Collagen 1 translation inhibitors and methods of use thereof

Abstract

To provide a compound that is a novel Collagen 1 translation inhibitor for treating fibrosis.SOLUTION: The present invention provides a compound represented by the structure of formula (I).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a novel collagen 1 translation inhibitor, a composition, and a method for preparing the same, and their use for treating fibrosis including pulmonary, hepatic, renal, cardiac, and dermal fibrosis, IPF, wound healing, scarring and gingival fibromatosis, systemic sclerosis, and alcoholic and non-alcoholic steatohepatitis (NASH).

Background Art

[0002] The formation of fibrous connective tissue is part of the normal healing process after tissue damage due to injury or inflammation. During this process, activated immune cells, including macrophages, stimulate the proliferation and activation of fibroblasts, resulting in the deposition of connective tissue. However, abnormal or excessive production of connective tissue can lead to the accumulation of fibrous material that interferes with the normal function of the tissue. Fibrous growth can proliferate and invade healthy surrounding tissue even after the original injury has healed. Such abnormal formation of excessive connective tissue that occurs during the repair or reaction process is referred to as fibrosis.

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

[0004] Physiologically, fibrosis acts to deposit connective tissue, which can obliterate the structure and function of the underlying organ or tissue. Defined by the pathological accumulation of extracellular matrix (ECM) proteins, fibrosis results in scarring and thickening of the affected tissue, which impedes normal organ function. In various conditions, the formation of fibrous tissue is characterized by the abnormal deposition of excessive amounts of collagen. The synthesis of collagen is also involved in several other pathological states. Clinical conditions and disorders associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, and autoimmune disorders, are distinguished by the excessive production of connective tissue that results in the disruption of normal tissue structure and function. These diseases can best be interpreted from the perspective of a perturbation of cellular function, the primary symptom of which is the excessive synthesis and deposition of collagen. The role of collagen in fibrosis has prompted attempts to develop drugs that inhibit its accumulation.

[0005] The excessive accumulation of collagen is a major pathological feature in various clinical conditions that characterize tissue fibrosis. These conditions include, for example, localized processes such as pulmonary fibrosis and cirrhosis of the liver, or more generalized processes such as progressive systemic sclerosis. Collagen deposition is a feature of different forms of skin fibrosis, including scleroderma, localized and systemic morphea, keloid, hypertrophic scar, familial cutaneous collagenoma, and collagen-type connective tissue nevi, in addition to dermatomyositis. Recent advances in the understanding of the normal biochemistry of collagen have made it possible to define specific levels of collagen biosynthesis and degradation at which pharmacological intervention may lead to a reduction in collagen deposition within tissues. Such compounds may provide novel means for reducing the excessive accumulation of collagen in disease.

[0006] In this specification, liver fibrosis, also referred to as hepatic fibrosis, can be caused by various types of chronic liver injury, particularly when inflammatory components are involved. Self-limiting acute liver injury (e.g., acute viral hepatitis A) does not necessarily distort the scaffold structure, even if it is severe, and typically does not cause fibrosis despite hepatocyte loss. However, factors such as chronic alcoholism, malnutrition, hemochromatosis, and exposure to poisons, toxins, or drugs can lead to chronic liver injury and liver fibrosis due to exposure to hepatotoxic chemicals. Liver scarring caused by other forms of injury associated with surgery or mechanical biliary obstruction can also result in liver fibrosis.

[0007] Fibrosis itself does not necessarily show symptoms, but it can lead to portal hypertension in which blood flow in the liver is distorted by scarring, or the development of cirrhosis in which the normal liver structure is destroyed by scarring, causing liver dysfunction. The degree of each of these pathological conditions determines the clinical symptoms of liver fibrosis. For example, congenital hepatic fibrosis affects portal vein branches and mainly preserves soft tissues. As a result, portal hypertension occurs while hepatocyte function remains preserved.

[0008] Treatment

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

[0010] Treatments aimed at reversing fibrosis are usually too toxic for long-term use (e.g., corticosteroids, penicillamine) or have not been proven effective (e.g., colchicine).

[0011] Many patients do not respond to available treatments for fibrotic disorders, and long-term treatments are limited by toxicity and side effects. Thus, a need remains to develop treatment modalities aimed at reducing fibrosis. The development of safe and effective treatments for established cirrhosis and portal hypertension, as well as for attenuating fibrosis, could be highly beneficial.

[0012] Attempts to treat idiopathic pulmonary fibrosis (IPF) with combinations of anti-inflammatory drugs (prednisone, azathioprine, and N-acetyl-l-cysteine (NAC)) have been unable to improve outcomes and instead have increased mortality. In 2014, two drugs, pirfenidone, a drug of unknown mechanism, and nintedanib, a tyrosine kinase inhibitor, were approved as treatments for IPF, mainly based on their ability to suppress decreases in forced vital capacity (FVC) and slow the rate of disease progression. However, to date, it is unclear whether these drugs improve symptoms such as dyspnea and cough, or whether the beneficial effects on functional decline translate into an extended survival period.

[0013] The compounds of the present invention target activated fibroblasts and collagen during the process of production, and thus can be used for the treatment of primary or secondary fibrosis, including systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis and autoimmune diseases, pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF), and localized processes such as, for example, pulmonary fibrosis and cirrhosis, or more generalized processes such as progressive systemic sclerosis. The compounds of the present invention target the overproduction of activated fibroblasts and collagen, and thus, when treating fibrosis including primary or secondary fibrosis such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis and autoimmune diseases, pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF), can also be used in localized processes such as, for example, pulmonary fibrosis and cirrhosis, or more generalized processes such as systemic progressive sclerosis. The compounds can be further useful in the treatment of different forms of cutaneous fibrosis, including scleroderma in addition to localized and systemic localized scleroderma, keloids, hypertrophic scars, familial cutaneous collagenoma, and collagen type connective tissue nevi. The compounds can be further useful in the treatment of liver fibrosis caused by liver scarring resulting from pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF), and other forms of injury associated with surgery or mechanical biliary obstruction. Such fibrosis can lead to portal hypertension where scarring distorts blood flow through the liver, or cirrhosis, as well as other fibrotic liver diseases including non-alcoholic steatohepatitis (NASH), and alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), and alcoholic fatty liver disease (AFLD), which can similarly be treated with the compounds of the present invention.

Summary of the Invention

Means for Solving the Problems

[0014] The present invention provides a compound, or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (e.g., deuterated analog), PROTAC, pharmaceutical product, or any combination thereof, represented by the structures of Formulas I, II, and I(a) - I(f), and the structures listed in Table 1 defined hereinbelow. In various embodiments, the compound is a collagen I translation inhibitor.

[0015] The present invention further provides a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, prodrug, isotope variant (e.g., deuterated analog), PROTAC, pharmaceutical product, or any combination thereof, represented by the structures of Formulas I, II, and I(a) - I(f), and the structures listed in Table 1 defined hereinbelow, and a pharmaceutically acceptable carrier.

[0016] The present invention further provides a method for treating fibrosis in a subject, suppressing it, reducing its severity, reducing its risk of onset, or inhibiting it, the method comprising administering to a subject suffering from fibrosis a compound represented by the structures of formulae I, II, and I(a)-(I(f)), and the structures listed in Table 1 defined hereinbelow, under conditions effective to treat fibrosis in the subject, suppress it, reduce its severity, reduce its risk of onset, or inhibit it. In some embodiments, the fibrosis is a systemic fibrotic disease. In some embodiments, the systemic fibrotic disease is systemic sclerosis, multifocal fibrosclerosis (IgG4-related fibrosis), nephrogenic systemic fibrosis, scleroderma graft-versus-host disease, or any combination thereof. In some embodiments, the fibrosis is an organ-specific fibrotic disease. In some embodiments, the organ-specific fibrotic disease is pulmonary fibrosis, cardiac fibrosis, renal fibrosis, pulmonary fibrosis, hepatic and 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 myocardial fibrosis is hypertension-related myocardial fibrosis, post-myocardial infarction, Chagas disease-induced myocardial fibrosis, or any combination thereof. In some embodiments, the renal fibrosis is diabetic and hypertensive nephropathy, urinary 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 pulmonary fibrosis (silicosis), asbestos-induced pulmonary fibrosis (asbestosis), chemotherapy agent-induced pulmonary fibrosis, or any combination thereof. In some embodiments, the hepatic and portal fibrosis is alcoholic and non-alcoholic hepatic fibrosis, hepatitis C-induced hepatic fibrosis, primary biliary cirrhosis, parasite-induced hepatic fibrosis (schistosomiasis), or any combination thereof.In some embodiments, the fibrosing myopathy is morphea, keloid, Dupuytren's disease, Peyronie's disease, myelofibrosis, oral submucous fibrosis, or any combination thereof. In some embodiments, the fibrosis is primary or secondary fibrosis. In some embodiments, the fibrosis is a result of systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, autoimmune disorder, tissue damage, inflammation, oxidative stress, or any combination thereof. In some embodiments, the fibrosis is liver fibrosis, pulmonary fibrosis, or skin fibrosis. In some embodiments, the subject has cirrhosis. In some embodiments, the skin fibrosis is scleroderma. In some embodiments, the skin fibrosis is a result of localized or generalized morphea, keloid, hypertrophic scar, familial cutaneous collagenoma, connective tissue nevus of the collagen type, or any combination thereof. In some embodiments, the liver fibrosis is a result of liver scarring or chronic liver injury. In some embodiments, the chronic liver impairment results from alcohol dependence, malnutrition, hemochromatosis, poisons, toxins, or drug exposure.

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

[0018] The present invention further provides a method for treating idiopathic pulmonary fibrosis (IPF) in a subject, suppressing it, reducing its severity, reducing its risk of onset, or inhibiting it, the method comprising administering a compound represented by the structures of formulas I, II, and I(a)-(I(f)), and the structures listed in Table 1 defined hereinbelow, to a subject suffering from idiopathic pulmonary fibrosis (IPF) under conditions effective to treat idiopathic pulmonary fibrosis (IPF) in the subject, suppress it, reduce its severity, reduce its risk of onset, or inhibit it.

[0019] The present invention further provides a method for treating a hepatic fibrotic disease in a subject, suppressing it, reducing its severity, reducing its risk of onset, or inhibiting it, the method comprising administering a compound represented by the structures of formulas I, II, and I(a)-(I(f)), and the structures listed in Table 1 defined hereinbelow, to a subject suffering from a hepatic fibrotic disease under conditions effective to treat the hepatic fibrotic disease in the subject, suppress it, reduce its severity, reduce its risk of onset, or inhibit it. In some embodiments, the hepatic fibrotic disease is portal hypertension, cirrhosis, congenital hepatic fibrosis, or any combination thereof.

[0020] The present invention further provides a method for treating cirrhosis in a subject, suppressing it, reducing its severity, reducing its risk of onset, or inhibiting it, the method comprising administering a compound represented by the structures of formulas I, II, and I(a)-(I(f)), and the structures listed in Table 1 defined hereinbelow, to a subject suffering from cirrhosis under conditions effective to treat cirrhosis in the subject, suppress it, reduce its severity, reduce its risk of onset, or inhibit it. In some embodiments, the cirrhosis is the result of hepatitis or alcohol dependence.

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

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

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

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

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

[0026] The present invention further provides a method for treating, suppressing, reducing the severity of, reducing the risk of onset of, or inhibiting an autoimmune disease or disorder in a subject, the method comprising administering a compound represented by the structures of Formulas I, II, and I(a)-(I(f)), and the structures listed in Table 1 defined hereinbelow, to a subject suffering from an autoimmune disease or disorder under conditions effective to treat, suppress, reduce the severity of, reduce the risk of onset of, or inhibit the autoimmune disease or disorder in the subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The patent application file includes at least one color drawing. Copies of the color drawings of this patent or the publication of the patent application will be provided by the Office upon payment of the claims and the necessary fees.

[0028] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of this specification. However, the invention, together with its objects, features, and advantages, can be best understood by reference to the following detailed description when read in conjunction with the accompanying drawings, with respect to both the construction of the operation and the method.

[0029]

Figure 1

Figure 2

Figure 3

Figure 4A

Figure 4B

DETAILED DESCRIPTION OF THE INVENTION

[0030] In various embodiments, the present invention provides a compound represented by the structure of formula (I):

[0031]

Chemical Formula

[0032] wherein rings A and B are each independently a single or fused aromatic or heteroaromatic ring system (e.g., A: phenyl, pyrimidine, 2-, 3-, or 4-pyridine, pyridazine, pyrazine, isothiazole, thiadiazole, imidazole, triazole, triazolopyrimidine, thiazole, oxazole, isoxazole, 1-methylimidazole, pyrrole, furan, thiophene, oxadiazole, or pyrazole; B: phenyl, pyrimidine, 2-, 3-, or 4-pyridazine, pyridazine, or pyrazine, thiazole, imidazole, indazole), or a single or fused C 3 -C 10 cycloalkyl (e.g., cyclopentyl), or a single or fused C 3 -C 10 heterocyclic ring (e.g., piperidine, A, B: tetrahydro-2H-pyran, thian 1,1-dioxide, tetrahydrofuran, oxazolone, oxazolidone, thiazolone, isothiazolinone, isoxazolidinone, imidazolidinone, pyrazolone, 2H-pyrrol-2-one, furanone, thiophenone, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine), and R 1 and R 2 are each independently 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 heterocyclic ring), CF 3 , CD 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 linear 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 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 linear or branched, or C 3 -C 8It is a cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 a linear or branched thioalkoxy, C 1 -C 5 a linear or branched haloalkoxy, C 1 -C 5 a linear or branched alkoxyalkyl, a substituted or unsubstituted C 3 -C 8 a cycloalkyl (e.g., cyclopropyl), a substituted or unsubstituted C 3 -C 8 a heterocyclic ring, a substituted or unsubstituted aryl, a substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 a linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 a cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or 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 3 and R 4 are each independently H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 (e.g., CH 2 -O-CH 3 )-O-R 8 -R 10 , R 8 -(C 3 -C 8 a cycloalkyl), R 8 -(C 3 -C 8 a heterocyclic ring), CF3 , CD 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 )(for example, CH 2 -NH-CH 3 , CH 2 -N(CH 3 ) 2 , CH 2 -NH-C(=O)-CH 3 ), 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 , linear 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 (for example, methyl, ethyl, CH 2 , -OCH 2 , -CH 2 , -O-CH 3 ), C 1 , -C 5A straight-chain or branched-chain substituted or unsubstituted alkenyl, C 1 -C 5 A straight-chain or branched-chain, or C 3 -C 8 A cyclic haloalkyl, a substituted or unsubstituted C 1 -C 5 A straight-chain or branched-chain, or C 3 -C 8 A cyclic alkoxy (e.g., methoxy, O-(CH 2 ) 2 -O-CH 3 ) and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 A straight-chain or branched-chain thioalkoxy, C 1 -C 5 A straight-chain or branched-chain haloalkoxy, C 1 -C 5 A straight-chain or branched-chain alkoxyalkyl, a substituted or unsubstituted C 3 -C 8 A cycloalkyl (e.g., cyclopropyl), a substituted or unsubstituted C 3 -C 8 A heterocyclic ring, a substituted or unsubstituted aryl, a substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 A straight-chain or branched-chain alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 A cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or or 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, R 5 is absent or is 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 heterocyclic ring), CF 3 , CD 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 linear 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 linear or branched, or C3 -C 8 cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy), optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or R 6 and R 7 are each independently 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 heterocyclic ring), CF 3 , CD 3 , OCD 3 , CN, NO2 、 -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 linear 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 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 )、 C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2) is an oxygen atom, C 1 -C 5 a straight-chain or branched-chain thioalkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkoxy, C 1 -C 5 a straight-chain or branched-chain alkoxyalkyl, a substituted or unsubstituted C 3 -C 8 a cycloalkyl (e.g., cyclopropyl), a substituted or unsubstituted C 3 -C 8 is replaced by a heterocyclic ring, a substituted or unsubstituted aryl, a substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 a straight-chain or branched-chain alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 a cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or or R 6 and R 7 are joined together to form a 3- to 6-membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopropyl), and Q 1 is NH, N(R), S, O, N-OH, or N-OMe, Q 2 is N or C(R), R is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) 2 , CF 3 , CN, NO 2 , C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2-CH 2 -O-CH 3 )、C 1 -C 5 Linear or branched alkoxy, C 1 -C 5 Linear or branched haloalkyl (e.g., CHF 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 ) 2 )、R 8 -Aryl (e.g., CH 2 -Ph), -R 8 -O-R 8 -O-R 10 (e.g., (CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 )、-R 8 -O-R 10 、-R 8 -R 10 (e.g., (CH 2 ) 2 -O-CH 3 )、Substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine) where the substitutions include F, Cl, Br, I, OH, SH, C 1 -C 5 Linear or branched alkyl, OH, alkoxy, N(R) 2 、CF 3 、phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 、or any combination thereof), G=X is C=O, C=S, S=O, SO2 、 CH 2 、 CHR, or C(R) 2 and each R 8 is independently [CH 2 p and p is from 1 to 10, R 9 is [CH] q 、 [C] q and q is from 2 to 10, R 10 and R 11 are each independently H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy (e.g., O-CH 3 ), C(O)R, or S(O) 2 R, or R 10 and R 11 are joined to form a substituted or unsubstituted C 3 -C 8 heterocyclic ring (e.g., piperazine, piperidine), substituents include F, Cl, Br, I, OH, C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched alkyl-OH (e.g., C(CH 3 )) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocyclic ring (e.g., piperidine), alkoxy, N(R) 2 、 CF 3 、 aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 、 or any combination thereof), ​m, n, l, and k are each independently an integer from 0 to 4 (e.g., 0, 1, or 2), X 6 , X 7 , and X 8 are each independently C or N, X 14 and X 15 are each independently C or N, a compound, or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (e.g., deuterated analog), PROTAC, pharmaceutical product, or any combination thereof, wherein R 5 which is C, X 6 , X 7 , and / or X 8 can only be attached to.

[0033] In various embodiments, the present invention relates to a compound represented by the structure of formula (II):

[0034]

Chemical formula

[0035] wherein, the A and B rings are each independently a single or fused aromatic or heteroaromatic ring system (e.g., A: phenyl, pyrimidine, 2-, 3-, or 4-pyridine, pyridazine, pyrazine, isothiazole, thiadiazole, imidazole, triazole, triazolopyrimidine, thiazole, oxazole, isoxazole, 1-methylimidazole, pyrrole, furan, thiophene, 1 oxadiazole, or pyrazole; B: phenyl, pyrimidine, 2-, 3-, or 4-pyridazine, pyridazine, or pyrazine, thiazole, imidazole, indazole), or a single or fused C 3 -C 10 cycloalkyl (e.g., cyclopentyl), or a single or fused C 3 -C 10A complex cyclic ring (e.g., piperidine, A, B: tetrahydro-2H-pyran, thian 1,1-dioxide, tetrahydrofuran, oxazolone, oxazolidinone, thiazolone, isothiazolinone, isoxazolidinone, imidazolidinone, pyrazolone, 2H-pyrrol-2-one, furanone, thiophenone, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine), R 1 and R 2 are each independently 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 complex cyclic ring), CF 3 、CD 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 linear or branched C(O)-haloalkyl, -C(O)NH 2 、C(O)NHR、C(O)N(R 10 )(R11 ), SO 2 R, SO 2 N(R 10 )(R 11 ), CH(CF 3 )(NH - R 10 ), C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkenyl, C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 a straight-chain or branched-chain thioalkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkoxy, C 1 -C 5 a straight-chain or branched-chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 a cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 a heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 a straight-chain or branched-chain alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 a cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or or R2 and R 1 are joined together to form a 5- or 6-membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring, R 3 and R 4 are each independently H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 , -O-R 8 -R 10 R 8 -(C 3 -C 8 -cycloalkyl), R 8 -(C 3 -C 8 -heterocyclic ring), CF 3 , CD 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 linear 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 a straight-chain or branched-chain substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -OCH 2 -CH 2 -O-CH 3 ), C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkenyl, C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic haloalkyl, a substituted or unsubstituted C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic alkoxy (e.g., methoxy, O-(CH 2 )) 2 -O-CH 3 ), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 a straight-chain or branched-chain thioalkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkoxy, C 1 -C 5 a straight-chain or branched-chain alkoxyalkyl, a substituted or unsubstituted C 3 -C 8 a cycloalkyl (e.g., cyclopropyl), a substituted or unsubstituted C 3 -C 8 a heterocyclic ring, a substituted or unsubstituted aryl, a substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 a straight-chain or branched-chain alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 a cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2or any combination thereof), or or 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, R 5 is absent or is 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 heterocyclic ring), CF 3 CD 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 linear 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 a straight-chain or branched-chain substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkenyl, C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 a straight-chain or branched-chain thioalkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkoxy, C 1 -C 5 a straight-chain or branched-chain alkoxyalkyl, a substituted or unsubstituted C 3 -C 8 a cycloalkyl (e.g., cyclopropyl), a substituted or unsubstituted C 3 -C 8 a heterocyclic ring, a substituted or unsubstituted aryl, a substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 a straight-chain or branched-chain alkyl, OH, alkoxy, N(R) 2 、CF 3 、aryl, phenyl, heteroaryl, C 3 -C 8 a cycloalkyl, a halophenyl, (benzyloxy)phenyl, CN, NO 2 、or any combination thereof), or R 6 and R 7 are each independently H, F, Cl, Br, I, OH, SH, R8 -OH, R 8 -SH, -R 8 -O-R 10 , R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocyclic ring), CF 3 , CD 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 linear 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 a straight or branched chain, or C 3 -C 8 a cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 a straight or branched chain, or C 3 -C 8 a cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 a straight or branched chain thioalkoxy, C 1 -C 5 a straight or branched chain haloalkoxy, C 1 -C 5 a straight or branched chain alkoxyalkyl, a substituted or unsubstituted C 3 -C 8 a cycloalkyl (e.g., cyclopropyl), a substituted or unsubstituted C 3 -C 8 a heterocyclic ring, a substituted or unsubstituted aryl, a substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 a straight or branched chain alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 a cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or or R 6 and R 7 are joined together to form a 3- to 6-membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring (e.g., cyclopropyl), and Q 1 is NH, N(R), S, O, N-OH, or N-OMe, and Q 2 is N or C(R), and R is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) 2, CF 3 , CN, NO 2 , C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 a straight-chain or branched-chain alkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkyl (e.g., CHF 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 ) 2 ), R 8 -aryl (e.g., CH 2 -Ph), -R 8 -O-R 8 -O-R 10 (e.g., (CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 ), -R 8 -O-R 10 , -R 8 -R 10 (e.g., (CH 2 ) 2 -O-CH 3) substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4 - pyridine)), where the substitution is F, Cl, Br, I, OH, SH, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), G = X is C = O, C = S, S = O, SO 2 , CH 2 , CHR, or C(R) 2 , each R 8 is independently [CH 2 p , p is from 1 to 10, R 9 is [CH] q , [C] q , q is from 2 to 10, R 10 and R 11 are each independently H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy (e.g., O-CH 3 ), C(O)R, or S(O) 2 R, or R 10 and R 11 are joined to form a substituted or unsubstituted C 3 -C 8 heterocyclic ring (e.g., piperazine, piperidine), where the substitution is F, Cl, Br, I, OH, C 1 -C 5 linear or branched alkyl, C 1 -C 5 ​Linear or branched alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocyclic ring (e.g., piperidine), alkoxy, N(R) 2 、CF 3 、aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 、or any combination thereof), m, n, l, and k are each independently an integer from 0 to 4 (e.g., 0, 1, or 2), X 6 、X 7 、and X 8 are each independently C or N, X 14 and X 15 are each independently C or N, a compound, or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (e.g., deuterated analog), PROTAC, pharmaceutical product, or any combination thereof, wherein R 5 is C for X 6 、X 7 、and / or X 8 and can only be bonded to.

[0036] In various embodiments, the present invention is a compound represented by the structure of formula I(a),

[0037]

Chemical formula

[0038] wherein, The B ring is a single or fused aromatic or heteroaromatic ring system (e.g., phenyl, pyrimidine, 2-, 3-, or 4-pyridine, pyridazine, or pyrazine, thiazole, imidazole, indazole), or a single or fused C 3 -C 10 cycloalkyl (e.g., cyclopentyl), or a single or fused C 3 -C 10 heterocyclic ring (e.g., piperidine, tetrahydropyran, thian 1,1-dioxide), and R 1 and R 2 are each independently 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 heterocyclic ring), CF 3 、CD 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 5Straight-chain or branched-chain 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 Straight-chain or branched-chain substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 Straight-chain or branched-chain substituted or unsubstituted alkenyl, C 1 -C 5 Straight-chain or branched-chain, or C 3 -C 8 Cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 Straight-chain or branched-chain, or C 3 -C 8 Cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 Straight-chain or branched-chain thioalkoxy, C 1 -C 5 Straight-chain or branched-chain haloalkoxy, C 1 -C 5 Straight-chain or branched-chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 Heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 Straight-chain or branched-chain alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8Cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 or any combination thereof), or 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 3 and R 4 are each independently H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 -O-R 8 -R 10 R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocyclic ring), CF 3 CD 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 linear 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 a straight-chain or branched-chain substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -OCH 2 -CH 2 -O-CH 3 ), C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkenyl, C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic haloalkyl, a substituted or unsubstituted C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic alkoxy (e.g., methoxy, O-(CH 2 )) 2 -O-CH 3 ), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 a straight-chain or branched-chain thioalkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkoxy, C 1 -C 5 a straight-chain or branched-chain alkoxyalkyl, a substituted or unsubstituted C 3 -C 8 a cycloalkyl (e.g., cyclopropyl), a substituted or unsubstituted C 3 -C 8 a heterocyclic ring, a substituted or unsubstituted aryl, a substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 a straight-chain or branched-chain alkyl, OH, alkoxy, N(R) 2 ), CF 3, aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or or 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, R 5 is absent or is 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 heterocyclic ring), CF 3 , CD 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 linear 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 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2or any combination thereof), or Q 1 is NH, N(R), S, O, N-OH, or N-OMe, Q 2 is N or C(R), R is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) 2 、CF 3 、CN, NO 2 、C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 、CH 2 -O-CH 2 -CH 2 -O-CH 3 )、C 1 -C 5 a straight-chain or branched-chain alkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkyl (e.g., CHF 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 ) 2 )、R 8 -aryl (e.g., CH 2 -Ph), -R 8 -O-R 8 -O-R 10 (e.g., (CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3)、-R 8 -O-R 10 、-R 8 -R 10 (For example, (CH 2 ) 2 -O-CH 3 )), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine)), where the substitution may be F, Cl, Br, I, OH, SH, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 、CF 3 、phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 、or any combination thereof), G=X is C=O, C=S, S=O, SO 2 、CH 2 、CHR, or C(R) 2 and each R 8 is independently [CH 2 p and p is from 1 to 10, R 9 is [CH] q 、[C] q and q is from 2 to 10, R 10 and R 11 are each independently H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy (e.g., O-CH 3 ), C(O)R, or S(O) 2 R, or R 10 and R 11 are joined to form a substituted or unsubstituted C 3 -C 8 ​Form a heterocyclic ring (e.g., piperazine, piperidine), Substitutions include F, Cl, Br, I, OH, C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocyclic ring (e.g., piperidine), alkoxy, N(R) 2 , CF 3 , aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), m, n, l, and k are each independently an integer from 0 to 4 (e.g., 0, 1, or 2), X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are each independently C or N, X 14 and X 15 are each independently C or N, a compound, or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (e.g., deuterated analog), PROTAC, pharmaceutical product, or any combination thereof, wherein R 5 which is C can only be bonded to X 6 , X 7 , and / or X 8 .

[0039] In various embodiments, the present invention relates to a compound represented by the structure of formula I(b):

[0040] [Chemical formula]

[0041] In the formula, The B ring is a single or fused aromatic or heteroaromatic ring system (e.g., phenyl, pyrimidine, 2-, 3-, or 4-pyridine, pyridazine, or pyrazine, thiazole, imidazole, indazole), or a single or fused C 3 -C 10 -cycloalkyl (e.g., cyclopentyl), or a single or fused C 3 -C 10 -heterocyclic ring (e.g., piperidine, tetrahydro-2H-pyran, thian 1,1-dioxide), and R 1 is 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 -heterocyclic ring), CF 3 、CD 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 、R8 -C(O)-R 10 、C(O)H、C(O)-R 10 、C 1 -C 5 linear 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 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R)2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 -cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or R 3 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 , -O-R 8 -R 10 , R 8 -(C 3 -C 8 -cycloalkyl), R 8 -(C 3 -C 8 -heterocyclic ring), CF 3 , CD 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 linear or branched C(O)-haloalkyl, -C(O)NH 2 , C(O)NHR, C(O)N(R 10 )(R 11 ), SO2 R, SO 2 N(R 10 )(R 11 ), CH(CF 3 )(NH-R 10 ), C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -OCH 2 -CH 2 -O-CH 3 ), C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkenyl, C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic haloalkyl, substituted or unsubstituted C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic alkoxy (e.g., methoxy, O-(CH 2 )) 2 -O-CH 3 ), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 a straight-chain or branched-chain thioalkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkoxy, C 1 -C 5 a straight-chain or branched-chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 a cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 a heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 a straight-chain or branched-chain alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8Cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or R 5 is absent or is 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 heterocyclic ring), CF 3 , CD 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 linear 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 ), C1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkyl (e.g., methyl, ethyl), C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkenyl, C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 a straight-chain or branched-chain thioalkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkoxy, C 1 -C 5 a straight-chain or branched-chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 a cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 is replaced by a heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 a straight-chain or branched-chain alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 a cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or Q 1 is NH, N(R), S, O, N-OH, or N-OMe, and Q 2 is N or C(R), and R is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) 2 、CF 3 、CN, NO 2 、C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 、CH 2 -O-CH 2 -CH 2 -O-CH 3 )、C 1 -C 5 a straight-chain or branched-chain alkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkyl (e.g., CHF 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 ) 2 )、R 8 -aryl (e.g., CH 2 -Ph), -R 8 -O-R 8 -O-R 10 (e.g., (CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 )、-R 8 -O-R 10 、-R 8 -R 10 (e.g., (CH 2 ) 2 -O-CH 3) substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4 - pyridine)), where the substitution may be F, Cl, Br, I, OH, SH, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), G = X is C = O, C = S, S = O, SO 2 , CH 2 , CHR, or C(R) 2 , each R 8 is independently [CH 2 p , p is from 1 to 10, R 9 is [CH] q , [C] q , q is from 2 to 10, R 10 and R 11 are each independently H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy (e.g., O-CH 3 ), C(O)R, or S(O) 2 R, or R 10 and R 11 are joined to form a substituted or unsubstituted C 3 -C 8 heterocyclic ring (e.g., piperazine, piperidine), where the substitution may be F, Cl, Br, I, OH, C 1 -C 5 linear or branched alkyl, C 1 -C 5 ​Linear or branched alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocyclic ring (e.g., piperidine), alkoxy, N(R) 2 、CF 3 、aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 、or any combination thereof), l is an integer from 0 to 4 (e.g., 0, 1, or 2), X 2 、X 3 、X 4 、X 5 、and X 6 are each independently C or N, a compound, or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (e.g., deuterated analog), PROTAC, pharmaceutical product, or any combination thereof, wherein R 5 can only be bonded to carbon atoms.

[0042] In various embodiments, the present invention relates to a compound represented by the structure of formula I(c):

[0043]

Chemical Formula

[0044] wherein, R 1 is 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 Complex cyclic ring), CF 3 , CD 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 Linear 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 Linear or branched, or C 3 -C 8 Cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 Linear or branched, or C 3 -C8 is a cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 a straight-chain or branched-chain thioalkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkoxy, C 1 -C 5 a straight-chain or branched-chain alkoxyalkyl, a substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), a substituted or unsubstituted C 3 -C 8 heterocyclic ring, a substituted or unsubstituted aryl, a substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 a straight-chain or branched-chain alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or R 3 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 -O-R 8 -R 10 R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocyclic ring), CF 3 , CD 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 R 8 -N(R10 )(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 linear 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, CH 2 -OCH 2 -CH 2 -O-CH 3 )、C 1 -C 5 linear or branched substituted or unsubstituted alkenyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl, substituted or unsubstituted C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy, O-(CH 2 ) 2 -O-CH 3 )), and optionally, at least one methylene group (CH 2 ) in the alkoxy is an oxygen atom, C1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 replaced by a heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or Q 2 is N or C(R), R is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) 2 , CF 3 , CN, NO 2 , C 1 -C 5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkyl (e.g., CHF 2 , CF 3 , CF 2 CH3 , 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), -R 8 -O-R 8 -O-R 10 (e.g., (CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 ), -R 8 -O-R 10 , -R 8 -R 10 (e.g., (CH 2 ) 2 -O-CH 3 ), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine), and the substitutions include F, Cl, Br, I, OH, SH, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 ; or any combination thereof), each R 8 is independently [CH 2 p , p is from 1 to 10, R 9 is [CH] q , [C] q , q is from 2 to 10, R 10 and R​11 each independently is H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy (e.g., O-CH 3 ), C(O)R, or S(O) 2 R, or R 10 and R 11 are joined to form a substituted or unsubstituted C 3 -C 8 heterocyclic ring (e.g., piperazine, piperidine), substituents include F, Cl, Br, I, OH, C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched alkyl-OH (e.g., C(CH 3 )) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocyclic ring (e.g., piperidine), alkoxy, N(R) 2 , CF 3 , aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), l is an integer from 0 to 4 (e.g., 0, 1, or 2), X 9 , X 10 , X 11 , X 12 , and X 13 each independently is C or N, a compound, or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (e.g., deuterated analog), PROTAC, pharmaceutical product, or any combination thereof.

[0045] In various embodiments, the present invention provides a compound represented by the structure of formula I(d):

[0046]

Chemical formula

[0047] wherein ring B is a single or fused aromatic or heteroaromatic ring system (e.g., phenyl, pyrimidine, 2-, 3-, or 4-pyridine, pyridazine, or pyrazine, thiazole, imidazole, indazole), or a single or fused C 3 -C 10 cycloalkyl (e.g., cyclopentyl), or a single or fused C 3 -C 10 heterocyclic ring (e.g., piperidine, tetrahydro-2H-pyran, thian 1,1-dioxide), R 1 and R 2 are each independently H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -S, -R 8 -O-R 10 、R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocyclic ring), CF 3 、CD 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)CF3 、 -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 linear 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 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 )、 C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C8 a complex cyclic ring, a substituted or unsubstituted aryl, or a substituted or unsubstituted benzyl (wherein the substitution is selected from F, Cl, Br, I, C 1 -C 5 a straight or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 a cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or 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 3 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 , -O-R 8 -R 10 , R 8 -(C 3 -C 8 a cycloalkyl), R 8 -(C 3 -C 8 a heterocyclic ring), CF 3 , CD 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 )(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 linear 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, CH 2 -OCH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched substituted or unsubstituted alkenyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl, substituted or unsubstituted C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy, O-(CH 2 )) 2 -O-CH 3 ), and optionally, at least one methylene group (CH 2 ) in the alkoxy is an oxygen atom, C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8Cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 is replaced by a heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or R is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) 2 , CF 3 , CN, NO 2 , C 1 -C 5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkyl (e.g., CHF 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) 2 )、R 8 -aryl (e.g., CH 2 -Ph), -R 8 -O-R 8 -O-R 10 (e.g., (CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 )、-R 8 -O-R 10 、-R 8 -R 10 (e.g., (CH 2 ) 2 -O-CH 3 )、substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4 - pyridine), and the substitutions include F, Cl, Br, I, OH, SH, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 、CF 3 、phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 、or any combination thereof), each R 8 is independently, [CH 2 p and p is from 1 to 10, R 9 is [CH] q 、[C] q and q is from 2 to 10, R 10 and R 11 are each independently H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy (e.g., O-CH 3 ), C(O)R, or S(O)​2 is R, or R 10 and R 11 combine to form a substituted or unsubstituted C 3 -C 8 heterocyclic ring (e.g., piperazine, piperidine), and the substitutions include F, Cl, Br, I, OH, C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocyclic ring (e.g., piperidine), alkoxy, N(R) 2 , CF 3 , aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), R 12 is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) 2 , CF 3 , CN, NO 2 , C 1 -C 5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkyl (e.g., CHF 2 , CF 3 , CF 2 CH 3 , CH 2 CF3 , 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 ), or a substituted or unsubstituted C 3 -C 8 -cycloalkyl (e.g., cyclopropyl), where the substitution may be F, Cl, Br, I, OH, SH, C 1 -C 5 -linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , phenyl, halophenyl, CN, NO 2 , or any combination thereof), l is an integer from 0 to 4 (e.g., 0, 1, or 2), or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (e.g., deuterated analog), PROTAC, pharmaceutical product, or any combination thereof.

[0048] In various embodiments, the present invention relates to a compound represented by the structure of formula I(d(i)):

[0049]

Chemical formula

[0050] wherein, R 1 and R 2 are each independently 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 (heterocyclic ring), CF 3 , CD 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 linear 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 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 ), C 1 -C5 a straight-chain or branched-chain, or C 3 -C 8 is a cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 a straight-chain or branched-chain thioalkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkoxy, C 1 -C 5 a straight-chain or branched-chain alkoxyalkyl, a substituted or unsubstituted C 3 -C 8 a cycloalkyl (e.g., cyclopropyl), a substituted or unsubstituted C 3 -C 8 a heterocyclic ring, a substituted or unsubstituted aryl, a substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 a straight-chain or branched-chain alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 a cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or 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 3 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 -O-R 8 -R 10 R 8 -(C 3 -C 8 a cycloalkyl), R 8 -(C 3 -C 8 a heterocyclic ring), CF 3 CD3 , 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 linear 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, CH 2 -OCH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched substituted or unsubstituted alkenyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl, substituted or unsubstituted C 1 -C 5 linear or branched, or C3 -C 8 Cyclic alkoxy (e.g., methoxy, O-(CH 2 ) 2 -O-CH 3 ) and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or R is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) 2 , CF 3 , CN, NO 2 , C 1 -C 5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), C 1 -C 5Linear or branched alkoxy, C 1 -C 5 Linear or branched haloalkyl (e.g., CHF 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 ) 2 ), R 8 -aryl (e.g., CH 2 -Ph), -R 8 -O-R 8 -O-R 10 (e.g., (CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 ), -R 8 -O-R 10 -R 8 -R 10 (e.g., (CH 2 ) 2 -O-CH 3 ), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine) where the substitutions include F, Cl, Br, I, OH, SH, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), each R 8 is independently, [CH 2 p and p is from 1 to 10, ​R 9 is [CH] q , [C] q and q is from 2 to 10, R 10 and R 11 are each independently H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy (e.g., O-CH 3 ), C(O)R, or S(O) 2 R, or R 10 and R 11 are joined to form a substituted or unsubstituted C 3 -C 8 heterocyclic ring (e.g., piperazine, piperidine), Examples of the substitution include F, Cl, Br, I, OH, C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched alkyl-OH (e.g., C(CH 3 ), 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocyclic ring (e.g., piperidine), alkoxy, N(R) 2 , CF 3 , aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), R 12 is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) 2 , CF 3 , CN, NO 2 , C 1 -C 5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 、CH 2 -O-CH 2 -CH 2 -O-CH 3 )、C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkyl (e.g., CHF 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 ) 2 )、or substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl) (substituents include F, Cl, Br, I, OH, SH, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 、CF 3 、phenyl, halophenyl, CN, NO 2 、or any combination thereof), where l is an integer from 0 to 4 (e.g., 0, 1, or 2), a compound, or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (e.g., deuterated analog), PROTAC, pharmaceutical product, or any combination thereof.

[0051] In various embodiments, the present invention provides a compound represented by the structure of formula I(e):

[0052]

Chemical Formula

[0053] wherein ring B is a single or fused aromatic or heteroaromatic ring system (e.g., phenyl, pyrimidine, 2-, 3-, or 4-pyridine, pyridazine, or pyrazine, thiazole, imidazole, indazole), or a single or fused C 3 -C 10 cycloalkyl (e.g., cyclopentyl), or a single or fused C 3 -C 10 heterocyclic ring (e.g., piperidine, tetrahydro-2H-pyran, thiane 1,1-dioxide), R 1 and R 2 are each independently 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 heterocyclic ring), CF 3 、CD 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)-R10 , 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 linear 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 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8A complex cyclic ring, a substituted or unsubstituted aryl, or a substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 a straight-chain or branched alkyl, OH, alkoxy, N(R) 2 、CF 3 、aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 、or any combination thereof), or R 3 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 、-O-R 8 -R 10 、R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 complex cyclic ring), CF 3 、CD 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 、C1 -C 5 linear 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, CH 2 -OCH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched substituted or unsubstituted alkenyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl, substituted or unsubstituted C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy, O-(CH 2 )) 2 -O-CH 3 ), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 -cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or R is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) 2 , CF 3 , CN, NO 2 , C 1 -C 5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkyl (e.g., CHF 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 ) 2 ), R 8 -aryl (e.g., CH 2 -Ph), -R 8 -O-R 8 -O-R 10 (e.g., (CH 2 ))2 -O-(CH 2 ) 2 -O-CH 3 )、-R 8 -O-R 10 、-R 8 -R 10 (for example, (CH 2 ) 2 -O-CH 3 )、substituted or unsubstituted aryl (for example, phenyl), substituted or unsubstituted heteroaryl (for example, pyridine (2, 3, and 4-pyridine)), where the substitution may be F, Cl, Br, I, OH, SH, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 、CF 3 、phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 、or any combination thereof), each R 8 is independently [CH 2 p , p is from 1 to 10, R 9 is [CH] q 、[C] q , q is from 2 to 10, R 10 and R 11 are each independently H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (for example, methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy (for example, O-CH 3 ), C(O)R, or S(O) 2 R, or R 10 and R 11 are joined to form a substituted or unsubstituted C 3 -C 8 heterocyclic ring (for example, piperazine, piperidine), ​Examples of substitutions include F, Cl, Br, I, OH, C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocyclic ring (e.g., piperidine), alkoxy, N(R) 2 , CF 3 , aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), R 12 is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) 2 , CF 3 , CN, NO 2 , C 1 -C 5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkyl (e.g., CHF 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 ), 2 ), or a substituted or unsubstituted C 3 -C 8 -cycloalkyl (e.g., cyclopropyl), where the substitution is F, Cl, Br, I, OH, SH, C 1 -C 5 -linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , phenyl, halophenyl, CN, NO 2 , or any combination thereof), where l is an integer from 0 to 4 (e.g., 0, 1, or 2), a compound, or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (e.g., deuterated analog), PROTAC, pharmaceutical product, or any combination thereof.

[0054] In various embodiments, the present invention relates to a compound represented by the structure of formula I(e(i)):

[0055]

Chemical formula

[0056] wherein, R 1 and R 2 are each independently 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 -heterocyclic ring), CF 3 , CD 3 , OCD 3 , CN, NO 2 , -CH2 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 linear 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 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is an oxygen atom, C 1 -C5 Straight or branched thioalkoxy, C 1 -C 5 Straight or branched chain haloalkoxy, C 1 -C 5 Linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 Heterocyclic rings, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substitutions include F, Cl, Br, I, C 1 -C 5 Straight or branched chain alkyl, OH, alkoxy, N(R) 2 , C.F. 3 , aryl, phenyl, heteroaryl, C 3 -C 8 Cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 or any combination thereof) R 3 H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -OR 10 , -OR 8 -R 10 , R 8 -(C 3 -C 8 Cycloalkyl), R 8 -(C 3 -C 8 Heterocyclic ring), CF 3 , CD 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 linear 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, CH 2 -OCH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched substituted or unsubstituted alkenyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl, substituted or unsubstituted C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy, O-(CH 2 )) 2 -O-CH 3 ), and optionally, at least one methylene group (CH 2 ) in the alkoxy is an oxygen atom, C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C1 -C 5 is replaced by a linear or branched alkoxyalkyl, a substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), a substituted or unsubstituted C 3 -C 8 heterocyclic ring, a substituted or unsubstituted aryl, a substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or R is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) 2 , CF 3 , CN, NO 2 , C 1 -C 5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkyl (e.g., CHF 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 ) 2 ), R 8 -aryl (e.g., CH 2 -Ph), -R 8 -O-R 8 -O-R 10 (e.g., (CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 ), -R 8 -O-R 10 , -R 8 -R 10 (e.g., (CH 2 ) 2 -O-CH 3 ), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4 - pyridine), and the substitutions include F, Cl, Br, I, OH, SH, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), each R 8 is independently, [CH 2 p , p is from 1 to 10, R 9 is, [CH] q , [C] q , q is from 2 to 10, R 10 and R 11 are each independently, H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ​)、C 1 -C 5 a straight-chain or branched-chain alkoxy (e.g., O-CH 3 ), C(O)R, or S(O) 2 is R, or R 10 and R 11 are joined to form a substituted or unsubstituted C 3 -C 8 heterocyclic ring (e.g., piperazine, piperidine), Examples of the substitution include F, Cl, Br, I, OH, C 1 -C 5 a straight-chain or branched-chain alkyl, C 1 -C 5 a straight-chain or branched-chain alkyl-OH (e.g., C(CH 3 )) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 a heterocyclic ring (e.g., piperidine), alkoxy, N(R) 2 , CF 3 , aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), R 12 is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) 2 , CF 3 , CN, NO 2 , C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 a straight-chain or branched-chain alkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkyl (e.g., CHF2 , 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 ), or substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), where the substitution includes F, Cl, Br, I, OH, SH, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , phenyl, halophenyl, CN, NO 2 , or any combination thereof), where l is an integer from 0 to 4 (e.g., 0, 1, or 2), a compound, or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (e.g., deuterated analog), PROTAC, pharmaceutical product, or any combination thereof.

[0057] In various embodiments, the present invention relates to a compound represented by the structure of formula I(f):

[0058] [Chemical formula]

[0059] wherein, The A' ring is a 5-membered heteroaromatic ring or a heterocyclic ring (e.g., thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazolyl, pyrazolyl, pyrrolyl, furanyl, thiophen-yl, triazolyl, thiadiazolyl, oxadiazolyl, pyrrolidine, 2-oxo-pyrrolidine, tetrahydrofuranyl, oxazolonyl, oxazolidinonyl, thiazolonyl, isothiazolinonyl, isoxazolidinonyl, imidazolidinonyl, pyrazolonyl, 2H-pyrrol-2-onyl, furanonyl, and thiophenonyl), R 1 and R 2 are each independently H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -S, -R 8 -O-R 10 、R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocyclic ring), CF 3 、CD 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 5Linear 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 Linear or branched, or C 3 -C 8 Cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 Linear or branched, or C 3 -C 8 Cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 Linear or branched thioalkoxy, C 1 -C 5 Linear or branched haloalkoxy, C 1 -C 5 Linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 Heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 Linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8Cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 or any combination thereof), or 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 3 is H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 -O-R 8 -R 10 R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocyclic ring), CF 3 CD 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 linear 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 a straight-chain or branched-chain substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -OCH 2 -CH 2 -O-CH 3 )、C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkenyl, C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic haloalkyl, substituted or unsubstituted C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic alkoxy (e.g., methoxy, O-(CH 2 ) 2 -O-CH 3 )), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 a straight-chain or branched-chain thioalkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkoxy, C 1 -C 5 a straight-chain or branched-chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 a cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 a heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 a straight-chain or branched-chain alkyl, OH, alkoxy, N(R) 2 、CF 3 、aryl, phenyl, heteroaryl, C3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), or R is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) 2 , CF 3 , CN, NO 2 , C 1 -C 5 linear or branched substituted or unsubstituted alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , CH 2 -O-CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkyl (e.g., CHF 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 ) 2 ), R 8 -aryl (e.g., CH 2 -Ph), -R 8 -O-R 8 -O-R 10 (e.g., (CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 ), -R 8 -O-R10 、 -R 8 -R 10 (For example, (CH 2 ) 2 -O-CH 3 ), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine), and the substitution includes F, Cl, Br, I, OH, SH, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), each R 8 is independently [CH 2 p , p is from 1 to 10, R 9 is [CH] q , [C] q , q is from 2 to 10, R 10 and R 11 are each independently H, C 1 -C 5 substituted or unsubstituted linear or branched alkyl (e.g., methyl, ethyl, CH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched alkoxy (e.g., O-CH 3 ), C(O)R, or S(O) 2 R, or R 10 and R 11 are joined to form a substituted or unsubstituted C 3 -C 8 heterocyclic ring (e.g., piperazine, piperidine), and the substitution includes F, Cl, Br, I, OH, C 1 -C 5 linear or branched alkyl, C 1 -C​5 A straight-chain or branched-chain alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 a heterocyclic ring (e.g., piperidine), an alkoxy, N(R) 2 , CF 3 , an aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), a compound wherein m, n, and l are each independently an integer from 0 to 4 (e.g., 0, 1, or 2), or a pharmaceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (e.g., deuterated analog), PROTAC, pharmaceutical product, or any combination thereof.

[0060] In some embodiments, A of Formula I, II, I(a), I(b), and / or I(c) is phenyl. In other embodiments, A is pyridinyl. In other embodiments, A is 2-pyridinyl. In other embodiments, A is 3-pyridinyl. In other embodiments, A is 4-pyridinyl. In other embodiments, A is pyrimidine. In other embodiments, A is pyridazine. In other embodiments, A is pyrazine. In other embodiments, A is pyrazole. In other embodiments, A is naphthyl. In other embodiments, A is benzothiazolyl. In other embodiments, A is benzimidazolyl. In other embodiments, A is quinolinyl. In other embodiments, A is isoquinolinyl. In other embodiments, A is indolyl. In other embodiments, A is tetrahydronaphthyl. In other embodiments, A is indenyl. In other embodiments, A is benzofuran-2(3H)-one. In other embodiments, A is benzo[d][1,3]dioxole. In other embodiments, A is tetrahydrothiophene 1,1-dioxide. In other embodiments, A is thiazole. In other embodiments, A is benzimidazole. In other embodiments, A is piperidine. In other embodiments, A is 1-methylpiperidine. In other embodiments, A is imidazole. In other embodiments, A is 1-methylimidazole. In other embodiments, A is thiophene. In other embodiments, A is isoquinoline. In other embodiments, A is indole. In other embodiments, A is 1,3-dihydroisobenzofuran. In other embodiments, A is benzofuran. In other embodiments, A is tetrahydro-2H-pyran. In other embodiments, A is single or fused C 3 -C 10It is a cycloalkyl ring. In other embodiments, A is cyclohexyl. In other embodiments, A is cyclopentyl. In other embodiments, A is cyclopentenyl. In other embodiments, A is cyclopentadienyl. In other embodiments, A is isothiazolyl. In other embodiments, A is thiadiazolyl. In other embodiments, A is triazolyl. In other embodiments, A is thiazolyl. In other embodiments, A is oxazolyl. In other embodiments, A is isoxazolyl. In other embodiments, A is pyrrolyl. In other embodiments, A is furanyl. In other embodiments, A is oxadiazolyl. In other embodiments, A is oxadiazolyl. In other embodiments, A is 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl, each being a separate embodiment according to the present invention. In other embodiments, A is tetrahydrofuranyl. In other embodiments, A is oxazolonyl. In other embodiments, A is oxazolidonyl. In other embodiments, A is thiazolonyl. In other embodiments, A is isothiazolinonyl. In other embodiments, A is isoxazolidinonyl. In other embodiments, A is imidazolidinonyl. In other embodiments, A is pyrazolonyl. In other embodiments, A is 2H-pyrrol-2-onyl. In other embodiments, A is furanonyl. In other embodiments, A is thiophenonyl. In other embodiments, A is thian 1,1 dioxide. In other embodiments, A is triazolopyrimidine.In other embodiments, A is 3H-[1,2,3]triazolo[4,5-d]pyrimidine, 1H-[1,2,3]triazolo[4,5-d]pyrimidine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyrimidine, [1,2,3]triazolo[1,5-a]pyrimidine, [1,2,3]triazolo[1,5-a]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, or [1,2,4]triazolo[1,5-c]pyrimidine, each of which is a separate embodiment according to the present invention. In other embodiments, A is 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine. In some embodiments, the A' ring of formula I(f) is a 5-membered heteroaromatic ring. In some embodiments, the A' ring of formula I(f) is thiazolyl. In other embodiments, A' is isothiazolyl. In other embodiments, A' is oxazolyl. In other embodiments, A' is isoxazolyl. In other embodiments, A' is imidazolyl. In other embodiments, A' is 1-methylimidazolyl. In other embodiments, A' is pyrazolyl. In other embodiments, A' is pyrrolyl. In other embodiments, A' is furanyl. In other embodiments, A' is thiophen-yl. In other embodiments, A' is triazolyl. In other embodiments, A' is thiadiazolyl. In other embodiments, A' is oxadiazolyl. In other embodiments, A' is 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl, each of which represents a separate embodiment according to the present invention. In some embodiments, the A' ring of formula I(f) is a 5-membered heterocyclic ring. In other embodiments, A' is pyrrolidine. In other embodiments, A' is 2-oxo-pyrrolidine. In other embodiments, A' is tetrahydrofuranyl. In other embodiments, A' is oxazolonyl. In other embodiments, A' is oxazolidinyl. In other embodiments, A' is oxazolidinyl. In other embodiments, A' is thiazolonyl.In other embodiments, A' is isothiazolinonyl. In other embodiments, A' is isoxazolidinonyl. In other embodiments, A' is imidazolidinonyl. In other embodiments, A' is pyrazolonyl. In other embodiments, A' is 2H-pyrrol-2-onyl. In other embodiments, A' is furanonyl. In other embodiments, A' is thiophenonyl.

[0061] In some embodiments, B of Formula I, II, I(a), I(b), I(c), I(d), and / or I(e) is a phenyl ring. In other embodiments, B is pyridinyl. In other embodiments, B is 2-pyridinyl. In other embodiments, B is 3-pyridinyl. In other embodiments, B is 4-pyridinyl. In other embodiments, B is pyrimidine. In other embodiments, B is pyridazine. In other embodiments, B is pyrazine. In other embodiments, B is thiazole. In other embodiments, B is imidazole. In other embodiments, B is indazole. In other embodiments, B is naphthyl. In other embodiments, B is indolyl. In other embodiments, B is benzimidazolyl. In other embodiments, B is benzothiazolyl. In other embodiments, B is quinoxalinyl. In other embodiments, B is tetrahydronaphthyl. In other embodiments, B is quinolinyl. In other embodiments, B is isoquinolinyl. In other embodiments, B is indenyl. In other embodiments, B is naphthalene. In other embodiments, B is tetrahydrothiophene 1,1-dioxide. In other embodiments, B is benzimidazole. In other embodiments, B is piperidine. In other embodiments, B is 1-methylpiperidine. In other embodiments, B is 1-methylimidazole. In other embodiments, B is thiophene. In other embodiments, B is isoquinoline. In other embodiments, B is indole. In other embodiments, B is 1,3-dihydroisobenzofuran. In other embodiments, B is benzofuran. In other embodiments, B is tetrahydro-2H-pyran. In other embodiments, B is a single or fused C 3 -C 10 cycloalkyl ring. In other embodiments, B is cyclohexyl. In other embodiments, B is cyclopentyl. In other embodiments, B is thiane 1,1-dioxide.

[0062] In some embodiments, X of the compound of formula I(a) 1 is C. In other embodiments, X 1 is N.

[0063] In some embodiments, X of the compound of formula I(a) and / or I(b) 2 is C. In other embodiments, X 2 is N.

[0064] In some embodiments, X of the compound of formula I(a) and / or I(b) 3 is C. In other embodiments, X 3 is N.

[0065] In some embodiments, X of the compound of formula I(a) and / or I(b) 4 is C. In other embodiments, X 4 is N.

[0066] In some embodiments, X of the compound of formula I(a) and / or I(b) 5 is C. In other embodiments, X 5 is N.

[0067] In some embodiments, X of the compound of formula I, I(a), and / or I(b) 6 is C. In other embodiments, X 6 is N.

[0068] In some embodiments, X of the compound of formula I and / or I(a) 7 is C. In other embodiments, X 7 is N.

[0069] In some embodiments, X of the compound of formula I and / or I(a) 8 is C. In other embodiments, X 8 is N.

[0070] In some embodiments, X of the compound of formula I(c) 9 is C. In other embodiments, X 9 is N.

[0071] In some embodiments, X of the compound of formula I(c) 10 is C. In other embodiments, X 10 is N.

[0072] In some embodiments, X of the compound of formula I(c) 11 is C. In other embodiments, X 11 is N.

[0073] In some embodiments, X of the compound of formula I(c) 12 is C. In other embodiments, X 12 is N.

[0074] In some embodiments, X of the compound of formula I(c) 13 is C. In other embodiments, X 13 is N.

[0075] In some embodiments, X of the compounds of formula I, II 14 is C. In other embodiments, X 12 is N.

[0076] In some embodiments, X of the compounds of formula I, II 15 is C. In other embodiments, X 13 is N.

[0077] In some embodiments, X 1 ~X 5 at least one of which is N. In some embodiments, X 1 ~X 5 at least two of which are N. In some embodiments, X 9 ~X13 At least one of which is N. X 1 ~X 13 If any of ~R 1 ~R 3 It should be understood that any of ~R cannot be attached thereto.

[0078] In some embodiments, R of Formulas I, II, I(a), I(b), I(c), I(d), I(d(i)), (Ie), I(e(i)), and I(f) 1 is H. In some embodiments, R 1 is C 1 -C 5 is a straight-chain 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 iso-butyl. In other embodiments, R 1 is 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.

[0079] In other embodiments, R of Formulas I, II, I(a), I(b), I(c), I(d), I(d(i)), (Ie), I(e(i)), and I(f) 1 is F. In other embodiments, R 1 is Cl. In other embodiments, R 1 is Br. In other embodiments, R 1 is I. In other embodiments, R 1 is R 8 -(C 3 -C8 is a cycloalkyl. In other embodiments, R 1 is CH 2 -cyclohexyl. In other embodiments, R 1 is R 8 -(C 3 -C 8 heterocyclic ring). In other embodiments, R 1 is CH 2 -imidazole. In other embodiments, R 1 is CH 2 -indazole. In other embodiments, R 1 is CF 3 . In other embodiments, R 1 is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl. In other embodiments, R 1 is CHF 2 . In other embodiments, R 1 is CN. In other embodiments, R 1 is CF 2 CH 2 CH 3 . In other embodiments, R 1 is CH 2 CH 2 CF 3 . In other embodiments, R 1 is CF 2 CH(CH 3 ) 2 . In other embodiments, R 1 is CF(CH 3 )-CH(CH 3 ) 2 . In other embodiments, R 1 is OCD 3 . In other embodiments, R 1 is NO 2 . In other embodiments, R 1 is NH 2 . In other embodiments, R 1 is R 8 -N(R10 )(R 11 ) is. In other embodiments, R 1 is CH 2 -NH 2 . In other embodiments, R 1 is CH 2 -N(CH 3 ) 2 ). In other embodiments, R 1 is R 9 -R 8 -N(R 10 )(R 11 ). In other embodiments, R 1 is C≡C-CH 2 -NH 2 . In other embodiments, R 1 is B(OH) 2 . In other embodiments, R 1 is NHC(O)-R 10 . In other embodiments, R 1 is NHC(O)CH 3 . In other embodiments, R 1 is NHCO-N(R 10 )(R 11 ). In other embodiments, R 1 is NHC(O)N(CH 3 ) 2 . In other embodiments, R 1 is COOH. In other embodiments, R 1 is C(O)O-R 10 . In other embodiments, R 1 is C(O)O-CH(CH 3 ) 2 . In other embodiments, R 1 is C(O)O-CH 3 . In other embodiments, R 1 is SO 2 N(R 10 )(R 11 ). In other embodiments, R 1 is SO 2 N(CH 3 ) 2 . In other embodiments, R1 is SO 2 NHC(O)CH 3 In other embodiments, R 1 is C 1 -C 5 a straight-chain 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 pentyl. In other embodiments, R 1 is propyl. In other embodiments, R 1 is benzyl. In other embodiments, R 1 is C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkenyl. In other embodiments, R 1 is CH=C(Ph) 2 In other embodiments, R 1 is 2-CH 2 -C 6 H 4 -Cl. In other embodiments, R 1 is 3-CH 2 -C 6 H 4 -Cl. In other embodiments, R 1 is 4-CH 2 -C 6 H 4 -Cl. 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 pentyl. In other embodiments, R 1is a substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). In other embodiments, R 1 is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy. In other embodiments, R 1 is methoxy. In other embodiments, R 1 is ethoxy. In other embodiments, R 1 is propoxy. In other embodiments, R 1 is isopropoxy. In other embodiments, R 1 is O-CH 2 -cyclopropyl. In other embodiments, R 1 is O-cyclobutyl. In other embodiments, R 1 is O-cyclopentyl. In other embodiments, R 1 is O-cyclohexyl. In other embodiments, R 1 is O-1-oxacyclobutyl. In other embodiments, R 1 is O-2-oxacyclobutyl. In other embodiments, R 1 is 1-butoxy. In other embodiments, R 1 is 2-butoxy. In other embodiments, R 1 is O-tBu. In other embodiments, R 1 is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy, and at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom (O). In other embodiments, R 1 is O-1-oxacyclobutyl. In other embodiments, R 1 is O-2-oxacyclobutyl. In other embodiments, R 1 is C 1 -C5 is a linear or branched haloalkoxy. In other embodiments, R 1 is OCF 3 In other embodiments, R 1 is OCHF 2 In other embodiments, R 1 is a substituted or unsubstituted C 3 -C 8 heterocyclic ring. In other embodiments, R 1 is oxazole. In other embodiments, R 1 is methyl-substituted oxazole. In other embodiments, R 1 is oxadiazole. In other embodiments, R 1 is methyl-substituted oxadiazole. In other embodiments, R 1 is imidazole. In other embodiments, R 1 is methyl-substituted imidazole. In other embodiments, R 1 is pyridine. In other embodiments, R 1 is 2-pyridine. In other embodiments, R 1 is 3-pyridine. In other embodiments, R 1 is 4-pyridine. In other embodiments, R 1 is tetrazole. In other embodiments, R 1 is pyrimidine. In other embodiments, R 1 is pyrazine. In other embodiments, R 1 is oxacyclobutane. In other embodiments, R 1 is 1-oxacyclobutane. In other embodiments, R 1 is 2-oxacyclobutane. In other embodiments, R 1 is indole. In other embodiments, R 1 is pyridine N-oxide. In other embodiments, R 1 is protonated pyridine N-oxide. In other embodiments, R 1 is deprotonated pyridine N-oxide. In other embodiments, R1 is 3-methyl-4H-1,2,4-triazole. In other embodiments, R 1 is 5-methyl-1,2,4-oxadiazole. In other embodiments, R 1 is substituted or unsubstituted aryl. In other embodiments, R 1 is phenyl. In other embodiments, R 1 is bromophenyl. In other embodiments, R 1 is 2-bromophenyl. In other embodiments, R 1 is 3-bromophenyl. In other embodiments, R 1 is 4-bromophenyl. In other embodiments, R 1 is substituted or unsubstituted benzyl. In other embodiments, R 1 is benzyl. In other embodiments, R 1 is R 8 -N(R 10 )(R 11 ). In other embodiments, R 1 is CH 2 -NH 2 . In other embodiments, as the substitution, C 1 -C 5 linear or branched alkyl (e.g., methyl), aryl, phenyl, heteroaryl (e.g., imidazole), and / or C 3 -C 8 cycloalkyl are included, each being a separate embodiment according to the present invention.

[0080] In some embodiments, R 2 in Formulas I, I(a), I(b), I(c), I(d), I(d(i)), (Ie), I(e(i)), and I(f) is H. In some embodiments, R 2 is C 1 -C 5 linear or branched substituted or unsubstituted alkyl. In other embodiments, R 2 is methyl. In other embodiments, R 2is 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 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.

[0081] In some embodiments, R of formulas I, II, I(a), I(b), I(c), I(d), I(d(i)), (Ie), I(e(i)), and I(f) 2 is F. In other embodiments, R 2 is Cl. In other embodiments, R 2 is Br. In other embodiments, R 2 is I. In other embodiments, R 2 is R 8 -(C 3 -C 8 cycloalkyl). In other embodiments, R 2 is CH 2 -cyclohexyl. In other embodiments, R 2 is R 8 -(C 3 -C 8 heterocyclic ring). In other embodiments, R 2 is CH 2 -imidazole. In other embodiments, R 2 is CF 3 . In other embodiments, R 2 is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl. In other embodiments, R 2 is CHF 2is. In other embodiments, R 2 is CN. In other embodiments, R 2 is CF 2 CH 2 CH 3 is. In other embodiments, R 2 is CH 2 CH 2 CF 3 is. In other embodiments, R 2 is CF 2 CH(CH 3 ) 2 is. In other embodiments, R 2 is CF(CH 3 )-CH(CH 3 ) 2 is. In other embodiments, R 2 is OCD 3 is. In other embodiments, R 2 is NO 2 is. In other embodiments, R 2 is NH 2 is. In other embodiments, R 2 is R 8 -N(R 10 )(R 11 ). In other embodiments, R 2 is CH 2 -NH 2 is. In other embodiments, R 2 is CH 2 -N(CH 3 ) 2 ). In other embodiments, R 2 is R 9 -R 8 -N(R 10 )(R 11 ). In other embodiments, R 2 is C≡C-CH 2 -NH 2 is. In other embodiments, R 2 is B(OH) 2 is. In other embodiments, R 2 is NHC(O)-R 10 is. In other embodiments, R 2is NHC(O)CH 3 . In other embodiments, R 2 is NHCO-N(R 10 )(R 11 ). In other embodiments, R 2 is NHC(O)N(CH 3 ) 2 . In other embodiments, R 2 is COOH. In other embodiments, R 2 is C(O)O-R 10 . In other embodiments, R 2 is C(O)O-CH(CH 3 ) 2 . In other embodiments, R 2 is C(O)O-CH 3 . In other embodiments, R 2 is SO 2 N(R 10 )(R 11 ). In other embodiments, R 2 is SO 2 N(CH 3 ) 2 . In other embodiments, R 2 is SO 2 NHC(O)CH 3 . In other embodiments, R 2 is C 1 -C 5 a straight-chain, 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 pentyl. In other embodiments, R 2 is propyl. In other embodiments, R 2 is benzyl. In other embodiments, R 2 is C 1 -C5 is a linear or branched, substituted or unsubstituted alkenyl. In other embodiments, R 2 is CH=C(Ph) 2 In other embodiments, R 2 is 2-CH 2 -C 6 H 4 -Cl. In other embodiments, R 2 is 3-CH 2 -C 6 H 4 -Cl. In other embodiments, R 2 is 4-CH 2 -C 6 H 4 -Cl. 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 pentyl. In other embodiments, R 2 is a substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl, cyclopentyl). In other embodiments, R 2 is C 1 -C 5 linear or branched, or C 3 -C 8 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 O-CH 2 -cyclopropyl. In other embodiments, R 2 is O-cyclobutyl. In other embodiments, R 2is O-cyclopentyl. In other embodiments, R 2 is O-cyclohexyl. In other embodiments, R 2 is O-1-oxacyclobutyl. In other embodiments, R 2 is O-2-oxacyclobutyl. In other embodiments, R 2 is 1-butoxy. In other embodiments, R 2 is 2-butoxy. In other embodiments, R 2 is O-tBu. In other embodiments, R 2 is C 1 -C 5 is a linear or branched haloalkoxy. In other embodiments, R 2 is OCF 3 . In other embodiments, R 2 is OCHF 2 . In other embodiments, R 2 is a substituted or unsubstituted C 3 -C 8 heterocyclic ring. In other embodiments, R 2 is oxazole or methyl-substituted oxazole. In other embodiments, R 2 is oxadiazole or methyl-substituted oxadiazole. In other embodiments, R 2 is imidazole or methyl-substituted imidazole. In other embodiments, R 2 is pyridine. In other embodiments, R 2 is 2-pyridine. In other embodiments, R 2 is 3-pyridine. In other embodiments, R 2 is 4-pyridine. In other embodiments, R 2 is tetrazole. In other embodiments, R 2 is pyrimidine. In other embodiments, R 2 is pyrazine. In other embodiments, R 2 is oxacyclobutane. In other embodiments, R 2is 1-oxacyclobutane. In other embodiments, R 2 is 2-oxacyclobutane. In other embodiments, R 2 is indole. In other embodiments, R 2 is pyridine N-oxide. In other embodiments, R 2 is protonated pyridine N-oxide. In other embodiments, R 2 is deprotonated pyridine N-oxide. In other embodiments, R 2 is 3-methyl-4H-1,2,4-triazole. In other embodiments, R 2 is 5-methyl-1,2,4-oxadiazole. In other embodiments, R 2 is substituted or unsubstituted aryl. In other embodiments, R 2 is phenyl. In other embodiments, R 2 is bromophenyl. In other embodiments, R 2 is 2-bromophenyl. In other embodiments, R 2 is 3-bromophenyl. In other embodiments, R 2 is 4-bromophenyl. In other embodiments, R 2 is substituted or unsubstituted benzyl. In other embodiments, R 2 is benzyl. In other embodiments, R 2 is R 8 -N(R 10 )(R 11 ). In other embodiments, R 2 is CH 2 -NH 2 . In other embodiments, examples of the substitution include C 1 -C 5 linear or branched alkyl (e.g., methyl), aryl, phenyl, heteroaryl (e.g., imidazole), and / or C 3 -C 8 cycloalkyl, each being a separate embodiment according to the present invention.

[0082] In some embodiments, R of Formula I, II, I(a), I(d), I(d(i)), and / or I(f) 1 and R 2 are joined together to form a pyrrole ring. In some embodiments, R 1 and R 2 are joined together to form a [1,3]dioxole ring. In some embodiments, R 1 and R 2 are joined together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R 1 and R 2 are joined together to form a benzene ring. In some embodiments, R 1 and R 2 are joined together to form a pyridine ring. In some embodiments, R 1 and R 2 are joined together to form an oxazine ring. In some embodiments, R 1 and R 2 are joined together to form a pyrimidine ring.

[0083] In some embodiments, R of Formula I, II, I(a), I(b), I(c), I(d), I(d(i)), (Ie), I(e(i)), and / or I(f) 3 is H. In other embodiments, R 3 is Cl. In other embodiments, R 3 is I. In other embodiments, R 3 is F. In other embodiments, R 3 is Br. In other embodiments, R 3 is OH. In other embodiments, R 3 is CD 3 . In other embodiments, R 3 is OCD 3 . In other embodiments, R 3 is R 8 -OH. In other embodiments, R 3 is CH2 is -OH. In other embodiments, R 3 is -R 8 -O-R 10 In other embodiments, R 3 is CH 2 -O-CH 3 In other embodiments, R 3 is -O-R 8 -R 10 In other embodiments, R 3 is CH 2 -O-CH 3 In other embodiments, R 3 is R 8 -N(R 10 )(R 11 ) In other embodiments, R 3 is CH 2 -NH-CH 3 In other embodiments, R 3 is CH 2 -NH 2 In other embodiments, R 3 is CH 2 -N(CH 3 ) 2 In other embodiments, R 3 is COOH. In other embodiments, R 3 is C(O)O-R 10 In other embodiments, R 3 is C(O)O-CH 2 CH 3 In other embodiments, R 3 is R 8 -C(O)-R 10 In other embodiments, R 3 is CH 2 C(O)CH 3 In other embodiments, R 3 is C(O)-R 10 In other embodiments, R 3 is C(O)-CH 3 In other embodiments, R 3 is C(O)-CH 2 CH 3is. In other embodiments, R 3 is C(O)-CH 2 CH 2 CH 3 is. In other embodiments, R 3 is C 1 -C 5 is a linear or branched C(O)-haloalkyl. In other embodiments, R 3 is C(O)-CF 3 is. In other embodiments, R 3 is C(O)N(R 10 )(R 11 ). In other embodiments, R 3 is C(O)N(CH 3 ) 2 ). In other embodiments, R 3 is SO 2 N(R 10 )(R 11 ). In other embodiments, R 3 is SO 2 N(CH 3 ) 2 . In other embodiments, R 3 is C 1 -C 5 is a linear or branched substituted or unsubstituted alkyl. In other embodiments, R 3 is methyl. In other embodiments, R 3 is ethyl. In other embodiments, R 3 is CH 2 -OCH 2 -CH 2 -O-CH 3 . In other embodiments, R 3 is propyl. In other embodiments, R 3 is isopropyl. In other embodiments, R 3 is t-Bu. In other embodiments, R 3 is isobutyl. In other embodiments, R 3 is pentyl. In other embodiments, R 3 is C(OH)(CH 3)(Ph). In other embodiments, R 3 is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl. In other embodiments, R 3 is CF 2 CH 3 . In other embodiments, R 3 is CF 2 -cyclobutyl. In other embodiments, R 3 is CH 2 CF 3 . In other embodiments, R 3 is CF 2 CH 2 CH 3 . In other embodiments, R 3 is CF 3 . In other embodiments, R 3 is CF 2 CH 2 CH 3 . In other embodiments, R 3 is CH 2 CH 2 CF 3 . In other embodiments, R 3 is CF 2 CH(CH 3 ) 2 . In other embodiments, R 3 is CF(CH 3 )-CH(CH 3 ) 2 . In other embodiments, R 3 is substituted or unsubstituted C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy. In other embodiments, R 3 is substituted C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy. In other embodiments, R 3 is O-(CH 2) 2 -O-CH 3 is. In other embodiments, R 3 is unsubstituted C 1 -C 5 linear or branched, or C 3 -C 8 is a cyclic alkoxy. In other embodiments, R 3 is methoxy. In other embodiments, R 3 is isopropoxy. In other embodiments, R 3 is substituted or unsubstituted C 3 -C 8 is a cycloalkyl. In other embodiments, R 3 is cyclopropyl. In other embodiments, R 3 is cyclopentyl. In other embodiments, R 3 is substituted or unsubstituted C 3 -C 8 is a heterocyclic ring. In other embodiments, R 3 is thiophene. In other embodiments, R 3 is oxazole. In other embodiments, R 3 is isoxazole. In other embodiments, R 3 is imidazole. In other embodiments, R 3 is furan. In other embodiments, R 3 is triazole. In other embodiments, R 3 is pyridine. In other embodiments, R 3 is 2-pyridine. In other embodiments, R 3 is 3-pyridine. In other embodiments, R 3 is 4-pyridine. In other embodiments, R 3 is pyrimidine. In other embodiments, R 3 is pyrazine. In other embodiments, R 3 is oxacyclobutane. In other embodiments, R 3 is 1-oxacyclobutane. In other embodiments, R 3is 2-oxacyclobutane. In other embodiments, R 3 is indole. In other embodiments, R 3 is 3-methyl-4H-1,2,4-triazole. In other embodiments, R 3 is 5-methyl-1,2,4-oxadiazole. In other embodiments, R 3 is substituted or unsubstituted aryl. In other embodiments, R 3 is phenyl. In other embodiments, R 3 is CH(CF 3 )(NH-R 10 ).

[0084] In some embodiments, R of Formula I, II, I(a), I(b), and / or I(c) 4 is H. In other embodiments, R 4 is Cl. In other embodiments, R 4 is I. In other embodiments, R 4 is F. In other embodiments, R 4 is Br. In other embodiments, R 4 is OH. In other embodiments, R 4 is CD 3 . In other embodiments, R 4 is OCD 3 . In other embodiments, R 4 is R 8 -OH. In other embodiments, R 4 is CH 2 -OH. In other embodiments, R 4 is -R 8 -O-R 10 . In other embodiments, R 4 is CH 2 -O-CH 3 . In other embodiments, R 4 is -O-R 8 -R 10 . In other embodiments, R 4 is CH 2 -O-CH3 is. In other embodiments, R 4 is R 8 -N(R 10 )(R 11 ). In other embodiments, R 4 is CH 2 -NH-CH 3 . In other embodiments, R 4 is CH 2 -NH 2 . In other embodiments, R 4 is CH 2 -N(CH 3 ) 2 . In other embodiments, R 4 is COOH. In other embodiments, R 4 is C(O)O-R 10 . In other embodiments, R 4 is C(O)O-CH 2 CH 3 . In other embodiments, R 4 is R 8 -C(O)-R 10 . In other embodiments, R 4 is CH 2 C(O)CH 3 . In other embodiments, R 4 is C(O)-R 10 . In other embodiments, R 4 is C(O)-CH 3 . In other embodiments, R 4 is C(O)-CH 2 CH 3 . In other embodiments, R 4 is C(O)-CH 2 CH 2 CH 3 . In other embodiments, R 4 is C 1 -C 5 a straight-chain or branched C(O)-haloalkyl. In other embodiments, R 4 is C(O)-CF 3 . In other embodiments, R 4 is C(O)N(R10 )(R 11 ) is. In other embodiments, R 4 is C(O)N(CH 3 ) 2 ). In other embodiments, R 4 is SO 2 N(R 10 )(R 11 ). In other embodiments, R 4 is SO 2 N(CH 3 ) 2 . In other embodiments, R 4 is C 1 -C 5 a linear or branched substituted or unsubstituted alkyl. In other embodiments, R 4 is methyl. In other embodiments, R 4 is C(OH)(CH 3 )(Ph). In other embodiments, R 4 is ethyl. In other embodiments, R 4 is CH 2 -OCH 2 -CH 2 -O-CH 3 . In other embodiments, R 4 is propyl. In other embodiments, R 4 is isopropyl. In other embodiments, R 4 is t-Bu. In other embodiments, R 4 is isobutyl. In other embodiments, R 4 is pentyl. In other embodiments, R 4 is C 1 -C 5 a linear or branched, or C 3 -C 8 a cyclic haloalkyl. In other embodiments, R 3 is CF 2 CH 3 . In other embodiments, R 3 is CF 2 -cyclobutyl. In other embodiments, R 4 is CH2 CF 3 is. In other embodiments, R 4 is CH 2 CH 2 CF 3 is. In other embodiments, R 4 is CF 3 is. In other embodiments, R 4 is CH 2 CH 2 CF 3 is. In other embodiments, R 4 is CH 2 CH 2 CF 3 is. In other embodiments, R 4 is CF 2 CH(CH 3 ) 2 is. In other embodiments, R 4 is CF(CH 3 )-CH(CH 3 ) 2 is. In other embodiments, R 4 is C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy. In other embodiments, R 4 is substituted C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy. In other embodiments, R 4 is O-(CH 2 ) 2 -O-CH 3 is. In other embodiments, R 4 is unsubstituted C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy. In other embodiments, R 4 is methoxy. In other embodiments, R 4 is isopropoxy. In other embodiments, R 4 is substituted or unsubstituted C 3-C 8 is a cycloalkyl. In other embodiments, R 4 is cyclopropyl. In other embodiments, R 4 is cyclopentyl. In other embodiments, R 4 is a substituted or unsubstituted C 3 -C 8 is a heterocyclic ring. In other embodiments, R 4 is thiophene. In other embodiments, R 4 is oxazole. In other embodiments, R 4 is isoxazole. In other embodiments, R 4 is imidazole. In other embodiments, R 4 is furan. In other embodiments, R 4 is triazole. In other embodiments, R 4 is pyridine. In other embodiments, R 4 is 2-pyridine. In other embodiments, R 4 is 3-pyridine. In other embodiments, R 4 is 4-pyridine. In other embodiments, R 4 is pyrimidine. In other embodiments, R 4 is pyrazine. In other embodiments, R 4 is oxacyclobutane. In other embodiments, R 4 is 1-oxacyclobutane. In other embodiments, R 4 is 2-oxacyclobutane. In other embodiments, R 4 is indole. In other embodiments, R 4 is 3-methyl-4H-1,2,4-triazole. In other embodiments, R 4 is 5-methyl-1,2,4-oxadiazole. In other embodiments, R 4 is a substituted or unsubstituted aryl. In other embodiments, R 4 is phenyl. In other embodiments, R 4 is CH(CF 3)(NH-R 10 ) is.

[0085] In some embodiments, R of Formula I, II, I(a), I(b), and / or I(c) 3 and R 4 are joined together to form a [1,3]dioxol ring. In some embodiments, R 3 and R 4 are joined together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R 3 and R 4 are joined together to form a benzene ring. In some embodiments, R 3 and R 4 are joined together to form a cyclopentene ring. In some embodiments, R 3 and R 4 are joined together to form an imidazole ring.

[0086] In some embodiments, R of Formula I, II, I(a), and / or I(b) 5 is absent. In some embodiments, R 5 is H. In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 is Br. In some embodiments, R 5 is I. In some embodiments, R 5 is OH. In some embodiments, R 5 is SH. In some embodiments, R 5 is R 8 -OH. In some embodiments, R 5 is R 8 -SH. In some embodiments, R 5 is -R 8 -O-R 10 is. In some embodiments, R 5 is R8 -(C 3 -C 8 is a cycloalkyl. In some embodiments, R 5 is R 8 -(C 3 -C 8 is a heterocyclic ring. In some embodiments, R 5 is CF 3 In some embodiments, R 5 is CD 3 In some embodiments, R 5 is OCD 3 In some embodiments, R 5 is CN. In some embodiments, R 5 is NO 2 In some embodiments, R 5 is -CH 2 CN. In some embodiments, R 5 is -R 8 CN. In some embodiments, R 5 is NH 2 In some embodiments, R 5 is NHR. In some embodiments, R 5 is N(R) 2 In some embodiments, R 5 is R 8 -N(R 10 )(R 11 ). In some embodiments, R 5 is R 9 -R 8 -N(R 10 )(R 11 ). In some embodiments, R 5 is B(OH) 2 In some embodiments, R 5 is -OC(O)CF 3 In some embodiments, R 5 is -OCH 2 Ph. In some embodiments, R 5 is NHC(O)-R 10It is. In some embodiments, R 5 is NHCO-N(R 10 )(R 11 ). In some embodiments, R 5 is COOH. In some embodiments, R 5 is -C(O)Ph. In some embodiments, R 5 is C(O)O-R 10 . In some embodiments, R 5 is R 8 -C(O)-R 10 . In some embodiments, R 5 is C(O)H. In some embodiments, R 5 is C(O)-R 10 . In some embodiments, R 5 is C 1 -C 5 a straight-chain or branched C(O)-haloalkyl. In some embodiments, R 5 is -C(O)NH 2 . In some embodiments, R 5 is C(O)NHR. In some embodiments, R 5 is C(O)N(R 10 )(R 11 ). In some embodiments, R 5 is SO 2 R, SO 2 N(R 10 )(R 11 ). In some embodiments, R 5 is CH(CF 3 )(NH-R 10 ). In some embodiments, R 5 is C 1 -C 5 a straight-chain or branched 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 1 -C5 is a straight-chain or branched-chain substituted or unsubstituted alkenyl. In some embodiments, R 5 is C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic haloalkyl. In some embodiments, R 5 is CHF 2 . In some embodiments, R 5 is C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic alkoxy. In some embodiments, R 5 is methoxy. In some embodiments, R 5 is C 1 -C 5 a straight-chain or branched-chain thioalkoxy. In some embodiments, R 5 is C 1 -C 5 a straight-chain or branched-chain haloalkoxy. In some embodiments, R 5 is C 1 -C 5 a straight-chain or branched-chain alkoxyalkyl. In some embodiments, R 5 is a substituted or unsubstituted C 3 -C 8 cycloalkyl. In some embodiments, R 5 is cyclopropyl. In some embodiments, R 5 is a substituted or unsubstituted C 3 -C 8 a heterocyclic ring. In some embodiments, R 5 is a substituted or unsubstituted aryl. In some embodiments, R 5 is a substituted or unsubstituted benzyl.

[0087] In some embodiments, R 6 of formula I or II is H. In some embodiments, R 6is F. In some embodiments, R 6 is Cl. In some embodiments, R 6 is Br. In some embodiments, R 6 is I. In some embodiments, R 6 is OH. In some embodiments, R 6 is SH. In some embodiments, R 6 is R 8 -OH. In some embodiments, R 6 is R 8 -SH. In some embodiments, R 6 is -R 8 -O-R 10 In some embodiments, R 6 is R 8 -(C 3 -C 8 cycloalkyl). In some embodiments, R 6 is R 8 -(C 3 -C 8 heterocyclic ring). In some embodiments, R 6 is CF 3 In some embodiments, R 6 is CD 3 In some embodiments, R 6 is OCD 3 In some embodiments, R 6 is CN. In some embodiments, R 6 is NO 2 In some embodiments, R 6 is -CH 2 CN. In some embodiments, R 6 is -R 8 CN. In some embodiments, R 6 is NH 2 In some embodiments, R 6 is NHR. In some embodiments, R 6 is N(R) 2is. In some embodiments, R 6 is R 8 -N(R 10 )(R 11 ). In some embodiments, R 6 is R 9 -R 8 -N(R 10 )(R 11 ). In some embodiments, R 6 is B(OH) 2 . In some embodiments, R 6 is -OC(O)CF 3 . In some embodiments, R 6 is -OCH 2 Ph. In some embodiments, R 6 is NHC(O)-R 10 . In some embodiments, R 6 is NHCO-N(R 10 )(R 11 ). In some embodiments, R 6 is COOH. In some embodiments, R 6 is -C(O)Ph. In some embodiments, R 6 is C(O)O-R 10 . In some embodiments, R 6 is R 8 -C(O)-R 10 . In some embodiments, R 6 is C(O)H. In some embodiments, R 6 is C(O)-R 10 . In some embodiments, R 6 is C 1 -C 5 a straight-chain or branched-chain C(O)-haloalkyl. In some embodiments, R 6 is -C(O)NH 2 . In some embodiments, R 6 is C(O)NHR. In some embodiments, R 6 is C(O)N(R 10 )(R11 ) is. In some embodiments, R 6 is SO 2 R. In some embodiments, R 6 is SO 2 N(R 10 )(R 11 ). In some embodiments, R 6 is CH(CF 3 )(NH-R 10 ). In some embodiments, R 6 is C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is C 1 -C 5 a straight-chain or branched-chain substituted or unsubstituted alkenyl. In some embodiments, R 6 is C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic haloalkyl. In some embodiments, R 6 is CHF 2 . In some embodiments, R 6 is C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic alkoxy. In some embodiments, R 6 is methoxy. In some embodiments, R 6 is C 1 -C 5 a straight-chain or branched-chain thioalkoxy. In some embodiments, R 6 is C 1 -C 5 a straight-chain or branched-chain haloalkoxy. In some embodiments, R 6 is C 1 -C 5It is a linear or branched alkoxyalkyl. In some embodiments, R 6 is a substituted or unsubstituted C 3 -C 8 cycloalkyl. In some embodiments, R 6 is cyclopropyl. In some embodiments, R 6 is a substituted or unsubstituted C 3 -C 8 heterocyclic ring. In some embodiments, R 6 is a substituted or unsubstituted aryl. In some embodiments, R 6 is a substituted or unsubstituted benzyl.

[0088] In some embodiments, R 7 in Formula I or II is H. In some embodiments, R 7 is F. In some embodiments, R 7 is Cl. In some embodiments, R 7 is Br. In some embodiments, R 7 is I. In some embodiments, R 7 is OH. In some embodiments, R 7 is SH. In some embodiments, R 7 is R 8 -OH. In some embodiments, R 7 is R 8 -SH. In some embodiments, R 7 is -R 8 -O-R 10 . In some embodiments, R 7 is R 8 -(C 3 -C 8 cycloalkyl). In some embodiments, R 7 is R 8 -(C 3 -C 8 heterocyclic ring). In some embodiments, R 7 is CF 3is. In some embodiments, R 7 is CD 3 is. In some embodiments, R 7 is OCD 3 is. In some embodiments, R 7 is CN. In some embodiments, R 7 is NO 2 is. In some embodiments, R 7 is -CH 2 CN. In some embodiments, R 7 is -R 8 CN. In some embodiments, R 7 is NH 2 is. In some embodiments, R 7 is NHR. In some embodiments, R 7 is N(R) 2 is. In some embodiments, R 7 is R 8 -N(R 10 )(R 11 ). In some embodiments, R 7 is R 9 -R 8 -N(R 10 )(R 11 ). In some embodiments, R 7 is B(OH) 2 is. In some embodiments, R 7 is -OC(O)CF 3 is. In some embodiments, R 6 is -OCH 2 Ph. In some embodiments, R 7 is NHC(O)-R 10 is. In some embodiments, R 7 is NHCO-N(R 10 )(R 11 ). In some embodiments, R 6 is COOH. In some embodiments, R 6 is -C(O)Ph. In some embodiments, R 7is C(O)O-R 10 In some embodiments, R 6 is R 8 -C(O)-R 10 In some embodiments, R 6 is C(O)H. In some embodiments, R 7 is C(O)-R 10 In some embodiments, R 7 is C 1 -C 5 a straight or branched chain C(O)-haloalkyl. In some embodiments, R 7 is -C(O)NH 2 In some embodiments, R 7 is C(O)NHR. In some embodiments, R 7 is C(O)N(R 10 )(R 11 ). In some embodiments, R 7 is SO 2 R. In some embodiments, R 7 is SO 2 N(R 10 )(R 11 ). In some embodiments, R 7 is CH(CF 3 )(NH-R 10 ). In some embodiments, R 7 is C 1 -C 5 a straight or branched chain substituted or unsubstituted alkyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is ethyl. In some embodiments, R 7 is C 1 -C 5 a straight or branched chain substituted or unsubstituted alkenyl. In some embodiments, R 7 is C 1 -C 5 a straight or branched chain, or C 3 -C 8It is a cyclic haloalkyl. In some embodiments, R 7 is CHF 2 In some embodiments, R 7 is C 1 -C 5 a straight-chain or branched-chain, or C 3 -C 8 a cyclic alkoxy. In some embodiments, R 7 is methoxy. In some embodiments, R 7 is C 1 -C 5 a straight-chain or branched-chain thioalkoxy. In some embodiments, R 7 is C 1 -C 5 a straight-chain or branched-chain haloalkoxy. In some embodiments, R 7 is C 1 -C 5 a straight-chain or branched-chain alkoxyalkyl. In some embodiments, R 7 is a substituted or unsubstituted C 3 -C 8 a cycloalkyl. In some embodiments, R 7 is cyclopropyl. In some embodiments, R 7 is a substituted or unsubstituted C 3 -C 8 a heterocyclic ring. In some embodiments, R 7 is a substituted or unsubstituted aryl. In some embodiments, R 7 is a substituted or unsubstituted benzyl.

[0089] In some embodiments, R 6 and R 7 in Formulas I, II, I(a), I(b), and I(c) are joined together to form a 3- to 6-membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring. In some embodiments, R 6 and R 7 are joined together to form a 3- to 6-membered aliphatic carbocyclic ring. In some embodiments, R6 and R 7 combine together to form a cyclopropyl group.

[0090] In some embodiments, R of formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) 8 is CH 2 Other embodiments, R 8 is CH 2 CH 2 Other embodiments, R 8 is CH 2 CH 2 CH 2 In some embodiments, p of formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) is 1. In other embodiments, p is 2. In other embodiments, p is 3.

[0091] In some embodiments, R of formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f)

[0092] is C≡C. 9 In some embodiments, q of formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) is 2.

[0093] In some embodiments, R of formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f)

[0094] is substituted or unsubstituted C 10 -C 1 -C 5 is a straight-chain or branched-chain alkyl. In other embodiments, R 10 is H. In other embodiments, R 10 is CH3 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 C 1 -C 5 is a straight-chain or branched-chain alkoxy. In other embodiments, R 10 is O-CH 3 is.

[0095] In some embodiments, R of formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) 11 is a substituted or unsubstituted C 1 -C 5 is a straight-chain or branched-chain alkyl. In other embodiments, R 10 is H. In other embodiments, R 11 is CH 3 is. In other embodiments, R 11 is CH 2 -CH 2 -O-CH 3 is. In other embodiments, R 11 is C 1 -C 5 is a straight-chain or branched-chain alkoxy. In other embodiments, R 11 is O-CH 3 is.

[0096] In some embodiments, R of formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) 10 and R 11 are joined to form a substituted or unsubstituted C 3 -C8 form a complex cyclic ring. In other embodiments, R 10 and R 11 combine to form a piperazine ring. In other embodiments, R 10 and R 11 combine to form a piperidine ring. In some embodiments, the substitution is F, Cl, Br, I, OH, C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched alkyl-OH (e.g., C(CH 3 ) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 complex cyclic ring (e.g., piperidine), alkoxy, N(R) 2 , CF 3 , aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof, each representing a separate embodiment of the present invention.

[0097] In some embodiments, R of formula I(d), I(d(i)), I(e), and / or I(e(i)) 12 is H. In other embodiments, R 12 is C 1 -C 5 linear or branched alkyl. In other embodiments, R 12 is methyl. In other embodiments, R 12 is ethyl. In other embodiments, R 12 is C 1 -C 5 linear or branched haloalkyl. In other embodiments, R 12 is CHF 2 . In other embodiments, R 12 is CF 3 . In other embodiments, R 12 is Cl. In other embodiments, R12 is CN. In other embodiments, R 12 is substituted or unsubstituted C 3 -C 8 cycloalkyl. In other embodiments, R 12 is cyclopropyl.

[0098] In some embodiments, R of Formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) is H. In other embodiments, R is C 1 -C 5 linear or branched alkyl. In other embodiments, R is methyl. In other embodiments, R is ethyl. In other embodiments, R is CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 is. In other embodiments, R is CH 2 -O-CH 2 -CH 2 -O-CH 3 is. In other embodiments, R is C 1 -C 5 linear or branched haloalkyl. In other embodiments, R is CHF 2 is. In other embodiments, R is CF 3 is. In other embodiments, R is -R 8 -O-R 8 -O-R 10 is. In other embodiments, R is (CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 is. In other embodiments, R is -R 8 -O-R 10 is. In other embodiments, R is -R 8 -R 10 is. In other embodiments, R is (CH 2 ) 2 -O-CH 3It is so. In other embodiments, R is Cl. In other embodiments, R is CN.

[0099] In some embodiments, m in Formulas I, II, I(a), and I(f) is 0. In some embodiments, m is 1.

[0100] In some embodiments, n in Formulas I, II, I(a), and I(f) is 0. In other embodiments, n is 1.

[0101] In some embodiments, k in Formulas I, II, and I(a) is 0. In other embodiments, k is 1.

[0102] In some embodiments, l in Formulas I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and I(f) is 0. In other embodiments, l is 1. In other embodiments, l is 2.

[0103] In some embodiments, Q in Formulas I, II, I(a), and I(b) 1 is NH. In other embodiments, Q 1 is Nr. In other embodiments, Q 1 is N-CH 3 In other embodiments, Q 1 is N-(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 In other embodiments, Q 1 is S. In other embodiments, Q 1 is O. In other embodiments, Q 1 is N-OH. In other embodiments, Q 1 is N-OMe.

[0104] In some embodiments, Q in Formulas I, II, I(a), I(b), and I(c)2 is C(R). In other embodiments, Q 2 is C-CH 3 In other embodiments, Q 2 is CH. In other embodiments, Q 2 is C-Cl. In other embodiments, Q 2 is C-CN. In other embodiments, Q 2 is C-CF 3 In other embodiments, Q 2 is C-CHF 2 In other embodiments, Q 2 is C-CH 2 -O-(CH 2 ) 2 -O-CH 3 In other embodiments, Q 2 is N.

[0105] In some embodiments, G = X in Formulas I, II, I(a), and I(b) is C=O. In other embodiments, G = X is CH 2 In various embodiments, the present invention is directed to the compounds, pharmaceutical compositions, and / or methods of using them presented in Table 1, each representing a distinct embodiment of the present invention.

[0106]

Table 1-1

[0107]

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

[0108] In the structures presented in the present invention where a carbon atom has less than 4 bonds, it is well understood that H atoms are present to complete the valence of carbon. In the structures presented in the present invention where a nitrogen atom has less than 3 bonds, it is well understood that H atoms are present to complete the valence of nitrogen.

[0109] In some embodiments, the present invention is directed to the compounds, pharmaceutical compositions, and / or methods of use thereof listed above, wherein the compounds are pharmaceutically acceptable salts, optical isomers, tautomers, hydrates, N-oxides, reverse amide analogs, prodrugs, isotope variants (deuterated analogs), PROTACs, pharmaceutical products, or any combination thereof. In some embodiments, the compound is a collagen I translation inhibitor.

[0110] In various embodiments, the A ring of Formula I and / or II 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-indazole, 3H-indole-3-one, purinyl, benzoxazolyl, 1,3-benzoxazole, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4,5,6,7-tetrahydro-1,3-benzothiazole, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 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, benzo[d][1,3]dioxole, thiadiazolyl, tetrahydrofuranyl, oxazolonyl, oxazolidinonyl, thiazolonyl, isothiazolinonyl, isoxazolidinonyl, imidazolidinonyl, pyrazolonyl, 2H-pyrrol-2-onyl, furanonyl, thiophenonyl, pyrrolidine, 2-oxo-pyrrolidine, [1,3]oxazolo[4,5-b]pyridine, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl, 3H-[1,2,3]triazolo[4,5-d]pyrimidine, 1H-[1,2,3]triazolo[4,5-d]pyrimidine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyrimidine, [1,2,3]triazolo[1,5-a]pyrimidine, [1,2,3]triazolo[1,5-c]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, [1,2,4] Triazolo[1,5 - c]pyrimidine, 6,7 - dihydro - 5H - pyrazolo[5,1 - b][1,3]oxazine, imidazo[2,1 - b][1,3]thiazole, 4H,5H,6H - cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H - imidazo[1,2 - a]pyridine, 7 - oxo - 6H,7H - [1,3]thiazolo[4,5 - d]pyrimidine, [1,3]thiazolo[5,4 - b]pyridine, 2H,3H - imidazo[2,1 - b][1,3]thiazole, thieno[3,2 - d]pyrimidin - 4(3H) - one, 4 - oxo - 4H - thieno[3,2 - d][1,3]thiazine, imidazo[1,2 - a]pyridine, 1H - imidazo[4,5 - b]pyridine, 1H - imidazo[4,5 - c]pyridine, 3H - imidazo[4,5 - c]pyridine, pyrazolo[1,5 - a]pyridine, imidazo[1,2 - a]pyrazine, imidazo[1,2 - a]pyrimidine, 1H - pyrrolo[2,3 - b]pyridine, pyrido[2,3 - b]pyrazine, pyrido[2,3 - b]pyrazin - 3(4H) - one, 4H - thieno[3,2 - b]pyrrole, quinoxalin - 2(1H) - one, 1H - pyrrolo[3,2 - b]pyridine, 7H - pyrrolo[2,3 - d]pyrimidine, oxazolo[5,4 - b]pyridine, thiazolo[5,4 - b]pyridine, thieno[3,2 - c]pyridine, and each definition is a separate embodiment according to the present invention, or A is C, 3 -C 8 cycloalkyl (e.g., cyclohexyl, cyclopentyl), or tetrahydropyran, tetrahydro - 2H - pyran, piperidine, 1 - methylpiperidine, tetrahydrothiophene 1,1 - dioxide, 1 - (piperidin - 1 - yl)ethanone, or morpholine, but not limited to these C 3 -C 8 is a heterocyclic ring. In some embodiments, A is C 3 -C 8 is a heterocyclic ring.

[0111] In some embodiments, when A is phenyl, R 1 and R 2At least one of them is not H, and at least one of n and m is not 0. In various embodiments, the A' ring of formula I(f) is a 5-membered heteroaromatic or heterocyclic ring. In some embodiments, the A' ring of formula I(f) is a 5-membered heteroaromatic ring. In some embodiments, the A' ring of formula I(f) is a 5-membered heterocyclic ring. Non-limiting examples of ring A' are thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1-methylimidazolyl, pyrazolyl, pyrrolyl, furanyl, thiophen-yl, triazolyl, thiadiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl, tetrahydrofuranyl, oxazolonyl, oxazolidinonyl, thiazolonyl, isothiazolinonyl, isoxazolidinonyl, imidazolidinonyl, pyrazolonyl, 2H-pyrrol-2-onyl, furanonyl, pyrrolidine, 2-oxo-pyrrolidine, and thiophenonyl, each representing a separate embodiment according to the present invention.

[0112] In various embodiments, the B ring of Formula I, II, I(a), I(b), I(d), and / or I(e) 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-indazole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazole, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4,5,6,7-tetrahydro-1,3-benzothiazole, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 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-b]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a] pyrimidine, pyrido[2,3-b]pyrazine, or pyrido[2,3-b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, 1,2,3,4-tetrahydroquinoxaline, 1-(pyridin-1(2H)-yl)ethanone, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thieno[3,2-c]pyridine, C, 3 -C 8 cycloalkyl, or tetrahydropyran, piperidine, 1-methylpiperidine, tetrahydrothiophene 1,1-dioxide, thian 1,1-dioxide, 1-(piperidin-1-yl)ethanone, or morpholine, including but not limited to C 3 -C 8 a heterocyclic ring, and each definition is a separate embodiment according to the present invention. In some embodiments, B is C 3 -C 8 a heterocyclic ring. In some embodiments, B is pyrimidine. In some embodiments, B is tetrahydro-2H-pyran. In other embodiments, B is C 3 -C 8 cycloalkyl. In other embodiments, B is cyclopentyl.

[0113] In some embodiments, when B is phenyl, R 3 and R 4 at least one of which is not H, and at least one of k and l is not 0.

[0114] In some embodiments, when A is C 3 -C 8 a heterocyclic ring, and B is C 3 -C 8 cycloalkyl, R 1 , R 2 , R 3 and R 4At least one of them is not H, and at least one of n, m, k, and l is not 0. In some embodiments, A is C 3 -C 8 a heterocyclic ring, and when B is C 3 -C 8 a cycloalkyl, at least one of R 1 and R 2 is not H, and at least one of n and m is not 0. In some embodiments, A is C 3 -C 8 a heterocyclic ring, and when B is C 3 -C 8 a cycloalkyl, at least one of R 3 and R 4 is not H, and at least one of k and l is not 0.

[0115] In some embodiments, when A is C 3 -C 8 a heterocyclic ring and B is 2, 3, or 4-pyridinyl, at least one of R 1 , R 2 , R 3 , and R 4 is not H, and at least one of n, m, k, and l is not 0. In some embodiments, when A is C 3 -C 8 a heterocyclic ring and B is 3-pyridinyl, at least one of R 1 , R 2 , R 3 , and R 4 is not H, and at least one of n, m, k, and l is not 0. In some embodiments, when A is C 3 -C 8 a heterocyclic ring and B is pyridinyl, at least one of R 1 and R 2 is not H, and at least one of n and m is not 0. In some embodiments, when A is C 3 -C 8When it is a complex cyclic ring and B is pyridinyl, R 3 and R 4 at least one of them is not H, and at least one of k and l is not 0.

[0116] In various embodiments, the compounds of formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) are substituted by R 1 , R 2 , R 3 , and R 4 . A single substituent may be present at the ortho, meta, or para position.

[0117] In various embodiments, R 1 and / or R 2 of formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) are each independently H.

[0118] In various embodiments, R 1 and / or R 2 of formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) are each independently 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 heterocyclic ring), CF 3 , CD 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , R 8 -N(R 10 )(R11 )、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 linear 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 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 )、C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5Linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 Heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, each representing a separate embodiment according to the present invention, and the substitutions include F, Cl, Br, I, C 1 -C 5 Linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 Cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof).

[0119] 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 joined together to form a pyrrole ring. In some embodiments, R 1 and R 2 are joined together to form a [1,3]dioxole ring. In some embodiments, R 1 and R 2 are joined together to form a furan-2(3H)-one ring. In some embodiments, R 1 and R 2 are joined together to form a benzene ring. In some embodiments, R 1 and R 2 are joined together to form a pyridine ring. In some embodiments, R 1 and R 2combine together to form a morpholine ring. In some embodiments, R 1 and R 2 combine together to form a piperazine ring. In some embodiments, R 1 and R 2 combine together to form an imidazole ring. In some embodiments, R 1 and R 2 combine together to form a pyrrole ring. In some embodiments, R 1 and R 2 combine together to form a cyclohexene ring. In some embodiments, R 1 and R 2 combine together to form a pyrazine ring.

[0120] In various embodiments, the compounds of Formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) are substituted by R 3 and R 4 . A single substituent may be present at the ortho, meta, or para position.

[0121] In various embodiments, R 3 and R 4 of Formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) are each independently H, F, Cl, Br, I, OH, SH, R 8 -OH, R 8 -SH, -R 8 -O-R 10 , -O-R 8 -R 10 , R 8 -(C 3 -C 8 cycloalkyl), R 8 -(C 3 -C 8 heterocyclic ring), CF 3 , CD 3 , OCD 3 , CN, NO 2 , -CH2 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 linear 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, CH 2 -OCH 2 -CH 2 -O-CH 3 ), C 1 -C 5 linear or branched substituted or unsubstituted alkenyl, C 1 -C 5 linear or branched, or C 3 -C 8 cyclic haloalkyl, substituted or unsubstituted C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy, O-(CH2 ) 2 -O-CH 3 ) and optionally, at least one methylene group (CH 2 ) in the alkoxy is replaced by an oxygen atom, C 1 -C 5 a straight-chain or branched-chain thioalkoxy, C 1 -C 5 a straight-chain or branched-chain haloalkoxy, C 1 -C 5 a straight-chain or branched-chain alkoxyalkyl, a substituted or unsubstituted C 3 -C 8 a cycloalkyl (e.g., cyclopropyl), a substituted or unsubstituted C 3 -C 8 a heterocyclic ring, a substituted or unsubstituted aryl, a substituted or unsubstituted benzyl (substituents include F, Cl, Br, I, C 1 -C 5 a straight-chain or branched-chain alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 a cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof), each representing a separate embodiment of the present invention.

[0122] 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 joined together to form a dioxolane ring [1,3] dioxolane ring. In some embodiments, R3 and R 4 combine together to form a dihydrofuran-2(3H)-one ring. In some embodiments, R 3 and R 4 combine together to form a furan-2(3H)-one ring. In some embodiments, R 3 and R 4 combine together to form a benzene ring. In some embodiments, R 3 and R 4 combine together to form an imidazole ring. In some embodiments, R 3 and R 4 combine together to form a pyridine ring. In some embodiments, R 3 and R 4 combine together to form a pyrrole ring. In some embodiments, R 3 and R 4 combine together to form a cyclohexene ring. In some embodiments, R 3 and R 4 combine together to form a cyclopentene ring. In some embodiments, R 4 and R 3 combine together to form a dioxepin ring.

[0123] In various embodiments, R of the compounds of Formulas I, II, I(a), and I(b) 5 is absent. In other embodiments, R 5 is 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 heterocyclic ring), CF 3 , CD 3 , OCD 3 , CN, NO 2 , -CH2 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 linear 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 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 ), C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in said alkoxy is an oxygen atom, C 1-C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1 -C 5 linear or branched alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 replaced by a heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl, each representing a separate embodiment of the present invention. In some embodiments, the substitution is F, Cl, Br, I, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof, each representing a separate embodiment of the present invention.

[0124] In various embodiments, R 6 and R 7 of the compounds of formula I and / or II are each independently 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 heterocyclic ring), CF 3 , CD 3 , OCD 3 , CN, NO 2 , -CH 2 CN, -R 8 CN, NH 2 , NHR, N(R) 2 , R 8 -N(R10 )(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 linear 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 linear or branched, or C 3 -C 8 cyclic haloalkyl (e.g., CHF 2 )、C 1 -C 5 linear or branched, or C 3 -C 8 cyclic alkoxy (e.g., methoxy), and optionally, at least one methylene group (CH 2 ) in the alkoxy is an oxygen atom, C 1 -C 5 linear or branched thioalkoxy, C 1 -C 5 linear or branched haloalkoxy, C 1-C 5 a straight-chain or branched-chain alkoxyalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted C 3 -C 8 replaced by a heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl, each representing a separate embodiment of the present invention. In various embodiments, the substitution includes F, Cl, Br, I, C 1 -C 5 a straight-chain or branched-chain alkyl, OH, alkoxy, N(R) 2 、CF 3 、aryl, phenyl, heteroaryl, C 3 -C 8 cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 、or any combination thereof, each representing a separate embodiment of the present invention.

[0125] In various embodiments, n of the compounds of Formula I, II, I(a), and / or I(f) is 0. In some embodiments, n is 0 or 1. In some embodiments, n is 1 to 3. In some embodiments, n is 1 to 4. In some embodiments, n is 0 to 2. In some embodiments, n is 0 to 3. In some embodiments, n is 0 to 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0126] In various embodiments, m of the compounds of formula I, II, I(a), and / or I(f) is 0. In some embodiments, m is 0 or 1. In some embodiments, m is 1 to 3. In some embodiments, m is 1 to 4. In some embodiments, m is 0 to 2. In some embodiments, m is 0 to 3. In some embodiments, m is 0 to 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0127] In various embodiments, l of the compounds of formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) is 0. In some embodiments, l is 0 or 1. In some embodiments, l is 1 to 3. In some embodiments, l is 1 to 4. In some embodiments, l is 1 or 2. In some embodiments, l is 0 to 3. In some embodiments, l is 0 to 4. In some embodiments, l is 1. In some embodiments, l is 2. In some embodiments, l is 3. In some embodiments, l is 4.

[0128] In various embodiments, k of the compounds of formula I, II, and I(a) is 0. In some embodiments, k is 0 or 1. In some embodiments, k is 1 to 3. In some embodiments, k is 1 to 4. In some embodiments, k is 0 to 2. In some embodiments, k is 0 to 3. In some embodiments, k is 0 to 4. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4.

[0129] Regarding the complex cyclic ring, it should be understood that n, m, l, and / or k are limited to the number of available positions for substitution, that is, the number obtained by subtracting 1 from the number of CH or NH groups. Thus, when the A and / or B ring is, for example, furanyl, thiophenyl, or pyrrolyl, n, m, l, and k are 0 to 2, and when the A and / or B ring is, for example, oxazolyl, imidazolyl, or thiazolyl, n, m, l, and k are either 0 or 1, and when the A and / or B ring is, for example, oxadiazolyl or thiadiazolyl, n, m, l, and k are 0.

[0130] In various embodiments, each R of the compounds of formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) 8 is independently CH 2 In some embodiments, R 8 is CH 2 CH 2 In some embodiments, R 8 is CH 2 CH 2 CH 2 In some embodiments, R 8 is CH 2 CH 2 CH 2 CH 2 In some embodiments, R

[0131] In various embodiments, p of the compounds of formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 1 to 3. In some embodiments, p is 1 to 5. In some embodiments, p is 1 to 10.

[0132] In some embodiments, R of the compounds of Formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) 9 is C≡C. In some embodiments, R 9 is C≡C-C≡C. In some embodiments, R 9 is CH=CH. In some embodiments, R 9 is CH=CH-CH=CH.

[0133] In some embodiments, q of the compounds of Formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) is 2. In some embodiments, q is 4. In some embodiments, q is 6. In some embodiments, q is 8. In some embodiments, q is from 2 to 6.

[0134] In various embodiments, R of the compounds of Formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) 10 is H. In some embodiments, R 10 is C 1 -C 5 a straight-chain 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 10is 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 C(O)R. In some embodiments, R 10 is S(O) 2 R.

[0135] In various embodiments, R of the compounds of Formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) 11 is H. In some embodiments, R 11 is C 1 -C 5 is a straight or branched chain alkyl. In some embodiments, R 11 is methyl. In some embodiments, R 11 is ethyl. In some embodiments, R 10 is propyl. In some embodiments, R 11 is isopropyl. In some embodiments, R 11 is butyl. In some embodiments, R 11 is isobutyl. In some embodiments, R 11 is t-butyl. In some embodiments, R 11 is cyclopropyl. In some embodiments, R 11 is pentyl. In some embodiments, R 11 is isopentyl. In some embodiments, R 11 is neopentyl. In some embodiments, R 11 is benzyl. In some embodiments, R 11 is C(O)R. In some embodiments, R 11 is S(O) 2 R.

[0136] In some embodiments, R of formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) 10 and R 11 are joined to form a substituted or unsubstituted C 3 -C 8 heterocyclic ring. In other embodiments, R 10 and R 11 are joined to form a piperazine ring. In other embodiments, R 10 and R 11 are joined to form a piperidine ring. In some embodiments, substitutions include F, Cl, Br, I, OH, C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched alkyl-OH (e.g., C(CH 3 )) 2 CH 2 -OH, CH 2 CH 2 -OH), C 3 -C 8 heterocyclic ring (e.g., piperidine), alkoxy, N(R) 2 , CF 3 , aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO 2 , or any combination thereof, each representing a separate embodiment of the present invention.

[0137] In various embodiments, R of the compounds of formula I(d), I(d(i)), I(e), and / or I(e(i)) 12 is H. In other embodiments, R 12 is F. In other embodiments, R 12 is Cl. In other embodiments, R 12 is Br. In other embodiments, R 12 is I. In other embodiments, R 12 is OH. In other embodiments, R 12is SH. In other embodiments, R 12 is N(R) 2 In other embodiments, R 12 is CF 3 In other embodiments, R 12 is CN. In other embodiments, R 12 is NO 2 In other embodiments, R 12 is C 1 -C 5 is a straight-chain or branched-chain alkyl. In other embodiments, R 12 is methyl. In other embodiments, R 12 is ethyl. In other embodiments, R 12 is CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 In other embodiments, R 12 is CH 2 -O-CH 2 -CH 2 -O-CH 3 In other embodiments, R 12 is C 1 -C 5 is a straight-chain or branched-chain alkoxy. In other embodiments, R 12 is C 1 -C 5 is a straight-chain or branched-chain haloalkyl. In other embodiments, R 12 is CHF 2 In other embodiments, R 12 is CF 3 In other embodiments, R 12 is CF 2 CH 3 In other embodiments, R 12 is CH 2 CF 3 CF 2 CH 2 CH 3 In other embodiments, R 12 is CH 2 CH 2CF 3 、CF 2 CH(CH 3 ) 2 is. In other embodiments, R 12 is CF(CH 3 )-CH(CH 3 ) 2 is. In other embodiments, R 12 is C 3 -C 8 substituted or unsubstituted cycloalkyl. In other embodiments, R 12 is cyclopropyl. In other embodiments, R 12 is F, Cl, Br, I, OH, SH, C 1 -C 5 linear or branched alkyl, OH, alkoxy, N(R) 2 , CF 3 , phenyl, halophenyl, CN, and NO 2 can be further substituted by at least one selected from.

[0138] In various embodiments, R of the compounds of Formula I, II, I(a), I(b), I(c), I(d), I(d(i)), I(e), I(e(i)), and / or I(f) is H. In other embodiments, R is F. In other embodiments, R is Cl. In other embodiments, R is Br. In other embodiments, R is I. In other embodiments, R is OH. In other embodiments, R is SH. In other embodiments, R is OH. In other embodiments, R is alkoxy. In other embodiments, R is N(R) 2 . In other embodiments, R is CF 3 . In other embodiments, R is CN. In other embodiments, R is NO 2 . In other embodiments, R is C 1 -C 5 linear or branched alkyl. In other embodiments, R is methyl. In other embodiments, R is ethyl. In other embodiments, R is CH 2 -CH2 -O-CH 2 -CH 2 -O-CH 3 is. In other embodiments, R is CH 2 -O-CH 2 -CH 2 -O-CH 3 is. In other embodiments, R is C 1 -C 5 is a linear or branched alkoxy. In other embodiments, R is C 1 -C 5 is a linear or branched haloalkyl. In other embodiments, R is CHF 2 is. 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 , CF 2 CH 2 CH 3 is. In other embodiments, R is CH 2 CH 2 CF 3 , 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 R 8 -aryl. In other embodiments, R is CH 2 -Ph. In other embodiments, R is -R 8 -O-R 8 -O-R 10 is. In other embodiments, R is (CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 ). In other embodiments, R is -R 8 -O-R 10 is. In other embodiments, R is -R 8 -R 10is. In other embodiments, R is (CH 2 ) 2 -O-CH 3 is. In other embodiments, R is C 1 -C 5 is a straight-chain or branched-chain alkoxy. In other embodiments, R is phenyl. In other embodiments, R is aryl. In other embodiments, R is heteroaryl. In other embodiments, two gem R substituents are joined together to form a 5- or 6-membered heterocyclic ring.

[0139] In various embodiments, Q of the compounds of Formulas I, II, I(a), and I(b) 1 is NH. In other embodiments, Q 1 is NR. In other embodiments, Q 1 is N-CH 3 is. In other embodiments, Q 1 is N-(CH 2 ) 2 -O-CH 3 is. In other embodiments, Q 1 is N-(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 is. In other embodiments, Q 1 is O. In other embodiments, Q 1 is S. In other embodiments, Q 1 is N-OH. In other embodiments, Q 1 is N-OMe.

[0140] In various embodiments, Q of the compounds of Formulas I, II, I(a), I(b), and I(c) 2 is N. In other embodiments, Q 2 is C(R). In other embodiments, Q 2 is C-CH 3 is. In other embodiments, Q 2 is C-CHF 2It is. In other embodiments, Q 2 is C-CF 3 It is. In other embodiments, Q 2 is C-CN. In other embodiments, Q 2 is C-Cl. In other embodiments, Q 2 is C-CH 2 -O-CH 2 -CH 2 -O-CH 3 It is. In other embodiments, Q 2 is C-C-.

[0141] In some embodiments, X of the compound of formula I-I(c) or II 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , and / or X 15 each is independently C. In other embodiments, N.

[0142] In some embodiments, X 1 ~X 5 at least one of is N. In some embodiments, X 1 ~X 5 at least two of are N. In some embodiments, X 9 ~X 13 at least one of is N. If any of X 1 ~X 13 is N, it should be understood that any of R 1 ~R 3 cannot be attached thereto.

[0143] In various embodiments, G=X of the compounds of Formulas I, II, I(a), and I(b) 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 In other embodiments, G=X is CH 2 In other embodiments, G=X is CHR. In other embodiments, G=X is C(R) 2is as follows. As used herein, "a single or fused aromatic or heteroaromatic ring system" means 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-benzoxazole, 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, isobenzofuranyl, benzofuran-2(3H)-one, benzothiophenyl, benzoxadiazole, benz[c][1,2,5]oxadiazolyl, benz[c]thiophenyl, benzodioxolyl, thiadiazolyl, [1,3]oxazolo[4,5-b]pyridine, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl, imidazo[2,1-b][1,3]thiazole, 4H,5H,6H-cyclopenta[d][1,3]thiazole, 5H,6H,7H,8H-imidazo[1,2-a]pyridine, 7-oxo-6H,7H-[1,3]thiazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2,1-b][1,3]thiazole, thieno[3,2-d]pyrimidin-4(3H)-one, 4-oxo-4H-thieno[3,2-d][1,3] Thiazine, imidazo[1,2-a]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-imidazo[4,5-c]pyridine, 3H-imidazo[4,5-c]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrido[2,3-b]pyrazine, pyrido[2,3-b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(1H)-one, 1H-pyrrolo[3,2-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thieno[3,2-c]pyridine, 3-methyl-4H-1,2,4-triazole, 5-methyl-1,2,4-oxadiazole, and the like, and can be any such ring, including but not limited to these.,

[0144] As used herein, the term "alkyl" can be any straight-chain or branched-chain alkyl group containing up to about 30 carbons, unless otherwise specified. In various embodiments, alkyl is C 1 -C 5 containing carbon. In some embodiments, alkyl is C 1 -C 6 containing carbon. In some embodiments, alkyl is C 1 -C 8 containing carbon. In some embodiments, alkyl is C 1 -C 10 containing carbon. In some embodiments, alkyl is C 1 -C 12 carbon. In some embodiments, alkyl is C 1 -C 20 carbon. In some embodiments, branched-chain alkyl is alkyl substituted with an alkyl side chain of 1 to 5 carbons. In various embodiments, the alkyl group can be unsubstituted. In some embodiments, the alkyl group is halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amide, alkylamide, dialkylamide, cyano, nitro, CO 2H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C 1 -C 5 a straight-chain 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 may be substituted by any combination thereof.

[0145] The alkyl group can be a single substituent or can be a component of larger substituents such as alkoxy, alkoxyalkyl, haloalkyl, arylalkyl, alkylamino, dialkylamino, alkylamide, alkylurea, etc. Preferred alkyl groups are methyl, ethyl, and propyl, and thus halomethyl, dichloromethyl, trichloromethyl, haloethyl, dichloroethyl, trichloroethyl, halopropyl, dichloropropyl, trichloropropyl, methoxy, ethoxy, propoxy, arylmethyl, arylethyl, arylpropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylamide, acetamide, propylamide, halomethylamide, haloethylamide, halopropylamide, methylurea, ethylurea, propylurea, 2, 3, or 4-CH 2 -C 6 H 4 -Cl, C(OH)(CH 3 )(Ph), etc.

[0146] 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 a single substituent or a component of a larger substituent such as arylalkyl, arylamino, arylamide, etc. In some embodiments, the term aryl according to the present invention also includes heteroaryl. 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, phenylamide, 3-methyl-4H-1,2,4-triazolyl, oxadiazolyl, 5-methyl-1,2,4-oxadiazolyl, isothiazolyl, thiadiazolyl, triazolyl, etc. Substituents include F, Cl, Br, I, C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 5 linear or branched alkoxy, C 1 -C 5 linear or branched haloalkoxy, CF 3 , phenyl, halophenyl, 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 any combination thereof, but not limited thereto.

[0147] As used herein, the term "alkoxy" refers to an ether group substituted by an alkyl group as defined above. Alkoxy refers to both straight-chain alkoxy groups and branched-chain alkoxy groups. Non-limiting examples of alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy.

[0148] As used herein, the term "aminoalkyl" refers to an amine group substituted by an alkyl group as defined above. Aminoalkyl refers to monoalkylamine, dialkylamine, or trialkylamine. Non-limiting examples of aminoalkyl groups are -N(Me) 2 , -NHMe, -NH 3 .

[0149] In some embodiments, a "haloalkyl" group refers to an alkyl group as defined above substituted by one or more halogen atoms, for example, F, Cl, Br, or I. The term "haloalkyl" includes, but is not limited to, fluoroalkyl, i.e., an alkyl group having at least one fluorine atom. Non-limiting examples of haloalkyl groups are 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 , and CF(CH 3 )-CH(CH 3 ) 2 .

[0150] The "halophenyl" group, in some embodiments, refers to a phenyl substituent substituted by one or more halogen atoms, such as F, Cl, Br, or I. In one embodiment, the halophenyl is 4-chlorophenyl.

[0151] The "alkoxyalkyl" group, in some embodiments, refers to an alkyl group as defined above substituted by an alkoxy group as defined above, such as methoxy, ethoxy, propoxy, i-propoxy, t-butoxy, etc. Non-limiting examples of alkoxyalkyl groups are -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 and so on.

[0152] The "cycloalkyl" or "carbocyclic" group, in various embodiments, refers to a ring structure containing carbon atoms as ring atoms, which can be saturated or unsaturated, substituted or unsubstituted, single or fused. In some embodiments, the cycloalkyl is a 3- to 10-membered ring. In some embodiments, the cycloalkyl is a 3- to 12-membered ring. In some embodiments, the cycloalkyl is a 6-membered ring. In some embodiments, the cycloalkyl is a 5- to 7-membered ring. In some embodiments, the cycloalkyl is a 3- to 8-membered ring. In some embodiments, the cycloalkyl group is halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amide, alkylamide, dialkylamide, cyano, nitro, CO 2H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C 1 -C 5 linear or branched 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 can be unsubstituted or substituted by any combination thereof. In some embodiments, the cycloalkyl ring can be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3- to 8-membered ring. In some embodiments, the cycloalkyl ring is a saturated ring. In some embodiments, the cycloalkyl ring is an unsaturated ring. Non-limiting examples of cycloalkyl groups include cyclohexyl, cyclohexenyl, cyclopropyl, cyclopropenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclobutyl, cyclobutenyl, cyclooctyl, cyclooctadienyl (COD), cyclooctatriene (COE), and the like.

[0153] A "heterocycle" or "heterocyclic" group, in various embodiments, refers to a ring structure that, as part of the ring, includes sulfur, oxygen, nitrogen, or any combination thereof in addition to carbon atoms. A "heteroaromatic ring" refers, in various embodiments, to an aromatic ring structure that, as part of the ring, includes sulfur, oxygen, nitrogen, or any combination thereof in addition to carbon atoms. In some embodiments, the heterocycle or heteroaromatic ring is a 3- to 10-membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3- to 12-membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 6-membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 5- to 7-membered ring. In some embodiments, the heterocycle or heteroaromatic ring is a 3- to 8-membered ring. In some embodiments, the heterocyclic group or heteroaromatic ring is halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amide, alkylamide, dialkylamide, cyano, nitro, CO 2 H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C 1 -C 5 a 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 2It may be unsubstituted or substituted by or any combination of these. In some embodiments, the heterocyclic ring or heteroaromatic ring may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3- to 8-membered ring. In some embodiments, the heterocyclic ring is a saturated ring. In some embodiments, the heterocyclic ring is an unsaturated ring. Non-limiting examples of heterocyclic rings or heteroaromatic ring systems include pyridine, piperidine, morpholine, piperazine, thiophene, pyrrole, benzodioxole, benzofuran-2(3H)-one, benzo[d][1,3]dioxole, indole, oxazole, isoxazole, imidazole, and 1-methylimidazole, furan, triazole, pyrimidine, pyrazine, oxacyclobutane (1- or 2-oxacyclobutane), naphthalene, tetrahydrothiophene 1,1-dioxide, thiazole, benzimidazole, piperidine, 1-methylpiperidine, isoquinoline, 1,3-dihydroisobenzofuran, benzofuran, 3-methyl-4H-1,2,4-triazole, oxadiazole, 5-methyl-1,2-oxadiazole, pyrazole, isothiazole, thiadiazole, tetrahydrofurazone, oxazolone, oxazolidone, thiazolone, isothiazolinone, isoxazolidinone, imidazolidinone, pyrazolone, 2H-pyrrol-2-one, furanone, thiophenone, thianone 1,1-dioxide, triazolopyrimidine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, or indole.

[0154] In various embodiments, the present invention provides a compound of the present invention, or an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (including but not limited to deuterated analog), PROTAC, polymorph, or crystal thereof, or a combination thereof. In various embodiments, the present invention provides an isomer of a compound of the present invention. In some embodiments, the present invention provides a metabolite of a compound of the present invention. In some embodiments, the present invention provides a pharmaceutically acceptable salt of a compound of the present invention. In some embodiments, the present invention provides a pharmaceutical product of a compound of the present invention. In some embodiments, the present invention provides a tautomer of a compound of the present invention. In some embodiments, the present invention provides a hydrate of a compound of the present invention. In some embodiments, the present invention provides an N-oxide of a compound of the present invention. In some embodiments, the present invention provides a reverse amide analog of a compound of the present invention. In some embodiments, the present invention provides a prodrug of a compound of the present invention. In some embodiments, the present invention provides an isotope variant (including but not limited to deuterated analog) of a compound of the present invention. In some embodiments, the present invention provides a PROTAC (proteolysis targeting chimera) of a compound of the present invention. In some embodiments, the present invention provides a polymorph of a compound of the present invention. In some embodiments, the present invention provides a crystal of a compound of the present invention. In some embodiments, the present invention provides a composition comprising a compound of the present invention described herein, or in some embodiments, an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotope variant (including but not limited to deuterated analog), PROTAC, polymorph, or crystal of a compound of the present invention, or a combination thereof.

[0155] In various embodiments, the term "isomer" includes, but is not limited to, stereoisomers such as optical isomers and analogs, structural isomers and analogs, and stereoisomers and analogs. In some embodiments, the isomer is a stereoisomer. In another embodiment, the isomer is an optical isomer.

[0156] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, R- and S-enantiomers, diastereomers, their racemic mixtures, and other mixtures thereof, as being within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, and mixtures thereof, are included in the present invention.

[0157] In various embodiments, the present invention encompasses the use of various stereoisomers of the compounds of the present invention. It will be understood by those skilled in the art that the compounds of the present invention may contain at least one chiral center. Thus, the compounds used in the methods of the present invention exist in optically active or racemic forms and may be isolated. Compounds according to the present invention may further exist as stereoisomers, enantiomerically enriched mixtures, racemic mixtures, or single diastereomers, diastereomer mixtures, or (R)(R), (R)(S), (S)(S), (S)(R), (R)(R)(R), (R)(R)(S), (R)(S)(R), (S)(R)(R), (R)(S)(S), (S)(R)(S), (S)(S)(R), or (S)(S)(S) stereoisomers, which may be, for example, enantiomers such as (R) or (S), but are not limited thereto. Some compounds may also exhibit polymorphism. It should be understood that the present invention encompasses any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, having properties useful for the treatment of the various conditions described herein.

[0158] In various embodiments, compounds 132 and 134 are stereoisomers. In various embodiments, compounds 132 and 134 are optical isomers. In one embodiment, compounds 132 and 134 are enantiomers. In one embodiment, compounds 132 and 134 are optically active. In one embodiment, compound 132 is a different enantiomer from compound 134. In one embodiment, compound 132 is the R isomer and compound 134 is the S isomer. In another embodiment, compound 132 is the S isomer and compound 134 is the R isomer. In one embodiment, the * on the piperidine carbon of compounds 132 and 134 represents a chiral center, and in some embodiments, the chiral center refers to the R isomer of the R isomer of compound 132 and the S isomer of compound 134, and in other embodiments, the S isomer of compound 132 and the R isomer of compound 134. The chiral center of compound 132 can be either in the R configuration or the S configuration as long as the corresponding chiral centers in compound 134 are in the S configuration or the R configuration, respectively.

[0159] Methods for preparing the optically active forms (e.g., by resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) are well known in the art.

[0160] The compounds of the invention can also exist in the form of racemic mixtures containing substantially equivalent amounts of stereoisomers. In some embodiments, the compounds of the invention can be prepared or otherwise isolated using known procedures to obtain stereoisomers that are substantially free (i.e., substantially pure) of their corresponding stereoisomers. By being substantially pure, the stereoisomers are intended to be at least about 95% pure, more preferably at least about 98% pure, and most preferably at least about 99% pure.

[0161] The compounds of the present invention may also be in the form of hydrates, which means that the compounds further contain a stoichiometric or non-stoichiometric amount of water that is bound by non-covalent intermolecular forces.

[0162] As used herein, when some chemical functional groups (e.g., alkyl or aryl) are said to be "substituted", it is defined herein that one or more substitutions are possible.

[0163] The compounds of the present invention may exist in one or more forms of the possible tautomers, and depending on the conditions, it may be possible to separate some or all of the tautomers into individual different entities. It should be understood that all possible tautomers, including all additional enol and keto tautomers and / or isomers, are encompassed herein. For example, but not limited to, the following tautomers are included:

[0164]

Chemical formula

[0165] Tautomerism of the pyrazolone ring:

[0166]

Chemical formula

[0167] The present invention includes "pharmaceutically acceptable salts" of the compounds of the present invention, which can be produced by the reaction of the compounds of the present invention with an acid or a base. Certain compounds, particularly those having an acidic or basic group, may also be in the form of salts, preferably pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the free base or free acid and are not undesirable in a biological or other respect. Salts are formed by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. Other salts are known to those skilled in the art and can be readily adapted for use in accordance with the present invention.

[0168] Suitable pharmaceutically acceptable salts of the amines of the compounds of the present invention can be prepared from inorganic acids or from organic acids. In various embodiments, examples of inorganic salts of amines are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromides, hydrochlorides, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphates, sulfates, sulfaminates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen-substituted alkylsulfonates, halogen-substituted arylsulfonates), sulfonates, and thiocyanates.

[0169] In various embodiments, examples of organic salts of amines can be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxyl, and sulfone classes of organic acids, and examples include acetate, arginine, aspartate, ascorbate, adipate, anthranilate, alginate, alkane carboxylate, substituted alkane carboxylate, alginate, benzenesulfonate, benzoate, bisulfate, butyrate, bicarbonate, bitartrate, carboxylate, citrate, camphorate, camphorsulfonate, cyclohexylsulfamate, cyclopentanepropionate, calcium edetate, cantharate, carbonate, clubranate, cinnamate, dicarboxylate, digluconate, dodecylsulfonate, dihydrochloride, decanoate, enanthate, ethanesulfonate, edetate, edisylic acid, estolate, esylate, fumarate, formate, fluoride, galacturonate, gluconate, glutamate, glycolate, gluconate, glucoheptanoate, glycerophosphate, gluceptate, glycolylarsanyl acid, glutarate, glutamate, heptanoate, hexanoate, hydroxymaleate, hydroxycarboxylic acid, hexylresorcinate, hydroxybenzoate, hydroxynaphthoate, hydrofluoric acid salt, lactate, lactobionate, laurate, malate, maleate, methylene bis(β - oxynaphthoate), malonate, mandelate, mesylate, methanesulfonate, methyl bromide, methyl nitrate, methylsulfonate, monopotassium maleate, mucate, monocarboxylate, nitrate, naphthalenesulfonate, 2 - naphthalenesulfonate, nicotinate, napsylate, N - methylglucamine, oxalate, octanoate, oleate, pamoate, phenylacetate, picrate, phenylbenzoate, pivalate, propionate, phthalate, pectinate, phenylpropionate, palmitate, pantothenate, polygalacturonate, pyruvate, quinate, salicylate, succinate, stearate, sulfanilate, basic acetate, tartrate, theophylline acetate, p - toluenesulfonate (tosylate), trifluoroacetate, terephthalate, tannate, theocurate, trihaloacetate, triethiodide,They are tricarboxylates, undecanoates, and valerates.

[0170] In various embodiments, examples of inorganic salts of carboxylic acids or hydroxyls can be selected from ammonium, lithium, sodium, potassium, alkali metals including cesium, alkaline earth metals including calcium, magnesium, aluminum, zinc, barium, choline, and quaternary ammonium.

[0171] In some embodiments, examples of organic salts of carboxylic acids or hydroxyls can be selected from arginine, aliphatic organic amines, alicyclic organic amines, organic amines including aromatic organic amines, benzathine, t-butylamine, ventamine (N-benzylphenethylamine), dicyclohexylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, hydrabamine, imidazole, lysine, methylamine, meglumine, N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, nicotinamine, organic amines, ornithine, pyridine, picolies, piperazine, procaine, tris(hydroxymethyl)methylamine, triethylamine, triethanolamine, trimethylamine, tromethamine, and urea.

[0172] In various embodiments, the salt can be formed by reacting a product in the form of a free base or free acid with one equivalent or more of a suitable acid or base by conventional means, for example, in a solvent or a medium in which the salt is insoluble, or in a solvent such as water, and then removing the solvent or medium by vacuum or freeze-drying, or by exchanging the ions of the existing salt with other ions, or by a suitable ion exchange resin.

[0173] Pharmaceutical composition Another aspect of the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to an aspect of the present invention. The pharmaceutical composition can contain one or more of the above-described compounds of the present invention. Typically, the pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to any suitable adjuvant, carrier, excipient, or stabilizer and can be in solid or liquid form such as tablets, capsules, powders, solutions, suspensions, or emulsions.

[0174] Typically, the composition contains from about 0.01 to 99 percent, preferably from about 20 to 75 percent, of the active compound, together with adjuvants, carriers, and / or excipients. Although the individual requirements can vary, the determination of the optimal range of the effective amounts of each component is within the skill of the art. Typical dosages include from about 0.01 to about 100 mg / kg body weight. Preferred dosages include from about 0.1 to about 100 mg / kg body weight. Most preferred dosages include from about 1 to about 100 mg / kg body weight. The therapeutic regimen for administration of the compounds of the present invention can also be readily determined by those skilled in the art. That is, the frequency of administration and the size of the dosage can preferably be established by routine optimization while minimizing any side effects.

[0175] Solid unit dosage forms can be of conventional types. The solid form can be, for example, capsules of the usual gelatin type containing the compound of the present invention, a carrier such as a lubricant, and an inert filler such as lactose, sucrose, or corn starch. In some embodiments, these compounds are tabletted in combination with a conventional tablet base such as lactose, sucrose, or corn starch, a binder such as acacia, corn starch, or gelatin, a disintegrant such as corn starch, potato starch, or alginic acid, and a lubricant such as stearic acid or magnesium stearate.

[0176] Tablets, capsules, etc. may also contain binders such as tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it may contain a liquid carrier such as fatty oil in addition to the materials of the above types.

[0177] Various other materials may be present as coating agents or to improve the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. Syrups may contain, in addition to the active ingredient, sucrose as a sweetener, methyl and propyl parabens as preservatives, dyes, and flavoring agents such as cherry or orange flavor.

[0178] In the case of oral therapeutic administration, these active compounds can incorporate excipients and can be used in the form of tablets, capsules, elixirs, suspensions, syrups, etc. Such compositions and preparations must contain at least 0.1% of the active compound. The percentage of the compound in these compositions can of course vary and can conveniently be about 2 to about 60% by weight of the unit. The amount of the active compound in such therapeutically useful compositions is such as to obtain a suitable dosage. Preferred compositions according to the invention are prepared such that the oral dosage unit contains about 1 mg to 800 mg of the active compound.

[0179] The active compounds of the present invention can be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they can be enclosed in hard or soft capsules, or they can be compressed into tablets, or they can be directly incorporated into the food in the diet.

[0180] Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy injectability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0181] The compounds or pharmaceutical compositions of the present invention can also be administered in injectable dosages by solutions or suspensions of these materials in a physiologically acceptable diluent with pharmaceutical adjuvants, carriers, or excipients. Such adjuvants, carriers, and / or excipients include, but are not limited to, sterile liquids such as water and oils, with or without the addition of surfactants and other pharmaceutically and physiologically acceptable components. Exemplary oils are of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, or mineral oil. In general, water, saline, dextrose aqueous solutions and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly in the case of injectable solutions.

[0182] These active compounds can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water and, if appropriate, mixed with surfactants such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oils. Exemplary oils are those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, especially for injectable solutions. Under normal storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms.

[0183] When used as an aerosol, the compounds of the invention in solution or suspension can be packaged in a pressurized aerosol container together with a suitable propellant, such as a hydrocarbon propellant like propane, butane, or isobutane containing conventional adjuvants. The materials of the invention can also be administered in a non-pressurized form, such as a nebulizer or atomizer.

[0184] In various embodiments, the compounds of the invention are administered in combination with an agent for treating fibrosis. In some embodiments, the agent for treating pulmonary fibrosis is at least one selected from pirfenidone and nintedanib. Other examples of agents that may be useful in treating pulmonary fibrosis, including IPF, in combination with the compounds of the invention include, but are not limited to, pioglitazone, tralokinumab, lebrikizumab, FG-3019, simtuzumab, STX-100, BMS-986020, rituximab, carbon monoxide, azithromycin, and cotrimoxazole. In various embodiments, the compounds of the invention are administered in combination with an agent for treating NASH.

[0185] When administering the compounds of the present invention, they can be administered systemically or, alternatively, directly to the specific site where fibrosis is present. Thus, administration can be achieved by any method effective to deliver the compound or pharmaceutical composition to the fibrotic cells. Exemplary modes of administration include, but are not limited to, oral administration, topical administration, transdermal administration, parenteral administration, subcutaneous administration, intravenous administration, intramuscular administration, intraperitoneal administration, intranasal, intrathoracic or intravesical instillation, intraocular administration, intraarterial administration, intralesional administration, or application to mucous membranes such as the nose, throat, and bronchus.

[0186] Biological activity In various embodiments, the present invention provides compounds and compositions comprising any of the embodiments described herein for use in any of the methods of the present invention. In various embodiments, the use of the compounds of the present invention or compositions containing them has utility in inhibiting, suppressing, enhancing, or stimulating a desired response in a subject, as will be understood by those skilled in the art. In some embodiments, the composition may further comprise additional active ingredients whose activity is useful for the particular use for which the compound of the present invention is administered.

[0187] The present invention relates to the treatment, inhibition, and reduction of fibrosis, including pulmonary and hepatic fibrosis. More specifically, embodiments of the present invention provide compositions and methods useful for the treatment and inhibition of fibrotic diseases, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), non-alcoholic fatty liver disease (NAFLD), and hepatic fibrosis associated with non-alcoholic steatohepatitis (NASH), using the use of a compound according to the present invention or a pharmaceutically acceptable salt thereof. In another embodiment, the human subject is suffering from pulmonary fibrosis. In another embodiment, the human subject is suffering from idiopathic pulmonary fibrosis (IPF). In another embodiment, the human subject is suffering from non-alcoholic fatty liver disease (NAFLD). In another embodiment, the human subject is suffering from non-alcoholic steatohepatitis (NASH). In another embodiment, the human subject is not suffering from non-alcoholic steatohepatitis (NASH).

[0188] Under various conditions, the formation of fibrous tissue is characterized by an abnormally large amount of collagen deposition. Collagen synthesis is also involved in several other pathological conditions. Clinical conditions and disorders associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, and autoimmune disorders, are distinguished by the excessive production of connective tissue that results in the disruption of normal tissue structure and function. These diseases can best be interpreted from the perspective of a disturbance in cellular function, the primary symptom of which is excessive collagen synthesis and deposition. The role of collagen in fibrosis has prompted attempts to develop drugs that inhibit its accumulation.

[0189] Excessive collagen accumulation is a major pathological feature in various clinical conditions characterized by tissue fibrosis. These conditions include, for example, localized processes such as pulmonary fibrosis and cirrhosis of the liver, or more general processes such as progressive systemic sclerosis. Collagen deposition is a feature of different forms of skin fibrosis, including scleroderma, localized and systemic localized scleroderma, keloids, hypertrophic scars, familial cutaneous collagenoma, and collagen-type connective tissue nevi, in addition to scleroderma. Recent advances in the understanding of the normal biochemistry of collagen have made it possible to define specific levels of collagen biosynthesis and degradation at which pharmacological intervention could lead to a reduction in collagen deposition within tissues. Such compounds could provide novel means for reducing the excessive accumulation of collagen in diseases.

[0190] Accordingly, in various embodiments, the present invention is a method of treating fibrosis in a subject, suppressing it, reducing its severity, reducing its risk of onset, or inhibiting it, the method comprising administering a compound according to the present invention to a subject suffering from fibrosis under conditions effective to treat fibrosis in the subject, suppress it, reduce its severity, reduce its risk of onset, or inhibit it. In some embodiments, the fibrosis is systemic. In some embodiments, the fibrosis is organ-specific. In some embodiments, the fibrosis is a result of wound healing. In some embodiments, the fibrosis is a result of scarring. In some embodiments, the fibrosis is primary or secondary fibrosis. In some embodiments, the fibrosis is a result of systemic sclerosis, progressive systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, an autoimmune disease, or any combination thereof, each representing a separate embodiment according to the present invention. In another embodiment, the human subject is suffering from pulmonary fibrosis. In another embodiment, the human subject is suffering from idiopathic pulmonary fibrosis (IPF). In some embodiments, the fibrosis is pulmonary fibrosis. In some embodiments, the subject has cirrhosis. In some embodiments, the fibrosis is hepatic fibrosis, pulmonary fibrosis, or dermal fibrosis. In some embodiments, the dermal fibrosis is scleroderma. In some embodiments, the dermal fibrosis is a result of localized or generalized localized scleroderma, keloid, hypertrophic scar, familial cutaneous collagenoma, connective tissue nevus of that collagen type, or any combination thereof, each representing a separate embodiment according to the present invention. In some embodiments, the fibrosis is caused by tissue injury, inflammation, oxidative stress, or any combination thereof, each representing a separate embodiment according to the present invention. In some embodiments, the fibrosis is gingival fibromatosis. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, each compound representing a separate embodiment according to the present invention.

[0191] Human fibrotic diseases are a major health problem worldwide due to the large number of affected individuals, incomplete knowledge of the causes of the fibrogenic process, marked heterogeneity in their etiologies and clinical symptoms, lack of appropriate and well-validated biomarkers, and most importantly, the absence of current effective disease-modifying therapeutics. Fibrotic diseases encompass a wide range of clinical entities, including systemic fibrotic diseases such as systemic sclerosis (SSc), sclerodermatous graft-versus-host disease, and nephrogenic systemic fibrosis, as well as radiation-induced fibrosis and numerous organ-specific diseases including cardiac, pulmonary, hepatic, and renal fibrosis. The etiological mechanisms of these diseases are quite diverse and in some cases remain elusive, but these diseases share the common feature that they are uncontrolled and there is progressive accumulation of fibrous tissue in the affected organs, leading to their dysfunction and ultimate failure. Despite the marked heterogeneity in the etiological mechanisms involved in the development of fibrotic diseases and their clinical symptoms, many studies have identified activated myofibroblasts as a common cellular element that ultimately participates in the replacement of normal tissue with non-functional fibrous tissue.

[0192] In various embodiments, the present invention is a method of treating, suppressing, reducing the severity of, reducing the risk of onset of, or inhibiting a systemic fibrotic disease in a subject, the method comprising administering a compound according to the present invention to a subject suffering from a systemic fibrotic disease under conditions effective to treat, suppress, reduce the severity of, reduce the risk of onset of, or inhibit the systemic fibrotic disease in the subject. In some embodiments, the systemic fibrotic disease is systemic sclerosis. In some embodiments, the systemic fibrotic disease is multicentric Castleman's disease (IgG4-related fibrosis). In some embodiments, the systemic fibrotic disease is nephrogenic systemic fibrosis. In some embodiments, the systemic fibrotic disease is sclerodermatous graft-versus-host disease.

[0193] In various embodiments, the invention is a method of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting an organ-specific fibrotic disease in a subject, the method comprising administering a compound according to the invention to a subject suffering from an organ-specific fibrotic disease under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the organ-specific fibrotic disease in the subject.

[0194] In some embodiments, the organ-specific fibrotic disease is pulmonary fibrosis. In some embodiments, the organ-specific fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0195] In some embodiments, the organ-specific fibrotic disease is cardiac fibrosis. In some embodiments, the cardiac fibrosis is hypertension-related cardiac fibrosis. In some embodiments, the cardiac fibrosis is post-myocardial infarction. In some embodiments, the cardiac fibrosis is Chagas disease-induced myocardial fibrosis.

[0196] In some embodiments, the organ-specific fibrotic disease is renal fibrosis. In some embodiments, the renal fibrosis is diabetic and hypertensive nephropathy. In some embodiments, the renal fibrosis is urinary 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.

[0197] In various embodiments, the present invention is a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting cardiac fibrosis in a subject, the method comprising administering a compound according to the present invention to a subject suffering from cardiac fibrosis under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit cardiac fibrosis in the subject. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, and each compound represents a separate embodiment according to the present invention.

[0198] In some embodiments, the organ-specific fibrotic disease is pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is silica-induced pulmonary fibrosis (silicosis). In some embodiments, the pulmonary fibrosis is asbestos-induced pulmonary fibrosis (asbestosis). In some embodiments, the pulmonary fibrosis is chemotherapy agent-induced pulmonary fibrosis.

[0199] In some embodiments, the organ-specific fibrotic disease is liver and portal fibrosis. In some embodiments, the liver and portal fibrosis is alcoholic and non-alcoholic liver fibrosis. In some embodiments, the liver and portal fibrosis is hepatitis C-induced liver fibrosis. In some embodiments, the liver and portal fibrosis is primary biliary cirrhosis. In some embodiments, the liver and portal fibrosis is parasite-induced liver fibrosis (schistosomiasis).

[0200] In some embodiments, the organ-specific fibrotic disease is radiation-induced fibrosis (various organs). In some embodiments, the organ-specific fibrotic disease is bladder fibrosis. In some embodiments, the organ-specific fibrotic disease is intestinal fibrosis. In some embodiments, the organ-specific fibrotic disease is peritoneal sclerosis.

[0201] In some embodiments, the organ-specific fibrotic disease is diffuse fasciitis. In some embodiments, the diffuse fasciitis is morphea, 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 submucous fibrosis of the oral mucosa.

[0202] In some embodiments, the organ-specific fibrotic disease is a result of wound healing. In some embodiments, the organ-specific fibrotic disease is a result of scarring.

[0203] Liver fibrosis, also referred to herein as hepatic fibrosis, can be caused by various types of chronic liver injury, particularly when an inflammatory component is involved. Self-limiting acute liver injury (e.g., acute viral hepatitis A), even if severe, does not necessarily distort the scaffold structure and typically does not cause fibrosis despite hepatocyte loss. However, factors such as chronic alcoholism, malnutrition, hemochromatosis, and exposure to poisons, toxins, or drugs can result in chronic liver injury and hepatic fibrosis due to exposure to hepatotoxic chemicals. Liver scarring caused by other forms of injury associated with surgery or mechanical biliary obstruction can also lead to hepatic fibrosis.

[0204] In various embodiments, the present invention is a method for treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting hepatic fibrosis in a subject, the method comprising administering a compound according to the present invention to a subject suffering from hepatic fibrosis under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit hepatic fibrosis in the subject. In some embodiments, hepatic fibrosis results from liver scarring. In some embodiments, hepatic fibrosis results from chronic liver injury. In some embodiments, chronic liver injury results from chronic alcohol dependence, malnutrition, hemochromatosis, toxins, poisons, or drug exposure, each representing a separate embodiment according to the present invention. In some embodiments, the subject has cirrhosis. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, each compound representing a separate embodiment according to the present invention.

[0205] Fibrosis itself does not necessarily present symptoms, but can lead to portal hypertension, in which blood flow through the liver is distorted by scarring, or to the development of cirrhosis, in which normal liver structure is destroyed by scarring, causing liver dysfunction. The degree of each of these pathologies determines the clinical symptoms of hepatic fibrosis. For example, congenital hepatic fibrosis affects portal vein branching and mainly preserves soft tissues. As a result, hepatocyte function is preserved while portal hypertension develops.

[0206] In various embodiments, the present invention is a method of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting a hepatic fibrotic disorder in a subject, the method comprising administering a compound according to the present invention to a subject suffering from a hepatic fibrotic disorder under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit the hepatic fibrotic disorder in the subject. In some embodiments, the hepatic fibrotic disorder is portal hypertension, cirrhosis, congenital hepatic fibrosis, or any combination thereof, each representing a separate embodiment of the present invention. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, each compound representing a separate embodiment of the present invention.

[0207] In various embodiments, the present invention is a method of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting portal hypertension in a subject, the method comprising administering a compound according to the present invention to a subject suffering from portal hypertension under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit portal hypertension in the subject. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, each compound representing a separate embodiment of the present invention.

[0208] In various embodiments, the present invention is a method of treating cirrhosis in a subject, suppressing it, reducing its severity, reducing its risk of onset, or inhibiting it, the method comprising administering a compound according to the present invention to a subject suffering from cirrhosis under conditions effective to treat cirrhosis in the subject, suppress it, reduce its severity, reduce its risk of onset, or inhibit it. In some embodiments, the cirrhosis is a result of hepatitis. In some embodiments, the cirrhosis is a result of alcohol dependence. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, each compound representing a separate embodiment of the present invention.

[0209] In various embodiments, the present invention is a method of treating human alcohol dependence in a subject, suppressing it, reducing its severity, reducing its risk of onset, or inhibiting it, the method comprising administering a compound according to the present invention to a subject suffering from alcohol dependence under conditions effective to treat alcohol dependence in the subject, suppress it, reduce its severity, reduce its risk of onset, or inhibit it. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, each compound representing a separate embodiment of the present invention.

[0210] Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) have similar causes and histopathology, but different etiologies and epidemiologies. NASH and ASH are advanced stages of non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is characterized by excessive fat accumulation (steatosis) in the liver without any other obvious cause of chronic liver disease (such as virus, autoimmunity, genes, etc.) and with an alcohol intake of 20 to 30 g / day or less. In contrast, AFLD is defined by the presence of steatosis and an alcohol intake of more than 20 to 30 g / day.

[0211] In various embodiments, the present invention is a method of treating non-alcoholic steatohepatitis (NASH) in a subject, suppressing it, reducing its severity, reducing its risk of onset, or inhibiting it, comprising administering a compound according to the present invention to a subject suffering from non-alcoholic steatohepatitis (NASH) under conditions effective to treat non-alcoholic steatohepatitis (NASH) in the subject, suppress it, reduce its severity, reduce its risk of onset, or inhibit it. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, and each compound represents a separate embodiment according to the present invention.

[0212] In various embodiments, the present invention is a method of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholic steatohepatitis (ASH) in a subject, the method comprising administering a compound according to the present invention to a subject suffering from alcoholic steatohepatitis (ASH) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit alcoholic steatohepatitis (ASH) in the subject. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, and each compound represents a separate embodiment of the present invention.

[0213] In various embodiments, the present invention is a method of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting non-alcoholic fatty liver disease (NAFLD) in a subject, the method comprising administering a compound according to the present invention to a subject suffering from non-alcoholic fatty liver disease (NAFLD) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit non-alcoholic fatty liver disease (NAFLD) in the subject. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, and each compound represents a separate embodiment of the present invention.

[0214] In various embodiments, the present invention is a method for treating, suppressing, reducing the severity of, reducing the risk of onset of, or inhibiting alcoholic fatty liver disease (AFLD) in a subject, the method comprising administering a compound according to the present invention to a subject suffering from alcoholic fatty liver disease (AFLD) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of onset of, or inhibit alcoholic fatty liver disease (AFLD) in the subject. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, and each compound represents a separate embodiment of the present invention.

[0215] In various embodiments, the present invention is a method for treating, suppressing, reducing the severity of, reducing the risk of onset of, or inhibiting pulmonary fibrosis in a subject, the method comprising administering a compound according to the present invention to a subject suffering from pulmonary fibrosis under conditions effective to treat, suppress, reduce the severity of, reduce the risk of onset of, or inhibit pulmonary fibrosis in the subject. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, and each compound represents a separate embodiment of the present invention.

[0216] Idiopathic pulmonary fibrosis (IPF) is an age-related refractory lung disease, and historically, treatment options have been limited. Recently, in 2014, two drugs, pirfenidone and nintedanib, were approved by the US Food and Drug Administration (FDA), heralding a new era in its management. Both drugs demonstrated efficacy in phase III clinical trials by delaying the rate of progression of IPF, and neither drug appears to be able to completely halt the progression of the disease. Advances in the understanding of IPF pathophysiology have led to an unprecedented expansion in the number of potential therapeutic targets. Drugs targeting some of these are under development at various stages of clinical development.

[0217] In various embodiments, the present invention is a method of treating, suppressing, reducing the severity of, reducing the risk of onset of, or inhibiting idiopathic pulmonary fibrosis (IPF) in a subject, the method comprising administering a compound according to the present invention to a subject suffering from idiopathic pulmonary fibrosis (IPF) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of onset of, or inhibit idiopathic pulmonary fibrosis (IPF) in the subject. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, each compound representing a separate embodiment according to the present invention. In some embodiments, the compound is administered in combination with an agent for treating IPF. In some embodiments, the compound is administered in combination with pirfenidone, nintedanib, or a combination thereof, each representing a separate embodiment according to the present invention.

[0218] In various embodiments, the present invention is a method of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting scleroderma in a subject, the method comprising administering a compound according to the present invention to a subject suffering from scleroderma under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit scleroderma in the subject. In some embodiments, the scleroderma is systemic sclerosis. In some embodiments, the scleroderma results from localized or generalized localized scleroderma, keloid, hypertrophic scar, familial cutaneous collagenoma, connective tissue nevus of that collagen type, or any combination thereof, each representing a separate embodiment of the present invention. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, each compound representing a separate embodiment of the present invention.

[0219] In various embodiments, the present invention is a method of treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting systemic sclerosis in a subject, the method comprising administering a compound according to the present invention to a subject suffering from systemic sclerosis under conditions effective to treat, suppress, reduce the severity of, reduce the risk of developing, or inhibit systemic sclerosis in the subject. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, each compound representing a separate embodiment of the present invention.

[0220] In various embodiments, the present invention is a method of treating, suppressing, reducing the severity of, reducing the risk of onset of, or inhibiting the overproduction of collagen I (Col I) in a subject, the method comprising administering a compound according to the present invention to a subject suffering from overproduction of collagen I (Col I) under conditions effective to treat, suppress, reduce the severity of, reduce the risk of onset of, or inhibit the overproduction of collagen I (Col I) in the subject. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, each compound representing a separate embodiment of the present invention.

[0221] In various embodiments, the present invention is a method of treating, suppressing, reducing the severity of, reducing the risk of onset of, or inhibiting an autoimmune disease or disorder in a subject, the method comprising administering a compound according to the present invention to a subject suffering from an autoimmune disease or disorder under conditions effective to treat, suppress, reduce the severity of, reduce the risk of onset of, or inhibit the autoimmune disease or disorder in the subject. In some embodiments, the compound is a collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1, each compound representing a separate embodiment of the present invention.

[0222] As used herein, subject or patient refers to any mammalian patient including, but not limited to, humans and other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice, and other rodents. In various embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the methods described herein may be useful for treating either male or female.

[0223] The following examples are presented to more fully illustrate preferred embodiments of the present invention. However, they should in no way be construed as limiting the broad scope of the invention.

Example

[0224] General

[0225] All compounds were profiled for their cellular potency in inhibiting collagen 1 (COL1) protein translation using a phenotypic screening platform.

[0226] Example 1

[0227] Synthesis details of the compounds of the present invention (Schemes 1 - 16)

[0228] General method

[0229] All reagents were of commercial grade and used as received without further purification unless otherwise specified. Solvents of reagent grade were used in all cases unless otherwise specified. Thin layer chromatography was performed using pre-coated silica gel F - 254 plates (thickness 0.25 mm). 1 H - NMR and 19 F - NMR spectra were recorded on a Bruker Bruker Avance 400 MHz or Avance III 400 MHz spectrometer. Chemical shifts are reported in ppm using residual solvent as the internal standard. Splitting patterns are represented as s (singlet), d (doublet), dd (doublet of doublets), t (triplet), dt (doublet of triplets), q (quartet), m (multiplet), and br s (broad singlet).

[0230] Abbreviations AcOH: Acetic acid amphos: Bis(di - tert - butyl(4 - dimethylaminophenyl)phosphine n - BuLi: n - butyllithium t-BuLi: tert-Butyllithium DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene dppb: 1,4-Bis(diphenylphosphino)butane dppf: 1,1'-Bis(diphenylphosphino)ferrocene DCM: Dichloromethane DIBAL-H: Diisobutylaluminum hydride DIPEA: N,N-Diisopropylethylamine DMAP: 4-(Dimethylamino)pyridine DMF: N,N-Dimethylformamide DMA: Dimethylacetamide DMSO: Dimethyl sulfoxide HATU: [O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate] HPLC: High Performance Liquid Chromatography MsCl: Methanesulfonyl chloride NBS: N-Bromosuccinimide rt: Room temperature T3P: Propylphosphonic anhydride TBAF: Tetrabutylammonium fluoride TCFH: N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate THF: Tetrahydrofuran TMS-OTf: Trimethylsilyl trifluoromethanesulfonate

[0231] General synthesis of the compounds of the present invention

[0232] The original general synthesis for the RHS-modified compounds (compound 110 analogs, see Table 1 for the structure) is shown in Scheme 1. This route involves the right-hand side (RHS) group R 2It is characterized by the indole formation reaction of the first step involving simultaneous introduction. During the following steps, the left side (LHS) of the molecule is manipulated to introduce an amide group at the end of the sequence.

[0233]

Chemical formula

[0234] Scheme 1. Synthetic route 1 up to analog 6

[0235] The first synthetic route involved reacting a substituted alkyne 1 with commercially available 4-amino-3-iodobenzonitrile 2 under Larock palladium-catalyzed cyclization conditions to afford 5-cyanoindole 3. The conversion of the nitrile group to the corresponding aminomethyl functional group was achieved by subjecting 3 to a one-pot reduction in an in-situ Boc protection sequence, followed by acid deprotection of the N-Boc amine. The resulting major amine intermediate 4a was isolated as the hydrochloride salt. The final amide analog 6 was prepared from the amine hydrochloride intermediate 4a under HATU amide coupling conditions using the heterocyclic carboxylic acid 5 as an array.

[0236]

Chemical formula

[0237] Scheme 2. Synthetic route 2 up to analog 6

[0238] An alternative and slightly shorter synthesis to route 1 is shown as route 2 in Scheme 2. According to this route, the nitrile intermediate 3 was reduced at 60 °C using lithium aluminum hydride in THF. The first step of Scheme 2 involves a Larock indole cyclization. R 2The substituted alkyne 1 was reacted with commercially available 4-amino-3-iodobenzonitrile 2 under palladium-catalyzed cyclization conditions to obtain the 5-cyanoindole intermediate 3. Conversion of the corresponding aminomethyl functional group of the cyano group was achieved by subjecting the intermediate 3 to lithium aluminum hydride reduction to obtain the amine intermediate 4b. In the final step, the intermediate 4b was reacted with the heterocyclic carboxylic acid 5 under HATU amide coupling conditions to obtain the final compound 6.

[0239] An alternative route (Route 3) to the RHS-modified analog 6 is shown below in Scheme 3, which 2 enables late-stage introduction of the R group.

[0240]

Chemical Structure

[0241] Scheme 3. Synthetic Route 3 to Analog 6 (Late-stage R 2 introduction)

[0242] Synthetic Route 3 starts with the borane reduction of 4-amino-3-iodobenzonitrile 2 and, after acidic workup, gives the aminomethyl intermediate 7 as the dihydrochloride. The intermediate 7 was then subjected to HATU amide coupling conditions using the heterocyclic carboxylic acid 5 to obtain the amide intermediate 8. The synthetic route was then completed by a Larock indole cyclization reaction. The 2 substituted alkyne 1 was reacted with the amide intermediate 8 under palladium-catalyzed cyclization conditions to obtain the final compound analog 6.

[0243] R 2 The substituted acetylene intermediate 1 was, as described above, a precursor for preparing the final compound 6 analog. 2 The substituted acetylene intermediate 1 was prepared by one of three approaches (A, B, and C) shown in Scheme 4.

[0244]

Chemical Structure

[0245] Scheme 4.R 2 Synthesis of Substituted Acetylene Intermediate

[0246] For approach A, methylation of commercially available acetylene 9 was carried out via deprotonation with n-butyllithium in THF and subsequent alkylation with methyl iodide to introduce R 2 Substituted acetylene intermediate 1 was prepared. Approach B was based on the decarboxylative alkynylation of a haloheteroaryl precursor using 2-butynoic acid 11 as the alkyne building block. Finally, approach C was initiated via the alkynylation of a haloheteroaryl precursor using 1-TMS-propyne 10 and introduced the methylacetylene moiety.

[0247] The synthesis of the amine bond analog 14 is shown below in Scheme 5.

[0248]

Chemical Structure

[0249] Scheme 5. Synthesis of Amine Bond Analog 14

[0250] Commercially available (4-methylpyrimidin-5-yl)methanol 12 was oxidized to 4-methylpyrimidine-5-carbaldehyde 13 in good yield by treatment with manganese(IV) oxide in THF at room temperature. The final step involves the reductive amination of aldehyde 13 using the indoleamine hydrochloride intermediate 4a with sodium triacetoxyborohydride and acetic acid in DCM at room temperature to afford the amine bond analog 14.

[0251] Support Modification

[0252] The synthesis of the benzimidazole analog 17 is shown below in Scheme 6.

[0253]

Chemical Structure

[0254] Scheme 6. Synthesis of benzimidazole analog 17

[0255] Commercially available 6-cyanobenzimidazole 15 was reduced to aminomethyl intermediate 16 using lithium aluminum hydride in THF at 60 °C. The amine intermediate 16 was then converted to amide benzimidazole analog 17 by HATU coupling using heterocyclic carboxylic acid 5 in the presence of DIPEA and DMF.

[0256] The synthesis of 1H-pyrrolo[3,2-b]pyridine analog 22 is shown below in Scheme 7.

[0257]

Chemical formula

[0258] Scheme 7. Synthesis of 1H-pyrrolo[3,2-b]pyridine analog 22

[0259] Commercially available 5-amino-6-iodopicolinonitrile 18 was reacted with 2-(prop-1-yn-1-yl)pyridine 19 via a palladium-catalyzed Larock cyclization reaction to deliver azaindole intermediate 20. Reduction of the nitrile functionality in 20 was achieved by a two-step process. In the first step, sodium borohydride was used in the presence of nickel(II) chloride and Boc-anhydride to reduce the cyano group of 20 under mild conditions to afford an N-Boc protected aminomethyl intermediate. This N-Boc protected aminomethyl intermediate was subjected to acidic N-Boc deprotection in the second step to afford aminomethylazaindole intermediate 21. The amine intermediate 21 was isolated as the free base rather than the hydrochloride salt. The amine intermediate 21 was amidated using heterocyclic carboxylic acid 5 under standard HATU amide coupling conditions to afford the final amide 1H-pyrrolo[3,2-b]pyridine analog 22.

[0260] 3-Des-methyl indole analog 26 was synthesized as shown below in Scheme 8.

[0261]

Chemical formula

[0262] Scheme 8. Synthesis of 3-des-methyl indole analog 26

[0263] Commercially available 5-aminomethyl indole 23 was coupled with heterocyclic carboxylic acid 5 using standard HATU conditions to obtain amide intermediate 24 in good yield. Amide intermediate 24 was reacted with 2-iodotoluene 25 in the presence of bis(acetonitrile)dichloropalladium(II), norbornene, and potassium hydrogen carbonate to obtain C2-arylated-3-des-methyl indole analog 26.

[0264] 2-Tetrahydro-2H-pyran-substituted 3-desmethyl indole analog 29 was synthesized via a modified route as shown below in Scheme 9.

Chemical formula

[0265] Scheme 9. Synthesis of 2-tetrahydro-2H-pyran-substituted 3-des-methyl indole analog 29

[0266] Initial key aminoiodo intermediate 8 was subjected to a Sonogashira reaction using 4-ethynyltetrahydro-2H-pyran 27 in the presence of bis(triphenylphosphine)palladium(II) dichloride, copper(I) iodide, and diethylamine in DMF to obtain aminoalkyne intermediate 28. Subsequent cyclization of aminoalkyne 28 to the final 2-tetrahydro-2H-pyran-indole 29 was achieved by heating while refluxing ethanol in the presence of gold(III) chloride.

[0267] The synthesis of the N-methylated indole analog 34 is described in detail below in Scheme 10.

[0268]

Chem.

[0269] Scheme 10. Synthesis of the N-methylated indole analog 34

[0270] The commercially available 5-cyanoindole 30 was subjected to a direct C2 arylation reaction with 2-iodotoluene 25 using palladium catalyst in the presence of bis(acetonitrile)dichloropalladium(II), norbornene, and potassium hydrogen carbonate to obtain the indole intermediate 31. The indole intermediate 31 was N-alkylated using methyl iodide in the presence of sodium hydride to obtain N-methylindole 32. Subsequently, the 5-nitrile moiety of the N-methylindole intermediate 32 was converted to the corresponding aminomethyl group by reduction with lithium aluminum hydride in THF at 60 °C to obtain the amine intermediate 33. The amine intermediate 33 was then subjected to a standard HATU amide coupling with the heteroaryl carboxylic acid 5 to obtain the final amide N-methylated indole analog 34.

[0271] The bis-methylated indole analog 40 was synthesized as described below in Scheme 11.

[0272]

Chem.

[0273] Scheme 11. Synthesis of the bis-methylated indole analog 40

[0274] Commercially available 1-ethynyl-2-methylbenzene 35 was methylated via a lithiation-alkylation sequence (Approach A of Scheme 4) to give 1-methyl-2-(prop-1-yn-1-yl)benzene 36. Under palladium-catalyzed conditions, Larock cyclization of intermediate 36 in the presence of 4-amino-3-iodobenzonitrile 2 gave 2-tolylindole-5-nitrile intermediate 37. The indole intermediate 37 was then N-alkylated using methyl iodide in the presence of sodium hydride to give N-methylindole 38. The 5-nitrile moiety in the N-methylindole intermediate 38 was reduced to the corresponding aminomethyl group at 60 °C using lithium aluminum hydride in THF to give amine intermediate 39. The amine intermediate 39 was subjected to standard HATU amide coupling with heteroaryl carboxylic acid 5 to give the final bis-methylated indole analog 40.

[0275]

Chem.

[0276] Scheme 12. Synthesis of N-Substituted 5-Acetamidoindole Analogs 45

[0277] Commercially available ethyl 2-(4-amino-3-iodophenyl)acetate 41 was reacted with various 2-substituted 1-methylalkynes 1 under palladium-catalyzed conditions at high temperature via Larock indole cyclization to give 5-substituted ethyl acetate indole intermediate 42. The ethyl ester moiety of intermediate 42 was hydrolyzed under basic conditions to give carboxylic acid intermediate 43. HATU amide bond formation between carboxylic acid intermediate 43 and various primary / secondary amines 44 gave the final N-substituted 5-acetamidoindole analogs 45.

[0278]

Chem.

[0279] Scheme 13. Synthesis of 4-, 6-, or 7-Monosubstituted 5-Amidomethylindole Analogs 49 (Late-Stage R2 Group introduction)

[0280] The synthetic scheme described in Scheme 13 is similar to the aforementioned Scheme 3 and includes the same sequence of steps and late-stage R 2 Group introduction. The commercially available substituted 4-amino-5-iodobenzonitrile 46 was reduced to the corresponding substituted 4-(aminomethyl)-2-iodoaniline 47 using borane in tetrahydrofuran at high temperature. The amide intermediate 48 was obtained by standard HATU amide coupling of the 4-(aminomethyl) portion of intermediate 47 with various heteroaryl carboxylic acids 5. The final step involves late-stage R 2 Group introduction via Larock indole cyclization. The 2-iodoaniline portion of intermediate 48 was reacted with 2-substituted 1-methylalkyne 1 under palladium catalyst conditions to obtain the final 4-, 6- or 7-monosubstituted 5-aminomethylindole analog 49.

[0281]

Chemical Structure

[0282] Scheme 14. Synthetic route 4 up to analog 6

[0283] (3-Methyl-1H-indol-5-yl)methanamine 50 was protected at the amino group with an N-Boc group using di-tert-butyl dicarbonate at ambient temperature in the presence of triethylamine to afford the intermediate tert-butyl ((3-methyl-1H-indol-5-yl)methyl)carbamate 51. The intermediate 51 was brominated at the 2-position of the indole ring using N-bromosuccinimide in carbon tetrachloride and DCM to afford the major intermediate tert-butyl ((2-bromo-3-methyl-1H-indol-5-yl)methyl)carbamate 52. The major heteroaryl bromide intermediate 52 was subjected to Suzuki cross-coupling with various heterocyclic boronic esters to generate intermediate 54. The N-Boc protecting group of intermediate 54 was removed under acidic conditions using a hydrogen chloride solution in dioxane to afford the benzylamine intermediate 4a as the hydrochloride salt. The synthetic approach in Scheme 14 was complementary to the synthesis in Scheme 1 and was compatible with different R 2 groups). The final amide analog 6 was prepared under HATU amide coupling conditions from the benzylamine hydrochloride intermediate 4a using the heterocyclic carboxylic acid 5 as an array.

[0284]

Chemical Structure

[0285] Scheme 15. Synthesis of analog 63

[0286] Compound analog 63 was prepared using the convergent synthetic approach described in Scheme 15.

[0287] Using a two-step synthetic sequence related to the first two steps of the synthesis of Scheme 14, benzyl ((2-bromo-3-methyl-1H-indol-5-yl)methyl)carbamate 56 having a 2-bromo substituent on the indole ring was synthesized. Step 1 of the first sequence involved protecting the amino group of (3-methyl-1H-indol-5-yl)methanamine 50 as an N-Cbz group using benzyl chloroformate at ambient temperature in the presence of triethylamine and DMAP to afford benzyl ((3-methyl-1H-indol-5-yl)methyl)carbamate 55. Step 2 of the first sequence involved bromination at the 2-position of the indole ring of intermediate 55 and using N-bromosuccinimide in carbon tetrachloride and DCM at ambient temperature to afford brominated intermediate 56.

[0288] In the second sequence, boronic ester, tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl methylcarbamate 59, was prepared in a single step from commercially available tert-butyl 2-bromobenzyl(methyl)carbamate 57 and bis(pinacolato)diboron 58 using palladium catalytic conditions in the presence of potassium acetate at elevated temperature. The heteroaryl bromide intermediate 56 and boronic ester intermediate 58 from the two synthetic sequences were then used in a Suzuki cross-coupling reaction under palladium catalytic conditions to generate the major 2-arylindole intermediate 60.

[0289] The N-Cbz protecting group of intermediate 60 was removed under neutral palladium-catalyzed hydrogenation conditions to afford benzylamine intermediate 61. In the penultimate step, HATU amide bond formation between benzylamine intermediate 61 and various heterocyclic carboxylic acids 5 afforded N-Boc protected 2-arylindole amide intermediate 62. The final N-Boc deprotection step under acidic conditions using trifluoroacetic acid in DCM at ambient temperature afforded the final compound analog 63.

[0290]

Chemical Structure

[0291] Scheme 16. Synthesis of Intermediate 67

[0292] The heteroaryl bromide intermediate 52 described above in Scheme 14 was subjected to a Suzuki cross-coupling reaction with commercially available 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester and reacted at a high temperature under palladium catalyst conditions to obtain Intermediate 65. Subsequently, Intermediate 66 was obtained by palladium-catalyzed hydrogenation of Intermediate 65 at ambient temperature. The amine Intermediate 67 was easily obtained under acidic conditions after deprotection of the N-Boc group of Intermediate 66. The benzylamine Intermediate 67 was isolated as the hydrochloride salt and then used in further chemistry.

[0293] Detailed Synthesis of Intermediates of the Compounds of the Present Invention Synthesis of 1-Fluoro-2-(prop-1-yn-1-yl)benzene [Chemical formula]

[0294] A solution of 1-ethynyl-2-fluorobenzene (1 mL, 8.82 mmol) in anhydrous THF (20 mL) was added dropwise with a solution of n-butyllithium (7 mL, 17.65 mmol in 2.5 M hexane) at -70 °C to -60 °C over 20 minutes. After stirring at this temperature for 1 hour, methyl iodide (2.7 mL, 44.12 mmol) was added dropwise and the reaction mixture was warmed to room temperature. After stirring for 2 hours, the reaction was quenched by adding a saturated solution of sodium thiosulfate (10 mL). The organic phase was separated and the aqueous phase was extracted with iso-hexane (2 × 20 mL). The combined organic extracts were dried (MgSO 4 )), filtered, and evaporated to obtain 1-fluoro-2-(prop-1-yn-1-yl)benzene as a pale yellow liquid.

[0295] Yield 1.25 g (quantitative). 1 H NMR (400 MHz, CDCl 3) δ 7.41 - 7.36 (m, 1H), 7.27 - 7.21 (m, 1H), 7.07 (dd, J = 1.2, 4.4 Hz, 1H), 7.03 (dq, J = 1.1, 5.0 Hz, 1H), 2.10 (s, 3H).

[0296] Synthesis of 2-(2-Fluorophenyl)-3-methyl-1H-indole-5-carbonitrile

[0297] [Chemical Structure]

[0298] A sealed tube was charged with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex containing 4-amino-3-iodobenzonitrile (1 g, 4.1 mmol), K 2 CO 3 (1.13 g, 8.2 mmol), LiCl (0.174 g, 4.1 mmol), and dichloromethane (0.335 g, 0.41 mmol). To this mixture was added a solution of 1-fluoro-2-(prop-1-yn-1-yl)benzene (0.687 g, 5.12 mmol) in anhydrous DMF (6 mL). The resulting suspension was degassed with nitrogen for several minutes, the reaction tube was sealed, and the mixture was heated at 100 °C for 4 hours. After cooling to room temperature, the reaction mixture was filtered through celite, washed with DMF, and concentrated. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was washed with water (50 mL) and brine (30 mL), dried (MgSO 4 ), filtered, and evaporated. The residue was purified by column chromatography on silica gel (5 - 25% EtOAc in cyclohexane) to afford 2-(2-fluorophenyl)-3-methyl-1H-indole-5-carbonitrile as a light brown solid.

[0299] Yield 433 mg (42%). 11H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 8.14 (d, J = 0.4 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.56 - 7.44 (m, 3H), 7.42 - 7.37 (m, 2H), 2.29 (d, J = 1.6 Hz, 3H).

[0300] Synthesis of tert-butyl ((2-(2-fluorophenyl)-3-methyl-1H-indol-5-yl)methyl)carbamate

Chemical Structure

[0301] To a suspension of 2-(2-fluorophenyl)-3-methyl-1H-indole-5-carbonitrile (352 mg, 1.41 mmol) in anhydrous MeOH (10 mL) were added nickel(II) chloride hexahydrate (33 mg, 0.14 mmol) and di-tert-butyl dicarbonate (920 mg, 4.22 mmol) at room temperature. Sodium borohydride (426 mg, 11.3 mmol) was added portionwise to the resulting solution over 15 minutes. After stirring at room temperature for 15 minutes, the reaction mixture was partitioned between ethyl acetate (50 mL) and saturated NaHCO 3 solution (50 mL). The organic phase was washed with brine (20 mL), dried (MgSO 4 ), filtered, and evaporated to give tert-butyl ((2-(2-fluorophenyl)-3-methyl-1H-indol-5-yl)methyl)carbamate as a yellow oil.

[0302] Yield 670 mg (quantitative). 1 1H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 7.65 - 7.57 (m, 1H), 7.51 (dd, J = 5.8, 5.8 Hz, 1H), 7.46 - 7.32 (m, 5H), 7.09 (d, J = 8.1 Hz, 1H), 4.26 (d, J = 5.8 Hz, 2H), 2.28 (s, 3H), 1.45 (s, 9H). The sample also contains di-tert-butyl dicarbonate.

[0303] Synthesis of (2-(2-Fluorophenyl)-3-methyl-1H-indol-5-yl)methanamine Hydrochloride

Chem.

[0304] tert-Butyl ((2-(2-fluorophenyl)-3-methyl-1H-indol-5-yl)methyl)carbamate (675 mg, 1.4 mmol) was treated with hydrogen chloride (4 M, 19 mL, 76 mmol) in dioxane at room temperature for 1.5 h. The reaction mixture was concentrated, triturated with diethyl ether (3 × 20 mL), and dried to afford (2-(2-fluorophenyl)-3-methyl-1H-indol-5-yl)methanamine hydrochloride as a light brown solid.

[0305] Yield 376 mg (91%). 1 H NMR (400 MHz, DMSO) δ 11.33 (s, 1H), 8.26 (br s, 3H), 7.73 (s, 1H), 7.64 (dd, J = 7.3, 7.3 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.47 - 7.38 (m, 3H), 7.28 (d, J = 8.6 Hz, 1H), 4.16 (d, J = 5.6 Hz, 2H), 2.31 (s, 3H).

[0306] Synthesis of tert-Butyl ((3-Methyl-2-(o-tolyl)-1H-indol-5-yl)methyl)carbamate

[0307]

Chem.

[0308] To a solution of 3-methyl-2-(o-tolyl)-1H-indole-5-carbonitrile (100 mg, 0.41 mmol) in anhydrous MeOH (4 mL), nickel(II) chloride hexahydrate (9.7 mg, 0.04 mmol) and di-tert-butyl dicarbonate (266 mg, 1.22 mmol) were added at room temperature. Then, sodium borohydride (123 mg, 3.25 mmol) was added portionwise over 11 minutes. After stirring at room temperature for 15 minutes, the reaction mixture was partitioned between ethyl acetate (25 mL) and saturated NaHCO 3 solution (25 mL). The organic phase was washed with brine (20 mL), dried (MgSO 4 ), filtered, and evaporated to give tert-butyl ((3-methyl-2-(o-tolyl)-1H-indol-5-yl)methyl)carbamate as a yellow oil.

[0309] Yield 173 mg (quantitative). 1 H NMR (400 MHz, DMSO) δ 10.70 - 10.67 (m, 1H), 7.17 - 7.14 (m, 3H), 7.11 (s, 3H), 7.05 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 4.02 (d, J = 5.8 Hz, 2H), 2.04 (s, 3H), 1.92 (s, 3H), 1.22 (s, 9H). The sample also contains di-tert-butyl dicarbonate.

[0310] Synthesis of (3-methyl-2-(o-tolyl)-1H-indol-5-yl)methanamine hydrochloride

[0311]

Chemical formula

[0312] tert-Butyl ((3-methyl-2-(o-tolyl)-1H-indol-5-yl)methyl)carbamate (173 mg, 0.41 mmol) was treated with hydrogen chloride (4 M, 5 mL, 20 mmol) in dioxane at room temperature for 2 h. The reaction mixture was concentrated, triturated with diethyl ether (3 × 20 mL), and dried to afford (3-methyl-2-(o-tolyl)-1H-indol-5-yl)methanamine hydrochloride as a beige solid.

[0313] Yield 92 mg (65%). 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 8.21 (br s, 3H), 7.68 (s, 1H), 7.35 - 7.45 (m, 5H), 7.24 (d, J = 8.3 Hz, 1H), 4.15 (d, J = 5.3 Hz, 2H), 2.27 (s, 3H), 2.19 (s, 3H).

[0314] Synthesis of 3-methyl-2-(pyridin-2-yl)-1H-indole-5-carbonitrile

[0315]

Chemical formula

[0316] In a sealed tube, 4-amino-3-iodobenzonitrile (439 mg, 1.80 mmol), K 2 CO 3[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex filled with (497 mg, 3.60 mmol), LiCl (76 mg, 1.80 mmol), and dichloromethane (147 mg, 0.18 mmol) was charged. To this mixture, a solution of 2-(prop-1-yn-1-yl)pyridine (232 mg, 1.98 mmol) in anhydrous DMF (3.5 mL) was added. The resulting suspension was degassed with nitrogen for several minutes, the reaction tube was sealed, and the mixture was heated at 100 °C for 19 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL), brine (10 mL) was added, the organic phase was transferred to a separatory funnel, and partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with water (30 mL) and brine (20 mL), dried (MgSO 4 ), filtered, and evaporated. The residue was purified by column chromatography on silica gel (5 - 40% EtOAc in isohexane) to give 3-methyl-2-(pyridin-2-yl)-1H-indole-5-carbonitrile as an off-white solid.

[0317] Yield 134 mg (32%). 1 H NMR (400 MHz, DMSO) δ 12.01 (s, 1H), 8.78 (d, J = 4.3 Hz, 1H), 8.24 (s, 1H), 8.05 - 7.99 (m, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.43 (dd, J = 6.1, 6.1 Hz, 1H), 2.66 (s, 3H).

[0318] Synthesis of tert-butyl ((3-methyl-2-(pyridin-2-yl)-1H-indol-5-yl)methyl)carbamate

[0319]

Chem.

[0320] A solution of 3-methyl-2-(pyridin-2-yl)-1H-indole-5-carbonitrile (134 mg, 0.57 mmol) in anhydrous MeOH (6 mL) was added with nickel(II) chloride hexahydrate (14 mg, 0.06 mmol) and di-tert-butyl dicarbonate (376 mg, 1.72 mmol) at room temperature. Then, sodium borohydride (174 mg, 4.60 mmol) was added portionwise over 14 minutes. After stirring at room temperature for 30 minutes, di-tert-butyl dicarbonate (210 mg, 0.96 mmol) was added, followed by sodium borohydride (150 mg, 3.96 mmol) added portionwise over 6 minutes. After stirring at room temperature for 2.5 hours, di-tert-butyl dicarbonate (150 mg, 0.69 mmol) was added, followed by sodium borohydride (80 mg, 2.11 mmol) added portionwise over 4 minutes. After stirring at room temperature for 30 minutes, the reaction mixture was partitioned between ethyl acetate (25 mL) and saturated NaHCO 3 solution (25 mL). The organic phase was washed with brine (20 mL), dried (MgSO 4 ), filtered, and evaporated to give tert-butyl ((3-methyl-2-(pyridin-2-yl)-1H-indol-5-yl)methyl)carbamate as a yellow oil.

[0321] Yield 238 mg (quantitative). 1 1H NMR (400 MHz, DMSO) δ 11.32 (s, 1H), 8.73 (d, J = 4.0 Hz, 1H), 7.97 - 7.92 (m, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.47 (s, 1H), 7.42 - 7.31 (m, 3H), 7.10 (d, J = 7.8 Hz, 1H), 4.28 - 4.22 (m, 2H), 2.62 (s, 3H), 1.47 (s, 9H). The sample also contains di-tert-butyl dicarbonate.

[0322] Synthesis of (3-methyl-2-(pyridin-2-yl)-1H-indol-5-yl)methanamine dihydrochloride

[0323]

Chem.

[0324] tert-Butyl ((3-methyl-2-(pyridin-2-yl)-1H-indol-5-yl)methyl)carbamate (238 mg, 0.57 mmol) was treated with hydrogen chloride (4 M, 7 mL, 28 mmol) in dioxane at room temperature for 1.5 h. The reaction mixture was concentrated, triturated with diethyl ether (3 × 20 mL), and dried to afford (3-methyl-2-(pyridin-2-yl)-1H-indol-5-yl)methanamine dihydrochloride as a yellow solid.

[0325] Yield 161 mg (91%). 1 H NMR (400 MHz, DMSO) δ 11.58 (s, 1H), 8.76 (d, J = 4.3 Hz, 1H), 8.28 (br s, 3H), 8.02 (dd, J = 7.7, 7.7 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.78 (s, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.31 (d, J = 7.8 Hz, 1H), 4.16 (d, J = 5.6 Hz, 2H), 2.65 (s, 3H).

[0326] Synthesis of 4-methylpyrimidine-5-carbaldehyde (13)

Chemical formula

[0327] Yield 137 mg (55%). 1 H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 9.27 (s, 1H), 9.15 (s, 1H), 2.83 (s, 3H).

[0328] Synthesis of 1-Methyl-2-(prop-1-yn-1-yl)benzene (36)

[0329]

Chemical formula

[0330] To a solution of 2-ethynyltoluene (1.6 mL, 12.91 mmol) in anhydrous THF (30 mL) was added dropwise a solution of n-butyllithium (2.5 M in hexane, 7.75 mL, 19.4 mmol) at -78 °C over 20 minutes. After stirring at this temperature for 1 hour, methyl iodide (1.2 mL, 19.4 mmol) was added dropwise and the reaction mixture was warmed to room temperature. After stirring for 24 hours, the reaction was quenched by adding a saturated solution of sodium thiosulfate (20 mL). The organic phase was separated and the aqueous phase was extracted with isohexane (2 × 30 mL). The combined organic extracts were dried (Na 2 SO 4 ), filtered, and evaporated to give 1-methyl-2-(prop-1-yn-1-yl)benzene (36) as a pale yellow liquid.

[0331] Yield 1.7 g (quantitative). 1 1H NMR (400 MHz, CDCl 3 ) δ 7.35 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 4.0 Hz, 2H), 7.14 - 7.07 (m, 1H), 2.41 (s, 3H), 2.09 (s, 3H).

[0332] Synthesis of 3-Methyl-2-(o-tolyl)-1H-indole-5-carbonitrile (37)

[0333]

Chemical formula

[0334] In a sealed tube, 4-amino-3-iodobenzonitrile (1 g, 4.1 mmol), K 2 CO 3[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex containing (1.13 g, 8.2 mmol), LiCl (0.174 g, 4.1 mmol), and dichloromethane (0.335 g, 0.41 mmol) was charged. To this mixture, a solution of 1-methyl-2-(prop-1-yn-1-yl)benzene (0.667 g, 5.12 mmol) in anhydrous DMF (6 mL) was added. The resulting suspension was degassed with nitrogen for several minutes, the reaction tube was sealed, and the mixture was heated at 100 °C for 18 h. After cooling to room temperature, the reaction mixture was filtered through celite, rinsed with ethyl acetate, and concentrated. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated, and the organic phase was washed with water (50 mL) and brine (30 mL), dried (MgSO 4 ), filtered, and evaporated. The residue was purified by column chromatography on silica gel (0 - 30% EtOAc in isohexane) to give 3-methyl-2-(o-tolyl)-1H-indole-5-carbonitrile (37) as a yellow solid.

[0335] Yield 540 mg (53%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.18 - 8.15 (br s, 1H), 7.94 (d, J = 0.8 Hz, 1H), 7.45 - 7.29 (m, 6H), 2.26 (s, 3H), 2.20 (s, 3H).

[0336] Synthesis of 1,3-dimethyl-2-(o-tolyl)-1H-indole-5-carbonitrile (38)

[0337]

Chemical formula

[0338] A solution of 3-methyl-2-(o-tolyl)-1H-indole-5-carbonitrile (96 mg, 0.39 mmol) in anhydrous DMF (2 mL) was added with methyl iodide (0.073 mL, 1.17 mmol) at room temperature, followed by the addition of sodium hydride (60%, 23 mg, 0.59 mmol). After stirring at room temperature for 1 hour, the reaction mixture was quenched by adding saturated NaHCO 3 aqueous solution (1 mL), and partitioned between ethyl acetate (15 mL) and water (15 mL). The layers were separated, and the organic phase was washed with diluted NaHCO 3 solution (10%, 10 mL) and brine (10 mL), dried (MgSO 4 ), filtered, and evaporated. The obtained residue was triturated with petroleum ether and evaporated to give 1,3-dimethyl-2-(o-tolyl)-1H-indole-5-carbonitrile (38) as an off-white solid.

[0339] Yield 86 mg (85%). 1 1H NMR (400 MHz, DMSO) δ 8.11 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.43 (s, 2H), 7.38 - 7.32 (m, 1H), 7.28 (d, J = 7.3 Hz, 1H), 3.31 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H).

[0340] Synthesis of (1,3-dimethyl-2-(o-tolyl)-1H-indol-5-yl)methanamine (39)

[0341]

Chem.

[0342] A solution of 1,3-dimethyl-2-(o-tolyl)-1H-indole-5-carbonitrile (85 mg, 0.33 mmol) in anhydrous THF (3 mL) was added with LiAlH 4(62 mg, 1.63 mmol) was added portionwise at room temperature. The reaction mixture was heated at 60 °C for 2 h. After cooling to 0 °C on ice, water (120 μL) and 2 N NaOH solution (120 μL) were added dropwise successively. The resulting mixture was diluted with ethyl acetate (20 mL), dried (MgSO 4 ), filtered, and evaporated to give (1,3-dimethyl-2-(o-tolyl)-1H-indol-5-yl)methanamine (39) as a pale yellow oil.

[0343] Yield 86 mg (quantitative). 1 H NMR (400 MHz, DMSO) δ 7.46 (s, 1H), 7.40 (d, J = 3.8 Hz, 2H), 7.37 - 7.30 (m, 2H), 7.24 (d, J = 7.1 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 3.81 (s, 2H), 3.38 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H), 1.90 (br s, 2H).

[0344] Synthesis of N-((1H-indol-5-yl)methyl)-4-methylpyrimidine-5-carboxamide

[0345]

Chemical formula

[0346] To a solution of 4-methylpyrimidine-5-carboxylic acid (104 mg, 0.752 mmol) in anhydrous DMF (3 mL) were added DIPEA (0.18 mL, 1.03 mmol) and HATU (312 mg, 0.821 mmol) successively, and the reaction mixture was stirred at room temperature for 10 min. Then, a solution of 5-(aminomethyl)indole (100 mg, 0.684 mmol) in anhydrous DMF (3 mL) was added, and the reaction was continued to stir at room temperature for 1.5 h. The mixture was partitioned between ethyl acetate (50 mL) and a diluted Na 2 CO 3 solution (10%, 50 mL). The layers were separated, and the organic phase was washed with a diluted solution of Na 2 CO 3 (10%, 25 mL) and brine (10 mL), and dried (MgSO4 ) It was filtered and evaporated. The residue was triturated with petroleum ether and evaporated to give N-((1H-indol-5-yl)methyl)-4-methylpyrimidine-5-carboxamide as an off-white solid.

[0347] Yield 134 mg (73%). 1 1H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 9.10 - 9.06 (m, 2H), 8.71 (s, 1H), 7.51 (s, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.32 (dd, J = 2.5, 2.5 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.40 (s, 1H), 4.53 (d, J = 5.6 Hz, 2H), 2.53 (s, 3H).

[0348] Synthesis of 2-(o-tolyl)-1H-indole-5-carbonitrile (31)

[0349]

Chemical formula

[0350] A sealed tube was charged with indole-5-carbonitrile (540 mg, 3.80 mmol), bicyclo[2.2.1]hepta-2-ene (715 mg, 7.60 mmol), KHCO 3 (761 mg, 7.60 mmol), and bis(acetonitrile)dichloropalladium(II) (99 mg, 0.38 mmol). A 0.5 M aqueous solution of N,N-dimethylacetamide (18.5 mL) was added at room temperature, followed by 2-iodotoluene (0.97 mL, 7.60 mmol). After stirring at 100 °C for 48 h, the reaction mixture was diluted with ethyl acetate (120 mL), filtered through MgSO 4 and partitioned between ethyl acetate (50 mL) and water (50 mL). The layers were separated, and the organic phase was washed with water (50 mL) and brine (20 mL) and dried (MgSO 4) It was filtered and evaporated. The residue was purified by column chromatography on silica gel (5 - 30% EtOAc in cyclohexane) to obtain 2-(o-tolyl)-1H-indole-5-carbonitrile (31) as a white solid.

[0351] Yield 68 mg (8%). 1 1H NMR (400 MHz, DMSO) δ 11.89 (s, 1H), 8.10 - 8.08 (m, 1H), 7.57 - 7.53 (m, 2H), 7.45 (dd, J = 1.6, 8.5 Hz, 1H), 7.39 - 7.32 (m, 3H), 6.73 (s, 1H), 2.46 (s, 3H).

[0352] Synthesis of 1-methyl-2-(o-tolyl)-1H-indole-5-carbonitrile (32)

[0353]

Chemical Structure

[0354] To a solution of 2-(o-tolyl)-1H-indole-5-carbonitrile (66 mg, 0.284 mmol) in anhydrous DMF (2 mL) was added methyl iodide (0.053 mL, 0.852 mmol) at room temperature, followed by sodium hydride (60%, 17 mg, 0.426 mmol). After stirring at room temperature for 2 hours, the reaction mixture was quenched by adding saturated NaHCO 3 aqueous solution (1 mL), and partitioned between ethyl acetate (15 mL) and water (15 mL). The layers were separated, and the organic phase was washed with diluted NaHCO 3 solution (10%, 10 mL) and brine (10 mL), dried (MgSO 4 ), filtered, and evaporated. The resulting residue was triturated with petroleum ether and evaporated to obtain 1-methyl-2-(o-tolyl)-1H-indole-5-carbonitrile (32) as an off-white solid.

[0355] Yield 51 mg (73%). 11H NMR (400 MHz, DMSO) δ 8.11 - 8.09 (m, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.54 (dd, J = 1.5, 8.6 Hz, 1H), 7.44 - 7.40 (m, 2H), 7.34 - 7.32 (m, 2H), 6.59 (s, 1H), 3.54 (s, 3H), 2.15 (s, 3H).

[0356] (1-Methyl-2-(o-tolyl)-1H-indol-5-yl)methanamine (33) synthesis

[0357]

Chemical Structure

[0358] To a solution of 1-methyl-2-(o-tolyl)-1H-indole-5-carbonitrile (56 mg, 0.227 mmol) in anhydrous THF (3 mL), LiAlH 4 (43 mg, 1.14 mmol) was added portionwise at room temperature. The reaction mixture was heated at 60 °C for 2 h. After cooling to 0 °C on ice, water (120 μL) and 2N aqueous NaOH solution (120 μL) were added dropwise successively. The resulting mixture was diluted with ethyl acetate (20 mL), dried (MgSO 4 ), filtered, and evaporated to give (1-methyl-2-(o-tolyl)-1H-indol-5-yl)methanamine (33) as a white solid.

[0359] Yield 57 mg (quantitative). 1 1H NMR (400 MHz, DMSO) δ 7.48 (s, 1H), 7.41 - 7.36 (m, 3H), 7.31 (dd, J = 3.2, 3.2 Hz, 2H), 7.15 (dd, J = 1.4, 8.5 Hz, 1H), 6.34 (s, 1H), 3.79 (s, 2H), 3.46 (s, 3H), 3.30 (br s, 2H), 2.16 (s, 3H).

[0360] Synthesis of 1-methyl-3-(prop-1-yn-1-yl)benzene

[0361]

Chemical Structure

[0362] A solution of 1-ethynyl-3-methylbenzene (1.1 mL, 8.61 mmol) in anhydrous THF (20 mL) was added dropwise with a solution of n-butyllithium (2.5 M in hexane, 5.2 mL, 13 mmol) at -78 °C over 15 minutes. After stirring at this temperature for 1 hour, methyl iodide (0.80 mL, 12.91 mmol) was added dropwise and the reaction mixture was warmed to room temperature. After stirring for 16 hours, the reaction was quenched by adding a saturated solution of sodium thiosulfate (10 mL). The layers were separated, the organic phase was separated, and the aqueous phase was extracted with / so-hexane (2 × 20 mL). The combined organic extracts were dried (MgSO 4 ), filtered, and evaporated to give 1-methyl-3-(prop-1-yn-1-yl)benzene as a yellow oil.

[0363] Yield 1.16 g (quantitative, trace solvent). 1 1H NMR (400 MHz, CDCl 3 ) δ 7.33 - 7.14 (m, 3H), 7.07 (d, J = 7.1 Hz, 1H), 2.31 (s, 3H), 2.04 (s, 3H).

[0364] Synthesis of 3-(prop-1-yn-1-yl)pyridine

Chemical formula

[0365] Compound 3-(prop-1-yn-1-yl)pyridine was prepared from 3-ethynylpyridine according to the same procedure as described for the synthesis of 1-methyl-3-(prop-1-yn-1-yl)benzene, except that it was purified by column chromatography on silica gel (0 - 20% EtOAc in cyclohexane) to give 3-(prop-1-yn-1-yl)pyridine as a yellow oil.

[0366] Yield 654 mg (57%). 1 1H NMR (400 MHz, CDCl3 )δ 8.62 (d, J = 1.0 Hz, 1H), 8.49 - 8.46 (m, 1H), 7.67 - 7.65 (m, 1H), 7.20 (dd, J = 5.3, 7.6 Hz, 1H), 2.08 (s, 3H).

[0367] Synthesis of 1 - methoxy - 3 - (prop - 1 - yn - 1 - yl)benzene

[0368]

Chemical Structure

[0369] Compound 1 - methoxy - 3 - (prop - 1 - yn - 1 - yl)benzene was prepared from 1 - ethynyl - 3 - methoxybenzene according to the same procedure as described for the synthesis of 1 - methyl - 3 - (prop - 1 - yn - 1 - yl)benzene and obtained as a pale yellow liquid. Without purification, it was advanced to the next step.

[0370] Yield 578 mg (quantitative). 1 H NMR (400 MHz, CDCl 3 )δ 7.19 (dd, J = 7.9, 7.9 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.92 (s, 1H), 6.82 (dd, J = 1.8, 8.3 Hz, 1H), 3.79 (s, 3H), 2.04 (s, 3H).

[0371] Synthesis of 1 - methoxy - 2 - (prop - 1 - yn - 1 - yl)benzene

[0372]

Chemical Structure

[0373] Compound 1 - methoxy - 2 - (prop - 1 - yn - 1 - yl)benzene was prepared from 1 - ethynyl - 2 - methoxybenzene according to the same procedure as described for the synthesis of 1 - methyl - 3 - (prop - 1 - yn - 1 - yl)benzene and obtained as a dark orange liquid. Without purification, it was advanced to the next step.

[0374] Yield 591 mg (quantitative). 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (dd, J = 1.3, 7.6 Hz, 1H), 7.27 - 7.21 (m, 1H), 6.87 (dd, J = 7.7, 13.0 Hz, 2H), 3.88 (s, 3H), 2.12 (s, 3H).

[0375] Synthesis of 2 - methyl - 3 - (prop - 1 - yn - 1 - yl)pyridine

[0376]

Chem.

[0377] Compound 2 - methyl - 3 - (prop - 1 - yn - 1 - yl)pyridine was prepared from 3 - ethynyl - 2 - methylpyridine according to the same procedure as described for the synthesis of 1 - methyl - 3 - (prop - 1 - yn - 1 - yl)benzene, except that it was purified by column chromatography on silica gel (0 - 25% Et 2 O in petroleum ether), and 2 - methyl - 3 - (prop - 1 - yn - 1 - yl)pyridine was obtained as a colorless oil.

[0378] Yield 273 mg (49%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.37 (dd, J = 1.8, 4.9 Hz, 1H), 7.61 (dd, J = 1.8, 7.7 Hz, 1H), 7.05 (dd, J = 4.9, 7.8 Hz, 1H), 2.65 (s, 3H), 2.11 (s, 3H).

[0379] Synthesis of 3 - fluoro - 2 - (prop - 1 - yn - 1 - yl)pyridine

[0380]

Chem.

[0381] Column chromatography on silica gel (0 - 25% Et in petroleum ether) 2 except for purification by, the compound 3 - fluoro - 2-(prop - 1 - yn - 1 - yl)pyridine was prepared from 2 - ethynyl - 3 - fluoropyridine according to the same procedure as described for the synthesis of 1 - methyl - 3-(prop - 1 - yn - 1 - yl)benzene, and 3 - fluoro - 2-(prop - 1 - yn - 1 - yl)pyridine was obtained as a colorless liquid.

[0382] Yield 300 mg (54%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, J = 4.8 Hz, 1H), 7.41 - 7.35 (m, 1H), 7.25 - 7.18 (m, 1H), 2.15 (s, 3H).

[0383] Synthesis of tert - butyl 4-(prop - 1 - yn - 1 - yl)piperidine - 1 - carboxylate

[0384]

Chemical formula

[0385] The compound tert - butyl 4-(prop - 1 - yn - 1 - yl)piperidine - 1 - carboxylate was prepared from tert - butyl 4 - ethynylpiperidine - 1 - carboxylate according to the same procedure as described for the synthesis of 1 - methyl - 3-(prop - 1 - yn - 1 - yl)benzene, and obtained as a pale yellow oil.

[0386] Yield 1.1 g (quantitative). 1 H NMR (400 MHz, CDCl 3 ) δ 3.75 - 3.65 (m, 2H), 3.22 - 3.09 (m, 2H), 2.54 - 2.46 (m, 1H), 1.80 (d, J = 2.4 Hz, 3H), 1.78 - 1.69 (m, 2H), 1.54 - 1.47 (m, 2H), 1.46 (s, 9H).

[0387] Synthesis of 4-(prop-1-yn-1-yl)tetrahydro-2H-pyran

[0388]

Chem.

[0389] Column chromatography on silica gel (0 - 15% Et in petroleum ether) 2 Except for purification by column chromatography on silica gel (0 - 15% Et in petroleum ether), compound 4-(prop-1-yn-1-yl)tetrahydro-2H-pyran was prepared from 4-ethynyltetrahydro-2H-pyran according to the same procedure as described for the synthesis of 1-methyl-3-(prop-1-yn-1-yl)benzene, and a 9:1 mixture of 4-(prop-1-yn-1-yl)tetrahydro-2H-pyran and 4-ethynyltetrahydro-2H-pyran was obtained as a colorless liquid. This was carried on to the next step without further purification.

[0390] Yield 209 mg. 1 1H NMR (400 MHz, CDCl 3 ) δ 3.92 - 3.85 (m, 2H), 3.50 - 3.43 (m, 2H), 2.59 - 2.51 (m, 1H), 1.81 (d, J = 2.3 Hz, 3H), 1.79 - 1.75 (m, 2H), 1.66 - 1.59 (m, 2H).

[0391] Synthesis of 4-methyl-3-(prop-1-yn-1-yl)pyridine

[0392]

Chem.

[0393] Column chromatography on silica gel (0 - 40% Et in petroleum ether) 2Except for purification by (O), compound 4-methyl-3-(prop-1-yn-1-yl)pyridine was prepared from 3-ethynyl-4-methylpyridine according to the same procedure as described for the synthesis of 1-methyl-3-(prop-1-yn-1-yl)benzene, and 4-methyl-3-(prop-1-yn-1-yl)pyridine was obtained as a colorless liquid.

[0394] Yield 175 mg (39%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.53 (s, 1H), 8.33 (d, J = 5.0 Hz, 1H), 7.09 (d, J = 5.0 Hz, 1H), 2.40 (s, 3H), 2.12 (s, 3H).

[0395] Synthesis of 1-(prop-1-yn-1-yl)-2-(trifluoromethyl)benzene

[0396]

Chemical formula

[0397] Except for purification by column chromatography on silica gel (100% cyclohexane), compound 1-(prop-1-yn-1-yl)-2-(trifluoromethyl)benzene was prepared from 1-ethynyl-2-(trifluoromethyl)benzene according to the same procedure as described for the synthesis of 1-methyl-3-(prop-1-yn-1-yl)benzene, and 1-(prop-1-yn-1-yl)-2-(trifluoromethyl)benzene was obtained as a colorless liquid.

[0398] Yield 96 mg (26%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.44 (dd, J = 7.6, 7.6 Hz, 1H), 7.34 (dd, J = 7.6, 7.6 Hz, 1H), 2.09 (s, 3H).

[0399] Synthesis of 2-(prop-1-yn-1-yl)pyrazine

[0400]

Chem.

[0401] Column chromatography on silica gel (0 - 40% Et in petroleum ether) 2 Except for purification by column chromatography on silica gel (0 - 40% Et in petroleum ether), compound 2-(prop-1-yn-1-yl)pyrazine was prepared from 2-ethynylpyrazine according to the same procedure as described for the synthesis of 1-methyl-3-(prop-1-yn-1-yl)benzene, and 2-(prop-1-yn-1-yl)pyrazine was obtained as a white solid.

[0402] Yield 333 mg (58%). 1 1H NMR (400 MHz, CDCl 3 ) δ 8.61 (d, J = 1.5 Hz, 1H), 8.51 - 8.49 (m, 1H), 8.44 (d, J = 2.5 Hz, 1H), 2.13 (s, 3H).

[0403] Synthesis of 2-(prop-1-yn-1-yl)pyrimidine

[0404]

Chem.

[0405] Column chromatography on silica gel (0 - 100% Et in petroleum ether) 2 Except for purification by column chromatography on silica gel (0 - 100% Et in petroleum ether), compound 2-(prop-1-yn-1-yl)pyrimidine was prepared from 2-ethynylpyrimidine according to the same procedure as described for the synthesis of 1-methyl-3-(prop-1-yn-1-yl)benzene, and 2-(prop-1-yn-1-yl)pyrimidine was obtained as a light brown solid.

[0406] Yield 236 mg (41%). 1 1H NMR (400 MHz, CDCl 3)δ 8.68 (d, J = 4.9 Hz, 2H), 7.20 (dd, J = 4.9, 4.9 Hz, 1H), 2.12 (s, 3H).

[0407] Synthesis of prop-1-yn-1-ylcyclopentane

[0408]

Chemical formula

[0409] Compound prop-1-yn-1-ylcyclopentane was prepared from ethynylcyclopentane according to the same procedure as described for the synthesis of 1-methyl-3-(prop-1-yn-1-yl)benzene and obtained as a yellow oil. This was carried forward to the next step without purification.

[0410] Yield 407 mg (88%). 1 1H NMR (400 MHz, CDCl 3 )δ 2.58 - 2.49 (m, 1H), 1.93 - 1.82 (m, 2H), 1.79 (d, J = 2.5 Hz, 3H), 1.74 - 1.65 (m, 2H), 1.60 - 1.50 (m, 4H).

[0411] Synthesis of 3-methyl-2-(prop-1-yn-1-yl)pyridine

[0412]

Chemical formula

[0413] Compound 3-methyl-2-(prop-1-yn-1-yl)pyridine was prepared from 2-ethynyl-3-methylpyridine according to the same procedure as described for the synthesis of 1-methyl-3-(prop-1-yn-1-yl)benzene, except that it was purified by column chromatography on silica gel (0 - 50% Et 2 O in petroleum ether) and obtained as a yellow oil.

[0414] Yield 291 mg (65%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (dd, J = 0.8, 4.0 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.09 (dd, J = 4.8, 7.8 Hz, 1H), 2.41 (s, 3H), 2.13 (s, 3H).

[0415] Synthesis of 1,3-difluoro-2-(prop-1-yn-1-yl)benzene

[0416]

Chemical Structure

[0417] Compound 1,3-difluoro-2-(prop-1-yn-1-yl)benzene was prepared from 2-ethynyl-1,3-difluorobenzene according to the same procedure as described for the synthesis of 1-methyl-3-(prop-1-yn-1-yl)benzene and obtained as a pale orange liquid. Without purification, it was carried on to the next step.

[0418] Yield 461 mg (77%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 - 7.16 (m, 1H), 6.90 - 6.85 (m, 2H), 2.15 (s, 3H).

[0419] Synthesis of 3-fluoro-4-(prop-1-yn-1-yl)pyridine

[0420]

Chemical Structure

[0421] Column chromatography on silica gel (0 - 25% Et in petroleum ether 2Except for being purified by (O), compound 3-fluoro-4-(prop-1-yn-1-yl)pyridine was prepared from 4-ethynyl-3-fluoropyridine according to the same procedure as described for the synthesis of 1-methyl-3-(prop-1-yn-1-yl)benzene, and 3-fluoro-4-(prop-1-yn-1-yl)pyridine was obtained as a white solid. Without further purification, the next step was proceeded.

[0422] Yield 165 mg (36%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.44 (s, 1H), 8.32 (d, J = 5.1 Hz, 1H), 7.29 - 7.25 (m, 1H), 2.14 - 2.08 (m, 3H).

[0423] Synthesis of tert-butyl 3-(prop-1-yn-1-yl)piperidine-1-carboxylate

[0424]

Chemical formula

[0425] Compound tert-butyl 3-(prop-1-yn-1-yl)piperidine-1-carboxylate was prepared from tert-butyl 3-ethynylpiperidine-1-carboxylate according to the same procedure as described for the synthesis of 1-methyl-3-(prop-1-yn-1-yl)benzene, and obtained as a pale yellow oil. Without further purification, the next step was proceeded.

[0426] Yield 590 mg (quantitative). 1 H NMR (400 MHz, CDCl 3 ) δ 3.92 - 3.81 (m, 1H), 3.80 - 3.70 (m, 1H), 2.99 - 2.82 (m, 2H), 2.40 - 2.30 (m, 1H), 1.97 - 1.88 (m, 1H), 1.78 (d, J = 2.0 Hz, 3H), 1.73 - 1.59 (m, 1H), 1.55 - 1.35 (m, 11H).

[0427] Synthesis of 1-chloro-2-(prop-1-yn-1-yl)benzene

[0428]

Chem.

[0429] Compound 1-chloro-2-(prop-1-yn-1-yl)benzene was prepared from 1-chloro-2-ethynylbenzene according to a procedure similar to that described for the synthesis of 1-methyl-3-(prop-1-yn-1-yl)benzene and obtained as a yellow oil.

[0430] Yield 662 mg (quantitative). 1 H NMR (400 MHz, CDCl 3 ) δ 7.44 - 7.41 (m, 1H), 7.38 - 7.35 (m, 1H), 7.22 - 7.15 (m, 2H), 2.12 (s, 3H).

[0431] Synthesis of 3-methyl-4-(prop-1-yn-1-yl)pyridine

[0432]

Chem.

[0433] To a suspension of bis(triphenylphosphine)palladium(II) dichloride (102 mg, 0.15 mmol) and 1,4-bis(diphenylphosphino)butane (124 mg, 0.29 mmol) in DMSO (20 mL), 4-bromo-3-methylpyridine (500 mg, 2.91 mmol), 2-butynoic acid (293 mg, 3.49 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 mL, 8.72 mmol) were added. The resulting suspension was degassed with nitrogen for several minutes, the reaction tube was sealed, and the mixture was heated at 110 °C for 1.5 h. After cooling to room temperature, the reaction mixture was quenched by adding water (10 mL), and Et 2It was extracted with O(3×30 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), then passed through a phase separator and evaporated. The resulting residue was purified by column chromatography on silica gel (0 - 65% Et in petroleum ether 2 O) to obtain 3-methyl-4-(prop-1-yn-1-yl)pyridine as a pale yellow oil.

[0434] Yield 102 mg (27%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.42 (s, 1H), 8.34 (d, J = 5.1 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 2.37 (s, 3H), 2.12 (s, 3H).

[0435] Synthesis of 2-fluoro-3-(prop-1-yn-1-yl)pyridine

[0436]

Chemical formula

[0437] Compound 2-fluoro-3-(prop-1-yn-1-yl)pyridine was prepared from 3-bromo-2-fluoropyrazine according to the same procedure as described for the synthesis of 3-methyl-4-(prop-1-yn-1-yl)pyridine, except that it was purified by column chromatography on silica gel (0 - 10% Et in petroleum ether 2 O) to obtain 2-fluoro-3-(prop-1-yn-1-yl)pyridine as a white solid.

[0438] Yield 134 mg (35%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (d, J = 4.5 Hz, 1H), 7.80 - 7.75 (m, 1H), 7.14 - 7.10 (m, 1H), 2.11 (s, 3H).

[0439] Synthesis of 1-methyl-5-(prop-1-yn-1-yl)-1H-pyrazole

[0440] [Chemical]

[0441] Column chromatography on silica gel (0 - 40% Et in petroleum ether) 2 except for purification by, 1 - methyl - 5 - (prop - 1 - yn - 1 - yl) - 1H - pyrazole was prepared from 5 - bromo - 1 - methyl - 1H - pyrazole according to the same procedure as described for the synthesis of 3 - methyl - 4 - (prop - 1 - yn - 1 - yl)pyridine, and 1 - methyl - 5 - (prop - 1 - yn - 1 - yl) - 1H - pyrazole was obtained as a colorless oil. This was carried on to the next step without further purification.

[0442] Yield 99 mg (88%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.39 (d, J = 2.0 Hz, 1H), 6.31 (d, J = 2.0 Hz, 1H), 3.90 (s, 3H), 2.11 (s, 3H).

[0443] Synthesis of 1 - ethyl - 2 - (prop - 1 - yn - 1 - yl)benzene

[0444] [Chemical]

[0445] except for purification by column chromatography on silica gel (100% petroleum ether), 1 - ethyl - 2 - (prop - 1 - yn - 1 - yl)benzene was prepared from 1 - bromo - 2 - ethylbenzene according to the same procedure as described for the synthesis of 3 - methyl - 4 - (prop - 1 - yn - 1 - yl)pyridine, and 1 - ethyl - 2 - (prop - 1 - yn - 1 - yl)benzene was obtained as a pale yellow liquid.

[0446] Yield 302 mg (67%). 11H NMR (400 MHz, CDCl 3 ) δ 7.36 (d, J = 7.4 Hz, 1H), 7.25 - 7.15 (m, 2H), 7.13 - 7.08 (m, 1H), 2.79 (q, J = 7.5 Hz, 2H), 2.09 (s, 3H), 1.23 (t, J = 7.5 Hz, 3H).

[0447] Synthesis of 2 - methyl - 4 - (prop - 1 - yn - 1 - yl)thiazole

[0448]

Chem.

[0449] Column chromatography on silica gel (0 - 10% Et 2 O in petroleum ether) was used for purification. Except for this, 2 - methyl - 4 - (prop - 1 - yn - 1 - yl)thiazole was prepared from 4 - bromo - 2 - methylthiazole according to the same procedure as described for the synthesis of 3 - methyl - 4 - (prop - 1 - yn - 1 - yl)pyridine, and 2 - methyl - 4 - (prop - 1 - yn - 1 - yl)thiazole was obtained as a yellow solid.

[0450] Yield 283 mg (73%). 1 1H NMR (400 MHz, CDCl 3 ) δ 7.15 (s, 1H), 2.68 (s, 3H), 2.04 (s, 3H).

[0451] Synthesis of 1 - cyclopropyl - 2 - (prop - 1 - yn - 1 - yl)benzene

[0452]

Chem.

[0453] Compound 1-cyclopropyl-2-(prop-1-yn-1-yl)benzene was prepared from 1-bromo-2-cyclopropylbenzene according to the same procedure as described for the synthesis of 3-methyl-4-(prop-1-yn-1-yl)pyridine, except that it was purified by column chromatography (isocratic, 100% petroleum ether) on silica gel, and 1-cyclopropyl-2-(prop-1-yn-1-yl)benzene was obtained as a pale yellow liquid.

[0454] Yield 230 mg (58%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.36 (dd, J = 1.3, 7.6 Hz, 1H), 7.16 (ddd, J = 1.3, 7.5, 7.5 Hz, 1H), 7.05 (ddd, J = 1.3, 7.5, 7.5 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 2.42 - 2.34 (m, 1H), 2.11 (s, 3H), 1.03 - 0.98 (m, 2H), 0.72 - 0.67 (m, 2H).

[0455] Synthesis of 2-methyl-6-(prop-1-yn-1-yl)pyridine

[0456]

Chem.

[0457] A sealed tube was charged with 2-bromo-6-methylpyridine (0.16 mL, 1.42 mmol), copper(I) iodide (81 mg, 0.43 mmol) and tetrakis(triphenylphosphine)palladium(0) (82 mg, 0.07 mmol), and then degassed with nitrogen. Anhydrous THF (2 mL), triethylamine (0.59 mL, 4.26 mmol), and 1-(trimethylsilyl)propyne (0.22 mL, 1.49 mmol) were added at room temperature, followed by dropwise addition of tetrabutylammonium fluoride (1 M in THF, 1.5 mL, 1.49 mmol) over 5 minutes. After stirring at room temperature for 16 hours, the reaction mixture was diluted with DCM / MeOH (1:1, 10 mL), dried over silica, and purified by column chromatography on silica gel (0 - 15% EtOAc in cyclohexane) to give 2-methyl-6-(prop-1-yn-1-yl)pyridine as a yellow oil.

[0458] Yield 140 mg (75%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 (dd, J = 7.7, 7.7 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 2.53 (s, 3H), 2.07 (s, 3H).

[0459] Synthesis of 2-fluoro-6-(prop-1-yn-1-yl)pyridine

[0460]

Chem.

[0461] The compound 2-fluoro-6-(prop-1-yn-1-yl)pyridine was prepared from 2-bromo-6-fluoropyridine according to a procedure similar to that described for the synthesis of 2-methyl-6-(prop-1-yn-1-yl)pyridine to give a pale yellow solid.

[0462] Yield 136 mg (71%). 1 H NMR (400 MHz, CDCl 3) δ 7.80 (dd, J = 7.8, 7.8 Hz, 1H), 7.55 (dd, J = 7.8, 7.8 Hz, 2H), 2.10 (s, 3H).

[0463] Synthesis of 1-methyl-2-(prop-1-yn-1-yl)-1H-imidazole

[0464]

Chem.

[0465] Except for purification by column chromatography on silica gel (0 - 100% EtOAc in petroleum ether), 1-methyl-2-(prop-1-yn-1-yl)-1H-imidazole was prepared from 2-iodo-1-methyl-1H-imidazole according to the same procedure as described for the synthesis of 2-methyl-6-(prop-1-yn-1-yl)pyridine, and 1-methyl-2-(prop-1-yn-1-yl)-1H-imidazole was obtained as a brown liquid. This was carried on to the next step without further purification.

[0466] Yield 110 mg (34%). 1 1H NMR (400 MHz, CDCl 3 ) δ 6.98 (s, 1H), 6.83 (s, 1H), 3.68 (s, 3H), 2.10 (s, 3H).

[0467] Synthesis of 4-(prop-1-yn-1-yl)pyrimidine

[0468]

Chem.

[0469] The compound 4-(prop-1-yn-1-yl)pyrimidine was prepared from 4-chloropyrimidine according to the same procedure as described for the synthesis of 2-methyl-6-(prop-1-yn-1-yl)pyridine, except that it was purified by column chromatography on silica gel (0 - 40% EtOAc in petroleum ether), and 4-(prop-1-yn-1-yl)pyrimidine was obtained as a brown solid. This was carried on to the next step without further purification.

[0470] Yield 148 mg (28%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.67 (d, J = 5.1 Hz, 1H), 7.30 (dd, J = 1.2, 5.1 Hz, 1H), 2.13 (s, 3H).

[0471] Synthesis of 2-methoxy-6-(prop-1-yn-1-yl)pyridine

[0472]

Chemical Structure

[0473] The compound 2-methoxy-6-(prop-1-yn-1-yl)pyridine was prepared from 2-bromo-6-methoxypyridine according to the same procedure as described for the synthesis of 2-methyl-6-(prop-1-yn-1-yl)pyridine, except that it was purified by column chromatography on silica gel (0 - 5% EtOAc in petroleum ether), and 2-methoxy-6-(prop-1-yn-1-yl)pyridine was obtained as a pale yellow liquid.

[0474] Yield 330 mg (84%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (dd, J = 7.3, 8.4 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 2.08 (s, 3H).

[0475] Synthesis of 4-Fluoro-2-(prop-1-yn-1-yl)pyridine

[0476]

Chem.

[0477] Except for purification by column chromatography on silica gel (0 - 30% EtOAc in petroleum ether), compound 4-fluoro-2-(prop-1-yn-1-yl)pyridine was prepared from 2-bromo-4-fluoropyridine according to the same procedure as described for the synthesis of 2-methyl-6-(prop-1-yn-1-yl)pyridine, and 4-fluoro-2-(prop-1-yn-1-yl)pyridine was obtained as an orange liquid.

[0478] Yield 335 mg (82%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.49 (dd, J = 5.7, 8.7 Hz, 1H), 7.09 (dd, J = 2.4, 9.3 Hz, 1H), 6.97 - 6.93 (m, 1H), 2.09 (s, 3H).

[0479] Synthesis of 5-Methoxy-2-(prop-1-yn-1-yl)pyridine

[0480]

Chem.

[0481] Except for purification by column chromatography on silica gel (0 - 30% EtOAc in petroleum ether), compound 5-methoxy-2-(prop-1-yn-1-yl)pyridine was prepared from 2-bromo-5-methoxypyridine according to the same procedure as described for the synthesis of 2-methyl-6-(prop-1-yn-1-yl)pyridine, and 5-methoxy-2-(prop-1-yn-1-yl)pyridine was obtained as an orange solid.

[0482] Yield 379 mg (97%).1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (d, J = 3.0 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.11 (dd, J = 3.0, 8.7 Hz, 1H), 3.86 (s, 3H), 2.06 (s, 3H).

[0483] Synthesis of 4-Methoxy-2-(prop-1-yn-1-yl)pyridine

[0484]

Chemical Structure

[0485] Except for purification by column chromatography on silica gel (0 - 50% EtOAc in petroleum ether), compound 4-methoxy-2-(prop-1-yn-1-yl)pyridine was prepared from 2-bromo-4-methoxypyridine according to the same procedure as described for the synthesis of 2-methyl-6-(prop-1-yn-1-yl)pyridine, and 4-methoxy-2-(prop-1-yn-1-yl)pyridine was obtained as a light brown liquid.

[0486] Yield 391 mg (quantitative). 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (d, J = 5.8 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.72 (dd, J = 2.4, 5.8 Hz, 1H), 3.83 (s, 3H), 2.07 (s, 3H).

[0487] Synthesis of 5-Methyl-4-(prop-1-yn-1-yl)pyrimidine

[0488]

Chemical Structure

[0489] Except for purification by column chromatography on silica gel (0 - 50% EtOAc in petroleum ether), compound 5 - methyl - 4-(prop - 1 - yn - 1 - yl)pyrimidine was prepared from 4 - bromo - 5 - methylpyrimidine according to the same procedure as described for the synthesis of 2 - methyl - 6-(prop - 1 - yn - 1 - yl)pyridine, and 5 - methyl - 4-(prop - 1 - yn - 1 - yl)pyrimidine was obtained as an orange solid. This was carried on to the next step without further purification.

[0490] Yield 456 mg (80%). 1 H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.69 (s, 1H), 2.31 (s, 3H), 2.18 (s, 3H).

[0491] Synthesis of 2-(prop - 1 - yn - 1 - yl)pyridine

[0492]

Chemical formula

[0493] Except for purification by column chromatography on silica gel (0 - 30% EtOAc in isohexane), compound 2-(prop - 1 - yn - 1 - yl)pyridine was prepared from 2 - bromopyridine according to the same procedure as described for the synthesis of 2 - methyl - 6-(prop - 1 - yn - 1 - yl)pyridine, and 2-(prop - 1 - yn - 1 - yl)pyridine was obtained as a brown liquid.

[0494] Yield 1.32 g (83%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.54 (d, J = 4.3 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.20 - 7.15 (m, 1H), 2.08 (s, 3H).

[0495] Synthesis of 2-(prop - 1 - yn - 1 - yl)-6-(trifluoromethyl)pyridine

[0496]

Chem.

[0497] The compound 2-(prop-1-yn-1-yl)-6-(trifluoromethyl)pyridine was prepared from 2-bromo-6-(trifluoromethyl)pyridine according to the same procedure as described for the synthesis of 2-methyl-6-(prop-1-yn-1-yl)pyridine, and obtained as a brown liquid.

[0498] Yield 160 mg (61%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (dd, J = 7.8, 7.8 Hz, 1H), 7.55 (dd, J = 7.8, 7.8 Hz, 2H), 2.10 (s, 3H).

[0499] Synthesis of 5-methyl-2-(prop-1-yn-1-yl)pyridine

[0500]

Chem.

[0501] Except for purification by column chromatography on silica gel (0 - 30% EtOAc in petroleum ether), the compound 5-methyl-2-(prop-1-yn-1-yl)pyridine was prepared from 2-bromo-5-methylpyridine according to the same procedure as described for the synthesis of 2-methyl-6-(prop-1-yn-1-yl)pyridine, and obtained as a light brown liquid.

[0502] Yield 358 mg (94%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, 1H), 7.41 (dd, J = 2.0, 7.8 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 2.32 (s, 3H), 2.07 (s, 3H).

[0503] Synthesis of 5-Fluoro-2-(prop-1-yn-1-yl)pyridine

[0504]

Chem.

[0505] Except for purification by column chromatography on silica gel (0 - 20% EtOAc in petroleum ether), 5-fluoro-2-(prop-1-yn-1-yl)pyridine was prepared from 2-bromo-5-fluoropyridine according to the same procedure as described for the synthesis of 2-methyl-6-(prop-1-yn-1-yl)pyridine, and 5-fluoro-2-(prop-1-yn-1-yl)pyridine was obtained as a light brown liquid.

[0506] Yield 291 mg (76%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.39 (d, J = 2.5 Hz, 1H), 7.39 - 7.30 (m, 2H), 2.07 (s, 3H).

[0507] Synthesis of 4-Methyl-3-(prop-1-yn-1-yl)pyridazine

[0508]

Chem.

[0509] Except for purification by column chromatography on silica gel (0 - 100% EtOAc in petroleum ether), compound 4 - methyl - 3-(prop - 1 - yn - 1 - yl)pyridazine was prepared from 3 - chloro - 4 - methylpyridazine according to the same procedure as described for the synthesis of 2 - methyl - 6-(prop - 1 - yn - 1 - yl)pyridine, and 4 - methyl - 3-(prop - 1 - yn - 1 - yl)pyridazine was obtained as an impure dark brown liquid (impurity = triphenylphosphine oxide). This was carried on to the next step without further purification.

[0510] Yield 200 mg (purity = 50%, yield = 19%). 1 1H NMR (400 MHz, DMSO) δ 9.00 (d, J = 4.6 Hz, 1H), 2.36 (s, 3H), 2.19 (s, 3H). Other aromatic signals are masked by impurity signals. m / z: [ESI + 133 (M + H) + 。

[0511] Synthesis of 3 - methyl - 2-(m - tolyl)-1H - indole - 5 - carbonitrile

[0512]

Chem.

[0513] A sealed tube was charged with 4 - amino - 3 - iodobenzonitrile (1.95 g, 7.99 mmol) and 1 - methyl - 3-(prop - 1 - yn - 1 - yl)benzene (1.30 g, 9.99 mmol) in anhydrous DMF (11 mL). To this solution, K 2 CO 3[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (2.21 g, 15.98 mmol), LiCl (0.34 g, 7.99 mmol), and dichloromethane (0.65 g, 0.799 mmol) were added. The resulting suspension was degassed with nitrogen for several minutes, the reaction tube was sealed, and the mixture was heated at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered through celite, washed with EtOAc, and concentrated. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated, and the organic phase was washed with 4% aqueous LiCl (50 mL) and brine (30 mL), dried (MgSO 4 ), filtered, and evaporated. The residue was purified by column chromatography on silica gel (0 - 20% EtOAc in cyclohexane) to afford 3-methyl-2-(m-tolyl)-1H-indole-5-carbonitrile as a light brown solid.

[0514] Yield 621 mg (32%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.30 (br s, 1H), 7.94 (s, 1H), 7.44 - 7.37 (m, 5H), 7.22 (d, J = 6.6 Hz, 1H), 2.45 (s, 6H).

[0515] Synthesis of 3-methyl-2-(pyridin-3-yl)-1H-indole-5-carbonitrile

[0516]

Chem.

[0517] Except for purification by column chromatography on silica gel (0 - 20% acetone in DCM), compound 3 - methyl - 2 - (pyridin - 3 - yl)-1H - indole - 5 - carbonitrile was prepared from 3-(prop - 1 - yn - 1 - yl)pyridine according to the same procedure as described for the synthesis of 3 - methyl - 2-(m - tolyl)-1H - indole - 5 - carbonitrile, and 3 - methyl - 2 - (pyridin - 3 - yl)-1H - indole - 5 - carbonitrile was obtained as a beige solid.

[0518] Yield 204 mg (20%). 1 H NMR (400 MHz, CDCl 3 ) δ 12.01 (br s, 1H), 8.98 (d, J = 1.5 Hz, 1H), 8.69 - 8.66 (m, 1H), 8.23 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.67 - 7.53 (m, 3H), 2.52 (s, 3H).

[0519] Synthesis of 2-(3 - methoxyphenyl)-3 - methyl - 1H - indole - 5 - carbonitrile

[0520]

Chemical formula

[0521] Except for purification by column chromatography on silica gel (0 - 25% EtOAc in cyclohexane), compound 2-(3 - methoxyphenyl)-3 - methyl - 1H - indole - 5 - carbonitrile was prepared from 1 - methoxy - 3-(prop - 1 - yn - 1 - yl)benzene according to the same procedure as described for the synthesis of 3 - methyl - 2-(m - tolyl)-1H - indole - 5 - carbonitrile, and 2-(3 - methoxyphenyl)-3 - methyl - 1H - indole - 5 - carbonitrile was obtained as a yellow oil. This was carried on to the next step without further purification.

[0522] Yield 406 mg (51%). 11H NMR (400 MHz, CDCl 3 ) δ 8.36 (br s, 1H), 7.94 (s, 1H), 7.45 - 7.39 (m, 3H), 7.17 - 7.14 (m, 1H), 7.11 - 7.07 (m, 1H), 6.97 - 6.94 (m, 1H), 3.88 (s, 3H), 2.46 (s, 3H).

[0523] Synthesis of 2-(2-Methoxyphenyl)-3-methyl-1H-indole-5-carbonitrile

[0524]

Chem.

[0525] The compound 2-(2-Methoxyphenyl)-3-methyl-1H-indole-5-carbonitrile was purified by column chromatography on silica gel (0 - 15% EtOAc in cyclohexane) and prepared from 1-methoxy-2-(prop-1-yn-1-yl)benzene according to the same procedure as described for the synthesis of 3-methyl-2-(m-tolyl)-1H-indole-5-carbonitrile, and 2-(2-Methoxyphenyl)-3-methyl-1H-indole-5-carbonitrile was obtained as an orange solid. This was carried on to the next step without further purification.

[0526] Yield 329 mg (42%). 1 1H NMR (400 MHz, CDCl 3 ) δ 8.98 (br s, 1H), 7.94 (s, 1H), 7.53 (dd, J = 1.5, 7.6 Hz, 1H), 7.43 - 7.35 (m, 3H), 7.14 - 7.03 (m, 2H), 3.91 (s, 3H), 2.42 (s, 3H).

[0527] Synthesis of 3-Methyl-2-(2-methylpyridin-3-yl)-1H-indole-5-carbonitrile

[0528]

Chem.

[0529] Except for purification by column chromatography on silica gel (0 - 10% acetone in DCM), the compound 3 - methyl - 2 - (2 - methylpyridin - 3 - yl) - 1H - indole - 5 - carbonitrile was prepared from 2 - methyl - 3 - (prop - 1 - yn - 1 - yl)pyridine according to the same procedure as described for the synthesis of 3 - methyl - 2 - (m - tolyl) - 1H - indole - 5 - carbonitrile, and 3 - methyl - 2 - (2 - methylpyridin - 3 - yl) - 1H - indole - 5 - carbonitrile was obtained as a brown solid. This was carried on to the next step without further purification.

[0530] Yield 141 mg (34%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (dd, J = 1.5, 4.8 Hz, 1H), 8.45 (br s, 1H), 7.96 (s, 1H), 7.65 (dd, J = 1.4, 7.7 Hz, 1H), 7.47 (dd, J = 1.4, 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.28 - 7.22 (m, 1H), 2.49 (s, 3H), 2.22 (s, 3H).

[0531] Synthesis of 2 - (3 - fluoropyridin - 2 - yl) - 3 - methyl - 1H - indole - 5 - carbonitrile

[0532]

Chem.

[0533] Except for purification by column chromatography on silica gel (0 - 7% acetone in toluene), 2-(3-fluoropyridin-2-yl)-3-methyl-1H-indole-5-carbonitrile was prepared from 3-fluoro-2-(prop-1-yn-1-yl)pyridine according to the same procedure as described for the synthesis of 3-methyl-2-(m-tolyl)-1H-indole-5-carbonitrile, and 2-(3-fluoropyridin-2-yl)-3-methyl-1H-indole-5-carbonitrile was obtained as an off-white solid. This was carried forward to the next step without further purification.

[0534] Yield 302 mg (68%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.23 (br s, 1H), 8.53 (d, J = 4.3 Hz, 1H), 8.02 (s, 1H), 7.59 - 7.52 (m, 1H), 7.45 (q, J = 8.3 Hz, 2H), 7.35 - 7.29 (m, 1H), 2.56 (d, J = 4.0 Hz, 3H).

[0535] Synthesis of tert-butyl 4-(5-cyano-3-methyl-1H-indol-2-yl)piperidine-1-carboxylate

[0536]

Chemical Structure

[0537] The compound tert-butyl 4-(5-cyano-3-methyl-1H-indol-2-yl)piperidine-1-carboxylate was prepared from tert-butyl 4-(prop-1-yn-1-yl)piperidine-1-carboxylate according to the same procedure as described for the synthesis of 3-methyl-2-(m-tolyl)-1H-indole-5-carbonitrile, except that it was purified by column chromatography on silica gel (0 - 25% EtOAc in cyclohexane). tert-Butyl 4-(5-cyano-3-methyl-1H-indol-2-yl)piperidine-1-carboxylate was obtained as an off-white solid. This was carried forward to the next step without further purification.

[0538] Yield 382 mg (27%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.83 (s, 1H), 7.83 (s, 1H), 7.35 - 7.34 (m, 2H), 4.31 - 4.29 (m, 2H), 3.10 - 3.00 (m, 1H), 2.87 - 2.85 (m, 2H), 2.27 (s, 3H), 1.85 (d, J = 12.2 Hz, 2H), 1.71 (dd, J = 12.2, 12.2 Hz, 2H), 1.51 (s, 9H).

[0539] Synthesis of 3-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-carbonitrile

[0540]

Chem.

[0541] Except for purification by column chromatography on silica gel (0 - 40% EtOAc in petroleum ether), the compound 3 - methyl - 2 - (tetrahydro - 2H - pyran - 4 - yl) - 1H - indole - 5 - carbonitrile was prepared from 4 - (prop - 1 - yn - 1 - yl)tetrahydro - 2H - pyran according to the same procedure as described for the synthesis of 2 - methyl - 6 - (prop - 1 - yn - 1 - yl)pyridine, and 3 - methyl - 2 - (tetrahydro - 2H - pyran - 4 - yl) - 1H - indole - 5 - carbonitrile was obtained as a light brown solid. This was carried on to the next step without further purification.

[0542] Yield 249 mg (54%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (s, 1H), 7.84 - 7.83 (m, 1H), 7.39 - 7.30 (m, 2H), 4.16 - 4.10 (m, 2H), 3.62 - 3.55 (m, 2H), 3.20 - 3.11 (m, 1H), 2.27 (s, 3H), 1.89 - 1.80 (m, 4H).

[0543] Synthesis of 3 - methyl - 2 - (2 - (trifluoromethyl)phenyl) - 1H - indole - 5 - carbonitrile

[0544]

Chem.

[0545] Except for purification by column chromatography on silica gel (0 - 25% EtOAc in cyclohexane), compound 3 - methyl - 2-(2-(trifluoromethyl)phenyl)-1H - indole - 5 - carbonitrile was prepared from 1-(prop - 1 - yn - 1 - yl)-2-(trifluoromethyl)benzene according to the same procedure as described for the synthesis of 3 - methyl - 2-(m - tolyl)-1H - indole - 5 - carbonitrile and obtained as an off - white solid. This was carried forward to the next step without further purification.

[0546] Yield 40 mg (32%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.31 (s, 1H), 7.96 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.69 - 7.63 (m, 1H), 7.63 - 7.56 (m, 1H), 7.52 - 7.43 (m, 2H), 7.43 - 7.37 (m, 1H), 2.21 (s, 3H).

[0547] Synthesis of 3 - methyl - 2-(pyrimidin - 2 - yl)-1H - indole - 5 - carbonitrile

[0548]

Chemical Structure

[0549] Compound 3 - methyl - 2-(pyrimidin - 2 - yl)-1H - indole - 5 - carbonitrile was prepared from 2-(prop - 1 - yn - 1 - yl)pyrimidine according to the same procedure as described for the synthesis of 3 - methyl - 2-(m - tolyl)-1H - indole - 5 - carbonitrile and obtained as an off - white solid. This was carried forward to the next step without further purification.

[0550] Yield 120 mg (32%). 1 H NMR (400 MHz, CDCl 3)δ 9.58(s,1H),8.78(d,J=4.9Hz,2H),8.03(s,1H),7.50-7.46(m,1H),7.43(dd,J=0.8,8.5Hz,1H),7.15(dd,J=4.9,4.9Hz,1H),2.81(s,3H).

[0551] Synthesis of tert-butyl 3-(5-cyano-3-methyl-1H-indol-2-yl)piperidine-1-carboxylate

[0552]

Chem.

[0553] Except for purification by reverse-phase column chromatography on RP-C18 silica gel (20 - 90% acetonitrile in water, 0.1% ammonium bicarbonate), tert-butyl 3-(5-cyano-3-methyl-1H-indol-2-yl)piperidine-1-carboxylate was prepared from tert-butyl 3-(prop-1-yn-1-yl)piperidine-1-carboxylate according to the same procedure as described for the synthesis of 3-methyl-2-(m-tolyl)-1H-indole-5-carbonitrile to give tert-butyl 3-(5-cyano-3-methyl-1H-indol-2-yl)piperidine-1-carboxylate as a beige solid. This was carried on to the next step without further purification.

[0554] Yield 423 mg (59%). m / z: [ESI + 340 (M + H) + (73% purity).

[0555] (3-Methyl-2-(m-tolyl)-1H-indol-5-yl)methanamine synthesis

[0556]

Chem.

[0557] A solution of 3-methyl-2-(m-tolyl)-1H-indole-5-carbonitrile (310 mg, 1.26 mmol) in anhydrous THF (12 mL) was added with LiAlH 4 (239 mg, 6.29 mmol) portionwise at room temperature. The reaction mixture was heated at 60 °C for 2 h. After cooling to 0 °C on ice, water (350 μL) and 2N aqueous NaOH solution (350 μL) were added dropwise successively. The resulting mixture was diluted with ethyl acetate (50 mL), dried (MgSO 4 ), filtered, and evaporated to give (3-methyl-2-(m-tolyl)-1H-indol-5-yl)methanamine as an off-white solid. This was carried on to the next step without further purification.

[0558] Yield 309 mg (98%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 - 7.99 (m, 1H), 7.52 (s, 1H), 7.40 - 7.32 (m, 4H), 7.18 - 7.13 (m, 2H), 3.98 (s, 2H), 2.46 (s, 3H), 2.43 (s, 3H). The NH 2 proton was obscured by the residual water peak.

[0559] Synthesis of (3-methyl-2-(pyridin-3-yl)-1H-indol-5-yl)methanamine

[0560]

Chemical formula

[0561] Compound (3-methyl-2-(pyridin-3-yl)-1H-indol-5-yl)methanamine was prepared from 3-methyl-2-(pyridin-3-yl)-1H-indole-5-carbonitrile according to the same procedure as described for the synthesis of (3-methyl-2-(m-tolyl)-1H-indol-5-yl)methanamine and obtained as a yellow solid. This was carried on to the next step without further purification.

[0562] Yield: 223 mg (quantitative). 1 H NMR (4...

Claims

1. A compound represented by the structure of formula (I): 【Chemistry 1】 During the ceremony, The A and B rings are each independently a single or fused aromatic or heteroaromatic ring system, or a single or fused C ３ -C １０ Cycloalkyl, or single or fused C ３ -C １０ is a heterocyclic ring, R １ and R ２ each independently represents 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 Heterocyclic ring), CF ３ , C.D. ３ , O.C.D. ３ , C.N., N.O. ２ , -CH ２ C.N., -R ８ C.N., 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 ), 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)OR １０ , R ８ -C(O)-R １０ , C(O)H, C(O)-R １０ , C １ -C ５ Straight or branched chain C(O)-haloalkyl, -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 ), CH(CF ３ ) (NH-R １０ ), C １ -C ５ Straight or branched chain substituted or unsubstituted alkyl), C １ -C ５ Straight or branched chain substituted or unsubstituted alkenyl, C １ -C ５ Linear or branched chain, or C ３ -C ８ Cyclic haloalkyl, C １ -C ５ Linear or branched chain, or C ３ -C ８ Cyclic alkoxy, optionally with at least one methylene group (CH ２ ) is an oxygen atom, C １ -C ５ Linear or branched thioalkoxy, C １ -C ５ Linear or branched haloalkoxy, C １ -C ５ Linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ Heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substitutions include F, Cl, Br, I, C １ -C ５ Linear or branched alkyl, OH, alkoxy, N(R) ２ , C.F. ３ , aryl, phenyl, heteroaryl, C ３ -C ８ Cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO ２ or any combination thereof) 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 ３ and R ４ each independently represents H, F, Cl, Br, I, OH, SH, R ８ -OH, R ８ -SH, -R ８ -O-R １０ , -O-R ８ -R １０ , R ８ - (C ３ -C ８ Cycloalkyl), R ８ - (C ３ -C ８ Heterocyclic ring), CF ３ , C.D. ３ , O.C.D. ３ , C.N., N.O. ２ , -CH ２ C.N., -R ８ C.N., 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 ), 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)OR １０ , R ８ -C(O)-R １０ , C(O)H, C(O)-R １０ , C １ -C ５ Straight or branched chain C(O)-haloalkyl, -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 ), CH(CF ３ ) (NH-R １０ ), C １ -C ５ Linear or branched substituted or unsubstituted alkyl, C １ -C ５ Straight or branched chain substituted or unsubstituted alkenyl, C １ -C ５ Linear or branched chain, or C ３ -C ８ Cyclic haloalkyl, substituted or unsubstituted C １ -C ５ Linear or branched chain, or C ３ -C ８ Cyclic alkoxy, optionally with at least one methylene group (CH ２ ) is an oxygen atom, C １ -C ５ Linear or branched thioalkoxy, C １ -C ５ Linear or branched haloalkoxy, C １ -C ５ Linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ Heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substitutions include F, Cl, Br, I, C １ -C ５ Linear or branched alkyl, OH, alkoxy, N(R) ２ , C.F. ３ , aryl, phenyl, heteroaryl, C ３ -C ８ Cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO ２ or any combination thereof) Or 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; R ５ is absent or is 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 Heterocyclic ring), CF ３ , C.D. ３ , O.C.D. ３ , C.N., N.O. ２ , -CH ２ C.N., -R ８ C.N., 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 ), 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)OR １０ , R ８ -C(O)-R １０ , C(O)H, C(O)-R １０ , C １ -C ５ Straight or branched chain C(O)-haloalkyl, -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 ), CH(CF ３ ) (NH-R １０ ), C １ -C ５ Linear or branched substituted or unsubstituted alkyl, C １ -C ５ Straight or branched chain substituted or unsubstituted alkenyl, C １ -C ５ Linear or branched chain, or C ３ -C ８ Cyclic haloalkyl, C １ -C ５ Linear or branched chain, or C ３ -C ８ Cyclic alkoxy, optionally with at least one methylene group (CH ２ ) is an oxygen atom, C １ -C ５ Linear or branched thioalkoxy, C １ -C ５ Linear or branched haloalkoxy, C １ -C ５ Linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ Heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substitutions include F, Cl, Br, I, C １ -C ５ Linear or branched alkyl, OH, alkoxy, N(R) ２ , C.F. ３ , aryl, phenyl, heteroaryl, C ３ -C ８ Cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO ２ or any combination thereof) R ６ and R ７ each independently represents 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 Heterocyclic ring), CF ３ , C.D. ３ , O.C.D. ３ , C.N., N.O. ２ , -CH ２ C.N., -R ８ C.N., 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 ), 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)OR １０ , R ８ -C(O)-R １０ , C(O)H, C(O)-R １０ , C １ -C ５ Straight or branched chain C(O)-haloalkyl, -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 ), CH(CF ３ ) (NH-R １０ ), C １ -C ５ Straight or branched chain substituted or unsubstituted alkyl), C １ -C ５ Straight or branched chain substituted or unsubstituted alkenyl, C １ -C ５ Linear or branched chain, or C ３ -C ８ Cyclic haloalkyl, C １ -C ５ Linear or branched chain, or C ３ -C ８ Cyclic alkoxy, optionally with at least one methylene group (CH ２ ) is an oxygen atom, C １ -C ５ Linear or branched thioalkoxy, C １ -C ５ Linear or branched haloalkoxy, C １ -C ５ Linear or branched alkoxyalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted C ３ -C ８ Heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted benzyl (substitutions include F, Cl, Br, I, C １ -C ５ Linear or branched alkyl, OH, alkoxy, N(R) ２ , C.F. ３ , aryl, phenyl, heteroaryl, C ３ -C ８ Cycloalkyl, halophenyl, (benzyloxy)phenyl, CN, NO ２ or any combination thereof) Or R ６ and R ７ are joined together to form a 3- to 6-membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; Q １ is NH, N(R), S, O, N—OH, or N—OMe; Q ２ is N or C(R); R is H, F, Cl, Br, I, OH, SH, OH, alkoxy, N(R) ２ , C.F. ３ , C.N., N.O. ２ , C １ -C ５ Linear or branched substituted or unsubstituted alkyl, C １ -C ５ Linear or branched alkoxy, C １ -C ５ Linear or branched haloalkyl, R ８ -aryl, -R ８ -O-R ８ -O-R １０ , -R ８ -O-R １０ , -R ８ -R １０ , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl (substitutions include F, Cl, Br, I, OH, SH, C １ -C ５ Linear or branched alkyl, OH, alkoxy, N(R) ２ , C.F. ３ , phenyl, halophenyl, (benzyloxy)phenyl, CN, NO ２ or any combination thereof), G=X is C=O, C=S, S=O, SO ２ , C.H. ２ , CHR, or C(R) ２ and Each R ８ is independently [CH ２ ] ｐ and p is 1 to 10; R ９ [CH] ｑ [C] ｑ and q is 2 to 10; R １０ and R １１ Each independently represents H, C １ -C ５ Substituted or unsubstituted straight or branched chain alkyl, C １ -C ５ Straight or branched chain alkoxy, C(O)R, or S(O) ２ R or R １０ and R １１ is bonded to a substituted or unsubstituted C ３ -C ８ forming a heterocyclic ring, Substitutions include F, Cl, Br, I, OH, C １ -C ５ Linear or branched alkyl, C １ -C ５ Linear or branched alkyl-OH, C ３ -C ８ Heterocyclic ring, alkoxy, N(R) ２ , C.F. ３ , aryl, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO ２ or any combination thereof), m, n, l, and k are each independently an integer from 0 to 4; X ６ , X ７ , and X ８ are each independently C or N; X １４ and X １５ is, each independently, C or N; or a pharma- ceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant, PROTAC, pharmaceutical product, or any combination thereof; In the formula, R ５ But, C is X ６ , X ７ and / or X ８ A compound that can only bind to

2. Represented by the structure of formula I(a): 【Chemistry 2】 During the ceremony, X １ , X ２ , X ３ , X ４ , and X ５ is, each independently, C or N; or a pharma- ceutically acceptable salt, optical isomer, tautomer, hydrate, N-oxide, reverse amide analog, prodrug, isotopic variant, PROTAC, pharmaceutical product, or any combination thereof.

3. 3. The compound of claim 1 or 2, represented by the structure of formula I(b): 【Chemistry 3】

4. Represented by the structure of formula I(c): 【Chemistry 4】 During the ceremony, X ９ , X １０ , X １１ , X １２ , and X １３ The compound according to any one of claims 1 to 3, wherein each is independently C or N.

5. Represented by the structure of formula I(d): 【Chemistry 5】 During the ceremony, R １２ But, H, C １ -C ５ Linear or branched, substituted or unsubstituted alkyl, F, Cl, Br, I, OH, SH, OH, N(R) ２ , C.F. ３ , C.N., N.O. ２ , C １ -C ５ Linear or branched alkoxy, C １ -C ５ Linear or branched chain haloalkyl, or C ３ -C ８ The compound of claim 1 which is cycloalkyl.

6. Represented by the structure of formula I(e): 【Chemistry 6】 During the ceremony, R １２ But, H, C １ -C ５ Linear or branched, substituted or unsubstituted alkyl, F, Cl, Br, I, OH, SH, OH, N(R) ２ , C.F. ３ , C.N., N.O. ２ , C １ -C ５ Linear or branched alkoxy, C １ -C ５ Linear or branched chain haloalkyl, or C ３ -C ８ The compound of claim 1 which is cycloalkyl.

7. Represented by the structure of formula I(f): 【Chemistry 7】 During the ceremony, 2. The compound of claim 1, wherein the A' ring is a 5-membered heteroaromatic or heterocyclic ring.

8. Represented by the structure of formula I(d(i)): 【Chemistry 8】 During the ceremony, R １２ But, H, C １ -C ５ Linear or branched, substituted or unsubstituted alkyl, F, Cl, Br, I, OH, SH, OH, N(R) ２ , C.F. ３ , C.N., N.O. ２ , C １ -C ５ Linear or branched alkoxy, C １ -C ５ Linear or branched chain haloalkyl, or C ３ -C ８ 8. The compound of any one of claims 1, 5, and 7, which is cycloalkyl.

9. Represented by the structure of formula I(e(i)): 【Chemistry 9】 During the ceremony, R １２ But, H, C １ -C ５ Linear or branched, substituted or unsubstituted alkyl, F, Cl, Br, I, OH, SH, OH, N(R) ２ , C.F. ３ , C.N., N.O. ２ , C １ -C ５ Linear or branched alkoxy, C １ -C ５ Linear or branched chain haloalkyl, or C ３ -C ８ 8. The compound of any one of claims 1, 6, and 7, which is cycloalkyl.

10. 2. The compound of claim 1 selected from the following: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】

11. A compound represented by the structure of the following compound: 【Table 2】

12. The compound of any one of claims 1 to 3, 5, and 6, wherein B is tetrahydropyran, pyridinyl, or phenyl.

13. The compound according to any one of claims 1 to 9, wherein l is 1 and k is 0.

14. R ３ But, H, CH ３ , or C.F. ３ The compound according to any one of claims 1 to 9,

15. 2. The compound of claim 1, wherein A is pyrimidine or pyrazolyl.

16. 8. The compound according to any one of claims 1, 2 and 7, wherein n is 1 and m is 0.

17. R １ But, CH ３ The compound according to any one of claims 1 to 9,

18. Q １ is NH or N(R) and R is CH ３ The compound according to any one of claims 1 to 3,

19. X ２ and X ４ is N and X １ , X ３ , and X ５ The compound according to claim 2 or 3, wherein is C.

20. The compound according to any one of claims 1 to 3, wherein G=X is C=O.

21. The compound according to any one of claims 1 to 20, wherein the compound is a collagen translation inhibitor.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 and a pharma- ceutically acceptable carrier.

23. 22. A compound according to any one of claims 1 to 21 for use in treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting fibrosis in a subject.

24. 24. The compound of claim 23, wherein the fibrosis is a systemic fibrotic disease.

25. 25. The compound of claim 24, wherein the systemic fibrotic disease is systemic sclerosis, multifocal fibrosclerosis (IgG4-associated fibrosis), nephrogenic systemic fibrosis, scleroderma graft-versus-host disease, or any combination thereof.

26. 24. The compound of claim 23, wherein the fibrosis is an organ-specific fibrotic disease.

27. 27. The compound of claim 26, wherein the organ-specific fibrotic disease is pulmonary fibrosis, cardiac fibrosis, renal fibrosis, pulmonary fibrosis, liver and portal vein fibrosis, radiation-induced fibrosis, bladder fibrosis, intestinal fibrosis, peritoneal sclerosis, diffuse fasciitis, wound healing, scarring, or any combination thereof.

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

29. 28. The compound of claim 27, wherein the cardiac fibrosis is hypertension-associated cardiac fibrosis, post-myocardial infarction, Chagas disease-induced myocardial fibrosis, or any combination thereof.

30. 28. The compound of claim 27, wherein the renal fibrosis is diabetic and hypertensive nephropathy, urinary obstruction induced renal fibrosis, inflammatory / autoimmune induced renal fibrosis, aristoloxic acid nephropathy, polycystic kidney disease, or any combination thereof.

31. 28. The compound of claim 27, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, silica-induced pulmonary fibrosis (silicosis), asbestos-induced pulmonary fibrosis (asbestosis), chemotherapy-induced pulmonary fibrosis, or any combination thereof.

32. 28. The compound of claim 27, wherein the liver and portal fibrosis is alcoholic and non-alcoholic liver fibrosis, Hepatitis C induced liver fibrosis, primary biliary cirrhosis, parasite-induced liver fibrosis (schistosomiasis), or any combination thereof.

33. 28. The compound of claim 27, wherein the diffuse fasciitis is localized scleroderma, keloid, Dupuytren's disease, Peyronie's disease, myelofibrosis, oral submucous fibrosis, or any combination thereof.

34. 24. The compound of claim 23, wherein the fibrosis is primary or secondary fibrosis.

35. 24. The compound of claim 23, wherein the fibrosis is the result of systemic sclerosis, graft-versus-host disease (GVHD), pulmonary fibrosis, an autoimmune disorder, tissue injury, inflammation, oxidative stress, or any combination thereof.

36. 24. The compound of claim 23, wherein the fibrosis is liver fibrosis, pulmonary fibrosis, or skin fibrosis.

37. 33. The compound of any one of claims 23 or 32, wherein the subject has cirrhosis of the liver.

38. 37. The compound of claim 36, wherein the skin fibrosis is scleroderma.

39. 37. The compound of claim 36, wherein the skin fibrosis is the result of localized or generalized localized scleroderma, keloids, hypertrophic scars, familial cutaneous collagenoma, connective tissue nevi of the collagen type, or any combination thereof.

40. 37. The compound of claim 36, wherein the liver fibrosis is the result of liver scarring or chronic liver injury.

41. 41. The compound of claim 40, wherein the chronic liver damage results from alcoholism, malnutrition, hemochromatosis, exposure to poisons, toxins, or drugs.

42. 22. A compound according to any one of claims 1 to 21 for use in treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting pulmonary fibrosis in a subject.

43. 43. The compound of claim 42, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

44. 22. A compound according to any one of claims 1 to 21 for use in treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting idiopathic pulmonary fibrosis (IPF) in a subject.

45. 22. A compound according to any one of claims 1 to 21 for use in treating, suppressing, reducing the severity of, reducing the risk of developing or inhibiting liver fibrotic disease in a subject.

46. 46. ​​The compound of claim 45, wherein the liver fibrotic disease is portal hypertension, liver cirrhosis, congenital hepatic fibrosis, or any combination thereof.

47. 22. A compound according to any one of claims 1 to 21 for use in treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting liver cirrhosis in a subject.

48. 48. The compound of claim 47, wherein the cirrhosis is the result of hepatitis or alcoholism.

49. 22. A compound according to any one of claims 1 to 21 for use in treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholic steatohepatitis (ASH) in a subject.

50. 22. A compound according to any one of claims 1 to 21 for use in treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting non-alcoholic steatohepatitis (NASH) in a subject.

51. 22. A compound according to any one of claims 1 to 21 for use in treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting alcoholic fatty liver disease (AFLD) in a subject.

52. 22. A compound according to any one of claims 1 to 21 for use in treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting non-alcoholic fatty liver disease (NAFLD) in a subject.

53. 22. A compound according to any one of claims 1 to 21 for use in treating, suppressing, reducing the severity of, reducing the risk of developing, or inhibiting an autoimmune disease or disorder in a subject.

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