4,5,6,7-tetrahydro-L-benzothiophene modulator of retinoic acid receptor-related (RAR) orphan nuclear receptor (RORS)

Abstract

To provide pharmaceutical compositions for the prevention or treatment of RORs-mediated or autoimmune diseases or antibody-mediated rejection in patients.SOLUTION: There is provided a 4,5,6,7-tetrahydrobenzo[b]thiophen derivative. The derivative is a modulators of RORγt and is a composition comprising one or more additional compounds selected from the group consisting of (a) a cytotoxic agent, (b) an antimetabolite, (c) an alkylating agent, (d) an anthracycline, (e) an antibiotic, (f) an anti-mitotic agent, (g) a hormone therapy, (h) a signal transduction inhibitor, (i) a gene expression modulator, (j) an apoptosis inducer, (k) an angiogenesis inhibitor, and (l) an immunotherapy agent.SELECTED DRAWING: None

Description

【Technical Field】 【0001】 The present invention relates to novel modulators of retinoic acid receptor-related (RARs) orphan nuclear receptors (ROR) alpha (RORα or RORA) and gamma (RORC, RORγ or RORγt), and their use in the control of autoimmune diseases, antibody-mediated allograft rejection, and the increase or decrease of the activity of RORα or RORγt, or other related diseases involving the control of their regulated genes and gene products, including many types of cancer, metabolism and inflammatory diseases. 【Background Art】 【0002】 Autoimmune diseases are conditions that result from abnormal immune responses against normal body parts. There are at least many types of autoimmune diseases. Almost all body parts can be involved. Common symptoms include low-grade fever and fatigue. Often, the symptoms come and go. 【0003】 The cause is generally unknown. Some autoimmune diseases such as lupus spread within families, and certain cases can be caused by infections or other environmental factors. Some common diseases generally considered to be autoimmune include celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. Diagnosis can be difficult to determine. 【0004】 Treatment varies depending on the type and severity of the condition. Non-steroidal anti-inflammatory drugs (NSAIDs) and immunosuppressive agents are often used. Intravenous immunoglobulins are also used. Treatment usually improves the symptoms but usually does not cure the disease. 【0005】 Chronic antibody damage is a serious threat to allograft outcomes and is therefore a center of active research. Antibody development plays a crucial role in the continuum of allograft rejection. In recent years, increased awareness of molecular and histological changes has provided a better understanding of antibody-mediated rejection (AMR) and potential therapeutic interventions. However, several pathways remain unclear, which explains the lack of effectiveness of some of the currently available drugs used to treat rejection. 【0006】 The retinoic acid receptor-associated (ROR) subfamily of orphan nuclear receptors was initially identified based on sequence similarities with the retinoic acid and retinoid X receptor families. Through the use of alternative promoters and exon splicing, the ROR gene encodes different isoforms of RORα, β, and γ, exhibiting expression and function in different tissues. RORγt is a specifically spliced ​​isoform of RORγ, differing only in its N-terminus by the presence of 21 additional amino acids in RORγ. Recently, the endogenous physiological ligands for RORγt have been identified as 7β-27-dihydroxycholesterol and two other cholesterol biosynthetic intermediates. 【0007】 RORγt is CD4 + CD8 + It is expressed only in immune system cells, including double-positive thymocytes 5, Th17, Tc17, and γδT cells, as well as subsets of innate lymphoid cells (ILCs) and regulatory T cells (Tregs). RORγt is a key transcription factor that promotes the differentiation of Th17 cells and is a product of IL-17A, IL-17F, and IL-22 in innate and adaptive immune cells, also known as “type 17” cells. IL-17A, IL-17F, and IL-22 stimulate tissue cells to generate a panel of inflammatory chemokines, cytokines, and metalloproteinases, leading to granulocyte recruitment to the site of inflammation. Th17 cell subsets have been shown to be the major pathogenic population in several models of autoimmune inflammation, including collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE). RORγt-deficient mice exhibit impaired Th17 cell differentiation in vitro, a significant reduction in the Th17 cell population in vivo, and decreased susceptibility to EAE and intestinal inflammation. RORγt-deficient T cells are unable to induce colitis in mouse T cell transplantation models. 【0008】 Human genetic studies have shown associations between genetic diversity in the Th17 cell surface receptors, IL-23R and CCR6, and susceptibility to inflammatory bowel disease (IBD), multiple sclerosis (MS), rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriasis. Clinical modulation of the IL-23 / IL-17 pathway through biology targeting IL-12 / 23, IL-23, IL-17A, or IL-17RA provides validation of its crucial role in human autoimmune diseases. RORγt is a nuclear receptor target in the IL-23 / IL-17 pathway and has been shown to be readily moduloable by oral small molecules. Indeed, other nuclear receptors have been successfully targeted by orally available small molecules, which are currently commercially available drugs. 【0009】 Modulators that inhibit the activity of RORs are needed to control autoimmune diseases and antibody-mediated rejection. Other modulators can activate RORs and may be useful in treating many types of lymphoma and cancer. Modulator effects are stimulant or inhibitory pharmacological effects. Modulators can be classified as activators or inhibitors. They can also be classified as agonists, antagonists, partial agonists, and inverse agonists. [Overview of the project] 【0010】 overview In one embodiment, compounds represented by formulas (I), (II), (III), or (IV), pharmaceutically acceptable salts thereof, or stereoisomers thereof are provided. [ka] In the formula, R1, R2, R3, and / or R4 groups represent H, a halogen atom, NO2, an alkoxy group having 1 to 6 carbon atoms, OH, NH2, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an N-dialkyl group, a haloalkoxy group, a hydroxyalkyl group having 1 to 6 carbon atoms, and / or -CO2 (an alkyl group having 1 to 6 carbon atoms); R5 is a substituted or unsubstituted 5 or 6-membered saturated or unsaturated heterocycle, or aryl group. ,a Lucuria Alain ring Haloaryl group, ring-substituted arylalkyl, ring-substituted alkylhexane, ring-substituted alkylcyclopentane, haloaryl group, benzene ring, phenyl group, pyridine ring, pyrimidine ring, pyridine ring, imidazole ring, diazole ring, triazole ring, thiadiazole ring, imidazolidine ring, tizolidinedion ring, pyrrolidine ring, piperazine ring, pipediline ring, pyridazine ring, pyrazine ring, triazine ring, 1H-pyrrole ring, 2H-pyrrole ring, pyrroline ring, pyrazolidine ring, pyrazolin ring, thiazole ring, isothiazole ring, isoxazole ring, haloalkyl group, Alternatively, it represents a cyanoalkyl group, a methylpyrimidine ring, toluene, a methylpyridine ring, a methylimidazole ring, a methyldiazole ring, a methyltriazole ring, a methylthiadiazole ring, a methylimidazolidine ring, a methyltizolidine ring, a methylpyrrolidine ring, a methylpiperazine ring, a methylpipediline ring, a methylpyridazine ring, a methylpyrazine ring, a methyltriazine ring, a methylpyrrole ring, a methylpyrroline ring, a methylpyrazolidine ring, a methylpyrazoline ring, a methylthiazole ring, a methylisothiazole ring, a methylisoxazole ring, or an arylalkyl group. 【0011】 R6 represents H, an alkyl group having 1 to 6 carbon atoms, or together with R5, 5 or 6 member They may form a ring structure; and R7 is a substituted or unsubstituted 5 or 6-membered saturated or unsaturated heterocycle, a cyclic alkylarene ring, a cyclic alkylhexane, a cyclic alkylcyclopentane, a substituted haloaryl group, a substituted benzene ring, a substituted phenyl group, a benzyl group, a pyrimidine ring, a pyridine ring, an imidazole ring, a diazole ring, a triazole ring, a thiadiazole ring, an imidazolidine ring, a tizolidinedion ring, a pyrrolidine ring, a piperazine ring, an aryl group, a haloaryl group, an alkylarene ring, a pipediline ring, a pyridazine ring, a pyrazine ring, a triazine ring, a 1H-pyrrole ring, a 2H-pyrrole ring, a pyrroline ring, a pyrazolidine ring, a pyrazolin ring, a thiazole ring, an i This represents a sothiazole ring, isoxazole ring, cyanoalkyl group (cyanolkyl), methylpyrimidine ring, toluene, methylpyridine ring, methylimidazole ring, methyldiazole ring, methyltriazole ring, methylthiadiazole ring, methylimidazolidine ring, methyltizolidine ring, methylpyrrolidine ring, methylpiperazine ring, methylpipediline ring, methylpyridazine ring, methylpyrazine ring, methyltriazine ring, methylpyrrole ring, methylpyrroline ring, methylpyrazolidine ring, methylpyrazoline ring, methylthiazole ring, methylisothiazole ring, methylisoxazole ring, or arylalkyl group. 【0012】 In one embodiment, compounds represented by formula (I), (II), (III), or (IV), pharmaceutically acceptable salts thereof, or stereoisomers thereof are: N-(3-(4-benzylpiperazine-1-carbonyl)-4,5,6,7-tetrahydro-benzo[b]thiophene-2-yl)-2-fluorobenzamide; N-(3-(benzylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)-5-chloro-2-(methylthio)pyrimidine-4-carboxamide; 5-Chloro-N-(3-{[(1,1-dioxidetetrahydro-3-thienyl)amino]-carbonyl}-6-methyl-4,5,6,7-tetrahydro-1-benzothien-2-yl)-2-(methylthio)-4-pyrimidine-carboxamide; N-(6-ethyl-3-{[(2-methylphenyl)amino]carbonyl}-4,5,6,7-tetrahydro-1-benzothien-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; N-{6-tert-butyl-3-[(4-methyl-1-piperazinyl)carbonyl]-4,5,6,7-tetrahydro-1-benzothien-2-yl}-2-fluorobenzamide; 2-Fluoro-N-{6-methyl-3-[(4-methyl-1-piperazinyl)carbonyl]-4,5,6,7-tetrahydro-1-benzothien-2-yl}benzamide; N-benzyl-2-[(trifluoroacetyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-benzyl-2-({[(4-methyl-2-pyrimidinyl)thio]acetyl}amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-benzyl-2-[(1-piperidinylacetyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-benzyl-2-{[(4-methyl-1-piperazinyl)acetyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-benzyl-2-{[(4-methyl-1-piperidinyl)acetyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-(3-(2-methylpyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)nicotinamide; N-(3-((2R,4R)-2,4-dimethylpiperidine-1-carbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)nicotinamide; N-(3-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)nicotinamide; N-(3-(3-ethylpyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)nicotinamide; N-benzyl-2-(2-((1-methyl-1H-imidazole-2-yl)thio)acetamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide; N-(3-(3-(hydroxymethyl)pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)nicotinamide; N-(6,6-dimethyl-3-(morpholine-4-carbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)pyrazine-2-carboxamide; N-(3-(((1-methyl-1H-1,2,4-triazole-3-yl)methyl)carbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)nicotinamide; (S)-N-(3-((1-cyanoethyl)carbamoyl)-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)nicotinamide; N-(3-((piperidine-4-ylmethyl)carbamoyl)-4,5,6,7-tetrahydro-benzo[b]thiophene-2-yl)nicotinamide; N-(3-benzoyl4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)pyrazine-2-carboxamide; and N-(3-benzoyl 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-5-methyl-2-(methylsulfonyl)pyrimidine-4-carboxamide. It is selected from the group consisting of the following. 【0013】 According to one aspect, there is provided a pharmaceutical composition comprising at least one compound represented by formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier. 【0014】 According to one aspect, there is provided the use of a compound represented by formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for modulating RORs in a patient and / or for controlling autoimmune diseases and antibody-related rejection reactions. 【0015】 According to one aspect, there is provided the use of a therapeutically effective amount of any one compound represented by formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for preventing or treating a RORs-mediated disease or autoimmune disease or an antibody-related rejection reaction in a patient in need of treatment. 【0016】 In one embodiment, the RORs-mediated disease or autoimmune disease is cancer, celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, asthma, dermatitis, fatty liver disease, Crohn's disease, cardiovascular disease, inflammatory disease, neuropathy, multiple sclerosis, and arteriosclerosis. 【0017】 In one embodiment, the cancer is prostate cancer, breast cancer, ovarian cancer, multiple myeloma, brain tumor, glioma, lung cancer, salivary gland cancer, stomach cancer, thymic epithelial cancer, thyroid cancer, leukemia, melanoma, lymphoma, gastric cancer, pancreatic cancer, kidney cancer, bladder cancer, colon cancer, and liver cancer. 【0018】 According to one aspect, (1) A first compound represented by formula (I), (II), (III), or (IV), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to any one of claims 1 to 2; (2) (a) A cytotoxic agent; (b) Antimetabolites; (c) Alkylating agent; (d) Anthracyclines; (e) antibiotics; (f) Mitotic inhibitors; (g) Hormone therapy; (h) Signal transduction inhibitors; (i) Gene expression modulators; (j) Apoptosis-inducing factors; (k) Angiogenesis inhibitors; (I) Immunotherapy agents; One or more additional compounds selected from the group consisting of; and (3) Pharmaceutically acceptable carriers A pharmaceutical composition containing the above is available. 【0019】 In one embodiment, the cytotoxic agent is taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracendione, mitoxantrone, mitramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, analogs or homologs thereof, or combinations thereof. 【0020】 In one embodiment, the antimetabolite is methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracildacarbazine, or a combination thereof. 【0021】 In one embodiment, the alkylating agent is mechloretamine, thiotepa chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum(II) (DDP) cisplatin, or a combination thereof. 【0022】 In one embodiment, the anthracycline is daunorubicin, doxorubicin, or a combination thereof. 【0023】 In one embodiment, the antibiotic is dactinomycin, bleomycin, mitramycin, anthramycin (AMC), or a combination thereof. 【0024】 In one embodiment, the mitotic inhibitor is vincristine, vinblastine, or a combination thereof. 【0025】 In one embodiment, the signal transduction inhibitor is imatinib, trastuzumab, or a combination thereof. 【0026】 In one embodiment, the gene expression modulator is siRNA, shRNA, antisense oligonucleotide, HDAC inhibitor, or a combination thereof. 【0027】 In one embodiment, the immunotherapy agent is a monoclonal antibody, a chimeric antigen receptor (CAR) T cell, or a combination thereof. 【0028】 In one embodiment, the hormone therapy is a luteinizing hormone-releasing hormone (LHRH) antagonist. 【0029】 In one embodiment, the apoptosis-inducing factor is recombinant human TNF-related apoptosis-inducing ligand (TRAIL). 【0030】 In one embodiment, the angiogenesis inhibitor is sorafenib, sunitinib, pazopanib, everolimus, or a combination thereof. 【0031】 In one embodiment, the first compound is N-(3-(4-benzylpiperazine-1-carbonyl)-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-fluorobenzamide; N-(3-(benzylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)-5-chloro-2-(methylthio)pyrimidine-4-carboxamide; 5-Chloro-N-(3-{[(1,1-dioxidetetrahydro-3-thienyl)amino]-carbonyl}-6-methyl-4,5,6,7-tetrahydro-1-benzothien-2-yl)-2-(methylthio)-4-pyrimidine-carboxamide; N-(6-ethyl-3-{[(2-methylphenyl)amino]carbonyl}-4,5,6,7-tetrahydro-1-benzothien-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; N-{6-tert-butyl-3-[(4-methyl-1-piperazinyl)carbonyl]-4,5,6,7-tetrahydro-1-benzothien-2-yl}-2-fluorobenzamide; 2-Fluoro-N-{6-methyl-3-[(4-methyl-1-piperazinyl)carbonyl]-4,5,6,7-tetrahydro-1-benzothien-2-yl}benzamide; N-benzyl-2-[(trifluoroacetyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-benzyl-2-({[(4-methyl-2-pyrimidinyl)thio]acetyl}amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-benzyl-2-[(1-piperidinylacetyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-benzyl-2-{[(4-methyl-1-piperazinyl)acetyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-benzyl-2-{[(4-methyl-1-piperidinyl)acetyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-(3-(2-methylpyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)nicotinamide; N-(3-((2R,4R)-2,4-dimethylpiperidine-1-carbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)nicotinamide; N-(3-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)nicotinamide; N-(3-(3-ethylpyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)nicotinamide; N-benzyl-2-(2-((1-methyl-1H-imidazole-2-yl)thio)acetamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide; N-(3-(3-(hydroxymethyl)pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)nicotinamide; N-(6,6-dimethyl-3-(morpholine-4-carbonyl)-4,5,6,7-teto Lahydrobenzo[b]thiophene-2-yl)pyrazine-2-carboxamide; N-(3-(((1-methyl-1H-1,2,4-triazole-3-yl)methyl)carbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)nicotinamide; (S)-N-(3-((1-cyanoethyl)carbamoyl)-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)nicotinamide; N-(3-((piperidine-4-ylmethyl)carbamoyl)-4,5,6,7-tetrahydro-benzo[b]thiophene-2-yl)nicotinamide; N-(3-benzoyl4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)pyrazine-2-carboxamide; N-(3-benzoyl 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-5-methyl-2-(methylsulfonyl)pyrimidine-4-carboxamide; The group is selected from the group consisting of these and combinations thereof. 【0032】 The features and advantages of the subject matter of this specification will become more apparent in light of the following detailed description of selected embodiments, as shown in the accompanying figures. As can be seen from the following description, all disclosed and claimed subject matter can be modified in various ways without departing from the claims. Accordingly, the drawings and description should be considered illustrative and not restrictive, and the entire scope of the subject matter is described in the claims. [Brief explanation of the drawing] 【0033】 Further features and advantages of this disclosure will become apparent from the following detailed description, which will be understood in conjunction with the attached drawings. [Figure 1] Figure 1 shows the RORγt regulatory genes in lymphocytes. The figure shows lymphocytes that secrete one, a few, or several cytokines regulated by the RORγt nuclear receptor. Lymphocytes are named based on the major cytokines they secrete (e.g., Th17, Tc17, TFH, Th17 / TFH, Th22, etc.). [Figure 2] Figure 2 shows four general chemical formulas of the substituted 4,5,6,7-tetrahydro-1-benzothiophene ring of the compounds of the present disclosure, where (I), (II), (III), and (IV). [Figure 3] Figures 3A-B show a two-step synthesis scheme for the compound represented by general formula (I), starting with a substituted 2-amino-4,5,6,7-tetrahydro-1-benzothiophene having R1-R4 groups, R5-MgBr+, and an asyl chloride derivative bonded to the R7 group. [Figure 4]Figures 4A-B show a two-step synthesis scheme for the compound represented by general formula (II), starting with a substituted 2-amino-4,5,6,7-tetrahydro-1-benzothiophene having R1-R4 groups, a secondary amine having R5 and R6 groups, and an asyl chloride bonded to the R7 group. [Figure 5] Figures 5A-B show a two-step synthesis scheme for the compound represented by general formula (III), which begins with a substituted 2-amino-4,5,6,7-tetrahydro-1-benzothiophene having R1-R4 groups, a secondary amine bonded to R5 and R6 groups, and a dichloromethyl sulfide bonded to R7. [Figure 6] Figures 6A-B show a two-step synthesis scheme for the compound represented by general formula (IV), starting with a substituted 2-amino-4,5,6,7-tetrahydro-1-benzothiophene having R1-R4 groups, a piperidine derivative bonded to the R5 group, and an asyl chloride bonded to the R7 group. [Modes for carrying out the invention] 【0034】 Detailed description of the invention This disclosure relates to the following chemical structures and group definitions, represented by formulas (I), (II), (III), and (IV) (wherein the formulas, as shown in Figure 2, “ * This relates to compounds represented by (where ) indicates a chiral center, their pharmaceutically acceptable salts, and their stereoisomers. [ka] 【0035】 The R1 to R7 groups of the compounds represented by formulas (I), (II), (III), and (IV) have the following definitions: The R1, R2, R3, and / or R4 groups represent H, a halogen atom, NO2, an alkoxy group having 1 to 6 carbon atoms, OH, NH2, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an N-dialkyl group, a haloalkoxy group, a hydroxyalkyl group having 1 to 6 carbon atoms, and / or -CO2 (an alkyl group having 1 to 6 carbon atoms); The R5 group is a substituted or unsubstituted 5 or 6-membered saturated or unsaturated heterocycle, aryl group, alkylarene ring, haloaryl group, cyclic alkylarene ring, cyclic alkylhexane, cyclic alkylcyclopentane, haloaryl group, benzene ring, benzyl group, phenyl group, pyridine ring, pyrimidine ring, pyridine ring, imidazole ring, diazole ring, triazole ring, thiadiazole ring, imidazolidine ring, tisolidine ring, pyrrolidine ring, piperazine ring, pipediline ring, pyridazine ring, pyrazi N-ring, triazine ring, 1H-pyrrole ring, 2H-pyrrole ring, pyrroline ring, pyrazolidine ring, pyrazoline ring, thiazole ring, isothiazole ring, isoxazole ring, haloalkyl group, cyanoalkyl group, methylpyrimidine ring, toluene, methylpyridine ring, methylimidazole ring, methyldiazole ring, methyltriazole ring, methylthiadiazole ring, methylimidazolidine ring, methyltizolidine ring, methylpyrrolidine ring, methylpiperazine ring, methylpipediline ring, methylpyridazine This represents a ring, a methylpyrazine ring, a methyltriazine ring, a methylpyrrole ring, a methylpyrroline ring, a methylpyrazolidine ring, a methylpyrazoline ring, a methylthiazole ring, a methylisothiazole ring, a methylisoxazole ring, or an arylalkyl group. 【0036】 The R6 group represents H, an alkyl group having 1 to 6 carbon atoms, or 5 or 6 together with R5. member They may form a ring structure; and The R7 group is a substituted or unsubstituted 5 or 6-membered saturated or unsaturated heterocycle, a cyclic alkylarene ring, a cyclic alkylhexane, a cyclic alkylcyclopentane, a substituted haloaryl group, a substituted benzene ring, a substituted phenyl group, a benzyl group, a pyrimidine ring, a pyridine ring, an imidazole ring, a diazole ring, a triazole ring, a thiadiazole ring, an imidazolidine ring, a tizolidinedion ring, a pyrrolidine ring, a piperazine ring, an aryl group, a haloaryl group, an alkylarene ring, a pipediline ring, a pyridazine ring, a pyrazine ring, a triazine ring, a 1H-pyrrole ring, a 2H-pyrrole ring, a pyrroline ring, a pyrazolidine ring, a pyrazolin ring, a thia This represents a zole ring, isothiazole ring, isoxazole ring, cyanoalkyl group, methylpyrimidine ring, toluene, methylpyridine ring, methylimidazole ring, methyldiazole ring, methyltriazole ring, methylthiadiazole ring, methylimidazolidine ring, methyltizolidine ring, methylpyrrolidine ring, methylpiperazine ring, methylpipediline ring, methylpyridazine ring, methylpyrazine ring, methyltriazine ring, methylpyrrole ring, methylpyrroline ring, methylpyrazolidine ring, methylpyrazoline ring, methylthiazole ring, methylisothiazole ring, methylisoxazole ring, or arylalkyl group. 【0037】 The present invention comprises compounds such as those shown, and (where possible) also comprises individual diastereomers, enantiomers, and epimers of the compounds, as well as mixtures of diastereomers and / or enantiomers, including racemic mixtures. While the specific stereochemistry disclosed herein is preferred, other stereoisomers, including diastereomers, enantiomers, epimers, and mixtures thereof, may also be useful. Inactive or low-activity diastereoisomers and enantiomers are useful for scientific studies on the mechanisms of targeting and activation of nuclear receptors. 【0038】 The compounds disclosed herein may be used in pharmaceutical compositions comprising (a) the compounds or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier. These compounds may also be used in pharmaceutical compositions comprising one or more other pharmaceutically active ingredients. These compounds may also be used in pharmaceutical compositions in which the compounds represented by formulas (I), (II), (III), and (IV) or pharmaceutically acceptable salts thereof are the sole active ingredient. 【0039】 According to one embodiment, the compound is a modulator of RORα and RORγt and is useful for controlling autoimmune diseases and antibody-mediated rejection. Such a compound may be useful in the treatment of autoimmune diseases and antibody-mediated rejection, and may also be useful in the treatment of other RORγt-related diseases or conditions. 【0040】 According to another embodiment, the compound may be administered directly to a patient requiring such treatment by oral, intravenous, topical, intranasal, intrapulmonary, subcutaneous (sustained-release implant or patch), sublingual, inhalation, or intramuscular administration. 【0041】 Both ROR alpha and ROR γt are expressed in lymphocytes during maturation. Irregularities in ROR gene expression can lead to cancer and autoimmune diseases. ROR γt is the master regulator of Th17. Th17 cells produce many pro-inflammatory and pleiotropic cytokines, including IL17A, IL17F (which is also anti-inflammatory), IL21, IL22, IL24, and IL26. In addition, Th17 cells secrete GM-CSF and TNF alpha. T-cytotoxic 17 is a type of lymphocyte that secretes all of the aforementioned cytokines. Follicular helper T cells secrete IL-21 and are involved in many inflammatory diseases and many types of cancer. 【0042】 These compounds bind to ROR alpha and ROR gamma and block the production of IL17A, IL21, IL17F, IL24, IL26, and other cytokines produced by helper T17, cytotoxic T17, follicular helper T cells, and cytotoxic T cell and helper T cell variants, as well as other cytokines produced by variants of B cells that produce the aforementioned cytokines. 【0043】 Th17 cells play a role in the escalation of macrophages and leukocytes that cause inflammation. RORC and RORA are highly expressed in certain types of cancer and autoimmune diseases. Patients who are on the waiting list for organ transplantation and are classified as highly sensitized have high activity of helper T17, follicular T cells, and all T cell variants that produce the aforementioned cytokines. This invention will provide therapeutic benefits to this category and to all other people receiving allogeneic transplantation. 【0044】 The compound is useful in treating immune system-related diseases whenever any of the aforementioned cytokines are directly or indirectly involved in the activation of the immune system. Such compounds are useful in treating cancers including those of the blood, liver, breast, and gastrointestinal tract. 【0045】 The types of autoimmune diseases that can be treated with the compound include, but are not limited to, cancer, celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, asthma, dermatitis, fatty liver disease, Crohn's disease, cardiovascular disease, inflammatory diseases, neuropathy, multiple sclerosis, and arteriosclerosis. 【0046】 The types of cancer that can be treated with the compound include, but are not limited to, prostate cancer, breast cancer, brain tumors, gliomas, lung cancer, salivary gland cancer, stomach cancer, thymic cell carcinoma, thyroid cancer, ovarian cancer, multiple myeloma, leukemia, melanoma, lymphoma, gastric cancer, kidney cancer, pancreatic cancer, bladder cancer, colon cancer, and liver cancer. 【0047】 The compounds may be useful in treating diseases and conditions characterized by increases, decreases, irregularities, or dysregulations of RORγt, RORγ, RORα, and other gene products regulated by IL17, IL21, IL22, IL24, IL26, and ROREs. 【0048】 RORC-related diseases Acromegaly, rheumatoid arthritis, malignant neoplasms of the breast, candidiasis, hypertrophy, cardiomyopathy, colorectal cancer, Crohn's disease, diabetes mellitus, diabetes mellitus vera, non-insulin-dependent diabetes mellitus vera, hamartoma, inflammatory bowel disease, mycobacterium infection, systemic sclerosis, tuberous sclerosis, joint swelling, lobomycosis, hepatitis, autoimmune malignant neoplasms of the lung, growth hormone-secreting pituitary adenoma, B-cell preacute lymphoblastic leukemia, malignant neoplasms of the prostate, prostate cancer, breast cancer, lung cancer, familial multiple follicular epithelioma, primary malignant neoplasm of the lung Biological lung cancer, colorectal cancer, Friedreich's ataxia 1, allergic rhinitis (disorder), congenital onychoplasty type 3, early rheumatoid arthritis, fetal or neonatal necrotizing enterocolitis, autoimmune diseases, Roberts-SC phoenix limb syndrome, functional impairment - skin disorders, obesity, lymphedema, smoking-related diseases, inflammation, sleep disorders, circadian rhythms, immunodeficiency - 42, antibody-mediated rejection, acute solid organ transplant rejection (liver, heart, lung, kidney), chronic solid organ graft rejection (liver, heart, lung, kidney), alloimmune hypersensitivity. 【0049】 RORA-related diseases Bipolar disorder, psychotic depression, depressive disorder, autism spectrum disorder, gastric neoplasm, seasonal affective disorder, achlorhydria Predisposition, age-related macular degeneration, atherosclerosis, choroidal carcinoma, dyslipidemia, smoking-related diseases, choroidal angiogenesis, sleep disorders, major depressive disorder, carcinogenesis, liver cancer, bone diseases, malignant neoplasms of the breast, malignant neoplasms of the colon, colitis, epithelial cysts, hepatitis B, hypothyroidism, liver diseases, hepatic neoplasms, metabolic diseases, neuroblastoma, degenerative polyarthritis, osteoporosis, skin diseases, post-traumatic stress disorder, liver failure, depressive symptoms, complete atrioventricular block, chronic, breast cancer, colon cancer, central nervous system blastoma, cerebellar atrophy, adenovirus infection, autism spectrum disorder, fatty liver disease, acute-chronic liver failure, antibody-mediated rejection, acute solid organ transplant rejection (liver, heart, lung, kidney), chronic solid organ transplant rejection (liver, heart, lung, kidney), alloimmune hypersensitivity. 【0050】 IL17A-related diseases Antibody-mediated rejection, acute solid organ transplant rejection (liver, heart, lung, kidney), chronic solid organ graft rejection (liver, heart, lung, kidney), alloimmune hypersensitivity, arthritis, experimental, autoimmune diseases, inflammation, colitis, pneumonia, hypersensitivity, graft-versus-host disease, cerebral ischemia, chronic alcoholism, CNS disorders, acute promyelocytic leukemia, lymphoproliferative disorders, necrosis, alcohol abuse, chemical and drug-induced liver injury, periodontal disease, chronic obstructive pulmonary disease, spondyloarthropathy, myocardial infarction, diabetes mellitus, hyperalgesia, myocardial reperfusion injury, dyslipidemia, pleurisy, pulmonary fibrosis, staphylococcus Skin infections, acute necrotizing pancreatitis, anti-glomerular basement membrane disease, rheumatoid arthritis, asthma, psoriasis, arthritis, systemic lupus erythematosus, periodontitis, multiple sclerosis, encephalomyelitis, ulcerative colitis, degenerative polyarthritis, inflammatory bowel disease, Behçet's syndrome, malignant neoplasia of the stomach, gingivitis, Sjögren's syndrome, juvenile arthritis, candidiasis, chronic mucocutaneous uveitis, Helicobacter pylori infection, Crohn's disease, atopic dermatitis, celiac disease, systemic sclerosis, dermatitis, cutaneous T-cell lymphoma, malignant neoplasm of the breast, carcinogenesis, gastric cancer, multiple myeloma, Job's syndrome, arteriosclerosis, colon Rectal cancer, colorectal cancer, inflammatory dermatitis, bronchiolitis obliterans, keratitis, coronary artery disease, bronchiolitis, cystic fibrosis, rheumatic nodules, respiratory syncytial virus infection, bone disease, indigestion, endometriosis, alcoholic hepatitis, osteonecrosis, bronchiolitis, thrombocytopenic purpura, ovarian neoplasms, infections, psoriatic arthritis, viral bronchiolitis, gastric neoplasms, smoking-related diseases, fungal infections, lupus erythematosus, eczema, lupus vulgaris, lupus erythematosus, discoid viral disease, bone destruction, capillary malformations (impairments), liver cancer, neutrophilia (impairments), insulin-dependent diabetes mellitus, neoplasm metastasis, Neoplasmic metastasis, skin disorders, ankylosing spondylitis, tuberculosis, hepatic fibrosis, non-infectious pneumonia, bacterial infections, non-small cell lung cancer, eosinophilia, lupus nephritis, osteopenia, allergic asthma, malignant neoplasms of the lung, cervical cancer, superficial ulcers, breast cancer, lung cancer, inflammatory diseases, primary malignant neoplasms of the lung, eosinophilic disorders, dysfunctional skin disorders, skin erosions, candidiasis, mucocutaneous candidiasis, malignant neoplasms of the colon, malignant neoplasms of the cervix, histiocytosis, Langerhans cells, lung neoplasms, primary Sjögren's syndrome, age-related macular degeneration, sepsis, psoriatic eczema, chronic periodontitis, persistent embryonic structures, Helicobacter pylori (H. pylori).Helicobacter pylori infection, chronic hepatitis B, colon cancer, cervical cancer, refractory anemia, primary biliary cirrhosis, dermatomyositis, diabetes mellitus, diabetes mellitus vera, encephalitis (St. Louis), hepatitis B, influenza, chronic lymphocytic leukemia, mucocutaneous lymphadenopathy, mycobacterium infection, nasal polyps, sepsis, ocular toxoplasmosis, Chagas disease, pulmonary tuberculosis, uveomeningoencephalitis syndrome, polyglandular autoimmune syndrome type 1, complete atrioventricular block, tumor progression, plaque psoriasis, hyperactivity, Hashimoto's disease, lung infection, acute coronary syndrome, mammary gland tumor, tumor, angiogenesis, allergic rhinitis (disorder), autoimmune arthritis, adenoma, alveolar bone loss, exogenous allergic alveolitis, Alzheimer's disease, bacterial pneumonia, dengue fever, fatty liver, gastritis Glioblastoma, glioma, glomerulonephritis, Graves' disease, pontine cystitis (multiple), hepatitis, hepatitis A, hypertension, arthropathy, cirrhosis, fungal infections, obesity, ovarian cancer, pelvic pain, peritonitis, pruneberry syndrome, cerebrovascular disease, giant cell arteritis, ulcers, vitiligo, corneal pannus, acute myocardial infarction, abdominal aortic aneurysm, Lyme arthritis, parasitemia, psoriasis vulgaris, MRSA-methicillin-resistant Staphylococcus aureus infection, respiratory syncytial virus (RSV) infection, acute anterior uveitis, neuropathy, pelvic pain in women, acute GVH disease, malignant neoplasms of the ovary, fungal keratitis, chronic inflammatory diseases, tumor immunity, painful bladder syndrome, vitiligo-related multiple autoimmune diseases (susceptibility 1), fatty liver disease, ischemic cerebrovascular disease, autoimmune polyendocrine disorders. Immunodeficiency syndrome type 1, interstitial pulmonary fibrosis, acne vulgaris, acquired immunodeficiency syndrome, amyotrophic lateral sclerosis, anemia, aneurysm, Barrett's esophagus, malignant neoplasia of the bladder, bladder neoplasm, bronchiectasis, brucerosis, oral candidiasis, malignant neoplasm of the endometrium, squamous cell carcinoma, cardiovascular disease, intracranial aneurysm, cervical neoplasm, colon disease, colon neoplasm, general variable immunodeficiency, allergic conjunctivitis, corneal disease, coronary artery artery sclerosis, coronary heart disease, Degerin-Sottas disease (disorder) delirium, diabetes mellitus, non-insulin-dependent diabetes, diabetic nephropathy, enterovirus infection, epilepsy, epithelium Hyperplasia, eye infections, giant cell tumors, adenitis, chronic granulomatous diseases, Guillain-Barré syndrome, cardiac arrest, severe dengue fever, chronic hepatitis, hepatitis C, herpes simplex infection, herpesvirus infections, HIV infection, Hodgkin's disease, hyperlipidemia, hypothyroidism, immune system disorders, kidney diseases, acute renal failure, chronic renal failure, leishmaniasis, cutaneous leishmaniasis, infection by Leishmania brasiliensis, visceral leishmaniasis, leprosy, lematous disease, chronic myeloid leukemia, liver disease, alcoholic liver disease, Lyme disease, lymphoma, malaria, cerebral malaria, Marinescoe-Sjögren's disease Syndrome, melanoma, mitral stenosis, myocarditis, nervous system disorders, nodules, osteosarcoma, pain, palmar and plantar pustulosis, pancreatitis, periodontitis (juvenile), pituitary adenoma, pneumococcal infection, polyps, prostatitis, pulmonary eosinophilia, Henoch-Schönlein purpura, adult respiratory distress syndrome, retroviral infections, salmonella infection, sarcoidosis, pulmonary sarcoidosis, schizophrenia, Sézary syndrome, inversion, gastric ulcer, synovitis, thrombocytopenia, thymoma, thyroid disease, tracheoma, tuberous sclerosis, urticaria, anterior uveitis, intermediate uveitis, vasculitis, intestinal pustulosis, malignant pleural effusion, adult onset Still's disease, autoimmune multiple endocrine disorders, liver failure, chronic sinusitis, deep vein thrombosis, chronic pain, active tuberculosis, secondary Sjögren's syndrome, lung adenocarcinoma (or disorder), lobomycosis, pustular psoriasis, systemic candidiasis, acute myocarditis, intervertebral disc disorders, adrenoleukodystrophy, allergic contact dermatitis, depigmentation disorder, autoimmune thyroid disease, autoimmune diabetes, interstitial lung disease, idiopathic hypereosinophilic syndrome, Ki-1 positive anaplastic large cell lymphoma, hepatic hemangioma, papillary thyroid disease, ankle arthritis, autoimmune hepatitis, Lewis lung cancer, chronic urticaria, cutaneous epithelial hyperplasia, childhood asthma,Congenital emphysema, infant colitis, colitis, acquired aplastic anemia, viral myocarditis, rhinovirus infection, Candida albicans infection, gastric adenocarcinoma, tumor necrosis, secondary bacterial pneumonia, asthmatic pulmonary eosinophilia, Lofgren's syndrome, stable angina pectoris, anterior wall myocardial infarction, aortic dissection, autoimmune enteropathy, systemic pustular psoriasis, malignant neoplasm of the prostate, hematological malignancies, leukocyte adhesion disorder type 1, non-alcoholic fatty liver disease, idiopathic crescent glomerulonephritis, primary antiphospholipid syndrome, endometrial cancer, puncture wounds, combined immunodeficiency, central sleep apnea, recurrent tumors Neurodegenerative disorders, X-linked lymphoproliferative disorder, osteosarcoma of bone, aquatic humoral disorders, prostate cancer, bladder cancer, respiratory diseases, acne, dissecting aortic aneurysm of the thoracic aorta, viral respiratory infections, corneal infections, midcerebral artery occlusion, acute pneumonia, allergic symptoms, Cockayne syndrome type 1, idiopathic inflammatory myopathy, gluten sensitivity, Helicobacter pylori infection, arteriopathies, Pseudomonas aeruginosa infection, endothelial dysfunction, chronic candidiasis, Plasmodium vivaxin malaria infection, mycosis fungoides / Sézary syndrome, chronic graft-versus-host disease, pancolitis, vasculitis, invasive ductal carcinoma, lymphocyte infiltration, chest Thyroid spindle cell tumor with adenoid differentiation, granulocytosis, pancreatic intraepithelial neoplasia, sporadic breast cancer, myocardial fibrosis, familial idiopathic cardiomyopathy, latent tuberculosis, cirrhosis, minimally invasive nephrotic syndrome, non-neoplastic disorders, severe sepsis, dose-sensitive sex reassignment, chronic myeloproliferative disorder, chronic myeloproliferative disorder with eosinophilia, childhood ataxia with hypomyelination of the central nervous system, amyotrophic lateral sclerosis 1, sporadic amyotrophic lateral cirrhosis, early coronary artery disease, type 1 crossed polydactyly, endometrial cancer, vulvar NK-T cell lymphoma, photoreceptor degeneration, chronic Lyme disease, cryopyrin-related conditions. Cycle syndromes, chronic kidney disease stage 5, destructive arthritis, adiponectin deficiency, sessile serrated adenoma / polyp, Diazani autoimmune lymphoproliferative syndrome, autosomal dominant hyperimmune globulin E syndrome, immune reconstitution inflammatory syndrome (IRIS), non-alcoholic steatohepatitis, myelodysplastic syndrome, granulomatosis with polyangiitis, familial hypophosphatemic Rickett syndrome, allergic diathesis, acute-chronic liver failure, aspirin-exacerbated respiratory disease, prerenal acute kidney injury, post-treatment Lyme disease syndrome, early rheumatoid arthritis, membranous lupus nephritis, fetal or neonatal necrotizing enterocolitis. 【0051】 IL21-related diseasesCeliac disease, systemic lupus erythematosus, common variable 11 immunodeficiency, experimental autoimmune encephalomyelitis, periodontal disease, rheumatoid arthritis, autoimmune disease, insulin-dependent diabetes mellitus, asthma, ulcerative colitis, Crohn's disease, infectious diseases, multiple sclerosis, Sézary syndrome, follicular lymphoma, acquired immunodeficiency syndrome, Hodgkin's disease, tropical malaria, juvenile arthritis, chronic lymphocytic leukemia, Addison's disease, alopecia areata, viral bronchiolitis, immediate-type hypersensitivity, respiratory syncytial virus infection, inflammatory bowel disease, lupus vulgaris, discoid lupus erythematosus, psoriasis, lupus erythematosus, hepatitis B, multiple Myeloma, viral diseases, diffuse large B-cell lymphoma, immune thrombocytopenic purpura, complete atrioventricular block, persistent embryonic structures, malignant neoplasia of the breast, malignant neoplasia of the colon, colitis, general variable immunodeficiency, atopic dermatitis, diabetes mellitus, diabetes mellitus vera, eczema, Graves' disease, adult T-cell lymphoma / leukemia, lymphoma, malignant neoplasia of the stomach, ovarian cancer, schistosomiasis, B-cell lymphoma, primary Sjögren's syndrome, chronic hepatitis B, chronic hepatitis C, breast cancer, colon cancer, stomach cancer, malignant neoplasia of the ovaries, X-linked severe combined immunodeficiency, pseudohyperkalemia Cardiff, acquired hypogammarhagic tuna Bulinemia, aplastic anemia, arthritis, Burkitt lymphoma, cerebral infarction, echinococcosis, glioblastoma, glioma, graft-versus-host disease, hepatitis, HIV infection, angioimmunoblastic lymphadenopathy, immunodeficiency syndrome, liver disease, hepatic neoplasm, chronic obstructive airway disease, melanoma, Mikulicz's disease, nasal polyps, neoplasm metastasis, neuroblastoma, degenerative polyarthritis, polyps, Henoch-Schönlein purpura, schizophrenia, systemic sclerosis, sialadenitis, cerebrovascular accident, toxoplasmosis, tuberous sclerosis, Harada's disease encephalitis syndrome, cutaneous T-cell lymphoma, severe combined immunodeficiency, Sikka syndrome, oral ulcers Surgery, idiopathic pulmonary hypertension, dacryodenitis, allergic asthma, malnutrition, autoimmune thyroid disease, cerebral cysts, pancreatic cancer, collagenous colitis, bone destruction, autoimmune thrombocytopenia, epithelial hyperplasia of the skin, familial lichen amyloid lichen, acquired aplastic anemia, platelet alloimmune thrombocytopenia, disseminated neuroblastoma, solid tumors, malignant lymphoma (lymphocytic, moderately differentiated, diffuse), hematological malignancies, lymphocytic colitis, ventriculosomiasis, thymic insensitivity, leukemia induction, Hashimoto's disease, central nervous system blastoma, allergic symptoms, acute cerebrovascular disease, pancreatitis, cerebral ischemia, ischemic stroke, progressive multiple sclerosis,Neuroblastoma stage 4s, inflammatory diseases, ALK-negative anaplastic large cell lymphoma, Sjögren's syndrome, benign prostatic hyperplasia, liver cancer, idiopathic pulmonary arterial hypertension, ischemic cerebrovascular disease, acute-chronic liver failure, early rheumatoid arthritis, selective immunoglobulin deficiency, antibody-type adaptation reactions, acute solid organ transplant rejection (liver, heart, lung, kidney), chronic solid organ graft rejection (liver, heart, lung, kidney), alloimmune hypersensitivity. 【0052】 IL22-related diseases Autoimmune hepatitis, middle cerebral artery infarction, chemical and drug-induced liver injury, asthma, myocarditis, Crohn's disease, psoriasis, inflammatory bowel disease, hepatitis C infection, liver cancer, autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus, HIV infection, chronic mucocutaneous candidiasis, pneumonia, inflammation, colitis, ulcerative colitis, viral bronchiolitis, neoplasms of the colon, respiratory syncytial virus infection, atopic dermatitis, eczema, chronic Lymphocytic leukemia, colon cancer, inflammatory skin disease, malignant neoplasm of the colon, dermatitis, multiple sclerosis, carcinogenesis, celiac disease, malignant neoplasia of the stomach, multiple myeloma, primary Sjögren's syndrome, gastric cancer, amyloidosis, arthritis, colorectal cancer, diabetes mellitus (insulin-dependent), hepatitis A, hepatitis B, liver disease, hepatic neoplasm, chronic obstructive airway disease, mycosis, tuberculosis, viral diseases, cutaneous T-cell lymphoma Multiglandular autoimmune syndrome type 1, complete atrioventricular block, immune thrombocytopenic purpura, colorectal cancer, functional impairment - skin disorders, bacterial infections, Behçet's syndrome, malignant neoplasia of the breast, candidiasis, non-small cell lung cancer, glioblastoma, Graves' disease, lymphoma, ovarian cancer, schistosomiasis, Sézary syndrome, skin diseases, uveitis, diffuse large B-cell lymphoma, malnutrition, Ki-1 positive anaplastic large cell lymphoma, hepatic fibrosis, remnant fetal structure, hyperactivity, breast cancer, Helicobacter pylori infection, malignant neoplasia of the ovary, Sjögren's syndrome, acute colitis, abscess, adenocarcinoma, adenovirus infection, Alzheimer's disease, aortic valve insufficiency, bacterial pneumonia, Burkitt lymphoma, oral candidiasis, vaginal candidiasis, squamous cell carcinoma, cerebral infarction, colon disease, cytomegalovirus infection, dejuvant Line Sottas disease (disorder), dengue fever, diabetes mellitus, diabetes mellitus vera, non-insulin-dependent diabetes mellitus, diarrhea, echinococcosis, erythema nodosum, gastroenteritis, gingival disease, glioma, graft-versus-host disease, severe dengue fever, angioimmunoblastic lymphadenopathy, immunodeficiency syndrome, influenza, myeloid leukemia, alcoholic liver disease, lupus vulgaris, discoid lupus erythematosus, lupus nephritis, melanoma, nasal polyps, nephritis, neuroblastoma, nodules, obesity, degenerative polyarthritis, palmar and plantar pustulosis, Pancreatitis, periodontal disease, polyps, Henoch-Schönlein purpura, rotavirus infection, schizophrenia, systemic sclerosis, sepsis, skin lesions, ankylosing spondylitis, cerebrovascular disease, thyroid disease, toxoplasmosis, tuberous sclerosis, urticaria pigmentosum, viral hepatitis, vitiligo, B-cell lymphoma, severe combined immunodeficiency, Sikka syndrome, retinal vasculitis, lobomycosis, idiopathic pulmonary hypertension, corneal pannus, depigmentation disorder, hidradenitis suppurativa, intestinal infections (disorders), autoimmune thyroid disease, tumor progression , brain cysts, pancreatic cancer, collagenous colitis, papillary thyroid carcinoma, malignant neoplasia of pulmonary mucosa-associated lymphoid tissue, lymphoma, sepsis, psoriatic eczema, psoriasis vulgaris, epithelial hyperplasia of the skin, cecum, familial amyloid lichen, acquired aplastic anemia, disseminated neuroblastoma, capillary malformations (disorders), systemic pustular psoriasis, methicillin-resistant Staphylococcus aureus (MRSA) infection, Helicobacter pylori (H. pylori) infection, hematological malignancies, microscopic colitis, lymphocytic colitis, proliferative glomerulonephritis of unknown findings, plaque psoriasis Lupus erythematosus, skin puncture wounds, hydatid cysts, chronic hepatitis B, chronic hepatitis C, leukemia induction, Hashimoto's disease, lung cancer, central nervous system blastoma, acute cerebrovascular disease, acute GVH disease, cerebral ischemia, intraperitoneal infection, neuroblastoma stage 4s, X-linked combined immunodeficiency, inflammatory diseases, chronic inflammatory diseases, primary malignant neoplasms of the lung, undifferentiated, ALK-negative large cell lymphoma, ALK-positive large cell lymphoma, gastric mucosa-associated lymphoid tissue (gastric MALT) lymphoma, intestinal graft-versus-host disease, benign prostatic hyperplasia, chromosome 11p11.2-deletion syndrome, immunosuppression, susceptibility to multiple autoimmune diseases associated with vitiligo, gene dose-sensitive sex reversal, exfoliation syndrome, pseudohyperkalemia Cardiff, immune reconstitution inflammatory syndrome (iris), idiopathic pulmonary arterial hypertension, enthesitis-associated arthritis, ulcerative colitis in remission, non-infectious pneumonia, early rheumatoid arthritis, antibody-mediated rejection, acute solid organ transplant rejection (liver, heart, lung, kidney), chronic solid organ graft rejection (liver, heart, lung, kidney), alloimmune hypersensitivity. 【0053】 IL24-related diseases Lung tumors, pancreatic tumors, major depressive disorder, breast tumors, prostate neoplasms, spontaneous miscarriage, unipolar depression, periodontal disease, melanoma, liver cancer, glioma, lung cancer, malignant neoplasms of the lung, malignant neoplasms of the breast, prostate cancer, breast cancer, primary malignant neoplasms of the lung, metastatic melanoma, malignant neoplasms of the prostate, glioblastoma, chronic lymphocytic leukemia, squamous cell carcinoma, adenocarcinoma, rheumatoid arthritis, non-small cell lung cancer, neoplasm metastasis, asthma, viral bronchiolitis, hepatitis C, HIV infection, respiratory syncytial virus infection, ovarian cancer, pancreatic cancer, ovarian malignancies Neoplastic angiogenesis, colorectal cancer, malignant neoplasms of the pancreas, glioblastoma multiforme, colorectal cancer, leukemia, psoriasis, epithelial ovarian cancer, tumor angiogenesis, renal cell carcinoma, liver and intrahepatic biliary tract cancer, solid tumors, malignant neoplasms of the liver, malignant glioma, kidney cancer, autoimmune diseases, ulcerative colitis, Crohn's disease, inflammatory bowel disease, influenza, acute lymphoblastic leukemia, leukemia, myeloid leukemia, retinoblastoma, secondary malignant neoplasms of the lung, carcinogenesis, gastric cancer, ovarian neoplasms, dysfunction-skin disorders, malignant neoplasms of the bladder, bladder tumors, encephalogenesis Malignant tumors of the colon, malignant tumors of the cervix, dermatitis, lymphocytic leukemia, acute myeloid leukemia, systemic lupus erythematosus, malignant neoplasia of the stomach, mesothelioma, experimental neoplasms, neuroblastoma, pustulosis of the palms and soles, juvenile periodontitis, salmonella infection, skin diseases, typhoid fever, urinary tract infections, viral diseases, vitiligo, tumor progression, acute urinary tract infections, epithelial hyperplasia of the skin, gastric adenocarcinoma, conventional (clear cell) renal cell carcinoma, cervical cancer, generalized psoriasis, malignant mesothelioma, multiple malignant tumors, disseminated malignancy Neoplasms, neuropathy, squamous cell carcinoma of the skin, secondary malignant neoplasms of lymph nodes, colon cancer, bladder cancer, central nervous system blastoma, microphthalmia (syndrome 7), malignant pleural mesothelioma, adenovirus infection, B lymphoblastic leukemia / lymphoma, squamous cell carcinoma of the head and neck, mesothelioma (malignant, clinically impaired) (impairment), pancreatic ductal adenocarcinoma, mammary tumor formation, susceptibility to multiple autoimmune diseases associated with vitiligo 1, progenitor cells or cells, lymphoblastic leukemia / lymphoma, mechanical allodynia, inflammatory dermatosis, mixed lineage leukemia, persistent oligoarticular juvenile Sexually idiopathic arthritis, cervical cancer. 【0054】 IL26-related diseases Rheumatoid arthritis, Crohn's disease, asthma, viral bronchiolitis, ulcerative colitis, insulin-dependent diabetes mellitus, inflammatory bowel disease, multiple sclerosis, respiratory syncytial virus infection, smoking-related diseases, chronic ulcerative colitis, obstructive bronchiolitis, graft-versus-host disease, malignant neoplasia of the stomach, pulmonary fibrosis, tuberculosis, gastric cancer, chronic graft-versus-host disease. 【0055】 Abbreviation Abbreviations and terms commonly used in the fields of organic chemistry, medicinal chemistry, pharmacology, and medicine, and well known to those skilled in the art in these fields, are used herein. Representative abbreviations and their definitions are listed below. 【0056】 Ac represents the acetyl group [CH3C(0)-], Ac2O represents acetic anhydride; APC represents antigen-presenting cell; 9-BBN represents 9-borabicyclo[3.3.1) represents nonane; Bn represents the benzyl group; BOC represents the tert-butyloxycarbonyl group; DIAD represents diisopropyl azodicarboxylic acid; DIBAL represents diisobutylaluminum hydride; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EDAC (or EDC) represents 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride; Et3N represents triethylamine; Et represents the ethyl group; siRNA represents ethyl acetate; EtOH represents ethanol.し;3-F-Ph represents a 3-fluorophenyl group, HCl represents hydrochloric acid; HOBt represents 1-hydroxybenzotriazole; HPLC represents high-performance liquid chromatography; LCMS represents HPLC with mass spectral detection; LG represents a leaving group; M represents molar concentration; mmol represents millimoles; Me represents a methyl group; MeOH represents methanol; MsCI represents methanesulfonyl chloride; NaHMDS represents sodium hexamethyldisilazane; NaOAc represents sodium acetate; NaOtBu represents sodium ∫ The abbreviations represent the la-methoxybenzyl group; RT represents room temperature; TBAF represents tetrabutylammonium fluoride; TBS represents the tert-butyldimethylsilyl group; tBu represents the tert-butyl group; Tf represents the triflate group; TFA represents trifluoroacetic acid; TFIF represents tetrahydrofuran; TLC represents thin-layer chromatography; TMAO represents trimethylamine oxide; DMF represents dimethylformamide; TMS represents the trimethylsilyl group; and TPAP represents tetrapropylammonium perlutenate. 【0057】 definition The term "alkyl," as well as other groups with the prefix "alk," such as alkoxy and alkanoyl groups, means a carbon chain that can be linear, branched, or a combination thereof, unless otherwise defined. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, and nonyl groups. Where a specified number of carbon atoms is accepted, for example, 3 to 10 carbon atoms, the term alkyl group also includes cycloalkyl groups and combinations of linear or branched alkyl chains with cycloalkyl structures. If the number of carbon atoms is not specified, 1 to 6 carbon atoms are intended. 【0058】 A "cycloalkyl group" is a part of an alkyl group, meaning a saturated carbon ring having a specific number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Generally, cycloalkyl groups are monocyclic unless otherwise specified. Unless otherwise defined, cycloalkyl groups are saturated. 【0059】 The term "alkoxy group" refers to an unbranched or branched alkoxide with a specified number of carbon atoms (e.g., alkoxy groups with 1 to 6 carbon atoms), or any number within this range [i.e., methoxy (Me0-), ethoxy, isopropoxy, etc.]. 【0060】 The term “alkylthio group” refers to an unbranched or branched alkyl sulfide with a specified number of carbon atoms (e.g., alkylthio groups with 1 to 6 carbon atoms) or any number within this range [i.e., methylthio group (MeS-), ethylthio group, isopropylthio group, etc.]. 【0061】 The term “alkylamino group” means an unbranched or branched alkylamine having a specified number of carbon atoms (e.g., alkylamino groups with 1 to 6 carbon atoms) or any number within this range [i.e., methylamino group (MeS-), ethylamino group, t-butylamino group, etc.]. 【0062】 The term “alkylsulfonyl group” means an unbranched or branched alkylsulfone having a specified number of carbon atoms (e.g., alkylsulfonyl groups with 1 to 6 carbon atoms) or any number within this range [i.e., methylsulfonyl group (MeSC), ethylsulfonyl group, isopropylsulfonyl group, etc.]. 【0063】 The term “alkylsulfinyl group” means an unbranched or branched alkyl sulfoxide of a specified number of carbon atoms (e.g., alkylsulfinyl groups with 1 to 6 carbon atoms) or any number within this range [i.e., methylsulfinyl group (MeSO-), ethylsulfinyl group, isopropylsulfinyl group, etc.]. 【0064】 The term “alkyloxycarbonyl group” means an unbranched or branched chain ester of a carboxylic acid derivative having a specified number of carbon atoms (e.g., alkyloxycarbonyl groups with 1 to 6 carbon atoms) or any number within this range [i.e., methyloxycarbonyl group (MeOCO-), ethyloxycarbonyl group, or butyloxycarbonyl group, etc.]. 【0065】 An "aryl group" refers to a monocyclic or polycyclic aromatic ring system containing a carbocyclic atom. Preferred aryl groups are monocyclic or bicyclic aromatic ring systems with 6-10 members. Phenyl and naphthyl groups are preferred aryl groups. The most preferred aryl group is the phenyl group. 【0066】 A “heterocyclyl group” means a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S, and N, and further containing an oxidized form of sulfur, i.e., SO and SO2. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, pipediline, 1,3-dioxolane, imidazolidin, imidazoline, pyrroline, pyrrolidine ring, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, 2-oxopiperidine-1-yl, 2-oxopyrrolidine-1-yl, 2-oxoazetidine-1-yl, 1,2,4-oxadiazine-5(6H)-on-3-yl, etc. 【0067】 "Heteroaryl" means an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from O, S, and N. For example, heteroaryls include heteroaryls fused to other types of rings such as aryl groups, cycloalkyl groups, and non-aromatic heterocycles. Examples of heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazole (especially 1,3,4-oxadiazole-2-yl and 1,2,4-oxadiazole-3-yl), thiadiazole, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadi This includes azolyl, dihydrobenzofuranyl, indolinyl, pyridadinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthilidinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, flazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, etc. In the case of heterocyclyl and heteroaryl groups, rings and ring systems containing 3 to 15 atoms are included, forming 1 to 3 rings. 【0068】 "Halogen" refers to fluorine, chlorine, bromine, and iodine. Chlorine and fluorine are generally preferred. When the halogen is substituted with an alkyl or alkoxy group (e.g., CF3O and CF3CH2O), fluorine is most preferred. 【0069】 As used herein, the term “composition” is intended to encompass products containing a particular component in a specific amount, as well as any products arising directly or indirectly from a particular combination of components in a specific amount. Such terms relating to pharmacochemicals are intended to encompass products containing an active ingredient and an inert component constituting a carrier, as well as any products obtained directly or indirectly from any combination of two or more components that constitute complex formation or aggregation, or from the dissociation of one or more other types of components, or from other types of reactions or interactions of one or more components. Therefore, a pharmaceutical composition encompasses any composition made by mixing a compound and a pharmaceutically acceptable carrier. “pharmaceutically acceptable” or “acceptable” means a carrier, diluent or excipient that can be mixed with other components of a formulation and is not harmful to their recipients. 【0070】 The compounds represented by structural formulas (I), (II), (III), and (IV) may contain one or more asymmetric centers and therefore may exist as racemates and racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers. The compounds are intended to encompass all isomeric forms, such as those of the compounds of structural formulas (I), (II), (III), and (IV). 【0071】 The compounds of structural formulas (I), (II), (III), and (IV) can be separated into their individual diastereoisomers by fractional crystallization from a suitable solvent such as methanol, ethyl acetate, or a mixture thereof, or by chiral chromatography using an optically active stationary phase. Absolute stereochemistry can be determined, if necessary, by X-ray crystallography of crystalline products or crystalline intermediates derivatized with reagents containing asymmetric centers of known absolute configurations. 【0072】 Alternatively, any stereoisomer of the compounds represented by general structural formulas (I), (II), (III), and (IV) can be obtained by stereospecific synthesis using optically pure starting materials or reagents with known absolute configurations. 【0073】 Figures 3A-B, 4A-B, 5A-B, and 6A-B show the synthesis of compounds represented by general formulas (I), (II), (III), and (IV). 【0074】 Figures 3A-B, 4A-B, 5A-B, and 6A-B show the synthesis of compounds 1 to 23 and their chemical analogs represented by general formulas (I), (II), (III), and (IV). The compounds synthesized and disclosed herein include 23 compounds named according to the International Union of Pure and Applied Chemistry (IUPAC) nomenclature as follows: 【0075】 Compound 1: N-(3-(4-benzylpiperazine-1-carbonyl)-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-fluorobenzamide; Compound 2: N-(3-(benzylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-5-chloro-2-(methylthio)pyrimidine-4-carboxamide; Compound 3: 5-Chloro-N-(3-{[(1,1-dioxidetetrahydro-3-thienyl)amino]-carbonyl}-6-methyl-4,5,6,7-tetrahydro-1-benzothien-2-yl)-2-(methylthio)-4-pyrimidine-carboxamide; Compound 4: N-(6-ethyl-3-{[(2-methylphenyl)amino]carbonyl}-4,5,6,7-tetrahydro-1-benzothien-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; Compound 5: N-{6-tert-butyl-3-[(4-methyl-1-piperazinyl)carbonyl]-4,5,6,7-tetrahydro-1-benzothien-2-yl}-2-fluorobenzamide; Compound 6: 2-Fluoro-N-{6-methyl-3-[(4-methyl-1-piperazinyl)carbonyl]-4,5,6,7-tetrahydro-1-benzothien-2-yl}benzamide; Compound 7: N-benzyl-2-[(trifluoroacetyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; Compound 8: N-benzyl-2-({[(4-methyl-2-pyrimidinyl)thio]acetyl}amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; Compound 9: N-benzyl-2-[(1-piperidinylacetyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; Compound 10: N-benzyl-2-{[(4-methyl-1-piperazinyl)acetyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; Compound 11: N-benzyl-2-{[(4-methyl-1-piperidinyl)acetyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; Compound 12: N-(3-(2-methylpyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)nicotinamide; Compound 13: N-(3-((2R,4R)-2,4-dimethylpiperidine-1-carbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)nicotinamide; Compound 14: N-(3-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)nicotinamide; Compound 15: N-(3-(3-ethylpyrrolidine-1-carbonyl)-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)nicotinamide; Compound 16: N-benzyl-2-(2-((1-methyl-1H-imidazole-2-yl)thio)acetamide)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide; Compound 17: N-(3-(3-(hydroxymethyl)pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)nicotinamide; Compound 18: N-(6,6-dimethyl-3-(morpholine-4-carbonyl)-4,5 ,6,7-tetrahydrobenzo[b]thiophene-2-yl)pyrazine-2-carboxamide; Compound 19: N-(3-(((1-methyl-1H-1,2,4-triazole-3-yl)methyl)carbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)nicotinamide; Compound 20: (S)-N-(3-((1-cyanoethyl)carbamoyl)-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)nicotinamide; Compound 21: N-(3-((piperidine-4-ylmethyl)carbamoyl)-4,5,6,7-tetrahydro-benzo[b]thiophene-2-yl)nicotinamide; Compound 22: N-(3-benzoyl 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)pyrazine-2-carboxamide; and Compound 23: N-(3-benzoyl 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-5-methyl-2-(methylsulfonyl)pyrimidine-4-carboxamide. 【0076】 In particular, compounds 1 to 23 may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts and general methodologies for their preparation are well known in the art. (e.g., P. Stahl et al., Handbook of Pharmaceuticals) Salts-Properties, Selection and Use, 2nd edition (Wiley-VCH, 2011); SM Berge et al., Pharmaceutical Salts, Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977). 【0077】 Those skilled in the art will understand that the compounds represented by formulas (I), (II), (III), and (IV), or their pharmaceutically acceptable salts, may contain four chiral centers represented by “*” in Figure 2. Furthermore, any number of chiral centers may arise in situations where the R1-R7 groups contain additional chiral centers. Compounds 1 to 23 disclosed herein are intended to include all individual enantiomers, as well as mixtures of enantiomers of the above compounds, including racemates. Those skilled in the art will also understand that the Kahn-Ingold-Prelogue (R) or (S) designations for all chiral centers vary depending on the substitution pattern of a particular compound. Single enantiomers or diastereomers may be prepared starting from chiral reagents or by stereoselective or stereospecific synthesis techniques. Alternatively, a single enantiomer or diastereomer can be isolated from the mixture by standard chiral chromatography or crystallization techniques at any convenient stage during the synthesis of compounds 1 to 23 and the compounds represented by general formulas (I), (II), (III), and (IV). The single enantiomers of compounds 1 to 23 and the compounds represented by general formulas (I), (II), (III), and (IV) disclosed herein are preferred embodiments. Compounds 1 to 23 and the compounds represented by general formulas (I), (II), (III), and (IV) are also preferably formulated as pharmaceutical compositions administered via various routes. Such pharmaceutical compositions and methods for producing them are well known in the art (i.e., A. Gennaro et al., Remington: The Science and Practice of Pharmacy, 21st edition, Mac Publishing Company, 2005). Particularly preferred are pharmaceutical compositions comprising compounds represented by formulas (I), (II), (III), or (IV). 【0078】 If necessary, the racemic mixture of compounds can be separated to isolate the individual enantiomers. Separation can be carried out by methods well known in the art, such as coupling the racemic mixture of compounds to enantiomerically pure compounds to form a diastereomer mixture, followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography. Often, coupling reactions are performed using enantiomerically pure acids or bases. This is the formation process. Next, the diastereomer derivative can be converted to the pure enantiomer by cleavage of the added chiral residue. The racemic mixture of compounds can also be separated directly by chromatography using a chiral stationary phase, a method well known in the art. 【0079】 Some of the compounds described herein contain olefin double bonds, and unless otherwise specified, this means that both E and Z geometric isomers are included. 【0080】 Some of the compounds described herein may exist as tautomers having different bond sites of hydrogen atoms with one or more double bond shifts. For example, ketones and their enol forms are keto-enol tautomers. Individual tautomers and mixtures thereof are included in the compounds. 【0081】 In compounds represented by the general formulas (I), (II), (III), and (IV), atoms exhibit their natural isotopic abundances, or one or more atoms may be artificially enriched with specific isotopes having the same number of atoms, but their atomic masses or mass numbers differ from those primarily found in nature. A compound means that it contains all appropriate isotopic variations of the compounds represented by the general formulas (I), (II), (III), and (IV). For example, various isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2It contains (H). Protium is the primary hydrogen isotope found in nature. Deuterium enrichment can yield certain therapeutic benefits, such as extending the half-life in vivo or reducing the required dosage, and can provide compounds useful as standards for characterizing biological samples. The isotopic enriched compounds in general formulas (I), (II), (III), and (IV) can be prepared without excessive experimentation by conventional techniques well known to those skilled in the art, or by similar processes described herein in the schemes and examples using appropriate congener enrichment reagents and / or intermediates. 【0082】 Salt and preparations As used herein, references to compounds represented by structural formulas (I), (II), (III), and (IV) are understood to include pharmaceutically acceptable salts, as well as pharmaceutically unacceptable salts when used as precursors to their free compounds, their pharmaceutically acceptable salts, or other synthetic operations, or in other synthetic operations. The term “pharmaceutically acceptable salt” means a salt prepared from a pharmaceutically acceptable, non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds included in the term “pharmaceutically acceptable salt” generally mean non-toxic salts of compounds prepared by reacting a free base with a suitable organic or inorganic acid. Representative salts of basic compounds include, but are not limited to, the following: acetates, benzenesulfons, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, camusylates, carbonates, chlorides, clavulanates, citrates, edetates, edisylates, estates, esylates, fumarates, gluceptates, glucons, glutamates, hexylresorcinates, hydrobroms, hydrochlorides, hydroxynaphthoates, iodides, isothionates, lactates, and lactobion. Acids, laurates, malates, maleates, mandelates, mesylates, methyl bromide, methyl nitrate, methyl sulfate, mucinates, napsates, nitrates, N-methylglucamine ammonium salts, oleates, oxalates, pamoates (embonates), palmitates, pantothenates, phosphates / diphosphates, polygalacturonic acid, salicylates, stearates, sulfates, acetates, succinates, tannates, tartrates, theocrates, tosylates, triethiodies, and valeric acid. Furthermore, if a compound has an acidic moiety, suitable pharmaceutically acceptable salts thereof are not limited to these, but include aluminum, ammonium, calcium, copper, ferric iron, lithium, magnesium, manganese, manganese, potassium, This includes salts derived from inorganic bases such as sodium and zinc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpipediline, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, pipediline, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine. 【0083】 Furthermore, if a carboxylic acid group or alcohol group is present in the compound, pharmaceutically acceptable esters of carboxylic acid derivatives such as methyl, ethyl, or pivaloyloxymethyl groups, or acyl derivatives of alcohols such as acetyl, pivaloyl, benzoyl, and aminoacyl groups, may also be used. This includes esters and acyl groups known in the art for modifying solubility or hydrolysis properties for use as sustained-release or prodrug formulations. 【0084】 Furthermore, solvates, especially hydrates, of the compounds represented by structural formulas (I), (II), (III), and (IV) are also included. 【0085】 According to one embodiment, the compounds represented by structural formulas (I), (II), (III), and (IV) may be included in various formulations for use as pharmaceuticals. Oral formulations may be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium such as peanut oil, liquid paraffin, or olive oil. 【0086】 The aqueous suspension comprises an active material mixed with an excipient suitable for the preparation of the aqueous suspension. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum; the dispersant or wetting agent may be a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide and a fatty acid such as polyoxyethylene stearate, or a condensation product of an ethylene oxide and a long-chain aliphatic alcohol such as heptadecaethylene-oxycentanol, or an ethylene oxide having a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or an ethylene oxide having a partial ester derived from a fatty acid and hexitol anhydride such as polyethylene sorbitan monooleate. The aqueous suspension may also contain, for example, one or more preservatives such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose, saccharin, or aspartame. 【0087】 Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings, as described above, may be added to provide a palatable oral formulation. These compositions can be preserved by adding antioxidants such as ascorbic acid. 【0088】 Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide active ingredients mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Further excipients such as sweeteners, flavorings, and colorants may also be present. 【0089】 The pharmaceutical ingredients may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids such as soybeans and lecithin, and esters or partial esters derived from fatty acids such as sorbitan monooleate and hexitol anhydride, and condensation products of the aforementioned partial esters such as polyoxyethylene sorbitan monooleate and ethylene oxide. The emulsion may also contain sweeteners and flavorings. 【0090】 Syrups and elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain analgesics, preservatives, flavorings, and colorings. Pharmaceutical compositions may be in the form of sterile, injectable aqueous or oily suspensions. These suspensions may be formulated according to known techniques using the appropriate dispersants or wetting agents and suspending agents described above. Sterile, injectable preparations may also be sterile, injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixative oils have traditionally been used as solvents or suspension media. For this purpose, any mixed fixative oils containing synthetic monoglycerides or diglycerides may be used. In addition, fatty acids such as oleic acid have been found to be used in the preparation of injectable preparations. 【0091】 The compounds can also be administered intranasally or by inhalation, typically in the form of a dry powder from a dry powder inhaler (alone, as a mixture such as a dry blend with lactose, or as mixed component particles mixed with phospholipids such as phosphatidylcholine), or as an aerosol spray from a pressurized vessel, pump, sprayer, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist), or inhaler, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. When used intranasally, the powder may contain bioadhesives such as chitosan or cyclodextrin. 【0092】 A pressurized container, pump, spray, atomizer, or inhaler contains, for example, a solution or suspension of a compound comprising ethanol, aqueous ethanol, or a suitable alternative for dispersion, solubilization, or sustained release of the active ingredient, a propellant as a solvent, and any surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid. 【0093】 Before use in dry powder or suspension formulations, pharmaceuticals are pulverized to a size suitable for inhalation delivery (usually less than 5 microns). 【0094】 This can be achieved by any suitable grinding method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid treatment for forming nanoparticles, high-pressure homogenization, or spray drying. 【0095】 Capsules (e.g., made from gelatin or HPMC), blisters, and cartridges for use in inhalers or inhalers may be formulated to contain a powder mixture of the compound, a suitable powder base such as lactose or starch, and performance enhancers such as L-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or 1 It may be a hydrate, preferably in the latter form. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. 【0096】 Suitable solution formulations for use in atomizers that generate fine mist using electrohydrodynamics may contain approximately 1 mg to 20 mg of the compound per operation, and the operation volume may vary from approximately 1 microliter to 1000 microliters. Typical formulations may include the compounds represented by formulas (I), (II), (III), and (IV), propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol. 【0097】 Appropriate flavors such as menthol and levomenthol, or sweeteners such as saccharin or sodium saccharin, may be added to these formulations intended for inhalation / intranasal administration. 【0098】 Formulations for inhalation / intranasal administration may be formulated to be immediate and / or sustained-release, for example, using poly(D,L-lactic acid-coglycolic acid (PGLA)). Sustained-release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release formulations. 【0099】 In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that dispenses a measured amount. The unit is typically configured to administer a measured single dose or "puff" containing 1 ng to 10 mg of the compound represented by formulas (I), (II), (III), and (IV). The total daily dose is typically 1 ng to 10 mg, which can be administered as a single dose or, more commonly, in divided doses throughout the day. 【0100】 All molecules are effective when started at nanomolar concentrations and do not cause cell death in cultures at high micromolar concentrations. 【0101】 The compounds represented by formulas (I), (II), (III), and (IV) can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore dissolves in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol. 【0102】 For topical use, creams, ointments, jellies, solutions, or suspensions containing the compounds represented by formulas (I), (II), (III), and (IV) are used. For the purposes of this application, topical application must include mouthwashes and oral rinses. 【0103】 usefulness The compounds specifically exemplified herein demonstrate good efficacy in modulating RORγt, as shown by their in vitro assays. 【0104】 According to one embodiment, RORγt inhibitors may improve the prevention or treatment of autoimmune diseases and may be useful in the prevention or treatment of autoimmune diseases. 【0105】 One embodiment provides a method for the treatment and control of cancer, which comprises administering an effective amount of compounds represented by formulas (I), (II), (III), and (IV) and anticancer agents to a patient in need of such treatment. 【0106】 In addition to primates such as humans, various other mammals can be treated using this method. For example, but not limited to, this method can be used to treat mammals including cattle, sheep, goats, horses, dogs, cats, guinea pigs, rats, or other rodents such as cows, sheep, horses, dogs, cats, and mice. However, this method can also be used on other species such as birds (chickens, etc.). 【0107】 Combination therapy Patients requiring immunotherapy may be treated with antigen-presenting cells (APCs) activated with compounds represented by formulas (I), (II), (III), and (IV), concurrently with other treatments known to the physician. The use of such multiple therapies may be particularly beneficial to the patient. Such therapies include, but are not limited to, surgical resection, radiotherapy, chemotherapy, targeted therapy, and other types of immunotherapy. Available chemotherapeutic agents include: a) Cytotoxic agents such as Taxol, Cytochalasin B, Gramicidin D, Ethidium bromide, Emetine, Mitomycin, Etoposide, Teniposide, Vincristine, Vinblastine, Colchicine, Doxorubicin, Daunorubicin, Dihydroxyanthracendione, Mitoxantrone, Mitramycin, Actinomycin D, 1-Dehydrotestosterone, Glucocorticoids, Procaine, Tetracaine, Lidocaine, Propranolol, and Puromycin, as well as their analogs or homologues; b) Antimetabolites such as methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, and 5-fluorouracildacarbazine; c) Alkylating agents such as mechloretamine, thiotepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum(II) (DDP) cisplatin; d) Anthracyclines such as daunorubicin and doxorubicin; e) Antibiotics such as dactinomycin, bleomycin, mitramycin, and anthramycin (AMC); f) Mitotic inhibitors such as vincristine and vinblastine; g) Targeted therapies that can be used include, but are not limited to, hormone therapies (such as degarelix and luteinizing hormone-releasing hormone (LHRH) antagonists that lower testosterone levels in prostate cancer), signaling inhibitors (such as imatinib and trastuzumab), gene expression modulators (e.g., HDAC inhibitors, panobinostat and bellinostat), apoptosis inhibitors (e.g., recombinant human TNF-related apoptosis-inducing ligand (TRAIL)), and angiogenesis inhibitors (such as sorafenib, sunitinib, pazopanib, and everolimus), and h) Immunotherapy agents that can be used include monoclonal antibody therapies (anti-CTLA4, anti-PD1) and chimeric antigen receptor (CAR) T cells. [Examples] 【0108】 The following examples are provided for illustrative purposes only and should not be construed as limiting the invention in any way. The scope of the invention is defined by the appended claims. 【0109】 Example 1 :Chemical synthesis Novel ROR modulators represented by formulas (I), (II), (III), and (IV), shown by compounds 1 to 23, can be synthesized according to Figures 3A-B, 4A-B, 5A-B, and 6A-B, or alternatively by combinatorial chemistry. 【0110】 Figure 3A shows the formylation reaction of the 2-amino-4,5,6,7-tetrahydro-1-benzothiophene reaction product. In this case, the 3-position of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene is substituted with a formaldehyde group. Subsequently, 3-position substitution 2 A ketone formation reaction occurs between the aldehyde moiety of -amino-4,5,6,7-tetrahydro-1-benzothiophene and the Grignard reagent bonded to the R5 group. The resulting ketone derivative was isolated and purified by chromatography. 【0111】 Figure 3B shows the coupling reaction between 3-keto-2-amino-4,5,6,7-tetrahydro-1-benzothiophene and a reactant containing an R7 group. In this case, the 2-amino group of the substituted 2-amino-4,5,6,7-tetrahydro-1-benzothiophene bonds with the acyl chloride derivative containing an R7 group, forming an amide bond. The final product was isolated by chromatography. 【0112】 In particular, the reaction shown in Figure 3B demonstrates the preparation of the compound represented by general formula (I) shown in Figure 2, where 3-keto-2-amino-4,5,6,7-tetrahydro-1-benzothiophene (substituted with groups R1-R5 at the positions defined as shown) is dissolved in an aqueous NaOH solution, and the acyl chloride derivative is dissolved in ether. 3-keto-2-amino-4,5,6,7-tetrahydro-1-benzothiophene (substituted with groups R1-R5 at the positions defined as shown) is added to an Erlenmeyer flask, and the acyl chloride derivative is added dropwise to an aqueous solution overnight at 20°C. The resulting mixture was purified by chromatography to isolate the compound represented by the formula. 【0113】 Figure 4A shows a one-pot substitution reaction of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene, POCl3, DMF, and a secondary amine having R5 and R8 groups. In this case, 2-amino-4,5,6,7-tetrahydro-1-benzothiophene is substituted at position 3 by an amide bonded to the R5 group. The resulting compound was then isolated by chromatography. 【0114】 Figure 4B shows the coupling reaction between 3-amide 2-amino-4,5,6,7-tetrahydro-1-benzothiophene and a reactant having an R7 group. In this case, the 2-amino group of the substituted 2-amino-4,5,6,7-tetrahydro-1-benzothiophene bonds with the acyl chloride derivative having an R7 group, forming an amide bond. The final product was then isolated by chromatography. 【0115】 In particular, the reaction shown in Figure 4B demonstrates the preparation of the compound represented by general formula (II) shown in Figure 2, where 3-amide-2-amino-4,5,6,7-tetrahydro-1-benzothiophene (substituted with groups R1-R6 at the positions defined as shown) is dissolved in NaOH solution, and the acyl chloride derivative is dissolved in ether. 3-amide-2-amino-4,5,6,7-tetrahydro-1-benzothiophene (substituted with groups R1-R6 at the positions defined as shown) is added to an Erlenmeyer flask, and the acyl chloride derivative is added dropwise to an aqueous solution overnight at 20°C. The resulting mixture was purified by chromatography to isolate the compound represented by the formula. 【0116】 Figure 5A shows a one-pot substitution reaction of the 2-amino-4,5,6,7-tetrathiophene ring. Similar to the reaction shown in Figure 4A, 2-amino-4,5,6,7-tetrahydro-1-benzothiophene is substituted at position 3 by an amide bonded to the R5 group. The resulting compound was then isolated by chromatography. 【0117】 Figure 5B shows the two-step preparation of the compound represented by general formula (III). In the first step, 3-amido-2-amino-4,5,6,7-tetrahydro-1-benzothiophene is bonded to a methyl thioether as shown below by benzaldehyde. The chloro-substituted product is then oxidized by the addition of TMAO to the reaction solvent. The final product can then be isolated by chromatography. 【0118】 In particular, the reaction shown in Figure 5B demonstrates the preparation of the compound represented by the general formula (III) shown in Figure 2. 【0119】 Similar to Figures 4A and 5A, Figure 6A shows a one-pot substitution reaction of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene (substituted with groups R1-R4 at the positions defined as shown) at the 3-position by an amide bonded to a piperazine having an N-R5 group. 【0120】 Figure 6B shows the coupling reaction between the 3-amide 2-amino-4,5,6,7-tetrahydro-1-benzothiophene reactant (substituted with groups R1-R5 at the positions defined as shown in the figure) and a reactant having an R7 group. In this case, the 2-amino group of the substituted 2-amino-4,5,6,7-tetrahydro-1-benzothiophene combines with the acyl chloride derivative having an R7 group to form an amide bond. The final product can then be isolated by chromatography. 【0121】 In particular, the reaction shown in Figure 6B demonstrates the preparation of the compound represented by general formula (IV) shown in Figure 2, where 3-amide-2-amino-4,5,6,7-tetrahydro-1-benzothiophene (substituted with groups R1-R5 at the positions defined as shown) is dissolved in an aqueous NaOH solution, and the acyl chloride derivative is dissolved in ether. 3-amide-2-amino-4,5,6,7-tetrahydro-1-benzothiophene (substituted with groups R1-R5 at the positions defined as shown) was added to an Erlenmeyer flask, and the acyl chloride derivative was added dropwise to the aqueous solution overnight at 20°C. The resulting mixture was purified by chromatography to isolate the compound represented by formula (IV). 【0122】 Alternatively, novel ROR modulators represented by formulas (I), (II), (III), or (IV) shown in compounds 1 to 23 can be synthesized by combinatorial chemistry. 【0123】 Combinatorial chemistry has emerged in recent decades as an approach for the rapid and efficient synthesis of numerous potential small molecule drug candidates. In typical synthesis, only a single target molecule is produced at the end of a synthetic scheme, with each step of the synthesis resulting in the production of only one product. Combinatorial synthesis, however, allows for the synthesis of a large library of molecules using identical reaction conditions, even when using only a single starting material, and enables screening of their biological activity. This pool of products is then divided into three equal parts, each containing three products, and each of the three separate pools reacts with a different reagent to produce nine unique compounds from the previous three. This process is then repeated until the required number of building blocks are added, generating many compounds. 【0124】 The use of solid-phase supports significantly simplifies the synthesis of large combinatorial libraries of compounds. This is achieved by immobilizing the starting materials on a solid support, then carrying out subsequent reactions until a sufficiently large library is constructed, after which the products are cleaved from the support. The use of solid-phase purification has also been demonstrated in liquid-phase synthesis schemes combined with standard liquid-liquid extraction purification techniques. 【0125】 Example 2 Affinity of compounds 1 to 23 Compounds 1 to 23 were tested in recombinant human RORγT-LBD GST-tagged cells using a time-resolved fluorescence energy transfer (TR-FRET) binding assay. The binding dynamics of the coactivator peptide RIP140 and RORγ T-LBD are measured by quantifying the ability of molecules to inhibit or enhance RORγ activity. [Table 1] [Table 2] [Table 3] 【0126】 Experimental conditions for performing the TR-FRET binding assay Add 15 μL of detection mix to 5 μL of compound in assay buffer for a total assay volume of 20 μL (50 mM Tris-HCl, pH 7.0, 150 mM NaCl, 50 mM KCl, 5 mM MgCl2, 1 mM DTT, 0.1% BSA, 0.001% Triton X); 5 nM GST-RORyt (LBD); 90 nM biotinylated RIP140-derived coactivator peptide (biotinyl-NH-Ahx-NSHQKVTLLQLLLGHKNEEN-CONH2); 50 nM SA-APC; 1.5 nM Eu-Anti GST IgG (1.0% DMSO). 【0127】 Protocol for performing a TR-FRET binding assay The compound dilution (200-fold dilution with pure DMSO) is 10 mM using 100% DMSO. The solution was prepared by creating a 0.5 mM dilution from the stock. Then, 11 4.67-fold dilutions of the compound were prepared, exceeding the starting concentration of 20 mM. For example, 25 μL of 10 mM compound was added to 475 μL of DMSO, and 4.07 μL of the resulting solution was titrated to 97.69 μL of DMSO. Subsequently, 2 μL of 200x test compound in 100% DMSO was diluted in 98 μL of assay buffer in a compound buffer dilution plate to obtain a 4x compound solution. 5 μL of this solution was added to 15 μL of assay buffer containing all assay components to obtain a final DMSO concentration of 0.5%. 【0128】 A 4x solution containing europium-labeled antibody and GST-RORγ (LBD) mixture was prepared. 5 μL of each solution was then added to each well of a 384-well plate, followed by 5 μL of each concentration of the compound (described above) pre-diluted in assay buffer. Assay controls (0% inhibition and 100% inhibition controls) were added to columns 1, 2, 23, and 24 of the 384-well assay optiplate. For the 0% inhibition control, 2 μL of 100% DMSO was added to 98 μL of assay buffer. For the 100% inhibition control, 2 μL of 20 μM GSK2981278 (200x, 100 nM final concentration) was added. 【0129】 The plate was shaken for 1 minute, centrifuged at 1000 rpm for 10 seconds, then incubated overnight at 4°C, followed by the addition of 5 μL of 4x biotinylated RIP140 peptide & streptavidin-APC, and then read with a plate reader. 【0130】 For assay screening, an Enspire® plate reader was used. The settings were as follows: Excitation: 320 nm, Emission A: 615 nm, Time delay: 220 μs, Window: 600 μs, Emission B: 699 nm (Delay time 400 μs, Window 800 μs), Number of flashes: 100. 【0131】 In the final assay plate arrangement, there are 16 compounds per 384-well plate. DMSO control (0% inhibition) is in columns 23 and 24. T0901317 control 25 μM (100% inhibition) is in columns 1 and 2. Titration of the compounds is performed in columns 3 through 22. 10-point IC50 curves were generated for each concentration with n=2. 【0132】 Data Analysis The RORγT FRET assay is an endpoint assay using acceptor / donor readings (luminescence ratio) multiplied by 10000. The assay dose-response test is performed at 10-fold dilutions for each compound curve, at two points per concentration. Conversion from raw data to % activity is performed using an assay control, where 100% activity is represented by the mean DMSO control. Zero percent activity is the mean of two wells for 100 nM, GSK2981278 compound control / row. IC curve fitting is performed using a GraphPad prism and fitted to the sigmoid dose-response (variable gradient) equation as follows: Y = 100 / (1 + 10^((LogIC50 - X)) * (ChillSlope) In the formula, X represents the logarithm of the concentration, and Y represents the normalized response. Y starts at the bottom (0%) and progresses in a sigmoid shape to the peak (100%). IC50 is the concentration of the agonist that gives the response midway between the bottom and the peak. This is not the same as the response at Y=50. Depending on the units in which Y is expressed, and the values ​​of the bottom and peak, nowhere can IC50 give a response close to "50". The prism reports both IC50 and its logarithm. 【0133】 result Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 were all found to have an average pIC50 value of 12 or higher. 【0134】 reference A representative example of this assay is Gündisch, U., Weiss, J., Kohl, F., Ryker, JC, Kaufmann, K., Karen, J., and Günthermann, C. (2017), Pharmacological inhibition of RORγt suppresses the Th17 pathway and reduces arthritis in vivo. PloS one, Vol. 12 (No. 11), e0188391, doi:10.1371 / Journal.pone.0188391. 【0135】 Example 3 Inhibition of T-helper 17 cell polarization by compounds 1 to 23 Compounds 1 through 23 were tested for their ability to inhibit Th17 polarization in human peripheral blood mononuclear cells. This assay measures the expressive effect of compounds on interleukin-17A (IL-17A) production. The IL-17A gene is regulated by the ROR response element (RORE). Compounds that bind to ROR(LBD) may inhibit the binding of RORγ to the ROREs DNA site. The compounds can also reduce the binding effect enhanced by the binding of coactivator proteins. [Table 4] [Table 5] [Table 6] [Table 7] 【0136】 Isolation of peripheral blood mononuclear cells Peripheral blood mononuclear cells were isolated by density gradient centrifugation. The principle of this method is that blood components have different densities and can be separated according to their relative densities. The lymphocyte isolation medium is a density gradient medium containing sodium diatrizoate, polysaccharides, and water, with a density of 1.08 g / mL. This medium is denser than lymphocytes, monocytes, and platelets, so they remain around the edge of the medium, while it is denser than granulocytes and erythrocytes, so they sink to the bottom. To isolate PBMCs, whole blood was diluted with 1XPBS, and then more than 14 mL of isolation medium was gently layered in a 50 mL centrifuge tube and centrifuged at 400Xg, with no acceleration and no deceleration for 30 to 40 minutes. Four layers were formed, each containing a different cell type, and the top layer containing plasma was removed by pipetting. The PBMC layer, a characteristically cloudy white "covering," was gently removed using a 10 ml pipette, and any remaining platelets were washed away with warm medium or PBS (1:3). The cells were then centrifuged at 400Xg for 10 minutes. The pelleted cells were counted, and viability was estimated using trypan blue staining. The cells were frozen for long-term storage. 【0137】 Storage of peripheral blood mononuclear cells To preserve PBMCs at ultra-low temperatures in liquid nitrogen, dimethyl sulfoxide (DMSO) was used as a cryoprotectant to reduce ice crystal formation and prevent cell damage. For freezing, 5 x 10⁻¹⁰ PBMCs were placed in a freezing medium containing 10% DMSO and 90% fetal bovine serum (FBS). 6 The samples were resuspended at cells / mL and stored overnight in a refrigerated container at -80°C to allow for gradual and uniform cooling. The following day, the samples were transferred to a liquid nitrogen tank for long-term storage. 【0138】 Preparation of 10% FBS RPMI complete medium A 500 ml bottle of RPMI at 4°C was opened in a biological safety cabinet. Half of the culture medium was transferred to a 500 ml 0.22 μm bottle-top filter (with the vacuum turned off). 59 ml of filtered heat-inactivated fetal bovine serum (FBS), 6 ml of penicillin-streptomycin solution (100X), 6.0 ml of L-glutamine (100X), 6.0 ml of MEM non-essential amino acids (100X), and 6.0 ml of sodium pyruvate were added, and the volume was increased to 500 ml by adding RPMI. The culture medium was stored at 4°C and used for 2 weeks. 【0139】 PBMC defrosting and pause To avoid impairing cell viability and function, the PBMCs were carefully thawed. The pull tubes were removed from liquid nitrogen, placed on ice, and then thawed in a 37°C water bath. If any small ice crystals remained at the bottom of the tube, 500 μL of warm complete RPMI medium supplemented with 10% FBS, 1% penicillin-streptomycin, and L-glutamine was added dropwise. The cells were then transferred to a Falcon tube containing 10 mL of warm medium and centrifuged at 400Xg for 10 minutes to wash away toxic DMSO. This washing process was repeated, and the cell pellets were then resuspended in medium for counting as described above. After thawing, the PBMCs were allowed to stand overnight to remove apoptotic cells, which improves viability and function, and the freshly thawed PBMCs were incubated in supplemented medium for approximately 18 hours. After this resting period, the cells were washed and used for culture. 【0140】 Th17 Polarization Protocol PBMCs were plated into 96-well plates using complete RPMI-1640 medium (10% FBS) and incubated at 37°C under a humidified 5% CO2 atmosphere. The cells were then treated with IL-6 10 ng / mL, IL-1B 10 ng / mL, and TGF-B Cells were treated with CD3 / CD28 (2 μL: 80,000 cells) for 12 days in the presence of 10 ng / mL of the compound and 10 ng / mL of IL-23. The culture medium was changed every other day throughout the entire period. The compound was added to the polarized cells for 48 hours on day 12. On the day of measurement, the CD3 / CD28 beads were removed, and at the end of the 48-hour incubation, the cells were treated with a cell stimulation cocktail for 5 hours. The plates were centrifuged at 400Xg for 10 minutes. The supernatant was collected for further testing, and the cells were resuspended in 1XPBS and washed twice at 400Xg before staining with surface and intracellular markers. 【0141】 Intracellular cytokine staining PBMC cell suspensions were stained with a viability dye (455 UV). The dye was used at a concentration of 1:1000 in 1XPBS. Cells were incubated in the dye solution at 4°C for 30 minutes. Using control wells, 50% of the cells in those wells were killed by heat (65°C for 1 minute), then returned to their respective wells and stained similarly for 30 minutes. The cells were then centrifuged at 400Xg for 10 minutes, and the staining solution was discarded. Before surface staining, the cells were washed twice with 1XPBS. After the final wash, the supernatant was discarded, and the plate was pulsed vortexed to completely dissociate the pellet. Anti-human antibodies against cell surface antigens, namely CD4, CD3, and CD8, were added to each well at a concentration of 1:1000 in PBS with 1% BSA. Cells were incubated at 4°C for 1 hour. The cells were then centrifuged at 400Xg and washed twice with 1XPBS. After the final wash, the supernatant was discarded, and the plate was pulsed vortexed to completely dissociate the pellet. The cells were then treated with FOXP3 fixation / permeabilization buffer (100 mL / well) at 4°C for 30 minutes. The plate was centrifuged at 400Xg, and after discarding the buffer, it was washed twice with FOXP3 permeabilization buffer (200 μL) and then centrifuged at 400Xg. Anti-human antibodies against IL17A, RORγt, IL21, IL22, and IFNγ were added to each well used in the permeabilization buffer at a concentration of 1:1000. The cells were incubated at 4°C for 1 hour. The cells were then centrifuged at 400Xg and washed twice with 1XPBS. Cell quantification, viability, and intracellular cytokine expression were analyzed by flow cytometry using a BD LSRFortessa flow cytometer. 【0142】 The degree of Th17 polarization is measured by the percentage of IL17A-positive cells relative to the total CD4 T cells. Inhibition of Th17 polarization is defined as a significant decrease in the percentage of IL17A-positive cells. Each test compound was tested three times at a concentration of 10 nM against eight replicas in a control well. Data were analyzed using one-way ANOVA and Bonferroni analysis. 【0143】 result Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 19, 20, 22, and 23 inhibited the polarization of Th17 cells by an average of 50% (30-70%), with p<0.05. 【0144】 reference For representative examples of this assay, see: Gaffen SL, Overview of IL-17 Function and Signaling, Cytokines, 2008, Vol. 43, pp. 402-407; Bettelli E, Korn T, Oukka M, Kuchroo VK, Induction and Effector Function of T(H)17 Cells, Nature, 2008, Vol. 453, pp. 1051-1057; Veldhoen M, Hirota K, Christensen J, O'Garra A, Stockinger B. Native agonists of aryl hydrocarbon receptors in culture medium are essential for optimal differentiation of Th17 cells. J. Exp. Med. 2009, Vol. 206, pp. 43-49; Laurence A, Tato CM, Davidson TS et al. STAT5-mediated interleukin-2 signaling suppresses the generation of T helper 17 cells. See Immunity, 2007, Vol. 26, pp. 371–381. 【0145】 Preferred embodiments have been described above and are shown in the accompanying drawings, but it will be apparent to those skilled in the art that modifications can be made without departing from the present disclosure. Such modifications are considered variations that may fall within the scope of the present disclosure.

Claims

[Claim 1] At least one of the following formulas: (I), (II), (III), or (IV): 【Chemistry 1】 (In the formula, R １ , R ２ , R ３ , and / or R ４ H, halogen atoms, NO ２ , alkoxy groups having 1 to 6 carbon atoms, OH, NH ２ , alkyl groups having 1 to 6 carbon atoms, number of carbon atoms Alkenyl groups with 1 to 6 carbon atoms, haloalkyl groups with 1 to 6 carbon atoms, N-dialkyl groups, haloalkoxy groups, hydroxyalkyl groups with 1 to 6 carbon atoms, and / or -CO ２ Represents an alkyl group having 1 to 6 carbon atoms; R ５ These include substituted or unsubstituted 5 or 6-membered saturated or unsaturated heterocycles, aryl groups, alkylarene rings, cyclic alkylhexane groups, cyclic alkylcyclopentanes, pyrimidine rings, imidazole rings, diazole rings, triazole rings, thiadiazole rings, imidazolidine rings, tizolidinated rings, pyrrolidine rings, piperazine rings, pipediline rings, pyridazine rings, pyrazine rings, triazine rings, 1H-pyrrole rings, 2H-pyrrole rings, pyrroline rings, pyrazolidine rings, pyrazoline rings, thiazole rings, isothiazole rings, isoxazole rings, and haloalkyl groups. Represents a group, a cyanoalkyl group, a methylpyrimidine ring, toluene, a methylpyridine ring, a methylimidazole ring, a methyldiazole ring, a methyltriazole ring, a methylthiadiazole ring, a methylimidazolidine ring, a methyltizolidine ring, a methylpyrrolidine ring, a methylpyrazine ring, a methylpyrrole ring, a methylpyrroline ring, a methylpyrazolidine ring, a methylpyrazoline ring, a methylthiazole ring, a methylisothiazole ring, or a methylisoxazole ring; R ６ represents H, an alkyl group having 1 to 6 carbon atoms, or R ５ may together form a 5- or 6-membered ring structure; and R ７ These include substituted or unsubstituted 5 or 6-membered saturated or unsaturated heterocycles, ring-substituted alkylhexane groups, ring-substituted alkylcyclopentanes, pyrimidine rings, imidazole rings, diazole rings, triazole rings, thiadiazole rings, imidazolidine rings, thizolidine rings, pyrrolidine rings, piperazine rings, aryl groups, alkylarene rings, pipediline rings, pyridazine rings, pyrazine rings, triazine rings, 1H-pyrrole rings, 2H-pyrrole rings, pyrroline rings, pyrazolidine rings, pyrazolin rings, thiazole rings, isothiazole rings, isoxazole rings, and thia. A compound represented by formula (II) (wherein R) (wherein R) (represents a noalkyl group, a methylpyrimidine ring, toluene, a methylpyridine ring, a methylimidazole ring, a methyldiazole ring, a methyltriazole ring, a methylthiadiazole ring, a methylimidazolidine ring, a methyltizolidine ring, a methylpyrrolidine ring, a methylpiperazine ring, a methylpipediline ring, a methylpyridazine ring, a methylpyrazine ring, a methyltriazine ring, a methylpyrrole ring, a methylpyrroline ring, a methylpyrazolidine ring, a methylpyrazolline ring, a methylthiazole ring, a methylisothiazole ring, or a methylisoxazole ring), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in the preparation of a pharmaceutical composition for modulating RORγ to prevent or treat RORγ-mediated diseases in patients requiring treatment (however, the pharmaceutical composition is represented by formula (II) (wherein R) １ represents H, and R ２ represents H, and R ３ R represents an alkyl group having 1 to 6 carbon atoms. ４ represents H, R ５ represents a substituted saturated heterocycle, R ６ represents H, and R ７ The '(')' represents a substituted unsaturated heterocycle. This does not include compounds represented by '('), their pharmaceutically acceptable salts, or their stereoisomers. [Claim 2] The pharmaceutical composition according to claim 1, wherein the RORγ-mediated disease is cancer, celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, asthma, dermatitis, fatty liver disease, Crohn's disease, cardiovascular disease, inflammatory disease, neuropathy, multiple sclerosis, and arteriosclerosis. [Claim 3] The pharmaceutical composition according to claim 2, wherein the cancer is prostate cancer, breast cancer, ovarian cancer, multiple myeloma, brain tumor, glioma, lung cancer, salivary gland cancer, stomach cancer, thymic epithelial carcinoma, thyroid cancer, leukemia, melanoma, lymphoma, gastric cancer, pancreatic cancer, kidney cancer, bladder cancer, colon cancer, and liver cancer. [Claim 4] (1) Formulas (I), (II), (III), or (IV): 【Chemistry 2】 (In the formula, R １ , R ２ , R ３ , and / or R ４ H, halogen atoms, NO ２ , alkoxy groups having 1 to 6 carbon atoms, OH, NH ２ , alkyl groups having 1 to 6 carbon atoms, alkenyl groups having 1 to 6 carbon atoms, haloalkyl groups having 1 to 6 carbon atoms, N-dialkyl groups, haloalkoxy groups, hydroxyalkyl groups having 1 to 6 carbon atoms, and / or -CO ２ Represents an alkyl group having 1 to 6 carbon atoms; R ５ These include substituted or unsubstituted 5 or 6-membered saturated or unsaturated heterocycles, aryl groups, alkylarene rings, cyclic alkylhexane groups, cyclic alkylcyclopentanes, pyrimidine rings, imidazole rings, diazole rings, triazole rings, thiadiazole rings, imidazolidine rings, tizolidinated rings, pyrrolidine rings, piperazine rings, pipediline rings, pyridazine rings, pyrazine rings, triazine rings, 1H-pyrrole rings, 2H-pyrrole rings, pyrroline rings, pyrazolidine rings, pyrazoline rings, thiazole rings, isothiazole rings, isoxazole rings, and haloalkyl groups. Represents a group, a cyanoalkyl group, a methylpyrimidine ring, toluene, a methylpyridine ring, a methylimidazole ring, a methyldiazole ring, a methyltriazole ring, a methylthiadiazole ring, a methylimidazolidine ring, a methyltizolidine ring, a methylpyrrolidine ring, a methylpyrazine ring, a methylpyrrole ring, a methylpyrroline ring, a methylpyrazolidine ring, a methylpyrazoline ring, a methylthiazole ring, a methylisothiazole ring, or a methylisoxazole ring; R ６ H represents an alkyl group having 1 to 6 carbon atoms, or R represents an alkyl group having 1 to 6 carbon atoms. ５ They may form a 5- or 6-membered ring structure together; and R ７ These include substituted or unsubstituted 5 or 6-membered saturated or unsaturated heterocycles, ring-substituted alkylhexane groups, ring-substituted alkylcyclopentanes, pyrimidine rings, imidazole rings, diazole rings, triazole rings, thiadiazole rings, imidazolidine rings, tizolidinated rings, pyrrolidine rings, piperazine rings, aryl groups, alkylarene rings, pipediline rings, pyridazine rings, pyrazine rings, triazine rings, 1H-pyrrole rings, 2H-pyrrole rings, pyrroline rings, pyrazolidine rings, pyrazolin rings, thiazole rings, isothiazole rings, isoxazole rings, and cyanoacrylate rings. The first compound represented by (representing a lukyl group, methylpyrimidine ring, toluene, methylpyridine ring, methylimidazole ring, methyldiazole ring, methyltriazole ring, methylthiadiazole ring, methylimidazolidine ring, methyltizolidine ring, methylpyrrolidine ring, methylpiperazine ring, methylpipediline ring, methylpyridazine ring, methylpyrazine ring, methyltriazine ring, methylpyrrole ring, methylpyrroline ring, methylpyrazolidine ring, methylpyrazoline ring, methylthiazole ring, methylisothiazole ring, or methylisoxazole ring), pharmaceutically acceptable salts thereof, or stereoisomers thereof; (2) (a) Cytotoxic agents; (b) Antimetabolites; (c) Alkylating agent; (d) Anthracyclines; (e) antibiotics; (f) Mitotic inhibitors; (g) Luteinizing hormone-releasing hormone (LHRH) antagonists; (h) Signal transduction inhibitors; (i) Gene expression modulators; (j) Apoptosis-inducing factors; (k) Angiogenesis inhibitors; and (l) Immunotherapy agents; One or more additional compounds selected from the group consisting of, (3) Pharmaceutically acceptable carriers A pharmaceutical composition for use in the preparation of agents for modulating RORγ, for preventing or treating RORγ-mediated diseases in patients requiring treatment (however, the pharmaceutical composition is of formula (II) (wherein R １ represents H, and R ２ represents H, and R ３ R represents an alkyl group having 1 to 6 carbon atoms. ４ represents H, R ５ represents a substituted saturated heterocycle, R ６ represents H, and R ７ (where represents a substituted unsaturated heterocycle.) This does not include the first compound represented by ), their pharmaceutically acceptable salts, or their stereoisomers. [Claim 5] The pharmaceutical composition according to claim 4, wherein the one or more additional compounds include a cytotoxic agent, the cytotoxic agent being taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracendione, mitoxantrone, mitramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoid, procaine, tetracaine, lidocaine, propranolol, puromycin, or a combination thereof. [Claim 6] The pharmaceutical composition according to claim 4, wherein the one or more additional compounds include an antimetabolite, the antimetabolite being methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracildacarbazine, or a combination thereof. [Claim 7] The pharmaceutical composition according to claim 4, wherein the one or more additional compounds include an alkylating agent, the alkylating agent being mechloretamine, thiotepachlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum(II) (DDP, cisplatin), or a combination thereof. [Claim 8] The pharmaceutical composition according to claim 4, wherein the one or more additional compounds include an anthracycline, and the anthracycline is daunorubicin, doxorubicin, or a combination thereof. [Claim 9] The pharmaceutical composition according to claim 4, wherein the one or more additional compounds include an antibiotic, the antibiotic being dactinomycin, bleomycin, mitramycin, anthramycin (AMC), or a combination thereof. [Claim 10] The pharmaceutical composition according to claim 4, wherein the one or more additional compounds include a mitotic inhibitor, and the mitotic inhibitor is vincristine, vinblastine, or a combination thereof. [Claim 11] The pharmaceutical composition according to claim 4, wherein the one or more additional compounds include a signal transduction inhibitor, the signal transduction inhibitor being imatinib, trastuzumab, or a combination thereof. [Claim 12] The pharmaceutical composition according to claim 4, wherein the one or more additional compounds comprise a gene expression modulator, the gene expression modulator being siRNA, shRNA, antisense oligonucleotide, HDAC inhibitor, or a combination thereof. [Claim 13] The pharmaceutical composition according to claim 4, wherein the one or more additional compounds include an immunotherapy agent, the immunotherapy agent being a monoclonal antibody, a chimeric antigen receptor (CAR) T cell, or a combination thereof. [Claim 14] The pharmaceutical composition according to claim 4, wherein the one or more additional compounds include an apoptosis-inducing factor, and the apoptosis-inducing factor is a recombinant human TNF-related apoptosis-inducing ligand (TRAIL). [Claim 15] The pharmaceutical composition according to claim 4, wherein the one or more additional compounds include an angiogenesis inhibitor, the angiogenesis inhibitor being sorafenib, sunitinib, pazopanib, everolimus, or a combination thereof.

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