 and 40 were refluxed in 6M aqueous hydrochloric acid, respectively, to give morpholinocarboxylic acids 38 and 41, respectively, as hydrochloride salts.

[0292] scaffold modification

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

[0294] [formation]

[0295] Commercially available 2-chlorophenyl-bromoketone 42 was heated with urea 43 in DMF in microwave at 130° C. to give cyclized aminooxazole 44. The desired target (oxazole analogue 45) (compound 368 ).

[0296] A general synthesis of combinatorial analogs combining morpholinoheteroaryl LHS moieties with RHS aryl / heteroaryl groups is shown in Scheme 11 (see Table 1 for structures). Scheme 11. General Synthesis of Combinatorial Analog 51 to Combinatorial Analog 55

[0297] [formation]

[0298] [1,1´-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) and sodium carbonate in dioxane and water at 100°C were used to give N-Boc4-bromothiazol-2-amine 20 and various borons. Suzuki coupling with acid or pinacol ester 4 allowed the synthesis of N-Boc aminothiazole intermediate 46.

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

[0300] Scheme 12 outlines the three-step synthesis of compound 60 (compound 376). Scheme 12. Synthesis of compound 60 (compound 376)

[0301] [formation]

[0302] In the first step, 4-(4-(tert-butoxycarbonyl)piperazine-1- Amide coupling of yl)benzoic acid 31 with 4-(2-chlorophenyl)thiazol-2-amine 56 was performed to deliver intermediate 57 in high yield. This amide coupling protocol facilitated scale-up and was an alternative approach to the T3P protocol described in Scheme 8. Removal of the N-Boc protecting group was accomplished by treating intermediate 57 with a 4M solution of HCl in dioxane to give aminothiazole intermediate 58. A final step amide coupling of aminothiazole intermediate 58 with 3-methoxypropanoic acid 59 using HATU coupling conditions provided final compound 60 (compound 376).

[0303] Scheme 13 outlines the single-step synthesis of compound 62 (compound 377) from intermediate 58. Scheme 13. Synthesis of compound 62 (compound 377)

[0304] [formation]

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

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

[0307] [formation]

[0308] Tetrakis(triphenylphosphine)palladium(0) and cesium carbonate were mixed in dioxane and water to give the bromothiazole intermediate (intermediate 13) and (2-(2-methoxyethoxy)phenyl)boronic acid 63 at 100 °C. Suzuki coupling with normal heating allowed the synthesis of compound 64 (compound 378).

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

[0310] A single step synthesis of compounds (amide N-methyl substituted analog 69) and 70 (compounds 399 and 400) (see Table 1 for structures) is shown in Scheme 15. Scheme 15. Synthesis of amide N-methyl substituted analogues 69 and 70

[0311] [formation]

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

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

[0314] [formation]

[0315] The first step of the synthesis involves the amide coupling reaction of 4-(2-chlorophenyl)thiazol-2-amine 56 and 4-(methoxycarbonyl)benzoic acid 75 in the presence of HATU and DIPEA in DMF, Intermediate 76 was obtained. In the second step of the synthesis, lithium hydroxide was used to hydrolyze the methyl ester intermediate 76 to give the carboxylic acid intermediate 77. The final step of the synthesis is an amide coupling reaction using reaction conditions similar to the first step. Various types of amines 78 were used to obtain the final bisamide 79 compounds.

[0316] The compound outlined in Scheme 17 (compound 430) was synthesized using a synthetic sequence similar to the above scheme. Scheme 17. (1r,3r)-N-(4-(2-chlorophenyl)thiazol-2-yl)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)cyclobutane-1-carboxamide 84 (compound 430 ) synthesis

[0317] [formation]

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

[0319] The piperazine sulfonamide analog Compound 91 (Compound 403) was accessed by the synthetic route shown in Scheme 18. Scheme 18. Synthesis of Piperazine Sulfonamide Analog Compound 91 (Compound 403)

[0320] [formation]

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

[0322] An alternative synthesis for preparing the piperazine key intermediate (piperazine intermediate 90) is shown in Scheme 19. Scheme 19. Alternative Synthesis of Piperazine Key Intermediate Amine (Piperazine Intermediate 90)

[0323] [formation]

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

[0325] Synthesis of the 2-substituted 2,7-diazaspiro[3.5]nonane intermediate 96 outlined in Scheme 20 was carried out using a synthetic sequence similar to Scheme 18 above. Scheme 20. Synthesis of 2-substituted 2,7-diazaspiro[3.5]nonane key intermediates (96)

[0326] [formation]

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

[0328] Synthesis of 2-substituted 2,6-diazaspiro[3.3]heptane intermediate 99 was carried out as shown in Scheme 21 using a synthetic sequence similar to Scheme 19 above. Scheme 21. Synthesis of 2-substituted 2,6-diazaspiro[3.3]heptane key intermediates (heptane intermediate 99)

[0329] [formation]

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

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

[0332] [formation]

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

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

[0335] [formation]

[0336] (3-Bromopyridin-2-yl)methanol 106 was protected as the acetate ester 107 with acetic anhydride in the presence of triethylamine and DMAP in DCM at room temperature. The acetic acid intermediate (acetic ester 107) was converted to bis(( pinacolato)diboron 108 to give the heteroaryl boronate reagent (boronic ester 109).

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

[0338] [formation]

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

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

[0341] [formation]

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

[0343] Scheme 26 summarizes the three-step synthesis of non-commercially available 4-substituted-2-aminethiazoles 122. Scheme 26. Synthesis of 4-(tetrahydro-2H-pyran-4-yl)thiazol-2-amine (122)

[0344] [formation]

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

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

[0347] [formation]

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

[0349] The non-commercially available 4-substituted-2-amine thiazoles 127 were synthesized using the Hantzsch thiazole cyclization reaction as outlined in Scheme 28. Scheme 28. Synthesis of 4-(2-(methoxymethyl)phenyl)thiazol-2-amine (127)

[0350] [formation]

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

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

[0353] [formation]

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

[0355] Scheme 30 summarizes the two-step synthesis of the commercially available 2-methoxy-4-morpholinobenzoic acid 130d. Scheme 30. Synthesis of 2-methoxy-4-morpholinobenzoic acid 130d.

[0356] [formation]

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

[0358] Scheme 31 summarizes the syntheses of three non-commercially available carboxylic acids 138a, 138b and 138c. Scheme 31. Synthesis of non-commercially available carboxylic acid 138

[0359] [formation]

[0360] In the first step, the commercially available allyl bromide methyl ester 133 and boronic ester 134 ( Suzuki coupling reaction of X=O or S) was carried out to give intermediate 135. In a second step, the double bond of 135 was reduced by hydrogenation using white (IV) oxide (Adams' catalyst) in methanol to give the methyl ester intermediate 136. For intermediate 136 where X is sulfur, the tetrahydro-2H-thiopyran moiety is oxidized to tetrahydro-2H-thiopyran 1,1-dioxide using oxone as an oxidizing agent in a mixed solvent of methanol, acetone and water at room temperature. yielded the methyl ester intermediate 137. In the final step of the synthesis, lithium hydroxide was used in aqueous THF to hydrolyze the methyl ester moiety of intermediate 136 or 137, delivering the carboxylic acid intermediate (carboxylic acid 138). The overall synthetic sequence was 4 steps for carboxylic acids 138a and 138b, but only 3 steps for carboxylic acid 138c.

[0361] The two-step syntheses of several other non-commercially available 5-(aminoalkyl)picolinic acids (141) are summarized in Scheme 32. Scheme 32. Synthesis of non-commercial 5-(aminoalkyl)picolinic acid (141)

[0362] [formation]

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

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

[0365] [formation]

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

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

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

[0369] [formation]

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

[0371] Scheme 35 summarizes the synthesis of non-commercially available 3-morpholinobicyclo[1.1.1]pentane-1-carboxylic acid 160 and (1R,3R)-3-morpholinocyclobutane-1-carboxylic acid 163. Scheme 35. Synthesis of non-commercially available carboxylic acids 160 and 163

[0372] [formation]

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

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

[0375] [formation]

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

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

[0378] [formation]

[0379] The first step of the synthesis is the preparation of 4-bromothiazol-2-amine 1 and 5-(4-(methylsulfonyl)piperazine- Amide coupling reaction of 1-yl)picolinic acid (144) was carried out to give amide intermediate 169. In the final step, a palladium-catalyzed Suzuki coupling reaction of 4-bromothiazolamide intermediate 169 and 2-[(dimethylamino)methyl]phenylboronic acid 170 led to the synthesis of final compound 171 (compound 460). Suzuki coupling reaction was carried out at 110° C. in an aqueous solution of dioxane using tetrakis(triphenylphosphine)palladium(0) as a catalyst and potassium carbonate as a base.

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

[0381] [formation]

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

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

[0384] [formation]

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

[0386] Scheme 40 outlines the synthesis of compound 186. Scheme 40. Synthesis of compound 186

[0387] [formation]

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

[0389] Scheme 41 outlines the synthesis of final compounds 188a and 189. Scheme 41. Synthesis of compounds 188a and 189 (compounds 437 and 451)

[0390] [formation]

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

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

[0393] [formation]

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

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

[0396] [formation]

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

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

[0399] [formation]

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

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

[0402] [formation]

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

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

[0405] [formation]

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

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

[0408] [formation]

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

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

[0411] [formation]

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

[0413] Detailed Synthetic Methods for Intermediate Compounds of the Invention

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

[0415] [formation]

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

[0417] Yield 1.32g (75%). 1 H NMR (400 MHz, DMSO) δ 12.82 (brs, 1H), 8.12 (d, J = 9.0 Hz, 2H), 7.39 (s, 1H), 7.21 (d, J = 9.0 Hz, 2H), 3.94 (s ,3H).

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

[0419] [formation]

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

[0421] Yield 898mg (54%). 1 H NMR (400MHz, DMSO) δ 13.09 (s, 1H), 9.11 (d, J = 2.0Hz, 1H), 8.32 (dd, J = 2.0, 8.0Hz, 1H), 7.46 (d, J = 8.0Hz ,1H),7.41(s,1H),2.58(s,3H).

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

[0423] [formation]

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

[0425] Yield 1.46g (79%). 1 H NMR (400 MHz, DMSO) δ 11.63 (brs, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.64 (s, 1H), 7.53 (dd ,J=2.2,8.5Hz,1H),1.51(s,9H).

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

[0427] [formation]

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

[0429] Yield 1g (96%). 1 H NMR (400 MHz, DMSO) δ 7.89 (d, J = 8.6 Hz, 1 H), 7.66 (s, 1 H), 7.48 (d, J = 8.6 Hz, 1 H), 7.11 (m, 3 H).

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

[0431] [formation]

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

[0433] Yield 168mg (75%). 1 H NMR (400MHz, CDCl 3 )δ7.40(dd,J=1.5,8.0Hz,1H),7.17(dd,J=6.9,8.4Hz,1H),6.66(dt,J=1.5,6.9Hz,1H),6.54(dd,J =1.5,8.4Hz,1H),4.06(dd,J=7.3,7.3Hz,4H),2.30-2.22(m,2H).

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

[0435] [formation]

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

[0437] Yield 1.2g (quantitative). 1 H NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 7.83 (dd, J = 1.9, 7.7 Hz, 1H), 7.57 (s, 1H), 7.55 (dd, J = 1.5, 7.8 Hz, 1H) ,7.42(dd,J=1.5,7.8Hz,1H),7.38(dd,J=1.9,7.7Hz,1H),1.44(s,9H).

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

[0439] [formation]

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

[0441] Yield 646 mg (86%). 1 H NMR (400 MHz, DMSO) δ 7.85 (dd, J = 1.8, 7.8 Hz, 1 H), 7.50 (dd, J = 1.2, 7.9 Hz, 1 H), 7.41 (dd, J = 1.2, 7.9 Hz, 1 H) ,7.36(dd,J=1.8,7.8Hz,1H),7.07(brs,2H),7.05(s,1H).

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

[0443] [formation]

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

[0445] Yield 320mg (68%). 1 H NMR (400 MHz, DMSO) δ 12.46 (brs, 1H), 8.07 (d, J = 9.0 Hz, 2H), 7.92 (dd, J = 1.5, 8.0 Hz, 1H), 7.63 (s, 1H), 7.58 (dd,J=1.5,8.0Hz,1H),7.45(dd,J=1.5,7.6Hz,1H),7.41(dd,J=1.5,7.6Hz,1H),7.04(d,J=9.0Hz, 2H), 3.51-3.44(m, 4H), 3.39-3.35(m, 4H), 1.44(s, 9H).

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

[0447] [formation]

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

[0449] Yield 978mg (76%). 1 H NMR (400MHz, DMSO) δ 13.13(s,1H), 9.21(s,2H), 7.42(s,1H), 4.03(s,3H).

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

[0451] [formation]

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

[0453] Yield 1.19g (58%). 1 H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 8.06 (d, J = 9.1 Hz, 2H), 7.36 (s, 1H), 7.08 (d, J = 9.1 Hz, 2H), 3.81-3.77 (m,4H),3.35-3.30(m,4H).

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

[0455] [formation]

[0456] To a solution of 4-(2-chlorophenyl)thiazol-2-amine (150 mg, 0.712 mmol) in pyridine (3 mL) was added phenyl chloroformate (0.11 mL, 0.854 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate (20 mL) and brine (20 mL). The layers were separated and the aqueous layer was further extracted with ethyl acetate (2x20 mL). Combine the organic layers and dry (MgSO 4 ), filtered and evaporated. The residue was purified by silica gel (0-25% ethyl acetate in cyclohexane) column chromatography to give phenyl (4-(2-chlorophenyl)thiazol-2-yl)carbamate as an off-white solid.

[0457] Yield 262mg (quantitative). 1 H NMR (400 MHz, DMSO) δ 12.49 (s, 1H), 7.87 (dd, J = 1.6, 7.8 Hz, 1H), 7.67 (s, 1H), 7.58 (dd, J = 1.6, 7.8 Hz, 1H) ,7.49(d,J=7.6Hz,2H),7.40(d,J=7.6Hz,2H),7.35(s,1H),7.33-7.28(m,2H).

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

[0459] [formation]

[0460] To a solution of 2-bromo-1-(pyridin-2-yl)ethan-1-one (300 mg, 1.50 mmol) in ethanol (5 mL) was added thiourea (171 mg, 2.25 mmol). The reaction was stirred under reflux for 4 hours and cooled to room temperature. The solvent was evaporated and the residue was treated with DCM (20 mL) and NaHCO 3 was partitioned into a saturated solution (20 mL) of The layers were separated and the aqueous layer was further extracted with DCM (2x20mL). Combine the organic layers and dry (MgSO 4 ) and filtered. Evaporation of the solvent gave 4-(pyridin-2-yl)thiazol-2-amine as a brown solid. This material was carried on as is without purification.

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

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

[0463] [formation]

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

[0465] Yield 230mg (52%). 1 H NMR (400MHz, CDCl 3 )δ7.98(dd,J=1.5,7.9Hz,1H),7.88(s,1H),7.41(dd,J=1.5,7.9Hz,1H),7.31(dt,J=1.5,7.6Hz,1H ),7.20(dt,J=1.5,7.6Hz,1H),4.72(s,2H).

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

[0467] [formation]

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

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

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

[0471] [formation]

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

[0473] Yield 350mg (quantitative). 1 H NMR (400 MHz, DMSO) δ 8.67 (d, J = 1.3 Hz, 1 H), 8.37 (d, J = 1.3 Hz, 1 H), 3.72 (s, 8 H). became unclear.

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

[0475] [formation]

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

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

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

[0479] [formation]

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

[0481] Yield 318mg (quantitative). 1 H NMR (400MHz, DMSO) δ7.92(d,J=9.7Hz,1H),7.40(d,J=9.7Hz,1H),3.78-3.70(m,8H). obscured by peaks.

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

[0483] [formation]

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

[0485] Yield 682mg (43%). 1 H NMR (400 MHz, DMSO) δ 11.62 (s, 1H), 8.48 (dd, J = 1.6, 4.7 Hz, 1H), 7.96 (dd, J = 1.6, 7.6 Hz, 1H), 7.40 (s, 1H) ,7.34(dd,J=4.7,7.6Hz,1H),2.66(s,3H),1.56(s,9H).

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

[0487] [formation]

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

[0489] Yield 474mg (quantitative). 1 H NMR (400 MHz, DMSO) δ 8.39 (dd, J = 1.8, 4.9 Hz, 1 H), 7.91 (dd, J = 1.8, 7.9 Hz, 1 H), 7.26 (dd, J = 4.9, 7.9 Hz, 1 H) ,7.08(s,2H),6.78(s,1H),2.63(s,3H).

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

[0491] [formation]

[0492] 4-(2.18 g, 7.12 mmol) DMAP (0.58 g, 4.75 mmol) and N-(3- Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1.09 g, 5.70 mmol) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was treated with saturated NH 4 Quenched with aqueous Cl (50 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous Na. 2 SO 4 dried with After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 1%-40% ethyl acetate in petroleum ether to give tert-butyl 4-(4-((4-(2-chlorophenyl)thiazole-2) as an off-white solid. -yl)carbamoyl)phenyl)piperazine-1-carboxylic acid ester was obtained.

[0493] Yield 1.70g (72%). 1 H NMR (300MHz, CDCl 3 )δ10.08(s,1H),7.85(d,J=8.9Hz,2H),7.80(dd,J=1.9,7.6,Hz,1H),7.49-7.40(m,2H),7.37-7.20( m,2H),6.90(d,J=8.9Hz,2H),3.61(t,J=5.3Hz,4H),3.35(t,J=5.3Hz,4H),1.51(s,9H). 1 H NMR (400 MHz, DMSO) δ 12.47 (s, 1H), 8.04 (d, J = 8.9 Hz, 2H), 7.91 (dd, J = 1.9, 7.7 Hz, 1H), 7.63 (s, 1H), 7.57 (dd,J=1.5,7.8Hz1H),7.45(td,J=1.5,7.5,1H),7.39(td,J=1.8,7.6Hz,1H),7.04(d,J=8.9Hz,2H), 3.47(t,J=6.3Hz,4H),3.35(t,J=6.3Hz,4H),1.43(s,9H).m / z:[ESI + ]499,501(M+H) + .

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

[0495] [formation]

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

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

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

[0499] [formation]

[0500] To a stirred solution of methyl 4-(3,6-dihydro-2H-thiopyran-4-yl)benzoate (0.40 g, 1.71 mmol) in methanol (8 mL) was added platinum(IV) oxide at room temperature under a nitrogen atmosphere. (0.80 g, 3.52 mmol) was added. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere (1.5 atm). The resulting mixture was filtered and the filter cake was washed with methanol (3 x 2 mL). The combined washings and filtrate were concentrated under reduced pressure. The residue was purified using reverse phase flash chromatography with the following conditions. Column: WelFlash TM C18-I, 20-40 μm, 330 g, eluent A: water (+10 mmol / L of NH 4 HCOs 3 ), eluent B: acetonitrile, gradient: 38%-58% B (25 min), flow rate: 90 mL / min, detector: UV220 / 254 nm. Fractions containing the desired product were pooled and concentrated under reduced pressure to give methyl 4-(tetrahydro-2H-thiopyran-4-yl)benzoate as an off-white solid.

[0501] Yield 0.18g (45%). 1 H NMR (400 MHz, DMSO) δ 7.90 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 3.84 (s, 3H), 2.86-2.73 (m, 2H), 2.69 -2.61(m,3H),2.07-2.01(m,2H),1.80-1.65(m,2H).No MS signal.

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

[0503] [formation]

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

[0505] Yield 160mg (78%). 1 H NMR (400 MHz, DMSO) δ 7.92 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 3.84 (s, 3H), 3.44-3.27 (m, 2H), 3.18 -3.08(m,2H),3.08-2.98(m,1H),2.16-2.04(m,4H).No MS signal.

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

[0507] [formation]

[0508] To a stirred solution of methyl 4-(1,1-dioxydotetrahydro-2H-thiopyran-4-yl)benzoate (160 mg, 0.596 mmol) in water (2 mL) and THF (2 mL) was added lithium hydroxide monohydrate at room temperature. Sodium (100 mg, 2.383 mmol) was added. The resulting mixture was stirred overnight at room temperature. 2M HCl aqueous solution and the mixture were concentrated under reduced pressure to adjust the pH value of the solution to 5. The residue was purified using reverse phase flash chromatography with the following conditions. Column: WelFlash™ C18-I, 20-40 μm, 330 g, eluent A: water (+10 mmol / L HCOOH), eluent B: acetonitrile, gradient: 5%-20% B (25 min), flow rate: 80 mL. / min, detector: UV220 / 254nm. Desired fractions were collected and concentrated under reduced pressure to give 4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)benzoic acid as an off-white solid.

[0509] Yield 142mg (94%). 1 H NMR (400 MHz, DMSO) δ 12.85 (brs, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 3.38-3.28 (m, 2H), 3.19 -3.08(m,2H),3.08-2.96(m,1H),2.16-2.05(m,4H).m / z:[ESI - ]253(M-H) - .

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

[0511] [formation]

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

[0513] Yield 1.71g (66%). 1 H NMR (400 MHz, DMSO) 8.77 (d, J = 2.0 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.98 (dd, J = 2.0, 8.0 Hz, 1 H), 6.58-6.48 (m,1H),3.88(s,3H),3.33-3.38(m,2H),2.87(t,J=5.6Hz,2H),2.71-2.65(m,2H).m / z:[ESI + ]236(M+H) + .

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

[0515] [formation]

[0516] The compound 5-(tetrahydro-2H-thiopyran-4- yl)picolinate was prepared and isolated as an off-white solid.

[0517] Yield 0.83g (48%). 1 H NMR (400 MHz, DMSO) 8.61 (d, J = 2.0 Hz, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.86 (dd, J = 2.0, 8.0 Hz, 1 H), 3.87 (s ,3H),2.86-2.72(m,3H),2.72-2.63(m,2H),2.12-2.01(m,2H),1.86-1.70(m,2H).m / z:[ESI + ]238(M+H) + .

[0518] 5-(1,1-Dioxydotetrahydro-2H-thiopyran-4-yl)methyl picolinate

[0519] [formation]

[0520] The 5-(1,1-dioxydotetrahydro-2H-thiopyran-4-yl)picolinate compound methyl was treated with methyl 5-picolinate (0.80 g, 3.37 mmol) and potassium peroxymonosulfate (Oxone®) (4.31 g). , 14.04 mmol) in a similar procedure for the synthesis of methyl 4-(1,1-dioxydotetrahydro-2H-thiopyran-4-yl)benzoate and isolated as an off-white solid.

[0521] Yield 0.65g (72%). 1 H NMR (400 MHz, DMSO) δ 8.66 (d, J = 2.0 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.96 (dd, J = 2.0, 8.0 Hz, 1 H), 3.88 (s ,3H),3.39-3.28(m,2H),3.20-3.07(m,3H),2.20-2.10(m,4H).m / z:[ESI + ]270(M+H) + .

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

[0523] [formation]

[0524] The compound 5-(1,1-dioxydotetrahydro-2H-thiopyran-4-yl)picolinate was treated with methyl 5-(1,1-dioxydotetrahydro-2H-thiopyran-4-yl)picolinate (0.50 g, 1.86 mmol) and lithium hydroxide monohydrate (0.30 g, 7.15 mmol) by a similar procedure for the synthesis of 4-(1,1-dioxydotetrahydro-2H-thiopyran-4-yl)benzoic acid. , isolated as an off-white solid.

[0525] Yield 0.30g (63%). 1 H NMR (400MHz, DMSO) δ 13.10 (brs, 1H), 8.62 (d, J = 2.0Hz, 1H), 8.00 (d, J = 8.0Hz, 1H), 7.89 (dd, J = 2.0, 8.0Hz ,1H),3.40-3.28(m,2H),3.19-2.99(m,3H),2.21-2.09(m,4H).m / z:[ESI + ]256(M+H) + .

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

[0527] [formation]

[0528] 5-bromopicolinate (216 mg, 1.00 mmol) methyl and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane ( 210 mg, 1.00 mmol), the compound 5-(3,6-dihydro-2H-thiopyran- 4-yl)picolinate was isolated as an off-white solid.

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

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

[0531] [formation]

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

[0533] Yield 50mg (50%). 1 H NMR (400 MHz, DMSO) 8.65 (d, J = 2.4 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.89 (dd, J = 2.4, 8.0 Hz, 1 H), 3.03-3.94 (m,2H),3.87(s,3H),3.51-3.41(m,2H),3.02-2.90(m,1H),1.77-1.68(m,4H).m / z:[ESI + ]222(M+H) + .

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

[0535] [formation]

[0536] From compound 5-(tetrahydro-2H-pyran-4-yl)methylpicolinate (50 mg, 0.226 mmol) and lithium hydroxide monohydrate (38 mg, 0.906 mmol), compound 5-(tetrahydro-2H-pyran-4 -yl)picolinic acid was prepared by a procedure similar to the synthesis of 4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)benzoic acid and isolated as an off-white solid.

[0537] Yield 39mg (83%). 1 H NMR (400MHz, CDCl 3 )δ8.61(d,J=2.0Hz,1H),8.22(d,J=8.0Hz,1H),7.82(dd,J=2.0,8.0Hz,1H),4.21-4.09(m,2H), 3.58 (dt, J=3.2, 11.6 Hz, 2H), 3.03-2.87 (m, 1H), 1.97-1.76 (m, 4H). No carboxylic acid OH protons were observed. m / z:[ESI + ]208(M+H) + .

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

[0539] [formation]

[0540] benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (3.80 g, 18.70 mmol), sodium periodate (16.00 g, 74.80 mmol), and 2,5-dihydro-1H-pyrrole-1-carboxylate (3.80 g, 18.70 mmol) in ethyl acetate (40 mL) and water (40 mL); To a stirred mixture of 6-lutidine (4.01 g, 37.42 mmol) at 0° C. was added potassium (VI) osmate dihydrate (0.34 g, 0.92 mmol). The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na. 2 SO 4 dried with After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-9% methanol in DCM to give benzyl bis(2-oxoethyl)carbamate as a dark brown semi-solid.

[0541] Yield 3.30g (75%). 1 H NMR (400 MHz, DMSO) δ 7.44-7.25 (m, 5H), 5.09 (s, 2H), 3.35 (s, 4H). No aldehyde CH protons were observed. No MS signal.

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

[0543] [formation]

[0544] A mixture of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (0.80 g, 4.50 mmol) and benzylbis(2-oxoethyl)carbamate (1.17 g, 4.97 mmol) in methanol (10 mL) was stirred. At 0° C., acetic acid (0.95 g, 15.82 mmol) and sodium cyanoborohydride (0.99 g, 15.75 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. Water (50 mL) was added to quench the reaction and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na. 2 SO 4 dried with After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using reverse-phase flash chromatography with the following conditions: Column: WelFlash™ C18-I, 20-40 μm, 330 g, eluent A: water (+10 mmol / L NH 4 HCOs 3 ), eluent B: acetonitrile, gradient: 40%-60% B (20 min), flow rate: 60 mL / min, detector: UV220 / 254 nm. The desired fractions were collected and concentrated under reduced pressure to give benzyl 4-(3-(methoxycarbonyl)bicyclo[1.1.1]pentan-1-yl)piperazine-1-carboxylate as an off-white solid. rice field.

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

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

[0547] [formation]

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

[0549] Yield 0.27g (76%). 1 H NMR (400 MHz, DMSO) δ 3.60 (s, 3H), 2.65 (t, J = 4.8 Hz, 4H), 2.26 (t, J = 4.8 Hz, 4H), 1.93 (s, 6H). Aliphatic NH was not observed. m / z:[ESI + ]211(M+H) + .

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

[0551] [formation]

[0552] To a stirred solution of methyl 3-(piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxylate (0.27 g, 1.28 mmol) and triethylamine (0.39 g, 3.85 mmol) in DCM (5 mL), Methanesulfonyl chloride (0.22 g, 1.92 mmol) was added dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified using reverse-phase flash chromatography with the following conditions: Column: WelFlash™ C18-I, 20-40 μm, 120 g, eluent A: water (+10 mmol / L NH 4 CO 3 ), eluent B: acetonitrile, gradient: 40%-60% B (20 min), flow rate: 60 mL / min, detector: UV220 / 254 nm. The desired fractions were collected and concentrated under reduced pressure to give methyl 3-(4-(methylsulfonyl)piperazin-1-yl)bicyclo[1.1.1]pentane-1-carboxylate as a pale yellow solid.

[0553] Yield 0.26g (70%). 1 H NMR (400MHz, DMSO) δ 3.61(s, 3H), 3.10(t, J = 4.8Hz, 4H), 2.87(s, 3H), 2.46(t, J = 4.8Hz, 4H), 1.97(s ,6H).m / z:[ESI + ]289(M+H) + .

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

[0555] [formation]

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

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

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

[0559] [formation]

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

[0561] Yield 0.37g (62%). 1 H NMR (400 MHz, DMSO) δ 3.61 (s, 3H), 3.59-3.54 (m, 4H), 2.38-2.29 (m, 4H), 1.96 (s, 6H).m / z: [ESI + ]212(M+H) + .

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

[0563] [formation]

[0564] From methyl 3-morpholinobicyclo[1.1.1]pentane-1-carboxylate (0.37 g, 1.75 mmol) and lithium hydroxide monohydrate (0.22 g, 5.24 mmol), the above 4-(1,1-dioxide Compound 3-morpholinobicyclo[1.1.1]pentane-1-carboxylic acid was prepared by a similar procedure for the synthesis of tetrahydro-2H-thiopyran-4-yl)benzoic acid and isolated as an off-white solid.

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

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

[0567] [formation]

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

[0569] Yield 0.60g (99%). 1 H NMR (400 MHz, DMSO) δ 3.99 (dd, J = 3.2, 12.4 Hz, 2H), 3.90 (q, J = 8.4 Hz, 1H), 3.74-3.61 (m, 2H), 3.65 (s, 3H) ,3.40-3.30(m,2H),3.18-3.09(m,1H),2.98-2.85(m,2H),2.70-2.56(m,2H),2.46-2.36(m,2H).m / z: [ESI + ]200(M+H) + .

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

[0571] [formation]

[0572] From methyl (1r,3r)-3-morpholinocyclobutane-1-carboxylic acid (0.60 g, 3.01 mmol) and lithium hydroxide monohydrate (0.38 g, 9.06 mmol), 4-(1,1-dioxide tetrahydro Compound (1r,3r)-3-morpholinocyclobutane-1-carboxylic acid was prepared in a similar manner to the synthesis of -2H-thiopyran-4-yl)benzoic acid and isolated as a pale yellow semi-solid.

[0573] Yield 0.4g (72%). 1 H NMR (400 MHz, DMSO) δ 12.51 (brs, 1H), 3.99-3.74 (m, 5H), 3.27 (d, J = 12.4 Hz, 2H), 3.08-2.96 (m, 1H), 2.94-2.81 ( m,2H),2.79-2.64(m,2H),2.41-2.28(m,2H).m / z:[ESI + ]186(M+H) + .

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

[0575] [formation]

[0576] Stir a mixture of methyl 5-bromopicolinate (0.63 g, 2.92 mmol) and 2-methyl-2,8-diazaspiro[4.5]decan-1-one hydrochloride (0.50 g, 2.44 mmol) in DMF (12 mL) 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.28 g, 0.48 mmol), palladium(II) acetate (55 mg, 0.245 mmol) and cesium carbonate at room temperature under a nitrogen atmosphere. (2.39 g, 7.34 mmol) was added. The resulting mixture was stirred at 100° C. overnight. The resulting mixture was cooled to room temperature, filtered, and the filter cake was washed with DMF (3 x 2 mL). The combined washings and filtrate were concentrated under reduced pressure. The residue was purified using reverse phase flash chromatography with the following conditions. Column: WelFlash TM C18-I, 20-40 μm, 330 g, eluent A: water (+10 mmol / L of NH 4 HCOs 3 ), eluent B: acetonitrile, gradient: 25%-45% B (25 min), flow rate: 80 mL / min, detector: UV220 / 254 nm. The desired fractions were collected and concentrated under reduced pressure to give methyl 5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)picolinate as an off-white solid. rice field.

[0577] Yield 440mg (59%). 1 H NMR (400 MHz, DMSO) 8.39 (d, J = 2.8 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.36 (dd, J = 2.8, 8.8 Hz, 1 H), 3.91 (dt ,J=4.0,13.6Hz,2H),3.81(s,3H),3.35-3.25(m,5H),3.13-3.01(m,2H),1.99(t,J=6.8Hz,2H),1.78- 1.70(m,2H),1.45(dd,J=4.0,13.6Hz,2H).m / z:[ESI + ]304(M+H) + .

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

[0579] [formation]

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

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

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

[0583] [formation]

[0584] 5-(2-Methyl-1-oxo-2,8-diazaspiro[ The compound 5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)picolinate was prepared by a procedure similar to the synthesis of 4.5]decane-8-yl)picolinate and was isolated as an off-white solid. .

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

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

[0587] [formation]

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

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

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

[0591] [formation]

[0592] From methyl 4-bromo-2-methoxybenzoate (500 mg, 2.04 mmol) and morpholine (267 mg, 3.07 mmol), the above methyl picolinate (2-methyl-1-oxo-2,8-diazaspiro[4.5]decane- 8-yl), compound methyl 2-methoxy-4-morpholinobenzoate was prepared and isolated as an off-white solid.

[0593] Yield 300mg (59%). 1 H NMR (400 MHz, DMSO) δ 7.63 (d, J = 8.8 Hz, 1 H), 6.54 (dd, J = 2.4, 8.8 Hz, 1 H), 6.51 (d, J = 2.4 Hz, 1 H), 3.80 (s ,3H),3.76-3.71(m,4H),3.70(s,3H),3.30-3.25(m,4H).m / z:[ESI + ]252(M+H) + .

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

[0595] [formation]

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

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

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

[0599] [formation]

[0600] To a solution of methyl 5-hydroxypicolinate (1.53 g, 9.99 mmol) in THF (50 mL) was added 1-methylpiperidin-4-ol (2.30 g, 19.97 mmol), triphenylphosphine (3.93 g, 14.98 mmol) and DIAD ( 3.03 g, 14.98 mmol) was added at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using reverse phase flash chromatography with the following conditions. Column: WelFlash TM C18-I, 20-40 μm, 330 g, eluent A: water (+10 mmol / L of NH 4 HCOs 3 ), eluent B: acetonitrile, gradient: 35%-55% B (25 min), flow rate: 80 mL / min, detector: UV220 / 254 nm. The desired fractions were collected and concentrated under reduced pressure to give methyl 5-((1-methylpiperidin-4-yl)oxy)picolinate as an off-white solid.

[0601] Yield 1.31g (52%). 1 H NMR (400 MHz, DMSO) δ 8.37 (d, J = 2.8 Hz, 1 H), 8.01 (d, J = 8.8 Hz, 1 H), 7.56 (dd, J = 2.8, 8.8 Hz, 1 H), 4.59 (tt ,J=4.0,8.0Hz,1H),3.84(s,3H),2.66-2.55(m,2H),2.26-2.13(m,5H),2.02-1.89(m,2H),1.73-1.59(m ,2H).m / z:[ESI + ]251(M+H) + .

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

[0603] [formation]

[0604] The compound 5-((1-methylpiperidin-4-yl)oxy)picolinate was treated with methyl 5-((1-methylpiperidin-4-yl)oxy)picolinate (1.31 g, 5.23 mmol) and lithium hydroxide Prepared from the hydrate (0.88g, 20.97mmol) by a similar procedure for the synthesis of 4-(1,1-dioxydotetrahydro-2H-thiopyran-4-yl)benzoic acid, isolated as an off-white solid. bottom.

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

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

[0607] [formation]

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

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

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

[0611] [formation]

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

[0613] Yield 0.85g (79%). 1 H NMR (400MHz, DMSO) δ 12.75 (brs, 1H), 7.78 (d, J = 8.8Hz, 1H), 6.98 (d, J = 2.4Hz, 1H), 6.93 (dd, J = 2.4, 8.8Hz ,1H),3.74-3.68(m,4H),3.29-3.25(m,4H).m / z:[ESI + ]242,244(M+H) + .

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

[0615] [formation]

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

[0617] Yield 1.22g (82%). 1 H NMR (400MHz, DMSO) δ 9.94 (s, 1H), 7.65 (d, J = 8.8Hz, 1H), 6.89 (dd, J = 2.4, 8.8Hz, 1H), 6.81 (d, J = 2.4Hz ,1H),3.79-3.68(m,4H),3.34-3.30(m,4H),2.55(s,3H).m / z:[ESI + ]206(M+H) + .

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

[0619] [formation]

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

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

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

[0623] [formation]

[0624] The compound 4-morpholino- 2-(Trifluoromethyl)benzaldehyde was prepared and isolated as an off-white solid.

[0625] Yield 916mg (68%). 1 H NMR (400 MHz, DMSO) δ 9.99 (q, J = 2.0 Hz, 1 H), 7.95 (d, J = 8.8 Hz, 1 H), 7.40-7.16 (m, 2 H), 3.84-3.69 (m, 4 H) ,3.48-3.40(m,4H).19FNMR(376MHz,DMSO)δ-55.81.m / z:[ESI + ]260(M+H) + .

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

[0627] [formation]

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

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

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

[0631] [formation]

[0632] 3-(Methoxycarbonyl)cyclobutane-1-carboxylic acid (1.00 g, 6.32 mmol), 4-(2-chlorophenyl)thiazol-2-amine (1.47 g, 6.98 mmol) and DIPEA (1.63 g) in DMF (20 mL) HATU (3.61 g, 9.49 mmol) was added in portions at 0 ℃ under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 16 hours under a nitrogen atmosphere. The solution was diluted with water (60 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with brine (20 mL) and dried over anhydrous Na. 2 SO 4 dried with After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to give methyl (1r,3r)-3-((4-(2-chlorophenyl)thiazole) as an off-white solid. -2-yl)carbamoyl)cyclobutane-1-carboxylate (A) (assumed) and methyl (1s,3s)-3-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)cyclobutane-1- Carboxylate (B) (assumed) was obtained.

[0633] A: Yield 0.81g (37%). 1 H NMR (400 MHz, DMSO) δ 12.23 (brs, 1H), 7.83 (dd, J = 2.0, 7.6 Hz, 1H), 7.61 (s, 1H), 7.55 (dd, J = 1.6, 7.6 Hz, 1H) ,7.46-7.33(m,2H),3.65(s,3H),3.48-3.36(m,1H),3.25-3.15(m,1H),2.55-2.38(m,4H).m / z:[ESI + ]351(M+H) + . B: Yield 1.00g (45%). 1 H NMR (400 MHz, DMSO) δ 12.27 (brs, 1H), 7.83 (dd, J = 2.0, 7.6 Hz, 1 H), 7.60 (s, 1 H), 7.54 (dd, J = 1.6, 7.6 Hz, 1 H) ,7.45-7.33(m,2H),3.62(s,3H),3.38-3.26(m,1H),3.23-3.13(m,1H),2.48-2.34(m,4H).m / z:[ESI + ]351(M+H) + .

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

[0635] [formation]

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

[0637] Yield 700mg (90%). 1 H NMR (400MHz, DMSO) δ12.21(brs,2H),7.83(dd,J=2.0,7.6Hz,1H),7.61(s,1H),7.55(dd,J=1.6,7.6Hz,1H) ,7.46-7.35(m,2H),3.46-3.36(m,1H),3.14-3.04(m,1H),2.49-2.35(m,4H).m / z:[ESI + ]337,339(M+H) + .

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

[0639] [formation]

[0640] The compound 4-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)methylbenzoate was converted to (1r,3r)-3-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl) 4-(Methoxycarbonyl)benzoic acid (3.00 g, 16.65 mmol) and 4-(2-chlorophenyl)thiazol-2-amine (2.46 g, 11.68 mmol) were obtained following a procedure similar to the synthesis of cyclobutane-1-carboxylic acid esters. ) and isolated as an off-white solid.

[0641] Yield 2.50g (57%). 1H NMR (400 MHz, DMSO) δ 13.03 (brs, 1H), 8.24 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 8.4 Hz, 2H), 7.91 (dd, J = 2.0, 7.6 Hz ,1H),7.72(s,1H),7.58(dd,J=1.6,7.6Hz,1H),7.51-7.39(m,2H),3.91(s,3H).m / z:[ESI + ]373,375(M+H) + .

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

[0643] [formation]

[0644] From methyl 4-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)benzoate (500 mg, 1.34 mmol) and lithium hydroxide monohydrate (225 mg, 5.36 mmol), 4-(1,1 The compound 4-((4-(2-chlorophenyl)thiazol-2-yl)carbamoyl)benzoic acid was prepared by a procedure analogous to the synthesis of -dioxidotetrahydro-2H-thiopyran-4-yl)benzoic acid. Isolated as a solid.

[0645] Yield 4...

Claims

1. A compound represented by Formula I below: or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, isotopic variant, reverse amide analog, or any combination thereof. 【Chemistry 1】 During the ceremony, The A ring is a single aromatic or heteroaromatic ring system selected from phenyl, pyrazole, pyrimidine, 2-, 3- or 4-pyridine, pyridazine or pyrazine, or a single saturated C ３ -C １０ It is a heterocyclic ring; The B ring is pyridazine, pyrazine, thiophene, thiazole, imidazole, or indazole, a single or fused C4-C １０ Cycloalkyl or single or fused saturated C ３ -C １０ It is a heterocyclic ring; R １ is F, Cl, Br, I, OH, SH, R ８ -OH, R ８ -SH, -R ８ -O-R １０ , -O-R ８ -O-R １０ , C.F. ３ , C.D. ３ , O.C.D. ３ , C.N., N.O. ２ , N.H. ２ , N.H.R., N.(R) ２ , R ８ -N(R １０ ) (R １１ ), NHC(O)-R １０ , COOH, C(O)OR １０ , C(O)-R １０ , -C(O)NH ２ , C(O)N(R １０ ) (R １１ ), S.O. ２ R, S.O. ２ N (R １０ ) (R １１ ), N.H.S.O. ２ (R １０ ), CH(CF ３ ) (NH-R １０ ), C １ -C ５ linear or branched alkyl, C 2-C ５ linear, branched or cyclic haloalkyl of C １ -C ５ linear, branched or cyclic alkoxy of C １ -C ５ linear or branched thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle or substituted or unsubstituted aryl; R ２ are H, F, Cl, Br, I, OH, SH, and CF ３ , C.D. ３ , O.C.D. ３ , C.N., N.O. ２ , N.H. ２ , C １ -C ５ straight or branched unsubstituted alkyl of １ -C ５ linear, branched or cyclic haloalkyl of C １ -C ５ is a straight chain, branched chain or cyclic alkoxy; R ３ is F, Cl, Br, I, OH, SH, CF ３ , C.D. ３ , O.C.D. ３ , C.N., N.O. ２ , N.H. ２ , N(R １０ ) (R １１ ), C(O)-R １０ , -C(O)NH ２ , C(O)N(R １０ ) (R １１ ), S.O. ２ R, S.O. ２ N (R １０ ) (R １１ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl of １ -C ５ linear, branched or cyclic haloalkyl of C １ -C ５ A straight chain, branched chain or cyclic alkoxy (optionally with at least one methylene group (CH ２ ) substituted with an oxygen atom), substituted or unsubstituted C ３ -C ８ Cycloalkyl or substituted or unsubstituted single, spirocyclic, fused or bridged C ３ -C １０ It is a heterocyclic ring; R ４ is H, F, Cl, Br, I, OH, SH, -R ８ -O-R １０ , C.F. ３ , C.D. ３ , O.C.D. ３ , C.N., N.O. ２ , N.H. ２ , N(R １０ ) (R １１ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl of １ -C ５ linear, branched or cyclic haloalkyl of C １ -C ５ linear, branched or cyclic alkoxy of C １ -C ５ linear or branched thioalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl or substituted or unsubstituted single, spirocyclic, fused or bridged C ３ -C １０ It is a heterocyclic ring; R ５ is H, C １ -C ５ or a linear or branched, substituted or unsubstituted alkyl of １ -C ５ is a straight chain, branched chain or cyclic haloalkyl; Q １ is S; G=X is C=O; R is H, OH, or C １ -C ５ is a substituted or unsubstituted alkyl of the formula: R ８ is [CH ２ ]p, where p is 1 to 3; R １０ and R １１ are each independently H, OH, substituted or unsubstituted C １ -C ５ linear or branched alkyl of C １ -C ５ linear or branched alkoxy, substituted or unsubstituted C ３ -C ８ Heterocycle, C(O)-alkyl, or S(O) ２ - alkyl; Or, R １０ and R １１ are bonded to each other to form a substituted or unsubstituted C ３ -C ８ Forming a heterocyclic ring; The substituents are F, Cl, Br, I, OH, SH, and CF ３ , C.N., N.O. ２ , C １ -C ５ linear or branched alkyl, methoxyethyl, C １ -C ５ Straight or branched C(O)-alkyl, C(O)-CH ２ -O-CH3, SO ２ -alkyl, C(O)-NH-alkyl, C １ -C ５ linear or branched alkyl-OH, C(CH ３ ) ２ CH ２ -OH, CH ２ CH ２ -OH, C ３ -C ８ Heterocycle, substituted or unsubstituted C １ -C ５ linear or branched alkoxy, N(R) ２ , N(R １０ ) (R １１ ), aryl, phenyl, heteroaryl, C ３ -C ８ cycloalkyl, or any combination thereof; n and l are, independently of each other, integers from 1 to 3; m and k are, independently, integers from 0 to 3; In addition, the compound is not N-[4-(2-chlorophenyl)-2-thiazolyl]-6-methyl-3-pyridinecarboxamide or N-[4-(2-chlorophenyl)-2-thiazolyl]-4-(4-morpholinyl)-2-pyridinecarboxamide.

2. A compound according to claim 1, The A ring is a single saturated C 3 -C 10 heterocycle selected from morpholine, piperidine, piperazine, tetrahydro-2H-pyran, azetidine, or pyrrolidin-2-one; Ring B is a single or fused C 4 -C 10 cycloalkyl selected from bicyclo[1.1.1]pentyl, cyclobutyl, cyclohexyl, or cyclopentyl, or a single or fused saturated C 3 -C 10 heterocycle selected from morpholine, piperidine, piperazine, tetrahydro-2H-pyran, azetidine, or pyrrolidin-2-one; R 1 is CH 2 OH, CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 3 , O-CH 2 -CH 2 -O-CH 3 , CH 2 -NH-CH 3 , CH 2 -NH-C(O)CH 3 , CH 2 -N(CH 3 ) 2 , NHCO-Ph, NHCO-CH 3 , C(O)NH-Ph, NHSO 2 CH 3 , methyl, ethyl, CHF 2 , methoxy, cyclopropyl, azetidine, pyridine, or phenyl; R 2 is methyl, ethyl, CHF 2 , or methoxy; R 3 is morpholine, piperazine, C(O)-piperidine, C(O)-pyrrolidine, C(O)N(CH 3 ) 2 , C(O)-piperazine, methyl, ethyl, CHF 2 , methoxy, 1-(methylsulfonyl)piperidine-4-oxy, 1-(methyl)piperidine-4-oxy, 1-(ethanone)piperidine-4-oxy, cyclopropyl, piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)etheone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2,8-diazaspiro[4.5]decan-1-one, or 2-oxa-7-azaspiro[3.5]nonane; R 4 is CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 , O-CH 2 -CH 2 -O-CH 3 , morpholine, piperazine, methyl, ethyl, CHF 2 , methoxy, 1-(methylsulfonyl)piperidine-4-oxy, 1-(methyl)piperidine-4-oxy, 1-(ethanone)piperidine-4-oxy, cyclopropyl, piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)ethanone, N-methylpiperazine-1-carboxamide , piperidin-4-ol, piperidin-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, diazaspiro[4.5]decan-1-one, or 2-oxa-7-azaspiro[3.5]nonane; R 5 is methyl, ethyl, or CHF 2 ; R is methyl, ethyl, CH2CH2OH, or CH2CH2OCH3; p is 2; R 10 and R 11 are each independently methyl, ethyl, CH 2 —CH 2 —O—CH 3 , O—CH 3 , 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro-2H-pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, or methyl-piperidine; or R 10 and R 11 join together to form morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, or 1-methylazetidine; n and l are, independently, 1 or 2; m and k are, independently of each other, 0; The isotopic variant is a deuterated analog; or any combination thereof.

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

4. A compound represented by formula V: or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, isotopic variant, reverse amide analog, or any combination thereof. 【Chemistry 2】 During the ceremony, R １ is F, Cl, Br, I, OH, SH, R ８ -OH, R ８ -SH, -R ８ -O-R １０ , -O-R ８ -O-R １０ , C.F. ３ , C.D. ３ , O.C.D. ３ , C.N., N.O. ２ , N.H. ２ , N.H.R., N.(R) ２ , R ８ -N(R １０ ) (R １１ ), R ９ -R ８ -N(R １０ ) (R １１ ), NHC(O)-R, NHC(O)-R １０ , COOH, C(O)OR １０ , C(O)-R １０ , -C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), S.O. ２ R, S.O. ２ N (R １０ ) (R １１ ), N.H.S.O. ２ (R １０ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl of １ -C ５ linear, branched or cyclic haloalkyl of C １ -C ５ linear, branched or cyclic alkoxy of C １ -C ５ linear or branched thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle or substituted or unsubstituted aryl; R 3 is F, Cl, Br, I, OH, SH, CF 3 , CD 3 , OCD 3 , CN, NO 2 , NH 2 , N(R 10 )(R 11 ), C(O)-R 10 , -C(O)NH 2 , C(O)N(R 10 )(R 11 ), SO 2 R, SO 2 N(R 11 ), linear or branched C 1 -C 5 , substituted or unsubstituted alkyl, C 1 -C 5 linear, branched or cyclic haloalkyl, C 1 -C 5 linear, branched or cyclic alkoxy (optionally with at least one methylene group (CH 2 ) in the alkoxy replaced by an oxygen atom), substituted or unsubstituted C 3 -C 8 ... cycloalkyl, substituted or unsubstituted single, spirocyclic, fused or bridged C 3 -C 10 heterocycles, or substituted or unsubstituted aryl; X ３ is N; X 4 and X 5 are independently C or N; R is H, OH, C １ -C ５ is a straight or branched chain, substituted or unsubstituted alkyl; R ８ is [CH ２ ]p, where p is 1 to 10; R １０ and R １１ are each independently H, OH, substituted or unsubstituted C １ -C ５ linear or branched alkyl of C １ -C ５ or a substituted or unsubstituted C ３ -C ８ It is a heterocyclic ring; Or, R １０ and R １１ are bonded to each other to form a substituted or unsubstituted C ３ -C ８ Forming a heterocyclic ring; The substituents are F, Cl, Br, I, OH, SH, and CF ３ , C.N., N.O. ２ , substituted or unsubstituted C １ -C ５ linear or branched alkyl, methoxyethyl, substituted or unsubstituted C １ -C ５ Straight or branched C(O)-alkyl, C(O)-CH ２ -O-CH ３ , S.O. ２ -alkyl, C(O)-NH-alkyl, C １ -C ５ linear or branched alkyl-OH, C(CH ３ ) ２ CH ２ -OH, CH ２ CH ２ -OH, C ３ -C ８ Heterocycle, substituted or unsubstituted C １ -C ５ linear or branched alkoxy, N(R) ２ , N(R １０ ) (R １１ ), aryl, phenyl, heteroaryl, C ３ -C ８ cycloalkyl, or any combination thereof.

5. A compound according to claim 1 or 4, R 1 is Cl, —R 8 —O—R 10 , or CH 2 —O—CH 3 ; R 3 is N(R 10 )(R 11 ) or a substituted or unsubstituted single, spirocyclic, fused or bridged C 3 -C 10 heterocycle; R is H or OH; R 10 is a substituted or unsubstituted C 3 -C 10 heterocycle, or methylpiperidine; Or, a compound wherein R 10 and R 11 are joined together to form a substituted or unsubstituted C 3 -C 8 heterocycle, or 1-methylazetidine.

6. The compound according to claim 4, R 1 is CH 2 OH, CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 3 , O-CH 2 -CH 2 -O-CH 3 , CH 2 -NH-CH 3 , CH 2 -NH-C(O)CH 3 , CH 2 -N(CH 3 ) 2 , NHCO-Ph, NHCO-CH 3 , C(O)NH-Ph, NHSO 2 CH 3 , methyl, ethyl, CHF 2 , methoxy, cyclopropyl, azetidine, pyridine, or phenyl; R 3 is morpholine, piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)etheone, N-methylpiperazine-1-carboxamide, piperidin-4-ol, piperidin-3-ol, morpholine, 3-methyl morpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2,8-diazaspiro[4.5]decan-1-one, or 2-oxa-7-azaspiro[3.5]nonane; R is methyl, ethyl, CH2CH2OH, or CH2CH2OCH3; p is 2; R 10 and R 11 are each independently methyl, ethyl, CH 2 —CH 2 —O—CH 3 , O—CH 3 , 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro-2H-pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, or methyl-piperidine; or R 10 and R 11 join together to form morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, or 1-methylazetidine; The isotopic variant is a deuterated analog; or any combination thereof.

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

8. A compound represented by formula VI below: or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, N-oxide, isotopic variant, reverse amide analog, or any combination thereof. 【Chemistry 3】 During the ceremony, R 1 is F, Cl, Br, I, OH, SH, R ８ -OH, R ８ -SH, -R ８ -O-R １０ , -O-R ８ -O-R １０ , C.F. ３ , C.D. ３ , O.C.D. ３ , C.N., N.O. ２ , N.H. ２ , N.H.R., N.(R) ２ , R ８ -N(R １０ ) (R １１ ), NHC(O)-R, NHC(O)-R １０ , COOH, C(O)OR １０ , C(O)-R １０ , -C(O)NH ２ , C(O)NHR, C(O)N(R １０ ) (R １１ ), S.O. ２ R, S.O. ２ N (R １０ ) (R １１ ), N.H.S.O. ２ (R １０ ), C １ -C ５ linear or branched alkyl of C １ -C ５ linear, branched or cyclic haloalkyl of C １ -C ５ linear, branched or cyclic alkoxy of C １ -C ５ linear or branched thioalkoxy of C １ -C ５ straight or branched chain haloalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ heterocycle or substituted or unsubstituted aryl; R 2 is H, F, Cl, Br, I, OH, SH, CF 3 , CD 3 , OCD 3 , CN, NO 2 , NH 2 , C 1 -C 5 straight or branched chain, substituted or unsubstituted alkyl, C 1 -C 5 straight, branched or cyclic haloalkyl, or C 1 -C 5 straight, branched or cyclic alkoxy; Or, R ２ and R １ are joined together to form a 5- or 6-membered, substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; R ４ is H, F, Cl, Br, I, OH, SH, -R ８ -O-R １０ , C.F. ３ , C.D. ３ , O.C.D. ３ , C.N., N.O. ２ , N.H. ２ , N(R １０ ) (R １１ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl of １ -C ５ linear, branched or cyclic haloalkyl of C １ -C ５ linear, branched or cyclic alkoxy of C １ -C ５ linear or branched thioalkoxy of C １ -C ５ linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl or substituted or unsubstituted single, spirocyclic, fused or bridged C ３ -C １０ It is a heterocyclic ring; X ３ is N; X １ , X ２ , X ４ , and X ５ are, independently of each other, C or N; X ６ is O, CH ２ , CHR, C(R １０ ) (R １１ ), NH, N—R, or N—C(O)—R 10 ; R is H, OH, NH ２ , NH(R １０ ), N(R １０ ) (R １１ ), C １ -C ５ linear or branched, substituted or unsubstituted alkyl, CH 2 CH 2 OH, or C １ -C ５ Substituted or unsubstituted SO ２ - alkyl; R ８ is [CH ２ ]p, where p is 1 to 10; R １０ and R １１ are each independently H, substituted or unsubstituted C １ -C ５ linear or branched alkyl of C １ -C ５ linear or branched alkoxy, substituted or unsubstituted C ３ -C ８ Heterocycle, C(O)-alkyl, or S(O) ２ - alkyl; Or, R １０ and R １１ are bonded to each other to form a substituted or unsubstituted C ３ -C ８ Forming a heterocyclic ring; The substituents are F, Cl, Br, I, OH, SH, and CF ３ , C.N., N.O. ２ , C １ -C ５ linear or branched alkyl, methoxyethyl, C １ -C ５ Straight or branched C(O)-alkyl, C(O)-CH ３ , C(O)-CH ２ -O-CH ３ , S.O. ２ -alkyl, C(O)-NH-alkyl, C １ -C ５ linear or branched alkyl-OH, C(CH ３ ) ２ CH ２ -OH, CH ２ CH ２ -OH, C ３ -C ８ Heterocycle, C １ -C ５ linear or branched alkoxy, N(R １０ ) (R １１ ), aryl, phenyl, heteroaryl, C ３ -C ８ cycloalkyl, or any combination thereof; n and l are, independently of each other, integers from 1 to 3; m and k are each independently an integer from 0 to 2.

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

10. The compound according to claim 8, R 1 is CH 2 OH, CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 3 , O-CH 2 -CH 2 -O-CH 3 , CH 2 -NH-CH 3 , CH 2 -NH-C(O)CH 3 , CH 2 -N(CH 3 ) 2 , NHCO-Ph, NHCO-CH 3 , C(O)NH-Ph, NHSO 2 CH 3 , methyl, ethyl, CHF 2 , methoxy, cyclopropyl, azetidine, pyridine, or phenyl; or R 2 and R 1 combine together to form benzene, 1,4-dioxane, 2,3-dihydro-1,4-dioxine, dioxole, or dioxolepyridine; R 4 is CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 , O-CH 2 -CH 2 -O-CH 3 , morpholine, piperazine, methyl, ethyl, CHF 2 , methoxy, 1-(methylsulfonyl)piperidine-4-oxy, 1-(methyl)piperidine-4-oxy, 1-(ethanone)piperidine-4-oxy, cyclopropyl, piperazine, 1-(2-methoxyethyl)piperazine, 1- or 4-methylpiperazine, 1- or 4-(methylsulfonyl)piperazine, 1- or 4-(methylsulfonyl)piperidine, 2-methoxy-1-(piperazin-1-yl)ethanone, 1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)ethanone, 2-(dimethylamino)-1-(piperazin-1-yl)propanone, 2-hydroxy-1-(piperazin-1-yl)ethanone, N-methylpiperazine-1-carboxamide , piperidin-4-ol, piperidin-3-ol, morpholine, 3-methylmorpholine, 3-hydroxypiperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1-dioxide, pyrazole, thiazole, imidazole, pyrrolidine, pyrrolidinone, octahydropyrrolo[1,2-α]pyrazine, 6-methyl-2,6-diazaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, 2-methoxy-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone, diazaspiro[4.5]decan-1-one, or 2-oxa-7-azaspiro[3.5]nonane; X 6 is CH(OH), CH(NH 2 ), CH(NH(CH 3 )), C(H)CH 2 CH 2 -OH, C(H)CH 2 -OH, 1-methylazetidine, N-CH 3 , N-SO 2 -CH 3 , NR 20 , N-CH 2 CH 2 -OCH 3 , N-C(O)O-tBu, N-C(O)-CH 2 CH 2 -OCH 3 , N-C(O)-CH 3 , N-C(O)-CH 2 -N(CH 3 ) 2 , N-C(O)-CH 2 -CH 2 -N(CH 3 ) 2, N-C(O)-CH2-OH, N-C(O)-CH2CH2 -OH, N-C(O)-NH-CH 3 , N-C(O)-1-methyl-2-pyrrolidine, N-C(O)-1-methyl-3-pyrrolidine, N-C(O)-1-methyl-3-piperidine, or N-C(O)-1-methyl-4-piperidine; R is NH(CH 3 ), methyl, ethyl, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , C(O)-methylpyrrolidine, C(O)-methylpiperidine, or C(O)-CH 3 ; p is 2; R 10 and R 11 are each independently methyl, ethyl, CH 2 —CH 2 —O—CH 3 , O—CH 3 , 1-(methylsulfonyl)piperidine, 1-(methylsulfonyl)piperazine, tetrahydro-2H-pyran, morpholine, thiomorpholine 1,1-dioxide, methyl-pyrrolidine, or methyl-piperidine; or R 10 and R 11 join together to form morpholine, piperazine, piperidine, pyrrolidine, 1-methylpyrrolidin-2-one, oxetane, azetidine, or 1-methylazetidine; n and l are, independently, 1 or 2; m and k are, independently of each other, 0; The isotopic variant is a deuterated analog; or any combination thereof.

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

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

13. 9. A compound according to claim 4 or 8, X ３ , X ４ , and X ５ At least two of the following are N:

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

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

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

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

18. A compound according to any one of claims 1 to 17, and a pharma- ceutically acceptable carrier.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

35. 20. Use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, liver cirrhosis, alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), alcoholic fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD), or an autoimmune disease in a subject. 【Table 5-1】 【Table 5-2】 【Table 5-3】 【Table 5-4】

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

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

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

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