IRHOM2 inhibitors and their use

Abstract

This application relates to an inhibitor of iRhom2 / ADAM17 activity that is useful in the treatment of various diseases.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 494,375, filed Apr. 5, 2023, which is hereby incorporated by reference in its entirety.

[0002] Sequence Listing This application contains a sequence listing that was electronically submitted as an XML file named 27601 - 0086WO1_SL_ST26.xml. The XML file created on Apr. 3, 2024 is 10,084 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety.

[0003] Field of the Invention This application relates to inhibitors of iRhom2 / ADAM17 activity that are useful in the treatment of various diseases.

Background Art

[0004] Background of the Invention EGFR (epidermal growth factor receptor) is present on the cell surface and is activated by the binding of its specific ligands, including epidermal growth factor and transforming growth factor α (TGFα). Upon activation by these growth factor ligands, EGFR transforms from an inactive monomeric form to an active homodimer (Yosef Yarden and Joseph Schlessinger (1987), 'Epidermal Growth-Factor Induces Rapid, Reversible Aggregation of the Purified Epidermal Growth-Factor Receptor', Biochemistry 26 (5):1443-1451). EGFR dimerization triggers downstream activation and signaling by several other proteins that associate with phosphorylated tyrosine through their own phosphotyrosine-binding SH2 domains. These downstream signaling proteins initiate several signaling cascades, primarily the MAPK, Akt, and JNK pathways, leading to DNA synthesis and cell proliferation (Oda K, Matsuoka Y, Funahashi A, Kitano H (2005), 'A comprehensive pathway map of epidermal growth factor receptor signaling'. Mol. Syst. Biol. l (1): 2005.0010). Such proteins modulate phenotypes, such as cell migration, adhesion, and proliferation.

[0005] Mutations leading to EGFR overexpression (known as upregulation) or overactivity have been associated with numerous cancers, including lung cancer, anal cancer (Walker F, Abramowitz L, Benabderrahrnane D, Duval X, Descatoire V, Herrin D, Lehy T, Aparicio T (November 2009), 'Growth factor receptor expression in anal squamous lesions: modifications associated with oncogenic human papillomavirus and human immunodeficiency virus', Hum. Pathol. 40 (11): 1517-27), and glioblastoma multiforme. In the latter case, a more or less specific mutation in EGFR, called EGFRvIII, is often observed (Kuan CT, Wikstrand CJ, Bigner DD (June 2001), 'EGF mutant receptor vIII as a molecular target in cancer therapy', Endocr. Relat. Cancer 8 (2): 83-96). Mutations, amplifications, or dysregulations of EGFR or its family members are linked to approximately 30% of all epithelial cancers. Mutations involving EGFR can lead to its steady-state activation, which can result in uncontrolled cell division. Consequently, EGFR mutations have been identified in several types of cancer and represent an expanding class of anti-cancer therapies (Zhang H, Berezov A, Wang Q, Zhang G, Drebin J, Murali R, Greene MI (August 2007), 'ErbB receptors: from oncogenes to targeted cancer therapies', J. Clin. Invest. 117 (8): 2051-8).

[0006] The identification of EGFR as an oncogene has led to the development of EGFR-targeted anticancer agents, including gefitinib and erlotinib for lung cancer, and cetuximab for colon cancer. Cetuximab and panitumumab are examples of monoclonal antibody inhibitors. Other monoclonals in clinical development include saltumumab, nimotuzumab, and matuzumab. Another approach is to use small molecules to inhibit the EGFR tyrosine kinase located on the cytoplasmic side of the receptor. Without kinase activity, EGFR cannot be activated, which is a prerequisite for the binding of downstream adapter proteins. By superficially halting the signaling cascade in cells that rely on this pathway for proliferation, tumor growth and migration are reduced. Gefitinib, erlotinib, and lapatinib (a mixed EGFR and ERBB2 inhibitor) are examples of small molecule kinase inhibitors.

[0007] The membrane-bound metalloproteinase TNFα-converting enzyme, TACE (also referred to as "ADAM17"), regulates the release of TNFα and EGFR ligands from cells. Therefore, inhibition of TACE activity is an alternative pathway through which EGFR activation can be blocked, and is a means of treating EGFR-dependent pathologies.

[0008] iRhom1 and its related iRhom2 have been found to work together to support the maturation of TACE (also referred to as ADAM17) and the shedding of the EGFR ligand TGFα (U.S. Patent Application No. 10,024,844; and Li X et al. (May 2015), 'iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling', PNAS 112(19): 6080-6085).

[0009] The iRhom2 / ADAM17 complex plays an essential role in regulating several translationally related signaling pathways, including the TNFα pathway (target of anti-TNF biologics such as etanercept or Humira), the IL-6 pathway (target of inhibitors such as tocilizumab), and the EGFR pathway (target of inhibitors such as Erbitux). Inhibitors of iRhom2 / ADAM17 would have the advantage of simultaneously targeting these three disease-causing pathways. Additionally, iRhom2 / ADAM17 inhibitors would selectively target the more pathogenic aspects of these pathways. In particular, the EGFR pathway has both protective functions in the skin and intestinal barriers, as well as pathogenic functions in cancer and autoimmune diseases, such as rheumatoid arthritis. Recent discoveries that HB-EGF macrophages play a crucial role in rheumatoid arthritis further highlight the potential of iRhom2 / ADAM17 inhibitors to block pathogenic HB-EGF without interfering with its role in EGFR ligand TGFα and the protection of the skin and intestinal barriers (Kuo D, et al., 'HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness', Sci. Transl. Med., 2019 May 08; 11(491): doi:10.1126 / scitranslmed.aau8587; and Maretzky T et al. (July 2013), 'iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding', PNAS 110(28): 11433-11438).

[0010] To our knowledge, no small molecule inhibitors of iRhom2 / ADAM17 activity have been disclosed to date. Therefore, the discovery of inhibitors of iRhom2 / ADAM17 activity with novel activity profiles remains clinically necessary. This application addresses this need and other needs. [Overview of the Initiative]

[0011] Abstract Compounds are provided herein that are inhibitors of iRhom2 / ADAM17 activity and are useful in the treatment of various diseases related to the inhibition of iRhom2 / ADAM17 function or iRhom2 / ADAM17 activity.

[0012] Some embodiments provide a method of inhibiting iRhom2 / ADAM17 activity, the method comprising a compound of formula (I):

Chemical formula

[0013] Some embodiments provide a method of inhibiting iRhom2 / ADAM17 activity, said method comprising a compound of formula (II):

Chemical formula

[0014] Some embodiments provide a method for inhibiting iRhom2 / ADAM17 activity, wherein the method is based on formula (III): [ka] This includes administering a compound of the compound, or a pharmaceutically acceptable salt thereof, to a patient.

[0015] Some embodiments provide a method for inhibiting iRhom2 / ADAM17 activity, wherein the method is based on formula (IV): [ka] A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, R 4 H, C 1-4 Haloalkyl, or C 1-4 It is alkyl; R 4a is -C 0-6 Alkyl (C 6-10 Ariel), -C 0-6 Alkyl (5-10 member heteroaryl), -C 0-6 Alkyl (C 3-10 Cycloalkyl, or C 0-6 It is an alkyl group (a heterocycloalkyl group with 4 to 10 members); R 4b is -C(O)-C 0-4 Alkyl (C 6-10 Aryl), -C(O)-C 0-4 Alkyl (5-10 member heteroaryl), -C(O)-C 0-4 Alkyl (C 3-10 Cycloalkyl), -C(O)-C 0-4 Alkyl (4-10 member heterocycloalkyl), -NHC(O)-C 0-4 Alkyl (C 6-10 Aryl), -NHC(O)-C 0-4 Alkyl (5-10 member heteroaryl), -NHC(O)-C 0-4 Alkyl (C 3-10 Cycloalkyl), -NHC(O)-C 0-4 Alkyl (4-10 member heterocycloalkyl), -C(O)OC 0-4 Alkyl (C 6-10 Aryl), -C(O)OC 0-4 Alkyl (5-10 member heteroaryl), -C(O)OC 0-4 Alkyl (C 3-10 Cycloalkyl), -C(O)OC 0-4 Alkyl (4-10 member heterocycloalkyl), -C(O)NH-C 0-4 Alkyl (C 6-10 Aryl), -C(O)NH-C 0-4 Alkyl (5-10 member heteroaryl), -C(O)NH-C 0-4 Alkyl (C 3-10 Cycloalkyl), -C(O)NH-C0-4 Alkyl (4-10 member heterocycloalkyl), -C(O)N(C 1-6 Alkyl)(C 0-4 Alkyl-C 6-10 Arial), -C(O)N(C 1-6 Alkyl)(C 0-4 Alkyl-(5-10 member heteroaryl),-C(O)N(C 1-6 Alkyl)(C 0-4 Alkyl-C 3-10 Cycloalkyl, or C(O)N(C 1-6 Alkyl)(C 0-4 It is an alkyl-(4-10 member heterocycloalkyl) group; Each R 4a or R 4b Hello, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-4 Alkyl (C 3-6 Cycloalkyl), C 1-6 Alkoxy, C 0-6 Alkyl (CN), C 0-6 Alkyl(OH), C 0-6 Alkyl (NO2), C 0-6 Alkyl (NH 2), -C 0-4 Alkyl(NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(N(C) 1-4 Alkyl)2), methylenedioxy, -C 0-4 Alkyl(S(C) 1-4 Alkyl)), -C 0-4 Alkyl(C(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(C(O)NH2), -C 0-4 Alkyl(C(O)NH(C 1-4 Alkyl)), -C 0-4 Alkyl(C(O)N(C 1-4 Alkyl)2), -C 0-4 Alkyl(C(O)O(C 1-4 Alkyl)), -C 0-4 alkyl(OC(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(OC(O)NH2), -C0-4 Alkyl(OC(O)NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(OC(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHC(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)O(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)NH2), -C 0-4 Alkyl(NHC(O)NH(C 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHS(O)(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHS(O)2(C) 1-4 Alkyl)), -C 0-4 Alkyl (NHS(O)2NH2), -C 0-4 Alkyl(NHS(O)2NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHS(O)2N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(S(O)(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)NH2), -C 0-4 Alkyl(S(O)NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(S(O)2(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)2NH2), -C 0-4 Alkyl(S(O)2NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)2N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHC(O)C 6-10 Ariel), -C 0-4 Alkyl(NHC(O)-(5-10 member heteroaryl)), -C0-4 Alkyl(NHC(O)C 3-10 Cycloalkyl, and C 0-4 (May be substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl(NHC(O)-(4-10 member heterocycloalkyl))) This includes administering the drug to the patient.

[0016] Some embodiments provide a method for treating a disease or disorder associated with inhibition of iRhom2 / ADAM17 activity, wherein the therapeutically effective dose is given by formula (I): [ka] A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, R 1 C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3-10 It is a cycloalkyl; R 1a C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3-10 It is a cycloalkyl; Each R 1 or R 1a Hello, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-4 Alkyl (C 3-6 Cycloalkyl), C 1-6 Alkoxy, C 0-6 Alkyl (CN), C 0-6 Alkyl(OH), C 0-6 Alkyl (NO2), C 0-6 Alkyl(NH2), -C 0-4 Alkyl(NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(N(C) 1-4 Alkyl)2), methylenedioxy, -C 0-4 Alkyl(S(C) 1-4 Alkyl)), -C 0-4 Alkyl(C(O)(C 1-4Alkyl)), -C 0-4 Alkyl(C(O)NH2), -C 0-4 Alkyl(C(O)NH(C 1-4 Alkyl)), -C 0-4 Alkyl(C(O)N(C 1-4 Alkyl)2), -C 0-4 Alkyl(C(O)O(C 1-4 Alkyl)), -C 0-4 alkyl(OC(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(OC(O)NH2), -C 0-4 Alkyl(OC(O)NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(OC(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHC(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)O(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)NH2), -C 0-4 Alkyl(NHC(O)NH(C 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHS(O)(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHS(O)2(C) 1-4 Alkyl)), -C 0-4 Alkyl (NHS(O)2NH2), -C 0-4 Alkyl(NHS(O)2NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHS(O)2N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(S(O)(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)NH2), -C 0-4 Alkyl(S(O)NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)N(C) 1-4 Alkyl)2), -C0-4 Alkyl(S(O)2(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)2NH2), -C 0-4 Alkyl(S(O)2NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)2N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHC(O)C 6-10 Ariel), -C 0-4 Alkyl(NHC(O)-(5-10 member heteroaryl)), -C 0-4 Alkyl(NHC(O)C 3-10 Cycloalkyl, and C 0-4 (May be substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl(NHC(O)-(4-10 member heterocycloalkyl))) This includes administering it to patients who require treatment for the aforementioned disease or disorder.

[0017] Some embodiments provide a method for treating a disease or disorder associated with inhibition of iRhom2 / ADAM17 activity, wherein the therapeutically effective dose is given by formula (II): [ka] A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, X is NH, N(C 1-4 Alkyl), O, S, S(O), S(O)2, C(O), CH2, CH(halo), C(halo)2, CH(C 1-4 Alkyl), or C(C 1-4 Alkyl)2; R 2 C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3-10 It is a cycloalkyl; Each R 2 Hello, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-4 Alkyl (C 3-6Cycloalkyl), C 1-6 Alkoxy, C 0-6 Alkyl (CN), C 0-6 Alkyl(OH), C 0-6 Alkyl (NO2), C 0-6 Alkyl(NH2), -C 0-4 Alkyl(NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(N(C) 1-4 Alkyl)2), methylenedioxy, -C 0-4 Alkyl(S(C) 1-4 Alkyl)), -C 0-4 Alkyl(C(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(C(O)NH2), -C 0-4 Alkyl(C(O)NH(C 1-4 Alkyl)), -C 0-4 Alkyl(C(O)N(C 1-4 Alkyl)2), -C 0-4 Alkyl(C(O)O(C 1-4 Alkyl)), -C 0-4 alkyl(OC(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(OC(O)NH2), -C 0-4 Alkyl(OC(O)NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(OC(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl ( NHC(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)O(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)NH2), -C 0-4 Alkyl(NHC(O)NH(C 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHS(O)(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHS(O)2(C) 1-4 Alkyl)), -C0-4 Alkyl (NHS(O)2NH2), -C 0-4 Alkyl(NHS(O)2NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHS(O)2N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(S(O)(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)NH2), -C 0-4 Alkyl(S(O)NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(S(O)2(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)2NH2), -C 0-4 Alkyl(S(O)2NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)2N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHC(O)C 6-10 Ariel), -C 0-4 Alkyl(NHC(O)-(5-10 member heteroaryl)), -C 0-4 Alkyl(NHC(O)C 3-10 Cycloalkyl, and C 0-4 (May be substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl(NHC(O)-(4-10 member heterocycloalkyl))) This includes administering it to patients who require treatment for the aforementioned disease or disorder.

[0018] Some embodiments provide a method for treating diseases or disorders associated with inhibition of iRhom2 / ADAM17 activity, wherein the therapeutically effective dose is given by formula (III): [ka] This includes administering a compound of the said compound, or a pharmaceutically acceptable salt thereof, to a patient who requires treatment for the said disease or disorder.

[0019] Some embodiments provide a method for treating a disease or disorder associated with inhibition of iRhom2 / ADAM17 activity, wherein the therapeutically effective dose is given by formula (IV): [ka] A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, R 4 H, C 1-4 Haloalkyl, or C 1-4 It is alkyl; R 4a is -C 0-6 Alkyl (C 6-10 Ariel), -C 0-6 Alkyl (5-10 member heteroaryl), -C 0-6 Alkyl (C 3-10 Cycloalkyl, or C0 -6 It is an alkyl group (a heterocycloalkyl group with 4 to 10 members); R 4b is -C(O)-C 0-4 Alkyl (C 6-10 Aryl), -C(O)-C 0-4 Alkyl (5-10 member heteroaryl), -C(O)-C 0-4 Alkyl (C 3-10 Cycloalkyl), -C(O)-C 0-4 Alkyl (4-10 member heterocycloalkyl), -NHC(O)-C 0-4 Alkyl (C 6-10 Aryl), -NHC(O)-C 0-4 Alkyl (5-10 member heteroaryl), -NHC(O)-C 0-4 Alkyl (C 3-10 Cycloalkyl), -NHC(O)-C 0-4 Alkyl (4-10 member heterocycloalkyl), -C(O)OC 0-4 Alkyl (C 6-10 Aryl), -C(O)OC 0-4 Alkyl (5-10 member heteroaryl), -C(O)OC 0-4 Alkyl (C 3-10Cycloalkyl), -C(O)OC 0-4 Alkyl (4-10 member heterocycloalkyl), -C(O)NH-C 0-4 Alkyl (C 6-10 Aryl), -C(O)NH-C 0-4 Alkyl (5-10 member heteroaryl), -C(O)NH-C 0-4 Alkyl (C 3-10 Cycloalkyl), -C(O)NH-C 0-4 Alkyl (4-10 member heterocycloalkyl), -C(O)N(C 1-6 Alkyl)(C 0-4 Alkyl-C 6-10 Arial), -C(O)N(C 1-6 Alkyl)(C 0-4 Alkyl-(5-10 member heteroaryl),-C(O)N(C 1-6 Alkyl)(C 0-4 Alkyl-C 3-10 Cycloalkyl, or C(O)N(C 1-6 Alkyl)(C 0-4 It is an alkyl-(4-10 member heterocycloalkyl) group; Each R 4a or R 4b Hello, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-4 Alkyl (C 3-6 Cycloalkyl), C 1-6 Alkoxy, C 0-6 Alkyl (CN), C 0-6 Alkyl(OH), C 0-6 Alkyl (NO2), C 0-6 Alkyl(NH2), -C 0-4 Alkyl(NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(N(C) 1-4 Alkyl)2), methylenedioxy, -C 0-4 Alkyl(S(C) 1-4 Alkyl)), -C 0-4 Alkyl(C(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(C(O)NH2), -C 0-4 Alkyl(C(O)NH(C1-4 Alkyl)), -C 0-4 Alkyl(C(O)N(C 1-4 Alkyl)2), -C 0-4 Alkyl(C(O)O(C 1-4 Alkyl)), -C 0-4 alkyl(OC(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(OC(O)NH2), -C 0-4 Alkyl(OC(O)NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(OC(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHC(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)O(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)NH2), -C 0-4 Alkyl(NHC(O)NH(C 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHS(O)(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHS(O)2(C) 1-4 Alkyl)), -C 0-4 Alkyl (NHS(O)2NH2), -C 0-4 Alkyl(NHS(O)2NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHS(O)2N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(S(O)(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)NH2), -C 0-4 Alkyl(S(O)NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(S(O)2(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)2NH2), -C0-4 Alkyl(S(O)2NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)2N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHC(O)C 6-10 Ariel), -C 0-4 Alkyl(NHC(O)-(5-10 member heteroaryl)), -C 0-4 Alkyl(NHC(O)C 3-10 Cycloalkyl, and C 0-4 (May be substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl(NHC(O)-(4-10 member heterocycloalkyl))) This includes administering it to patients who require treatment for the aforementioned disease or disorder.

[0020] In some embodiments, the compound is administered to the patient in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient.

[0021] In some embodiments, the compound is administered to the patient in combination with one or more additional therapeutic agents. [Brief explanation of the drawing]

[0022] [Figure 1a] The sequences of KL2-AP (sequence ID number 1) and the translation result (sequence ID number 2) as described in Example 2 are shown. [Figure 1b] The sequences of KL2-AP (sequence ID number 1) and the translation result (sequence ID number 2) as described in Example 2 are shown. [Figure 2a] The sequences of TGFα-AP (sequence ID number 3) and the translation result (sequence ID number 4) as described in Example 2 are shown. [Figure 2b] The sequences of TGFα-AP (sequence ID number 3) and the translation result (sequence ID number 4) as described in Example 2 are shown. [Figure 3a]Results from a TNFα release assay are presented, demonstrating that compounds 1 and 2 interfere with LPS-induced shedding of TNFα in human THP-1 macrophage cells. The data show the effect of the test compounds on the absolute amount of TNFα released. [Figure 3b] Results from a TNFα release assay are shown, demonstrating that compounds 3, 4, 5, and 7 interfere with LPS-induced shedding of TNFα in human THP-1 macrophage cells. The data show the effect of the test compounds on the absolute number of TNFα released. [Figure 4a] Results from a TNFα release assay are presented, demonstrating that compounds 1 and 2 interfere with LPS-induced shedding of TNFα in human THP-1 macrophage cells. The data show the effect of the test products on TNFα release in terms of inhibition percentage. [Figure 4b] Results from a TNFα release assay are shown, demonstrating that compounds 3, 4, 5, and 7 interfere with LPS-induced shedding of TNFα in human THP-1 macrophage cells. The data show the effect of the test compounds on TNFα release in terms of inhibition percentage. [Figure 5a] The results from the TNFα release assay demonstrate that compounds 1 and 2 interfere with LPS-induced shedding of TNFα in human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. The data show the effect of the test compounds on the absolute amount of TNFα released. [Figure 5b] Results from a TNFα release assay are shown, demonstrating that compounds 3, 4, 5, and 7 interfere with LPS-induced shedding of TNFα in human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. The data show the effect of the test compounds on the absolute amount of TNFα released. [Figure 6a]The results from the TNFα release assay demonstrate that compounds 1 and 2 interfere with LPS-induced shedding of TNFα in human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. The data show the effect of the test products on TNFα release in terms of inhibition percentage. [Figure 6b] Results from a TNFα release assay are shown, demonstrating that compounds 3, 4, 5, and 7 interfere with LPS-induced shedding of TNFα in human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. The data show the effect of the test compounds on TNFα release in terms of inhibition percentage. [Figure 7a] Results from an IL-6R release assay are presented, demonstrating that compounds 1 and 2 interfere with PMA-induced shedding of IL-6R in human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. The data show the effect of the test compounds on the absolute number of IL-6R released. [Figure 7b] Results from IL-6R release assays are presented, demonstrating that compounds 4, 5, and 7 interfere with PMA-induced shedding of IL-6R in human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. The data show the effect of the test compounds on the absolute number of IL-6R released. [Figure 8a] The results from the IL-6R release assay demonstrate that compounds 1 and 2 interfere with PMA-induced shedding of IL-6R in human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. The data show the effect of the test products on IL-6R release in terms of inhibition percentage. [Figure 8b] Results from IL-6R release assays are presented, demonstrating that compounds 4, 5, and 7 interfere with PMA-induced shedding of IL-6R in human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. The data show the effect of the test products on IL-6R release in terms of inhibition percentage. [Figure 9a]The results from the HB-EGF release assay demonstrate that compounds 1 and 2 interfere with PMA-induced shedding of HB-EGF in THP1 cells. The data show the effect of the test compounds on the absolute number of HB-EGF released. [Figure 9b] Results from the HB-EGF release assay are shown, demonstrating that compounds 3, 4, 5, and 7 interfere with PMA-induced shedding of HB-EGF in THP1 cells. The data show the effect of the test compounds on the absolute number of HB-EGF released. [Figure 10a] The results from the HB-EGF release assay demonstrate that compounds 1 and 2 interfere with PMA-induced shedding of HB-EGF in THP1 cells. The data show the effect of the test products on HB-EGF release in terms of inhibition percentage. [Figure 10b] Results from the HB-EGF release assay are shown, demonstrating that compounds 3, 4, 5, and 7 interfere with PMA-induced shedding of HB-EGF in THP1 cells. The data show the effect of the test compounds on HB-EGF release in terms of inhibition percentage. [Figure 11a] The results from the HB-EGF release assay demonstrate that compounds 1 and 2 interfere with PMA-induced shedding of HB-EGF in human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. The data show the effect of the test compounds on the absolute amount of HB-EGF released. [Figure 11b] Results from the HB-EGF release assay are presented, demonstrating that compounds 3, 4, 5, and 7 interfere with PMA-induced shedding of HB-EGF in human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. The data show the effect of the test compounds on the absolute amount of HB-EGF released. [Figure 12a]The results from the HB-EGF release assay demonstrate that compounds 1 and 2 interfere with PMA-induced shedding of HB-EGF in human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. The data show the effect of the test products on HB-EGF release in terms of inhibition percentage. [Figure 12b] Results from HB-EGF release assays are presented, demonstrating that compounds 3, 4, 5, and 7 interfere with PMA-induced shedding of HB-EGF in human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. The data show the effect of the test compounds on HB-EGF release in terms of inhibition percentage. [Figure 13a] Results from a TGFα release assay are presented, demonstrating that compounds 1 and 2 slightly interfere with PMA-induced shedding of TGFα in human PC3 prostate cancer cells. The data show the effect of the test compounds on the absolute number of TGFα released. [Figure 13b] Results from a TGFα release assay are shown, demonstrating that compounds 3, 4, 5, and 7 slightly interfere with PMA-induced shedding of TGFα in human PC3 prostate cancer cells. The data show the effect of the test compounds on the absolute number of TGFα released. [Figure 14a] Results from a TGFα release assay are presented, demonstrating that compounds 1 and 2 slightly interfere with PMA-induced shedding of TGFα in human PC3 prostate cancer cells. The data show the effect of the test products on TGFα release in terms of inhibition percentage. [Figure 14b] Results from a TGFα release assay are shown, demonstrating that compounds 3, 4, 5, and 7 slightly interfere with PMA-induced shedding of TGFα in human PC3 prostate cancer cells. The data show the effect of the test products on TGFα release in terms of inhibition percentage. [Modes for carrying out the invention]

[0023] Detailed explanation In some embodiments, the Disclosure provides a method for inhibiting iRhom2 / ADAM17 activity, comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof to a patient.

[0024] In some embodiments, the Disclosure provides a method for treating a disease or disorder associated with inhibition of iRhom2 / ADAM17 activity, comprising administering a therapeutically effective amount of a compound of the Disclosure, or a pharmaceutically acceptable salt thereof, to a patient in need of treatment for the disease or disorder.

[0025] I. Compounds of the Disclosure Equation (I): [ka] A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, R 1 C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3-10 It is a cycloalkyl; R 1a C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3-10 It is a cycloalkyl; Each R 1 or R 1a Hello, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-4 Alkyl (C 3-6 Cycloalkyl), C 1-6 Alkoxy, C 0-6 Alkyl (CN), C 0-6 Alkyl(OH), C 0-6 Alkyl (NO2), C 0-6 Alkyl(NH2), -C 0-4 Alkyl(NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(N(C) 1-4 Alkyl)2), methylenedioxy, -C0-4 Alkyl(S(C) 1-4 Alkyl)), -C 0-4 Alkyl(C(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(C(O)NH2), -C 0-4 Alkyl(C(O)NH(C 1-4 Alkyl)), -C 0-4 Alkyl(C(O)N(C 1-4 Alkyl)2), -C 0-4 Alkyl(C(O)O(C 1-4 Alkyl)), -C 0-4 alkyl(OC(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(OC(O)NH2), -C 0-4 Alkyl(OC(O)NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(OC(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHC(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)O(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)NH2), -C 0-4 Alkyl(NHC(O)NH(C 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHS(O)(C) 1-4 Alkyl)) , -C 0-4 Alkyl(NHS(O)2(C) 1-4 Alkyl)), -C 0-4 Alkyl (NHS(O)2NH2), -C 0-4 Alkyl(NHS(O)2NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHS(O)2N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(S(O)(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)NH2), -C 0-4Alkyl(S(O)NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(S(O)2(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)2NH2), -C 0-4 Alkyl(S(O)2NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)2N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHC(O)C 6-10 Ariel), -C 0-4 Alkyl(NHC(O)-(5-10 member heteroaryl)), -C 0-4 Alkyl(NHC(O)C 3-10 Cycloalkyl, and C 0-4 (May be substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl(NHC(O)-(4-10 member heterocycloalkyl))) This is presented herein.

[0026] In some embodiments, R 1 This is Halo and C 1-6 C may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups. 6-10 It is Ariel.

[0027] In some embodiments, R 1 teeth [ka] That is the case.

[0028] In some embodiments, R 1a Hello, C 1-6 Alkyl, C 1-4 Alkyl(NHC(O)C 1-4 Alkyl), C 1-4 Alkyl(C(O)C 1-4 Alkyl), C 1-4Alkyl(C(O)NHC) 1-4 Alkyl), C 1-4 Alkyl(OC(O)C 1-4 Alkyl) and C 1-4 Alkyl((O)COC) 1-4 It is a 5-10 member heteroaryl that may be substituted with 1, 2, or 3 substituents selected from the group consisting of alkyls.

[0029] In some embodiments, R 1a Hello, C 1-6 Alkyl, C 1-4 Alkyl(NHC(O)C 1-4 Alkyl), C 1-4 Alkyl(C(O)C 1-4 Alkyl), C 1-4 Alkyl(C(O)NHC) 1-4 Alkyl), C 1-4 Alkyl(OC(O)C 1-4 Alkyl) and C 1-4 Alkyl((O)COC) 1-4 It is an indole which may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups.

[0030] In some embodiments, R 1a teeth [ka] That is the case.

[0031] In some embodiments, the compound of formula (I) is [ka] or a pharmaceutically acceptable salt thereof.

[0032] Formula (II): [ka] A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, X is NH, N(C 1-4 Alkyl), O, S, S(O), S(O)2, C(O), CH2, CH(halo), C(halo)2, CH(C 1-4 Alkyl), or C(C 1-4 Alkyl)2; R 2 C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3-10 It is a cycloalkyl; Each R 2 Hello, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-4 Alkyl (C 3-6 Cycloalkyl), C 1-6 Alkoxy, C 0-6 Alkyl (CN), C 0-6 Alkyl(OH), C 0-6 Alkyl (NO2), C 0-6 Alkyl(NH2), -C 0-4 Alkyl(NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(N(C) 1-4 Alkyl)2), methylenedioxy, -C 0-4 Alkyl(S(C) 1-4 Alkyl)), -C 0-4 Alkyl(C(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(C(O)NH2), -C 0-4 Alkyl(C(O)NH(C 1-4 Alkyl)), -C 0-4 Alkyl(C(O)N(C 1-4 Alkyl)2), -C 0-4 Alkyl(C(O)O(C 1-4 Alkyl)), -C 0-4 alkyl(OC(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(OC(O)NH2), -C 0-4 Alkyl(OC(O)NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(OC(O)N(C) 1-4 Alkyl)2), -C 0-4Alkyl(NHC(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)O(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)NH2), -C 0-4 Alkyl(NHC(O)NH(C 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHS(O)(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHS(O)2(C) 1-4 Alkyl)), -C 0-4 Alkyl (NHS(O)2NH2), -C 0-4 Alkyl(NHS(O)2NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHS(O)2N(C) 1-4 Alkyl)2), -C 0-4 Alkyl (S (O)(C 1-4 Alkyl)), -C 0-4 Alkyl(S(O)NH2), -C 0-4 Alkyl(S(O)NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(S(O)2(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)2NH2), -C 0-4 Alkyl(S(O)2NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)2N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHC(O)C 6-10 Ariel), -C 0-4 Alkyl(NHC(O)-(5-10 member heteroaryl)), -C 0-4 Alkyl(NHC(O)C 3-10 Cycloalkyl, and C 0-4(May be substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl(NHC(O)-(4-10 member heterocycloalkyl))) This is presented herein.

[0033] In some embodiments, X is NH.

[0034] In some embodiments, R 2 Hello, C 1-6 Alkyl, -C(O)(C 1-4 Alkyl), -C(O)NH2, -C(O)NH(C 1-4 Alkyl), -C(O)N(C 1-4 Alkyl)2,-C(O)O(C 1-4 Alkyl), S(O)(C 1-4 Alkyl), -S(O)NH2, -S(O)NH(C 1-4 Alkyl), -S(O)N(C 1-4 Alkyl)2,-S(O)2(C 1-4 Alkyl), -S(O)2NH2, -S(O)2NH(C 1-4 Alkyl, and S(O)2N(C 1-4 C may be substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl)2. 6-10 It is Ariel.

[0035] In some embodiments, R 2 teeth [ka] That is the case.

[0036] In some embodiments, the compound of formula (II) is [ka] or a pharmaceutically acceptable salt thereof.

[0037] Formula (III): [ka] Compounds thereof, or pharmaceutically acceptable salts thereof, are presented herein.

[0038] Formula (IV): [ka] A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, R 4 H, C 1-4 Haloalkyl, or C 1-4 It is alkyl; R 4a is -C 0-6 Alkyl (C 6-10 Ariel), -C 0-6 Alkyl (5-10 member heteroaryl), -C 0-6 Alkyl (C 3-10 Cycloalkyl, or C 0-6 It is an alkyl group (a heterocycloalkyl group with 4 to 10 members); R 4b is -C(O)-C 0-4 Alkyl (C 6-10 Aryl), -C(O)-C 0-4 Alkyl (5-10 member heteroaryl), -C(O)-C 0-4 Alkyl (C 3-10 Cycloalkyl), -C(O)-C 0-4 Alkyl (4-10 member heterocycloalkyl), -NHC(O)-C 0-4 Alkyl (C 6-10 Aryl), -NHC(O)-C 0-4 Alkyl (5-10 member heteroaryl), -NHC(O)-C 0-4 Alkyl (C 3-10 Cycloalkyl), -NHC(O)-C 0-4 Alkyl (4-10 member heterocycloalkyl), -C(O)OC 0-4 Alkyl (C 6-10 Aryl), -C(O)OC 0-4 Alkyl (5-10 member heteroaryl), -C(O)OC 0-4 Alkyl (C 3-10Cycloalkyl), -C(O)OC 0-4 Alkyl (4-10 member heterocycloalkyl), -C(O)NH-C 0-4 Alkyl (C 6-10 Aryl), -C(O)NH-C 0-4 Alkyl (5-10 member heteroaryl), -C(O)NH-C 0-4 Alkyl (C 3-10 Cycloalkyl), -C(O)NH-C 0-4 Alkyl (4-10 member heterocycloalkyl), -C(O)N(C 1-6 Alkyl)(C 0-4 Alkyl-C 6-10 Arial), -C(O)N(C 1-6 Alkyl)(C 0-4 Alkyl-(5-10 member heteroaryl),-C(O)N(C 1-6 Alkyl)(C 0-4 Alkyl-C 3-10 Cycloalkyl, or C(O)N(C 1-6 Alkyl)(C 0-4 It is an alkyl-(4-10 member heterocycloalkyl) group; Each R 4a or R 4b Hello, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-4 Alkyl (C 3-6 Cycloalkyl), C 1-6 Alkoxy, C 0-6 Alkyl (CN), C 0-6 Alkyl(OH), C 0-6 Alkyl (NO2), C 0-6 Alkyl(NH2), -C 0-4 Alkyl(NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(N(C) 1-4 Alkyl)2), methylenedioxy, -C 0-4 Alkyl(S(C) 1-4 Alkyl)), -C 0-4 Alkyl(C(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(C(O)NH2), -C 0-4Alkyl(C(O)NH(C 1-4 Alkyl)), -C 0-4 Alkyl(C(O)N(C 1-4 Alkyl)2), -C 0-4 Alkyl(C(O)O(C 1-4 Alkyl)), -C 0-4 alkyl(OC(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(OC(O)NH2), -C 0-4 Alkyl(OC(O)NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(OC(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHC(O)(C 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)O(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)NH2), -C 0-4 Alkyl(NHC(O)NH(C 1-4 Alkyl)), -C 0-4 Alkyl(NHC(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHS(O)(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHS(O)2(C) 1-4 Alkyl)), -C 0-4 Alkyl (NHS(O)2NH2), -C 0-4 Alkyl(NHS(O)2NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(NHS(O)2N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(S(O)(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)NH2), -C 0-4 Alkyl(S(O)NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(S(O)2(C) 1-4 Alkyl)), -C 0-4Alkyl(S(O)2NH2), -C 0-4 Alkyl(S(O)2NH(C) 1-4 Alkyl)), -C 0-4 Alkyl(S(O)2N(C) 1-4 Alkyl)2), -C 0-4 Alkyl(NHC(O)C 6-10 Ariel), -C 0-4 Alkyl(NHC(O)-(5-10 member heteroaryl)), -C 0-4 Alkyl(NHC(O)C 3-10 Cycloalkyl, and C 0-4 (May be substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl(NHC(O)-(4-10 member heterocycloalkyl))) This is presented herein.

[0039] In some embodiments, R 4 It is methyl.

[0040] In some embodiments, R 4a is halo and OC(O)(C 1-4 -C may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups. 1-6 Alkyl (C 6-10 It is Ariel.

[0041] In some embodiments, R 4a teeth, [ka] Selected from the group consisting of

[0042] In some embodiments, R 4b is -C(O)NH-C 1-4 Alkyl (C 6-10 Aryl), -C(O)NH-C 1-4 Alkyl (5-10 member heteroaryl), -C(O)NH-C 1-4 Alkyl (C 3-10 Cycloalkyl), -C(O)NH-C 1-4Alkyl (4-10 member heterocycloalkyl), -C(O)N(C 1-6 Alkyl)(C 1-4 Alkyl-C 6-10 Arial), -C(O)N(C 1-6 Alkyl)(C 1-4 Alkyl-(5-10 member heteroaryl),-C(O)N(C 1-6 Alkyl) (C 1-4 Alkyl-C 3-10 Cycloalkyl, or C(O)N(C 1-6 Alkyl)(C 1-4 It is an alkyl-(4-10 member heterocycloalkyl) group.

[0043] In some embodiments, R 4b -C(O)NH-C 1-4 It is an alkyl group (a heteroaryl group with 5 to 10 members).

[0044] In some embodiments, R 4b teeth, [ka] Selected from the group consisting of

[0045] In some embodiments, the compound of formula (IV) is [ka] or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the compound of formula (IV) is [ka] or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the compound of formula (IV) is [ka] or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the compound of formula (IV) is [ka] or a pharmaceutically acceptable salt thereof.

[0049] The specific compounds used in the methods of this disclosure are listed in Table 1 below. The compounds in Table 1 were obtained from commercial suppliers through Evotec (Hamburg, Germany), namely AKos Consulting & Solutions GmbH (Lorrach, Germany) and MolPort (Beacon, NY, USA); or directly from commercial suppliers, namely Ambinter (Orleans, France) and AKos Consulting & Solutions GmbH (Lorrach, Germany).

[0050] Table 1 lists representative commercial suppliers for each compound, along with their respective Evotec ID numbers and / or commercial ID numbers.

[0051] [Table 1]

[0052] For clarity, certain features of this disclosure described in the context of separate embodiments may also be combined and provided in a single embodiment (which is intended to be combined as if written in a multi-paragraph dependent form). Conversely, the various features of the Disclosure described in the context of a single embodiment for the sake of brevity may also be provided separately or in any preferred partial combination. Therefore, it is assumed that the features described as embodiments of the compounds of the Disclosure may be combined in any preferred combination.

[0053] In various places in this specification, certain characteristics of compounds are disclosed in groups or ranges. Such disclosures are particularly intended to include each and every individual partial combination of members of such groups and ranges. For example, the term "C 1-6 The term "alkyl" is particularly intended to disclose (but is not limited to) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups individually.

[0054] The term "n-membered" (where n is an integer) typically describes the number of ring-forming atoms in a part of a ring that has n ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydronaphthalene is an example of a 10-membered cycloalkyl group.

[0055] Variables defining divalent linking groups may be mentioned in various places in this specification. Each linking substituent is specifically intended to include both forward and backward forms of the linking substituent. For example, -NR(CR'R'') n - is -NR(CR'R'') n - and (CR'R'') n This includes both NR- and each of these forms, and it is intended to disclose each of these forms individually. When a structure requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if a structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it is understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0056] The term "substituted" means that an atom or group of atoms formally replaces a hydrogen atom as a "substituent" bonded to another group. Unless otherwise indicated, the term "substituted" refers to any level of substitution, e.g., mono, di, tertiary, quaternary, or pentasubstituted, where such substitutions are permitted. Substituents are independently selected, and substitutions may be at any chemically accessible position. It should be understood that substitutions in a given atom are limited by their valence. It should be understood that substitutions in a given atom result in a chemically stable molecule. The phrase "may be substituted" means either unsubstituted or substituted. The term "substituted" means that a hydrogen atom has been removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.

[0057] The term “C n-m The symbol indicates a range including the endpoints, where n and m are integers and indicate the number of carbon atoms. For example, C 1-4 , and C 1-6 This includes, among others.

[0058] The term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group that may be linear or branched. n-m "Alkyl" refers to an alkyl group having n to m carbon atoms. An alkyl group formally corresponds to an alkane in which one CH bond is replaced by an alkyl group bond site to the rest of the compound. In some embodiments, alkyl groups contain 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and sec-butyl; and higher-order homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, and 1,2,2-trimethylpropyl.

[0059] The term "alkenyl," used alone or in combination with other terms, refers to a linear or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene in which one CH bond is replaced by the bonding site of the alkenyl group to the rest of the compound. n-m "Alkenyl" refers to an alkenyl group having n to m carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, and sec-butenyl.

[0060] The term "alkynyl," used alone or in combination with other terms, refers to a linear or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds. An alkynyl group formally corresponds to an alkyne, in which one CH bond is replaced by an alkyl group bond site to the rest of the compound. n-m "Alkynyl" refers to an alkynyl group having n to m carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyne-1-yl, and propyne-2-yl. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0061] The term "alkylene," used alone or in combination with other terms, refers to a divalent alkyl linking group. An alkylene group formally corresponds to an alkane in which two CH bonds are replaced by the bonding site of an alkylene group to the residue of the compound. n-m "Alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, and 2-methyl-propane-1,3-diyl.

[0062] The term "alkoxy," used alone or in combination with other terms, refers to a group of the formula -O-alkyl (wherein the alkyl group is as defined above). n-m "Alkoxy" refers to an alkoxy group in which the alkyl group has n to m carbon atoms. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0063] The term "amino" refers to the group in the formula -NH2.

[0064] The term "carbamyl" refers to the group of the formula -C(O)NH2.

[0065] The term "carbonyl," used alone or in combination with other terms, refers to the -C(=O)- group, which is sometimes written as C(O).

[0066] The term "cyano" or "nitrile" refers to the base of the formula -C≡N, sometimes written as -CN.

[0067] The term "halo" or "halogen," used alone or in combination with other terms, refers to fluoro, chloro, bromo, and iodine. In some embodiments, "halo" refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halo group is F.

[0068] The term "haloalkyl," as used herein, refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. n-m "Haloalkyl" This is a carbon atom having n to m carbon atoms and at least one to a maximum of {2(n to m) + 1} halogen atoms. n-mThis refers to an alkyl group, where the halogen atom may be the same or different. In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups are CF3, C2F 5、 This includes CHF2, CCl3, CHCl2, and C2Cl5, among others. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0069] The term "haloalkoxy," used alone or in combination with other terms, refers to a group of the formula -O-haloalkyl (wherein the haloalkyl group is as defined above). n-m A "haloalkoxy" refers to a haloalkoxy group in which the haloalkyl group has n to m carbon atoms. Examples of haloalkoxy groups include trifluoromethoxy. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0070] The term "oxo" refers to an oxygen atom as a divalent substituent that, when bonded to carbon, forms a carbonyl group, or when bonded to a heteroatom, forms a sulfoxide, sulfone, or N-oxide group. In some embodiments, the heterocyclic group may be substituted with one or two oxo (=O) substituents.

[0071] The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings that possess aromatic characteristics (i.e., having (4n+2) delocalized π (pi) electrons (where n is an integer)).

[0072] The term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group that may be monocyclic or polycyclic (for example, having two fused rings). n-m"Aryl" refers to an aryl group having n to m ring carbon atoms. Examples of aryl groups include phenyl, naphthyl, indanyl, and indenyl. In some embodiments, the aryl group has 6 to about 10 carbon atoms. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has 10 carbon atoms. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is naphthyl.

[0073] As used herein, the term "heteroatom" includes boron, phosphorus, sulfur, oxygen, and nitrogen.

[0074] The terms “heteroaryl” or “heteroaromatic,” used alone or in combination with other terms, refer to monocyclic or polycyclic aromatic heterocycles having at least one heteroatom ring member selected from boron, phosphorus, sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl portion can be an N-oxide. In some embodiments, the heteroaryl has 5 to 14 ring atoms, including a carbon atom and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5 to 14 or 5 to 10 ring atoms, including a carbon atom and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5-membered or 6-membered heteroaryl ring. In other embodiments, the heteroaryl is an 8-membered, 9-membered, or 10-membered fused bicyclic heteroaryl ring. Exemplary heteroaryl groups include pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, pyrrolyl, pyrazolyl, This includes, but is not limited to, azolyl, oxazolyl, thiazolyl, imidazolyl, furanil, thiophenyl, quinolinil, isoquinolinil, naphthilidinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridines), indolyl, benzothiophenyl, benzofuranil, benzoisoxazolyl, imidazo[1,2-b]thiazolyl, and purinyl.

[0075] A five-membered heteroaryl ring is a heteroaryl group having five ring atoms, wherein one or more (e.g., one, two, or three) ring atoms are independently selected from N, O, and S. Exemplary five-membered heteroaryl rings include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0076] A six-membered heteroaryl ring is a heteroaryl group having six ring atoms, where one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered heteroaryl rings are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0077] The term "cycloalkyl," used alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic) containing cyclized alkyl and alkenyl groups. n-m A "cycloalkyl" refers to a cycloalkyl group having n to m ring-member carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro rings. Cycloalkyl groups have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming carbon atoms (C 3-14) may have. In some embodiments, the cycloalkyl group has 3 to 14 members, 3 to 10 members, 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is C 3-6 These are monocyclic cycloalkyl groups. The ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfide group. Cycloalkyl groups also include cycloalkylides. In some embodiments, cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Moles having one or more aromatic rings condensed to a cycloalkyl ring (i.e., having a common bond with the cycloalkyl ring), such as benzo or thienyl derivatives of cyclopentane and cyclohexane, are also included in the definition of cycloalkyl. Cycloalkyl groups containing condensed aromatic rings can be bonded through any ring-forming atoms, including the ring-forming atoms of the condensed aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, and bicyclo[2.1.1]hexanyl. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0078] The term "heterocycloalkyl," used alone or in combination with other terms, refers to a non-aromatic ring or ring system which may optionally contain one or more alkenylene groups as part of its ring structure, having at least one heteroatom ring member independently selected from boron, nitrogen, sulfur, oxygen, and phosphorus, and having 4 to 14 ring members, 4 to 10 ring members, 4 to 7 ring members, or 4 to 6 ring members. The cyclic group is included in the term "heterocycloalkyl". Heterocycloalkyl groups can include monocyclic, bicyclic, or polycyclic (e.g., having two or three fused or bridged rings) ring systems or spiro rings. In some embodiments, the heterocycloalkyl group is a monocyclic group having one, two, or three heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally oxidized to form oxo or sulfide groups or other oxidized links (e.g., C(O), S(O), C(S), or S(O)2, N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl groups can be bonded through ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Moles having one or more aromatic rings fused to a heterocycloalkyl ring (i.e., having a common bond with the heterocycloalkyl ring), such as piperidine, morpholine, and benzo or thienyl derivatives of azepines, are also included in the definition of heterocycloalkyl. Heterocycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atoms, including the ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, tropanyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, and thiomorpholino.

[0079] In certain contexts, the definition or embodiment refers to a specific ring (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be bonded to any ring member as long as the valence of the atom is not exceeded. For example, the azetidine ring may be bonded at any position on the ring, while the azetidine-3-yl ring is bonded at position 3.

[0080] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inert starting materials are known in the art, and are performed, for example, by separation of racemic mixtures or stereoselective synthesis. Many geometric isomers, such as olefins and C=N double bonds, may also exist in the compounds described herein, and all such stable isomers are assumed in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described, and these may be isolated as mixtures of isomers or as separated isomers.

[0081] The separation of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. One method involves fractional recrystallization using chiral separation acids, which are optically active, salt-forming organic acids. Suitable separation agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids, such as the D and L forms of β-camphorsulfonic acid. Other suitable separation agents for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, and 1,2-diaminocyclohexane.

[0082] The separation of racemic mixtures can also be performed by elution on a column packed with an optically active separation agent (e.g., dinitrobenzoylphenylglycine). A suitable elution solvent composition can be determined by those skilled in the art.

[0083] The compounds of the present invention also include tautomer forms. Tautomer forms result from the swapping of single bonds with adjacent double bonds, along with the accompanying transfer of protons. Tautomer forms include prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge. Exemplary prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomer forms may be in equilibrium or may be sterically locked into one form by appropriate substitution.

[0084] The compounds of the present invention may also contain all isotopes of an atom occurring in the intermediate or final compound. An isotope is an atom having the same atomic number but a different mass number. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the present invention may be replaced or substituted with isotopes of that atom in natural or unnatural abundance. In some embodiments, the compound contains at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of this disclosure may be replaced or substituted with deuterium. In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art.

[0085] When used herein, the term “compound” means all stereoisomers, geometric isomers, tautomers, and isotopes of the structure described. The term also means the compounds of the present invention, whether by method of preparation, e.g., synthesis, through biological processes (e.g., metabolism or enzymatic transformation), or a combination thereof.

[0086] All compounds and their pharmaceutically acceptable salts may be found together with other substances, such as water and solvents (e.g., hydrates and solvates), or may be isolated. In the solid state, the compounds and salts described herein may exist in various forms, and may take the form of solvates, for example, containing hydrates. Compounds may be in any solid state form, such as polymorphs or solvates, and therefore, unless explicitly indicated otherwise, references herein to compounds and salts should be understood to encompass any solid state form of the compounds.

[0087] The term "medically acceptable" is used herein to mean a compound, material, composition and / or drug form that, within reasonable medical judgment and corresponding to a reasonable benefit-risk ratio, is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications.

[0088] As used herein, the terms “ambient temperature” and “room temperature” are understood in the art to generally refer to the approximate temperature of the room in which the reaction is carried out, for example, a temperature of about 20°C to about 30°C, or the reaction temperature.

[0089] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. The term “pharmaceutically acceptable salt” means a compound obtained by converting the present acid or base portion into its salt form. The term refers to a derivative of the disclosed compound that has been modified. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues, such as mineral or organic acid salts of amines; and acidic residues, such as alkali or organic salts of carboxylic acids. The pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol) or acetonitrile (MeCN) are preferred. A list of preferred salts can be found in Remington's Pharmaceutical Sciences, 17 th These are found in Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include the N-oxide form.

[0090] II. Assays We developed two separate screenings to identify novel small molecule inhibitors of iRhom2 / ADAM17 activity. As demonstrated by genetic studies in mice, inactivation of iRhom2 in mice blocks TNFα release from myeloid macrophages (McIlwain DR et al. (Jan 2012), 'iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS', Science 335(6065): 229-32). Therefore, the primary screening for small molecule inhibitors of iRhom2 / ADAM17 was for inhibitors that block TNFα release from LPS-stimulated THP-1 human myeloid cells, a process dependent on iRhom2 and ADAM17. Since TNFα release from THP-1 cells can be blocked at many stages of the LPS / TLR4 / iRhom2 / ADAM17 pathway, a secondary screening was performed in a different human cell type, human embryonic kidney cells (HEK 293), for another iRhom2 / ADAM17 selective substrate, Kit-ligand 2 (KL-2) (Maretzky T et al. (July 2013), 'iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding', PNAS 110(28): 11433-11438).

[0091] A tertiary counter-screening was also performed to monitor TGFα release, but since TGFα is a substrate of iRhom1 / ADAM17 and iRhom2 / ADAM17, its release should not be blocked by iRhom2 selective inhibitors (Maretzky T et al. (July 2013), 'iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding', PNAS 110(28): 11433-11438; and Li X et al. (May 2015), 'iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling', PNAS 112(19): 6080-6085).

[0092] Additional screening for TNFα release in human THP-1 macrophage cells or human peripheral blood mononuclear cells (PBMCs) stimulated with LPS isolated from healthy donors was also performed to assess TNFα inhibition. Screening for IL-6R release in PBMCs isolated from healthy donors was also performed to assess IL-6R inhibition. Screening for HB-EGF release in human THP-1 macrophage cells or human PBMCs stimulated with PMA isolated from healthy donors was also performed to assess HB-EGF inhibition. Screening for TGFα release in human PC3 prostate cancer cells stimulated with PMA was also performed to assess TGFα inhibition.

[0093] The conditions and results of assays using the compounds of this disclosure are presented in the Examples.

[0094] III. Use of Compounds The compounds of this disclosure can inhibit the function of iRhom2 / ADAM17 or inhibit iRhom2 / ADAM17 activity, and are therefore useful in the treatment of diseases and disorders associated with relevant signaling pathways, such as TNFα, IL-6, and EGFR. In some embodiments, this disclosure provides methods for inhibiting the function of iRhom2 / ADAM17 or inhibiting iRhom2 / ADAM17 activity. The methods include administering to an individual or patient any compound of any of the formulas described herein, or any of the compounds described in any of the claims herein, or a pharmaceutically acceptable salt or stereoisomer thereof. The compounds of this disclosure may be used alone, in combination with other agents or treatments, or as adjuvants or neoadjuvants for the treatment of diseases or disorders, including cancer or infectious diseases. Any of the compounds of this disclosure, including any of the embodiments, may be used for the uses described herein.

[0095] In some embodiments, the Disclosure provides methods for treating disorders or impairments associated with inhibition of iRhom2 / ADAM17 function or inhibition of iRhom2 / ADAM17 activity. The methods include administering a therapeutically effective amount of any compound of any of the formulas described herein, or any of the compounds described in any of the claims herein, or a salt or stereoisomer thereof, to an individual or patient in need.

[0096] In some embodiments, the disease or disorder associated with inhibition of the function of iRhom2 / ADAM17, or inhibition of the activity of iRhom2 / ADAM17, is traumatic brain injury. Traumatic brain injury (TBI) is a major cause of temporary or permanent cognitive impairment and disability. TBI can be triggered by any type of severe head trauma or impact, such as after a fall while cycling, skiing, running or riding an electric bicycle, a car accident or other injury, such as an injury during combat. TBI leads to the activation of immune cells in the brain called microglia. In response to such injury, these cells, which are in a quiescent state in a normal and healthy brain, become activated and release pro-inflammatory cytokines such as TNFα. Dysregulated release of TNFα is known to cause cognitive impairment in mice and is presumed to have the same effect in human patients. 1 Since iRhom2 is required for the release of TNFα from microglia 2 , inhibition of the function of iRhom2 / ADAM17, or inhibition of the activity of iRhom2 / ADAM17, should alleviate or prevent some or all of the consequences of TBI, including headache, cognitive impairment, depression and dementia. In some embodiments, methods of treating traumatic brain injury are provided herein. The methods include administering to a patient that needs it a therapeutically effective amount of a compound of the formula described herein, or a compound described in any of the claims and described herein, or a salt thereof. The expected effect is the reduction or prevention of the symptoms of TBI.

[0097] In some embodiments, the disease or disorder associated with inhibition of the function of iRhom2 / ADAM17, or inhibition of the activity of iRhom2 / ADAM17, is Alzheimer's disease. Alzheimer's disease (AD) and the resulting dementia are devastating conditions that affect the lives of the affected individuals as well as their families and caregivers. ADAM17-dependent release of TNFα in immune cells is regulated by iRhom2 2Interestingly, recent studies have reported a very significant association between changes in iRhom2 (also referred to as RHBDF2) methylation and AD in humans. 3 Since the iRhom2 / ADAM17-dependent release of TNFα from microglia and cerebral leukocytes contributes to the neuroinflammatory stage of AD, inhibition of iRhom2 / ADAM17 function or activity may offer an attractive new target for the treatment of AD. In some embodiments, Alzheimer's A method for treating Imer's disease is provided herein. The method comprises administering a therapeutically effective amount of a compound of a formula described herein, or a compound described in any of the claims herein, or a salt thereof, to a patient in need. The expected effects are reduction or prevention of AD symptoms, reduction of neuroinflammation, and reduction of brain damage, leading to an increased quality of life and cognitive ability compared to untreated patients.

[0098] In some embodiments, the disease or disorder associated with inhibition of iRhom2 / ADAM17 function, or inhibition of iRhom2 / ADAM17 activity, is hemophilic arthropathy. Hemophilic arthropathy (HA) is one of the most serious consequences of bleeding disorders, such as hemophilia A or B. HA is caused by bleeding into the joints of hemophilia patients, and depending on the severity of symptoms that develop over time, HA can have a devastating impact on the patient's life. 4~7 Blood entering the joints can activate the iRhom2 / ADAM17 / TNFα signaling pathway, which is known to cause osteoporosis in addition to joint erosion and injury in HA patients. 8Therefore, inhibitors of iRhom2 / ADAM17 function or activity may function as novel treatments for HA-associated joint injury and bone erosion. In some embodiments, methods for treating hemophilic arthropathy are provided herein. The method comprises administering a therapeutically effective amount of a compound of the formula described herein, or a compound described in any of the claims and described herein, or a salt thereof, to a patient in need. The expected effects are reduction or prevention of joint erosion and injury, as well as osteoporosis and osteopenia in patients with HS, leading to improved quality of life and mobility in the affected patient. The compounds of the present invention may be combined with other treatments for HA patients, such as factor VIII supplementation, to enhance the effects of the treatment and further increase the quality of life of the affected patient.

[0099] In some embodiments, the disease or disorder associated with inhibition of iRhom2 / ADAM17 function, or inhibition of iRhom2 / ADAM17 activity, is hemorrhagic stroke. Hemorrhagic stroke (HS) is caused by bleeding into the brain. The primary consequence of HS is damage to brain tissue through displacement caused by bleeding that does not have an outlet within the enclosed cavities of the skull. However, the secondary consequence is resulting neuroinflammation, which is presumed to be a consequence of activation of microglia by blood and hemolytic products, in a manner similar to how macrophages (very similar to microglia) can be activated in patients with hemophilic arthropathy. 8 See also Example 3). Microglial activation results in the release of TNFα, leading to negative complications such as cognitive impairment and dementia, as described above for AD and TBI. In HA patients, blood-triggered TNFα production is iRhom2-dependent. 8Inhibition of iRhom2 / ADAM17 function, or inhibition of iRhom2 / ADAM17 activity, is expected to help prevent some or all of the catastrophic consequences of HS. In some embodiments, methods for treating hemorrhagic stroke are provided herein. The methods include administering a therapeutically effective amount of a compound of the formula described herein, or a compound described in any of the claims herein, or a salt thereof, to a patient in need. The expected effects are reduction or prevention of HS symptoms, reduction of neuroinflammation, and reduction of brain damage, leading to an increased quality of life and cognitive ability compared to untreated patients.

[0100] In some embodiments, the disease or disorder associated with the inhibition of iRhom2 / ADAM17 function or activity is cytokine storm and macrophage activation syndrome. Cytokine storm (CS) and macrophage activation syndrome (MAS) are considered to be decisive contributing factors to the pathogenesis of COVID-19 and other acute respiratory syndromes caused by coronaviruses (CoV), influenza viruses, and other acute injuries to the lungs. Other causes of viral infections or cytokine storms include TNFα and interleukin-6 receptor (IL-6) from macrophages. This results in the activation of the release of iRhom2, which in turn can lead to disease exacerbation and severe or even fatal outcomes for affected patients. iRhom2 is required for the release of TNFα and IL-6R from macrophages. 9~11(Data regarding IL-6R is not shown), iRhom2 is an excellent target for the treatment of CS / MAS. In some embodiments, methods of treating cytokine storm, macrophage activation syndrome are provided herein. The methods include administering to a patient in need thereof a therapeutically effective amount of a compound of the formula described herein, or a compound described in any of the claims and described herein, or a salt thereof. The expected effect is reduction of CS / MAS, which is then predicted to significantly improve the outcome of other consequences of CS / MAS, including acute respiratory distress syndrome, and injury to internal organs such as the liver, kidney, heart and intestine.

[0101] In some embodiments, a disease or disorder associated with inhibition of the function of iRhom2 / ADAM17, or inhibition of iRhom2 / ADAM17 activity is rheumatoid arthritis. Rheumatoid arthritis (RA) is a debilitating destructive inflammatory joint disease that affects approximately 0.5% - 1% of the population. The TNFα and IL-6 / IL-6R pathways are currently considered to be excellent targets for the treatment of RA. However, despite the success of these inhibitors of individual pro-inflammatory pathways, a significant number of patients treated with anti-TNF biologics (e.g., Humira, etanercept) do not respond and are then switched to an IL-6 pathway inhibitor (e.g., tocilizumab), and vice versa. Inhibitors of the function or activity of iRhom2 / ADAM17 promise excellent protection from RA, because they 9~11 simultaneously block both TNFα 12 and IL-6R (data regarding IL-6R is not shown) as well as the newly linked HB-EGF / EGFR pathway. In some embodiments, methods of treating rheumatoid arthritis are provided herein. The methods include administering to a patient in need thereof a therapeutically effective amount of a compound of the formula described herein, or a compound described in any of the claims and described herein, or a salt thereof. The expected effect is reduction of RA and excellent protection by simultaneously blocking all three disease-causing pathways.

[0102] In some embodiments, the disease or disorder associated with inhibition of iRhom2 / ADAM17 function or activity is systemic lupus erythematosus-glomerulonephritis. Systemic lupus erythematosus (SLE) is a disease in which the deposition of immune complexes affects the Fcγ receptor (FcγR). 13 It is a prototype autoimmune disease that leads to the recruitment and activation of neutrophils and monocytes via the C5a receptor (C5aR). FcγR and complement play essential roles in immune complex-induced inflammation and subsequent organ damage. Engagement of FcγR and complement receptors on neutrophils (first responder) and monocytes triggers the production of active oxidants, the release of proteolytic enzymes, phagocytosis, and the upregulation of growth factors, including chemokines, cytokines, most notably TNFα, and HB-EGF. 14 Studies in mice have shown that inactivation of iRhom2, which is required for the release of TNFα and HB-EGF from cells, protects against lethal and severe glomerulonephritis (GN) in mouse models of SLE. 15 Furthermore, patients with SLE-GN also experience symptoms caused by the activation of iRhom2 / ADAM17. 16 Because it has dysregulated HB-EGF signaling 14 Inhibitors of iRhom2 / ADAM17 function or activity are used to treat patients with SLE-GN. In some embodiments, methods for treating systemic lupus erythematosus-glomerulonephritis are provided herein. The method comprises administering a therapeutically effective amount of a compound of the formula described herein, or a compound described in any of the claims herein, or a salt thereof, to a patient in need. The expected effect is reduction and protection of SLE-GN by simultaneously blocking both disease-causing pathways (TNFα, HB-EGF).

[0103] Any of the compounds or embodiments thereof described herein are expected to have satisfactory pharmacological profiles and promising biopharmaceutical properties, such as toxicological profiles, metabolic and pharmacokinetic properties, solubility, and permeability. It will be understood that determining appropriate biopharmaceutical properties, such as cytotoxicity in cells or inhibition of a particular target or channel to determine potential toxicity, is within the scope of the knowledge of those skilled in the art.

[0104] The terms “individual” or “patient,” used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans.

[0105] The term "therapeutic dose" refers to the amount of an active compound or pharmaceutical agent that elicits a biological or pharmacokinetic response in a tissue, system, animal, individual, or human, as determined by researchers, veterinarians, physicians, or other clinicians.

[0106] As used herein, the terms “to treat” or “treatment” mean one or more of the following: (1) inhibition of disease; for example, inhibition of disease, condition or disorder in an individual experiencing or exhibiting the pathology or symptoms of disease, condition or disorder (i.e., cessation of further occurrence of pathology and / or symptoms); and (2) remission of disease; for example, remission of disease, condition or disorder in an individual experiencing or exhibiting the pathology or symptoms of disease, condition or disorder (i.e., reversal of pathology and / or symptoms), for example, a reduction in the severity of disease.

[0107] In some embodiments, the compounds of the present invention are useful in preventing the onset of or reducing the risk of any of the diseases described herein; for example, in preventing the onset of or reducing the risk of the onset of a disease, condition, or disorder in an individual who may have a predisposition to the disease, condition, or disorder but has not yet experienced or shown any of the pathology or symptoms of the disease.

[0108] Combination therapy The compounds of this disclosure, or pharmaceutically acceptable salts thereof, may be used in combination with one or more additional therapeutic agents for the treatment of diseases such as traumatic brain injury, Alzheimer's disease, hemorrhagic stroke, hemophilic arthropathy, cytokine storm / macrophage activation syndrome, rheumatoid arthritis, and systemic lupus erythematosus-glomerulonephritis.

[0109] When more than one drug is administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (for example, for more than two drugs).

[0110] In some embodiments, one or more additional therapeutic agents for the treatment of hemophilic arthropathy include coagulation factor replacement, such as FVIII replacement therapy.

[0111] In some embodiments, one of the additional therapeutic agents for the treatment of rheumatoid arthritis comprises one or more agents selected from methotrexate, anti-TNF bioagents, or anti-IL-6 bioagents.

[0112] IV. Formulation, dosage form, and administration When used as a pharmaceutical, the compounds of this disclosure may be administered in the form of pharmaceutical compositions. Therefore, this disclosure provides compositions comprising the compounds described herein, or pharmaceutically acceptable salts thereof, or any of their embodiments, and at least one pharmaceutically acceptable carrier or excipient. These compositions can be prepared in methods well known in the pharmaceutical art and can be administered by various routes, depending on whether a topical or systemic treatment is indicated and the area to be treated. Administration may be topical (including transdermal, epithelial, ophthalmic, and mucosal delivery, including intranasal, vaginal, and rectal delivery), transpulmonary (e.g., by nebulizer, by inhalation or blowing of powder or aerosol; intratracheal or intranasal), oral, or parenteral. Parenteral administration may include intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose, or, for example, by a continuous perfusion pump. Pharmaceutical compositions and preparations for topical administration may include transdermal patches, ointments, lotions, creams, gels, droplets, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, and thickeners may be necessary or desirable.

[0113] The Disclosure also includes pharmaceutical compositions containing, in combination with one or more pharmaceutically acceptable carriers or excipients, a compound of the Disclosure or a pharmaceutically acceptable salt thereof as an active ingredient. In some embodiments, the compositions are suitable for topical administration. In the preparation of the compositions of the Disclosure, the active ingredient is typically mixed with an excipient, diluted with an excipient, or encapsulated in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. Where the excipient acts as a diluent, it may be a solid, semi-solid, or liquid material acting as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, caches, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), for example, ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders containing up to 10% by weight of the active compound.

[0114] In the preparation of a formulation, the active compound may be ground to provide an appropriate particle size before being combined with other components. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size may be adjusted by grinding to, for example, about 40 mesh to provide a substantially uniform distribution in the formulation.

[0115] The compounds of this disclosure may be ground using known grinding procedures, such as wet grinding to obtain particle sizes suitable for tablet formation and other formulation types. Finely divided (nanoparticle-like) preparations of the compounds of this disclosure may be prepared by methods known in the art (see, for example, International Publication No. 2002 / 000196).

[0116] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations may further contain lubricants, such as talc, magnesium stearate, and mineral oil; humectants; emulsifiers and suspending agents; preservatives, such as methyl- and propyl hydroxybenzoates; sweeteners; and flavoring agents. The compositions of this disclosure can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art.

[0117] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide in w / w.

[0118] In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. The composition is a sustained-release composition containing an agent. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof, and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is Avicel PH102™. In some embodiments, the lactose monohydrate is Fast-flo 316™. In some embodiments, hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4M Premier®) and / or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV®). In some embodiments, polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105®).

[0119] In some embodiments, a wet granulation process is used to produce the composition. In some embodiments, a dry granulation process is used to produce the composition.

[0120] The composition may be formulated in unit dose forms, each dose containing the active ingredient in an amount of approximately 5 to approximately 1,000 mg (1 g), more typically approximately 50 mg to approximately 400 mg. In some embodiments, each dose contains approximately 50 mg of the active ingredient. In some embodiments, each dose contains approximately 100 mg of the active ingredient. In some embodiments, each dose contains approximately 200 mg of the active ingredient. In some embodiments, each dose contains approximately 300 mg of the active ingredient. In some embodiments, each dose contains approximately 400 mg of the active ingredient.

[0121] In some embodiments, the compound is administered to the patient in a daily dose ranging from about 50 mg / day to about 400 mg / day. In some embodiments, the compound is administered to the patient in a daily dose ranging from about 50 mg / day to about 300 mg / day, about 50 mg / day to about 300 mg / day, about 50 mg / day to about 200 mg / day, about 50 mg / day to about 100 mg / day, about 50 mg / day to about 75 mg / day, about 50 mg / day to about 60 mg / day, about 300 mg / day to about 400 mg / day, about 200 mg / day to about 400 mg / day, or about 100 mg / day to about 300 mg / day.

[0122] In some embodiments, the compound is administered to the patient at a daily dose of approximately 50 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of approximately 100 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of approximately 200 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of approximately 300 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of approximately 400 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of approximately 500 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of approximately 750 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of approximately 1000 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of approximately 10 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of approximately 1 mg / day.

[0123] In some embodiments, the daily dose is approximately 1 mg / day to approximately 1000 mg / day. The dosage ranges from approximately 10 mg / day to approximately 750 mg / day, approximately 10 mg / day to approximately 500 mg / day, approximately 10 mg / day to approximately 400 mg / day, approximately 10 mg / day to approximately 300 mg / day, approximately 10 mg / day to approximately 200 mg / day, approximately 10 mg / day to approximately 100 mg / day, approximately 10 mg / day to approximately 50 mg / day, approximately 50 mg / day to approximately 500 mg / day, approximately 50 mg / day to approximately 400 mg / day, approximately 50 mg / day to approximately 300 mg / day, approximately 50 mg / day to approximately 200 mg / day, or approximately 50 mg / day to approximately 100 mg / day. In one embodiment, the method includes administering a single dose of the composition to the patient. In one embodiment, the method includes administering the composition to the patient multiple times. In one embodiment, the method includes administering the composition to the patient 1 to 4 times a day.

[0124] The term "unit dosage form" refers to physically separate units suitable as unit dosages for human subjects and other mammals, where each unit contains a predetermined amount of active material calculated to produce a desired therapeutic effect in combination with suitable pharmaceutically acceptable excipients.

[0125] The components used to formulate the pharmaceutical composition are of high purity and substantially free of potentially harmful impurities (e.g., at least national food grade, generally at least analytical grade, and more typically at least pharmaceutical grade). Particularly for human consumption, the composition is preferably produced or formulated under Good Manufacturing Practices (PPE) as defined in the applicable regulations of the U.S. Food and Drug Administration. For example, a preferred formulation may be sterile and / or substantially isotonic and / or fully compliant with all PPE standards of the U.S. Food and Drug Administration.

[0126] Active compounds may be effective over a wide range of dosages and are generally administered at therapeutically effective doses. However, it should be understood that the actual amount of compound administered is usually determined by the physician, depending on relevant circumstances, including the condition being treated, the chosen route of administration, the actual compound administered, the individual patient's age, weight, and response, as well as the severity of the patient's symptoms.

[0127] The therapeutic dose of the compounds disclosed herein may vary depending, for example, the specific use in which the treatment is performed, the method of administration of the compound, the patient's health condition and circumstances, and the judgment of the prescribing physician. The proportion or concentration of the compounds disclosed herein in a pharmaceutical composition may vary depending on a number of factors, including the dose, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds disclosed herein may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are about 1 μg / kg to about 1 g / kg per day based on body weight. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg per day based on body weight. In some embodiments, the dose range is approximately 0.02 mg / kg to approximately 20 mg / kg, approximately 0.05 mg / kg to approximately 10 mg / kg, 0.1 mg / kg to approximately 10 mg / kg, 0.2 mg / kg to approximately 8 mg / kg, 0.5 mg / kg to approximately 5 mg / kg, 1 mg / kg to approximately 5 mg / kg, or 2 mg / kg to approximately 3 mg / kg per day based on body weight. In some embodiments, the dose is approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 2 mg / kg, approximately 3 mg / kg, approximately 4 mg / kg, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, or approximately 10 mg / kg per day based on body weight.

[0128] The dosage is likely to depend on variables such as the type and progression of the disease or disorder, the patient's overall health status, the relative biological efficacy of the selected compound, the formulation of excipients, and the route of administration. The effective dose can be extrapolated from dose-response curves derived from in vitro or animal model study systems.

[0129] To prepare solid compositions such as tablets, the main active ingredient is mixed with pharmaceutical excipients. This forms a solid pre-formulation composition containing a homogeneous mixture of the compounds of the present disclosure. When these pre-formulation compositions are referred to as homogeneous, the active ingredient is typically uniformly dispersed throughout the composition, and as a result, the composition can be easily further divided into equally effective unit dosage forms, such as tablets, pills, and capsules. This solid pre-formulation is then further divided into the above-mentioned unit dosage forms, for example, containing about 0.1 to about 1000 mg of the active ingredient of the present disclosure.

[0130] The tablets or pills of this disclosure may be coated or otherwise formulated to provide a dosage form that offers the benefit of prolonged action. For example, the tablets or pills may contain an internal dosage component and an external dosage component, the latter in the form of an envelope of the former. The two components may be separated by an enteric coating, which works to resist disintegration in the stomach and to allow the internal component to pass through the duodenum intact or to delay its release. A variety of materials can be used for such enteric coatings or coatings, and such materials include numerous polymer acids, as well as mixtures of polymer acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0131] Liquid forms in which the compounds and compositions of this disclosure may be incorporated for oral or injectable administration include aqueous solutions, preferably flavored syrups, aqueous or oily suspensions, and flavored emulsions containing edible oils, such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar medicinal vehicles.

[0132] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions may be administered orally or via nasal respiratory routes for topical or systemic effects. Compositions may be atomized using an inert gas. Atomized solutions may be inhaled directly from an atomizing device, or the atomizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solutions, suspensions, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0133] Topical formulations may contain one or more conventional carriers. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, and white petrolatum. Carrier compositions for creams may be water-based, combined with glycerol and one or more other components, such as glycerin monostearate, PEG-glycerin monostearate, and cetyl stearyl alcohol. Gels may be formulated using isopropyl alcohol and water, preferably in combination with other components, such as glycerol and hydroxyethylcellulose. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of the compounds of the present disclosure. Topical formulations may be preferably packaged in, for example, 100 g tubes, optionally accompanied by instructions for a selective indication, such as the treatment of psoriasis or other skin conditions.

[0134] The amount of compound or composition administered to a patient varies depending on what is being administered, the purpose of administration (e.g., prevention or treatment), the patient's condition, and the method of administration. In therapeutic applications, a composition may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially cessate the symptoms of the disease and its complications. The effective dose depends on the disease condition being treated, as well as, at the discretion of the attending physician, on factors such as the severity of the disease, and the patient's age, weight, and overall condition.

[0135] The compositions administered to the patient may be in the form of the pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or by sterile filtration. Aqueous solutions may be packaged for immediate use or lyophilized, and the lyophilized preparations may be combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations is typically 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be understood that the use of certain excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0136] The therapeutic dose of the compounds disclosed herein may vary, for example, according to the specific use in which the treatment is performed, the method of administration of the compound, the patient's health status and condition, and the judgment of the prescribing physician. The proportion or concentration of the compounds disclosed herein in a pharmaceutical composition may vary depending on a number of factors, including the dose, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds disclosed herein may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are about 1 μg / kg to about 1 g / kg per body weight per day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg per body weight per day. The dose is likely to depend on variables such as the type and progression of the disease or disorder, the overall health status of the specific patient, the relative biological efficacy of the selected compound, the formulation of excipients, and the route of administration. The effective dose may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0137] V. Labeled compounds and assay methods The compounds of this disclosure may be even more useful in the study of biological processes in normal and abnormal tissues. Therefore, another aspect of this disclosure relates to labeled compounds of this disclosure (such as radiolabeled or fluorescently labeled) that are useful in assays as well as imaging techniques, both in vitro and in vivo, for localizing and quantifying iRhom2 in tissue samples, including human, and for identifying iRhom2 ligands by inhibitory binding of labeled compounds. Thus, this disclosure includes iRhom2 binding assays containing such labeled compounds.

[0138] This disclosure further includes isotopically labeled compounds of the Disclosure. An “isotopically” or “radioactively labeled” compound is a compound of the Disclosure in which one or more atoms are replaced or substituted with atoms having an atomic mass or mass number different from that typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the compounds of the Disclosure are: 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 This includes, but is not limited to, hydrogen (I). For example, one or more hydrogen atoms in the compounds of this disclosure may be replaced by deuterium atoms.

[0139] One or more constituent atoms of the compounds presented herein may be replaced or substituted with isotopes of that atom in natural or unnatural abundance. In some embodiments, the compound contains at least one deuterium atom. In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound may be replaced or substituted with deuterium atoms.

[0140] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry, Alan F. Thomas (New York, NY, Appleton-Century- Crofts, 1971; The Renaissance of H / D Exchange, Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling, James R. Hanson, Royal Society of Chemistry, (2011). Isotope-labeled compounds are used in various studies, such as NMR spectroscopy and metabolic experiments. , and / or can be used in assays.

[0141] Substitution with heavier isotopes, such as deuterium, may result in certain therapeutic benefits, such as increased in vivo half-life or reduced required dosage, due to greater metabolic stability, and may therefore be preferable in some situations (see, for example, A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolic sites may result in one or more therapeutic benefits.

[0142] The radionuclides incorporated into the radiolabeled compounds of the present invention depend on the specific application of the radiolabeled compound. For example, for in vitro PD-L1 protein labeling and competitive assays, 3 H, 14 C, 82 Br, 125 I, 131 I, 35 Compounds incorporating S are generally the most useful. For radioimaging applications, 11 C, 18 F, 125 I, 123 I, 124 I, 131 I,75 Br, 76 Br or 77 Br may be useful.

[0143] "Radioactively labeled" or "labeled compound" is understood to be a compound incorporating at least one radionuclide. In some embodiments, the radionuclide is: 3 H, 14 C, 125 I, 35 S and 82 Selected from the group consisting of Br.

[0144] This disclosure may further include methods for incorporating radioisotopes into the compounds of this disclosure. Methods for incorporating radioisotopes into organic compounds are well known in the art, and those skilled in the art will readily recognize methods applicable to the compounds of this disclosure.

[0145] The labeled compounds of this disclosure may be used in screening assays for identifying and / or evaluating compounds. For example, a newly synthesized or identified labeled compound (i.e., a test compound) may be evaluated for its ability to bind to iRhom2 by monitoring its concentration changes when in contact with iRhom2 through tracking of the label. For example, a (labeled) test compound may be evaluated for its ability to reduce the binding of another compound (i.e., a standard compound) that is known to bind to iRhom2. Thus, the ability of a test compound to compete with a standard compound for binding to the iRhom2 protein is directly correlated to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is not. Thus, to evaluate competition between the standard compound and the test compound, the concentration of the labeled standard compound is monitored and the relative binding affinity of the test compound is thus confirmed.

[0146] VI. Kit The disclosure also includes a pharmaceutical kit useful in the treatment or prevention of a disease or disorder associated with the activity of iRhom2 / ADAM17, for example, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of the compound disclosed herein. Such a kit may further include one or more of various conventional pharmaceutical kit components, for example, a container containing one or more pharmaceutically acceptable carriers, additional containers as readily apparent to those skilled in the art, and so on. Instructions, either as inserts or labels, indicating the amount of components to be administered, guidelines for administration, and / or guidelines for mixing the components, may also be included in the kit.

[0147] The following abbreviations may be used herein: AD (Alzheimer's disease); AP (Alkaline phosphatase); CS / MAS (Cytokine storm and macrophage activation syndrome); DMSO (Dimethyl sulfoxide); DNA (Deoxyribonucleic acid); g (Gram); HA (Hemophilic arthropathy); HB-EGF (Heparin-binding epidermal growth factor); HEK (Human embryonic kidney); HS (Hemorrhagic stroke); HTRF (Homogeneous time-resolved fluorescence); IC 50 (Concentration required to achieve 50% inhibition of activity); kg (kilogram); KL-2 or KitL2 (Kit ligand-2); LPS (lipopolysaccharide); M (molar concentration); mg (milligram); min. (minute); mL (milliliters); mM (millimolecular concentration); NaOH (sodium hydroxide); nL (nanoliters); nM (nanomolar concentration); μg (micrograms); μL (microliters); μM (micromolar concentration); PMA (phorbol-12-myristate-13-acetate); pNP (para-nitrophenylphenol); pNPP (para-nitrophenyl phosphate); RA (rheumatoid arthritis); RT (room temperature); SLE-GN (systemic lupus erythematosus-glomerulonephritis); TBI (traumatic brain injury); TNFα (tumor necrosis factor alpha); XC 50 (The concentration required to achieve 50% inhibition of activity).

[0148] The present invention is described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-deterministic parameters that may be changed or modified to produce essentially the same results. The compounds of this disclosure have been found to inhibit iRhom2 / ADAM17 activity according to at least one assay described herein.

[0149] References 1. Sriram K, O'Callaghan JP. Divergent roles for tumor necrosis factor-alpha in the brain. J Neuroimmune Pharmacol. 2007;2(2):140-153. 2. Li X, Maretzky T, Weskamp G, et al. iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling. Proc Natl Acad Sci US A. 2015;112(19):6080-6085. 3. De Jager PL, Srivastava G, Lunnon K, et al. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci. 2014;17(9):1156-1163. 4. Simpson ML, Valentino LA. Management of joint bleeding in hemophilia. Expert Rev Hematol. 2012;5(4):459-468. 5. Stephensen D, Rodriguez-Merchan EC. Orthopedic co-morbidities in the elderly haemophilia population: a review. Haemophilia. 2013;19(2):166-173. 6. Haxaire C, Blobel CP. With blood in the joint - what happens next? Could activation of a pro-inflammatory signalling axis leading to iRhom2 / TNFalpha-convertase-dependent release of TNFalpha contribute to haemophilic arthropathy? Haemophilia. 2014;20 Suppl 4:11-14. 7. Blobel C, Haxaire C, Kalliolias G, DiCarl E, Salmon J, Srivastava A. Blood induced arthropathy in hemophilia - Mechanisms and heterogeneity. Seminars in Thrombosis and Hemostasis. 2015;(in press). 8. Haxaire C, Hakobyan N, Pannellini T, et al. Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2 / ADAM17 / TNF-alpha pathway. Blood. 2018;132(10):1064-1074. 9. McIlwain DR, Lang PA, Maretzky T, et al. iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS. Science. 2012;335(6065):229-232. 10. Adrain C, Zettl M, Christova Y, Taylor N, Freeman M. Tumor necrosis factor s ignaling requires iRhom2 to promote trafficking and activation of TACE. Science. 2012;335(6065):225-228. 11. Issuree PD, Maretzky T, McIlwain DR, et al. iRHOM2 is a critical pathogenic mediator of inflammatory arthritis. J Clin Invest. 2013;123(2):928-932. 12. Kuo D, Ding J, Cohn IS, et al. HBEGF(+) macrophages in rheumatoid arthritis induce fibroblast invasiveness. Sci Transl Med. 2019;11(491). 13. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol. 2008;8(1):34-47. 14. Bollee G, Flamant M, Schordan S, et al. Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis. Nat Med. 2011;17(10):1242-1250. 15. Qing X, Chinenov Y, Redecha P, et al. iRhom2 promotes lupus nephritis through TNF-alpha and EGFR signaling. J Clin Invest. 2018;128(4):1397-1412. 16. Maretzky T, McIlwain DR, Issuree PD, et al. iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding. Proc Natl Acad Sci US A. 2013;110(28):11433-11438. [Examples]

[0150] Example 1a. Primary screening: Release of TNFα stimulated by LPS / PMA from THP-1 cells. THP-1 cells were plated in 384 or 1,536 wells and transferred to the Ultra High Throughput Screening (uHTS) platform Mark III. TNFα shedding was initiated by LPS stimulation of the THP-1 cells. The amount of released TNFα was detected using corresponding HTRF antibodies labeled with europium cryptotate (donor) and d2 (acceptor). The HTRF signal was generated by the proximity of europium cryptotate and d2. All detection reagents were purchased from Cisbio. TNFα detection was performed according to the producer's protocol (Cisbio TNFα (h) Kit Part # 62HTNFAPEG & 62HTNFAPEH product insert; https: / / www.cisbio.com / media / asset / c / i / cisbio_dd_pi_62htnfapeg-62htnfapeh.pdf, accessed September 28, 2020).

[0151] 7.5 nL of the compound and control in DMSO [10 μM in the assay; 0.25% DMSO in the 3 μL assay] were lysed in 2 μL cell suspension [2.4 E6 / mL; 4800 cells / well; culture without PenStrep] pre-incubated with 1 μL of LPS [100 ng / mL in the 3 μL assay] at 37°C, 5% CO2 for 15 minutes. Cells were incubated with 2 μL of HTRF mix [1:300 fc] at 37°C, 5% CO2 for 3 hours. After incubation at room temperature for at least 2 hours, HTRF readout was performed. Data evaluation for normalization against a 50 μM bathymast control (=100% activation) was then applied. As an additional control, cell performance and assay sensitivity were monitored over time using 300 nM bathymast.

[0152] Example 1b. Primary screening: Release of TNFα stimulated by LPS / PMA from THP-1 cells. THP-1 cells were plated in low-volume 384-well cells with an inhibitor or 10 μM BB94 (10,000 cells / well in 12.6 μL of RPMI medium) and incubated overnight. The following day, THP-1 cells were stimulated with 100 ng / mL LPS (1.8 μL of 800 ng / mL LPS stock) at 37°C for 3 hours to initiate TNFα shedding. The amount of released TNFα was detected using corresponding HTRF antibodies labeled with europium cryptotate (donor) and d2 (acceptor). Null was generated by the proximity of europium cryptotate and d2. All detection reagents were purchased from Cisbio. TNFα detection was performed according to the producer's protocol (Cisbio TNFα (h) Kit Part # 62HTNFAPEG & 62HTNFAPEH product insert; https: / / www.cisbio.com / media / asset / c / i / cisbio_dd_pi_62htnfapeg-62htnfapeh.pdf, accessed September 28, 2020).

[0153] Low-volume 384-well plates were pre-coated with either 15 μL of reaction solution containing a 20 μM final concentration of the small molecule library compound, or 0.75 μL of BB94 200 μM stock (0.25% final concentration) in 5% DMSO. 12.6 μL of cell suspension [8E5 / mL; 10,000 cells / well; culture medium] was added and the plates were pre-incubated overnight at 37°C, 5% CO2. The following day, 1.8 μL of 800 ng / mL of LPS stock was added [100 ng / mL final concentration in the 15 μL assay], and the cells were incubated at 37°C, 5% CO2 for 3 hours. Subsequently, 3 μL of HTRF mix [used as a 1:3 dilution of cisbio HTRF human TNF] was added, and the plates were incubated for a further 2 hours at 25°C. After 2 hours of incubation at room temperature, HTRF readout was performed. Next, data evaluation for normalization against a 10 μM bacimatt control (= 100% activation) was applied.

[0154] Example 2a. Cell generation for Examples 3a and 4a (secondary screening and counter-screening) First, expression plasmids for alkaline phosphatase (AP)-fused KL2 and TGFα were designed, generated through gene synthesis, and subsequently subcloned into pcDNA3.1(+) / Hygro expression vectors. The sequences of KL2-AP (sequence ID 1) and the resulting sequence (sequence ID 2) are shown in Figures 1a and 1b. The sequences of TGFα-AP (sequence ID 3) and the resulting sequence (sequence ID 4) are shown in Figures 2a and 2b. Subsequently, DNA amplification was performed to obtain a sufficient amount of expression vector. The quality of the DNA and gene sequences was confirmed by restriction digestion and Sanger sequencing. In parallel, cell cultures of THP-1 and HEK-293 cells were initiated. Master and working cell banks were prepared. Both cell lines were scaled up and transfected with their respective constructs by electroporation. During cell culture, cell density and viability were monitored to ensure optimal conditions for transfection. After PMA stimulation, AP-linked KL2 or TGFα was detected by measuring AP activity in the supernatant. Initial experiments on TGFα shedding showed favorable results with HEK-293. In contrast, THP-1 cells were found not to be a suitable transfection host, resulting in loss of cell viability after transfection. We decided to proceed with HEK-293 for both selectivity assays and to establish polyclonal cell lines that stably express AP-linked KL2 or TGFα.

[0155] Following electroporation, cells were further cultured in the presence of the selected antibiotic, hygromycin B, to generate a stably transfected polyclonal cell pool. For both assays, KL2 and TGFα shedding, the respective selected pools proved suitable. Final assay conditions were determined for the selected pools. For all experiments, bacimast (30 μM) was used as a positive control for complete inhibition of KL2 or TGFα shedding.

[0156] Example 2b. Cell generation for Examples 3b and 4b (secondary screening and counter-screening) Expression plasmids for alkaline phosphatase (AP)-fused human KL2 and TGFα were previously designed, generated through gene synthesis, and subsequently subcloned into pcDNA3.1(+) / Hygro expression vectors. KL2-AP (sequence ID number 1) and The sequence of the translation result (sequence ID number 2) is shown in Figures 1a and 1b. The sequences of TGFα-AP (sequence ID number 3) and the translation result (sequence ID number 4) are shown in Figures 2a and 2b. Subsequently, DNA amplification was performed to obtain a sufficient amount of expression vector. The quality of the DNA and gene sequences was confirmed by restriction digestion and Sanger sequencing. In parallel, cell culture of HEK-293 cells was started. Master and working cell banks were prepared, scaled up, and transfected with their respective constructs by electroporation. During cell culture, cell density and viability were monitored to ensure optimal conditions for transfection. After PMA stimulation, AP-linked KL2 or TGFα was detected by measuring AP activity in the supernatant.

[0157] Following electroporation, cells were further cultured in the presence of the selected antibiotic, hygromycin B, to generate a stably transfected polyclonal cell pool. For both assays, KL2 and TGFα shedding, the respective selected pools proved suitable. Final assay conditions were determined for the selected pools. For all experiments, bacimast (BB94, 10 μM) was used as a positive control for complete inhibition of KL2 or TGFα shedding.

[0158] Example 3a. Secondary screening: Release of KL2 stimulated by PMA from HEK-293 cells. 60 μL of cells (40,000 / well) were added to a sterile 384-well plate. After incubation overnight at 37°C (5% CO2), 50 μL of medium was removed and 20 μL of pre-diluted compound was added to the cells. After incubation for 15 minutes, 20 μL of PMA (final concentration 500 ng / mL) was added. The cells were incubated at 37°C (5% CO2) for 2 hours. Next, 20 μL of supernatant was transferred to a fresh plate and 20 μL of pNPP (final concentration 5 mM) was added. The AP reaction was carried out at room temperature for 1 hour. The reaction was stopped by adding 20 μL of NaOH (final concentration 1 M), and the absorbance of pNP was measured at 405 nm.

[0159] Example 3b. Secondary screening: Release of KL2 stimulated by PMA from HEK-293 cells. The wells of a sterile 384-well flat-bottom clear plate for the KL2-AP assay were coated with 10 μL of 0.1 mg / mL of poly-d-lysine at 25°C for 3–4 hours or overnight at 4°C, then washed twice with PBS and dried on paper towels. 60 μL of cells (40,000 / well) were added to the sterile 384-well plate and incubated overnight in Optimem (containing 2% FCS and 1% Pen-strep) at 37°C (5% CO2). After overnight incubation, 55 μL of medium was removed using a BioTek EL406 and 10 μL of pre-diluted compound was added to the cells at a final concentration of 20 μM. After 15 minutes of incubation, 15 μL of PMA (final concentration of 100 ng / mL) was added. The cells were incubated for 2 hours at 37°C (5% CO2). Next, the plate was centrifuged at 1000 rpm for 5 minutes, and 3 μL of the supernatant was transferred to a fresh 384-well plate. 9 μL of AP Balance Buffer was added per well. 12 μL of pNPP p-nitrophenyl phosphate (final 1M pNPP) was added. The AP reaction was carried out at 37°C for 1 hour. The reaction was stopped by adding 12 μL of NaOH (final concentration 1M), the plate was centrifuged to remove air bubbles, and the absorbance of pNP was measured at 405 nm.

[0160] Example 4a. Counterscreening: Release of PMA-stimulated TGFα from HEK-293 cells. 60 μL of cells (20,000 / well) were added to a sterile 384-well plate. After incubation overnight at 37°C (5% CO2), 50 μL of medium was removed and 20 μL of pre-diluted compound was added to the cells. After incubation for 15 minutes, 20 μL of PMA (final concentration 100 ng / mL) was added. The cells were incubated at 37°C (5% CO2) for 2 hours. Next, 20 μL of supernatant was transferred to a fresh plate and 20 μL of pNPP (final concentration 5 mM) was added. The AP reaction was carried out at room temperature for 1 hour. The reaction was stopped by adding 20 μL of NaOH (final concentration 1 M), and the absorbance of pNP was measured at 405 nm.

[0161] Example 4b. Counterscreening: Release of TGFα stimulated by PMA from HEK-293 cells. The wells of a sterile 384-well flat-bottom clear plate for the TGF-AP assay were coated with 10 μL of 0.1 mg / mL of poly-d-lysine at 25°C for 3-4 hours or overnight at 4°C, then washed twice with PBS and dried on paper towels. 60 μL of cells (20,000 / well) were added to the sterile 384-well plate and incubated overnight in Optimem (containing 2% FCS and 1% Pen-strep) at 37°C (5% CO2). After overnight incubation, 55 μL of medium was removed using a BioTek EL406 and 10 μL of pre-diluted compound was added to the cells at a final concentration of 20 μM. After 15 minutes of incubation, 15 μL of PMA (final concentration of 100 ng / mL) was added. The cells were incubated for 2 hours at 37°C (5% CO2). Next, the plate was centrifuged at 1000 rpm for 5 minutes, and 12 μL of the supernatant was transferred to a fresh 384-well plate. 12 μL of pNPP p-nitrophenyl phosphate (final 1M pNPP) was added. The AP reaction was carried out at 37°C for 1 hour. The reaction was stopped by adding 12 μL of NaOH (final concentration 1M), the plate was centrifuged to remove air bubbles, and the absorbance of pNP was measured at 405 nm.

[0162] Example 5. Treatment of traumatic brain injury Patients suffering from traumatic brain injury (TBI) are treated with the compound of the present invention in capsule or tablet form at doses of 1 to 400 mg / day, for example, 50 to 400 mg / day, either as a single dose or in divided doses. The expected effect is reduction or prevention of TBI symptoms.

[0163] Example 6. Treatment of Alzheimer's disease Patients suffering from Alzheimer's disease (AD), or those determined to be at risk of AD based on genetic predisposition, predictive cognitive tests, or disease biomarkers, are treated with the compound of the present invention in capsule or tablet form at doses of 1 to 400 mg / day, for example, 50 to 400 mg / day, either as a single dose or in divided doses. The expected effects are reduction or prevention of AD symptoms, reduction of neuroinflammation, and reduction of brain damage, leading to increased quality of life and cognitive ability compared to untreated patients.

[0164] Example 7. Treatment of hemophilic arthropathy Patients suffering from hemophilic arthropathy (HA) or acute or chronic intra-articular hemorrhage symptoms are treated with the compound of the present invention in capsule or tablet form at doses of 1 to 400 mg / day, for example, 50 to 400 mg / day, either as a single dose or in divided doses. The expected effects are the reduction or prevention of joint erosion and injury, as well as osteoporosis and osteopenia in patients with HA, leading to improved quality of life and mobility in affected patients. Inhibitors of iRhom2 / ADAM17 activity may be combined with other treatments for HA patients, such as factor VIII supplementation, to enhance the effects of the treatment and further increase the quality of life of affected patients.

[0165] Example 8. Treatment of hemorrhagic stroke Patients suffering from hemorrhagic stroke (HS) should take 1 to 400 mg / day, for example, 50 to 400 mg / day, in capsule or tablet form, either as a single dose or in divided doses, according to the present invention. The patient is treated with a compound. The expected effects are a reduction or prevention of HS symptoms, a reduction in neuroinflammation, and a reduction in brain damage, leading to an increased quality of life and cognitive ability compared to untreated patients.

[0166] Example 9. Treatment of cytokine storm and macrophage activation syndrome Patients suffering from cytokine storm and macrophage activation syndrome (CS / MAS) are treated with the compound of the present invention in capsule or tablet form at doses of 1 to 400 mg / day, for example, 50 to 400 mg / day, either as a single dose or in divided doses. The expected effect is a reduction in CS / MAS, which is then predicted to significantly improve the outcomes of other CS / MAS consequences, including acute respiratory syndrome and damage to internal organs, such as the liver, kidneys, heart, and intestines.

[0167] Example 10. Treatment of rheumatoid arthritis Patients suffering from rheumatoid arthritis (RA) are treated with the compound of the present invention in capsule or tablet form at doses of 1 to 400 mg / day, for example, 50 to 400 mg / day, either as a single dose or in divided doses. The expected effects are reduction of RA and superior protection by simultaneously blocking all three disease-causing pathways.

[0168] Example 11. Treatment of systemic lupus erythematosus-glomerulonephritis Patients suffering from systemic lupus erythematosus-glomerulonephritis (SLE-GN) are treated with the compound of the present invention in capsule or tablet form at doses of 1 to 400 mg / day, for example, 50 to 400 mg / day, either as a single dose or in divided doses. The expected effect is reduction and protection of SLE-GN by simultaneously blocking both disease-causing pathways (TNFα, HB-EGF).

[0169] Results from Examples 1a, 3a and 4a for the compounds disclosed herein The compounds of this disclosure were evaluated in primary screening (Example 1a), secondary screening (Example 3a), and counter-screening (Example 4a), and the results are shown in Table 2.

[0170] [Table 2]

[0171] Results from Examples 1b, 3b, and 4b for the compounds disclosed herein The compounds of this disclosure were evaluated in primary screening (Example 1b), secondary screening (Example 3b), and counter-screening (Example 4b), and the results are shown in Table 3.

[0172] [Table 3]

[0173] Example 12: Analysis of the inhibitory effect of the compound of the present invention on LPS-induced TNFα shedding in human THP-1 macrophage cells in vitro. In the following study, ELISA-based TNFα release assays were performed to investigate the inhibitory effects of compounds 1, 2, 3, 4, 5, and 7 on LPS-induced release of endogenous TNFα from human THP-1 macrophage cells. The ELISA-based TNFα release assays used in this example are described below.

[0174] In short, on day 1, Nunc black MaxiSorp® 96-well plates (Thermo Fisher Scientific, USA) were coated overnight at 4°C with 100 μl / well of mouse anti-human TNFα capture antibody (provided as part of the DuoSet ELISA kit) in 4 μg / ml TBS. On day 2, the capture antibody solution was removed, and the MaxiSorp® plates were blocked at room temperature for 3 hours with 300 μl / well of TBS and 1% BSA. Meanwhile, 20,000 THP-1 (American Type Culture Collection, USA) cells in 80 μl of standard growth medium were seeded into each well of a Greiner CELLSTAR V-bottom 96-well plate (Thermo Fisher Scientific, USA), and pre-incubated for 30 minutes at 37°C, 5% CO2 with 20 μl / well of standard growth medium supplemented with 50 μM bacimast (BB94, Abcam, UK) as a positive control (for a final concentration of 10 μM in a resulting 100 μl sample volume), 50 μM of the compound of the present invention (for a final concentration of 10 μM in a resulting 100 μl sample volume), and 50 μM DMSO (Carl Roth, Germany) for stimulating and unstimulating controls (for a final concentration of 10 μM in a resulting 100 μl sample volume). Subsequently, cells (except for unstimulated controls) were stimulated at 37°C and 5% CO2 for 2 hours with 20 μl / well of LPS (Sigma-Aldrich, USA) in 300 ng / ml growth medium at a final concentration of 50 ng / ml. The cells were then pelleted by centrifugation of the 96-well plates. In parallel, the barrier buffer was removed from the MaxiSorp® plates, and the plates were washed four times with 350 μl / well of TBS-T (Carl Roth, Germany) using a 96-head plate washer (Tecan Group, Switzerland). To avoid drying, 30 μl of TBS was immediately added to each well of the MaxiSorp® plate, followed by the transfer of 70 μl of cell-free supernatant per sample.Additionally, 100 μl of recombinant human TNFα protein (provided as part of the DuoSet ELISA kit), diluted to the defined concentration in TBS, was added to the plate as a standard reference. Then, 50 ng was added. Add 100 μl / well of biotinylated goat anti-human TNFα detection antibody (provided as part of the DuoSet ELISA kit) to a TBS and incubate the plate at room temperature for 2 hours, protected from direct light. 96-head plate washer (Tecan TBS-T (Carl Group, Switzerland) 350 μl / well The plates were washed four times with Carl Roth (Germany), and after the fourth cycle, all traces of buffer were carefully removed. Then, 100 μl of streptavidin-AP (R&D Systems, USA), diluted 1:10,000 in TBS, was added to each well, and the plates were incubated at room temperature for 30 minutes, again protected from direct light. Another round of four washes was performed using 350 μl / well of TBS-T (Carl Roth, Germany) in a 96-head plate washer (Tecan Group, Switzerland). After the fourth cycle, all traces of buffer were carefully removed. Then, 100 μl of AttoPhos substrate solution (Promega, USA) was added for incubation at room temperature in the dark for 1 hour. Fluorescence from each well was collected using an infinite M1000 PRO (Tecan Group, Switzerland) microplate reader at an excitation wavelength of 435 nm and an emission wavelength of 555 nm.

[0175] Figures 3a and 4a show representative results from this experiment, demonstrating the effect of the test products on LPS-induced release of TNFα from THP-1 cells in absolute numbers (Figure 3a) and inhibition percentages (Figure 4a). Batymast (BB94), a small molecule inhibitor of metalloproteinase, acts as a positive control, resulting in 87.4% inhibition of LPS-induced release of TNFα, while either compound 1 or compound 2 at equal concentrations inhibits LPS-induced release of TNFα from THP-1 cells by 100.1% and 94.6%, respectively.

[0176] Figures 3b and 4b show representative results from this experiment, demonstrating the effect of the test products on LPS-induced release of TNFα from THP-1 cells in absolute numbers (Figure 3b) and inhibition percentages (Figure 4b). Batymast (BB94), as a small molecule inhibitor of metalloproteinase, acts as a positive control, resulting in 94.9% inhibition of LPS-induced release of TNFα, while any of compounds 3, 4, 5, or 7 at equal concentrations inhibit LPS-induced release of TNFα from THP-1 cells by 93.1%, 58.2%, 66.1%, and 85.8%, respectively.

[0177] The delta between the stimulated buffer and the unstimulated buffer was defined as 100% inhibition.

[0178] Example 13: Analysis of the inhibitory effect of the compound of the present invention on LPS-induced TNFα shedding in primary human material from healthy donors in vitro. In the following study, an ELISA-based TNFα release assay was performed to investigate the inhibitory effects of compounds 1, 2, 3, 4, 5, and 7 on LPS-induced release of endogenous TNFα from primary human material obtained from healthy donors using peripheral blood mononuclear cells (PBMCs). The ELISA-based TNFα release assay used in this example is described below.

[0179] In short, on day 1, Nunc black MaxiSorp® 96-well plates (Thermo Fisher Scientific, USA) were coated overnight at 4°C with 100 μl / well of mouse anti-human TNFα capture antibody (provided as part of the DuoSet ELISA kit) in 4 μg / ml TBS. On day 2, the capture antibody solution was removed, and the MaxiSorp® plates were blocked at room temperature for 3 hours with 300 μl / well of TBS and 1% BSA. On the other hand, 20,000 PBMCs (SciRhom GmbH, Germany) from healthy donors in 80 μl of normal growth medium were seeded into each well of a Greiner CELLSTAR V-bottom 96-well plate (Thermo Fisher Scientific, USA), and pre-incubated for 30 minutes at 37°C, 5% CO2 with 20 μl / well of standard growth medium supplemented with 50 μM batimassat (BB94, Abcam, UK) as a positive control (for a final concentration of 10 μM in a resulting 100 μl sample volume), 50 μM of the compound of the present invention (for a final concentration of 10 μM in a resulting 100 μl sample volume), and 50 μM DMSO (Carl Roth, Germany) as a stimulating and non-stimulating control (for a final concentration of 10 μM in a resulting 100 μl sample volume). Subsequently, cells (except for unstimulated controls) were stimulated at 37°C and 5% CO2 for 2 hours with 20 μl / well of LPS (Sigma-Aldrich, USA) in 300 ng / ml growth medium at a final concentration of 50 ng / ml. The cells were then pelleted by centrifugation of the 96-well plates. In parallel, the barrier buffer was removed from the MaxiSorp® plates, and the plates were washed four times with 350 μl / well of TBS-T (Carl Roth, Germany) using a 96-head plate washer (Tecan Group, Switzerland). To avoid drying, 30 μl of TBS was immediately added to each well of the MaxiSorp® plate, followed by the transfer of 70 μl of cell-free supernatant per sample.Additionally, 100 μl of recombinant human TNFα protein (provided as part of the DuoSet ELISA kit), diluted to a defined concentration in TBS, was added to the plate as a standard reference. Then, 100 μl / well of biotinylated goat anti-human TNFα detection antibody (provided as part of the DuoSet ELISA kit) in 50 ng / ml TBS was added, and the plate was incubated at room temperature for 2 hours, protected from direct light. The plates were washed four times with 350 μl / well of TBS-T (Carl Roth, Germany) in a 96-head plate washer (Tecan Group, Switzerland), and after carefully removing all traces of buffer following the fourth cycle, 100 μl of streptavidin-AP (R&D Systems, USA), diluted 1:10,000 in TBS, was added to each well, and the plates were incubated at room temperature for 30 minutes, again protected from direct light. Four separate rounds of washing were performed using 350 μl / well of TBS-T (Carl Roth, Germany) in a 96-head plate washer (Tecan Group, Switzerland). After carefully removing all traces of buffer following the fourth cycle, 100 μl of AttoPhos substrate solution (Promega, USA) was added for incubation at room temperature in the dark for 1 hour. Fluorescence from each well was collected using an infinite M1000 PRO (Tecan Group, Switzerland) microplate reader at an excitation wavelength of 435 nm and an emission wavelength of 555 nm.

[0180] Figures 5a and 6a show representative results from this experiment, demonstrating the effect of the test products on LPS-induced release of TNFα from human peripheral blood mononuclear cells (PBMCs) in absolute numbers (Figure 5a) and inhibition percentages (Figure 6a). Batymast (BB94), as a small molecule inhibitor, acts as a positive control, resulting in 99.5% inhibition of LPS-induced release of TNFα, while either compound 1 or compound 2 at equal concentrations inhibits LPS-induced release of TNFα from human peripheral blood mononuclear cells (PBMCs) by 99.5% and 98.6%, respectively.

[0181] Figures 5b and 6b show representative results from this experiment, demonstrating the effect of the test products on LPS-induced release of TNFα from human peripheral blood mononuclear cells (PBMCs) in absolute numbers (Figure 5b) and inhibition percentages (Figure 6b). Batymast (BB94), as a small molecule inhibitor, acts as a positive control, resulting in a 114.9% inhibition of LPS-induced release of TNFα, while equal concentrations of any of compounds 3, 4, 5, or 7 inhibit LPS-induced release of TNFα from human peripheral blood mononuclear cells (PBMCs) by 76.3%, 42.0%, 51.3%, and 72.5%, respectively.

[0182] The delta between the stimulated buffer and the unstimulated buffer was defined as 100% inhibition.

[0183] Example 14: Analysis of the inhibitory effect of the compound of the present invention on PMA-induced interleukin-6 receptor (IL-6R) shedding in primary human material from healthy donors in vitro. In the following study, an ELISA-based IL-6R release assay was performed to analyze the inhibitory effects of compounds 1, 2, 3, 4, 5, and 7 on PMA-induced release of endogenous IL-6R from primary human material obtained from healthy donors using peripheral blood mononuclear cells (PBMCs). The ELISA-based IL-6R release assay used in this example is described below.

[0184] In short, on day 1, Nunc black MaxiSorp® 96-well plates (Thermo Fisher Scientific, USA) were coated overnight at 4°C with 100 μl / well of mouse anti-human IL-6R capture antibody (provided as part of the DuoSet ELISA kit) in 2 μg / ml TBS.

[0185] 40,000 PBMCs (SciRhom GmbH, Germany) from healthy donors in 80 μl of standard growth medium were seeded into each well of a Greiner CELLSTAR V-bottom 96-well plate (Greiner Bio-One, Germany). The plates were then pre-incubated for 30 minutes at 37°C, 5% CO2 with 20 μl / well of standard growth medium supplemented with 50 μM bacimast (BB94, Abcam, UK) as a positive control (for a final concentration of 10 μM in a resulting 100 μl sample volume), 50 μM of the compound of the present invention (for a final concentration of 10 μM in a resulting 100 μl sample volume), and 50 μM DMSO (Carl Roth, Germany) as a stimulating and non-stimulating control (for a final concentration of 10 μM in a resulting 100 μl sample volume). Subsequently, cells (except for unstimulated controls) were stimulated at 37°C and 5% CO2 for 22 hours using 20 μl / well of PMA (Sigma-Aldrich, USA) at a final concentration of 25 ng / ml in growth medium.

[0186] On day 2, the capture antibody solution was removed, and the MaxiSorp® plate was blocked at room temperature for 2-3 hours with 300 μl / well of TBS and 1% BSA. Meanwhile, the 96-well plate was centrifuged to pellet the cells. In parallel, the blocking buffer was removed from the MaxiSorp® plate, and the plate was washed four times using 350 μl per well of TBS-T (Carl Roth, Germany) in a 96-head plate washer (Tecan Group, Switzerland). To avoid drying, 30 μl of TBS was immediately added to each well of the MaxiSorp® plate, followed by the transfer of 70 μl of cell-free supernatant per sample. Additionally, 100 μl of recombinant human IL-6R protein (provided as part of the DuoSet ELISA kit), diluted to the defined concentration in TBS, was added to the plate as a standard reference. The plate was incubated at room temperature for 2 hours. The plates were washed four times with 350 μl of TBS-T (Carl Roth, Germany) per well using a 96-head plate washer (Tecan Group, Switzerland). After the fourth cycle, all traces of buffer were carefully removed, and then 100 μl of biotinylated goat anti-human IL-6R detection antibody (provided as part of the DuoSet ELISA kit) was added per well in 100 ng / ml TBS. The plates were incubated at room temperature for 2 hours, protected from direct light. The plates were then washed four times with 350 μl of TBS-T (Carl Roth, Germany) per well using a 96-head plate washer (Tecan Group, Switzerland). After the fourth cycle, all traces of buffer were carefully removed, and then 100 μl of streptavidin-AP (R&D Systems, USA), diluted 1:10,000 in TBS, was added to each well. The plates were incubated at room temperature for 30 minutes, again protected from direct light.Four separate rounds of washing were performed using 350 μl of TBS-T (Carl Roth, Germany) per well in a 96-head plate washer (Tecan Group, Switzerland). After carefully removing all traces of buffer following the fourth cycle, 100 μl of AttoPhos substrate solution (Promega, USA) per well was added for incubation at room temperature in the dark for 1 hour. Fluorescence from each well was collected using an infinite M1000 (Tecan Group, Switzerland) microplate reader at an excitation wavelength of 435 nm and an emission wavelength of 555 nm.

[0187] Figures 7a and 8a show representative results from this experiment, demonstrating the effect of the test products on PMA-induced release of IL-6R from PBMCs from healthy donors in absolute numbers (Figure 7a) and inhibition percentages (Figure 8a). Batymast (BB94), a small molecule inhibitor of metalloproteinase, acts as a positive control, resulting in 100.3% inhibition of PMA-induced release of IL-6R, while either compound 1 or compound 2 at equal concentrations inhibits PMA-induced release of IL-6R from PBMCs from healthy donors by 112.0% and 111.3%, respectively.

[0188] Figures 7b and 8b show representative results from this experiment, demonstrating the effectiveness of the test products on PMA-induced release of IL-6R from PBMCs from healthy donors in absolute numbers (Figure 7b) and inhibition percentages (Figure 8b). Batymast (BB94), a small molecule inhibitor of metalloproteinase, acts as a positive control, resulting in 98.5% inhibition of PMA-induced release of IL-6R, while any of compounds 3, 4, 5, and 7 at equal concentrations inhibit PMA-induced release of IL-6R from PBMCs from healthy donors by 0%, 6.2%, 6.5%, and 59.1%, respectively.

[0189] The delta between the stimulated buffer and the unstimulated buffer was defined as 100% inhibition.

[0190] Example 15: Analysis of the inhibitory effect of the compound of the present invention on PMA-induced HB-EGF shedding in human THP-1 macrophage cells in vitro. In the following study, ELISA-based HB-EGF release assays were performed to analyze the inhibitory effects of compounds 1, 2, 3, 4, 5, and 7 on PMA-induced release of endogenous HB-EGF from human THP-1 macrophage cells. The ELISA-based HB-EGF release assay used in this example is described below.

[0191] In short, on day 1, Nunc black MaxiSorp® 96-well plates (Thermo Fisher Scientific, USA) were coated overnight at 4°C with 100 μl / well of mouse anti-human HB-EGF capture antibody (provided as part of the DuoSet ELISA kit) in 2 μg / ml TBS.

[0192] 40,000 THP-1 cells (American Type Culture Collection, USA) in 80 μl of standard growth medium were seeded into each well of a Greiner CELLSTAR V-bottom 96-well plate (Greiner Bio-One, Germany), and pre-incubated for 30 minutes at 37°C, 5% CO2 with 20 μl / well of standard growth medium supplemented with 50 μM bacimast (BB94, Abcam, UK) as a positive control (for a final concentration of 10 μM in a resulting 100 μl sample volume), 50 μM of the compound of the present invention (for a final concentration of 10 μM in a resulting 100 μl sample volume), and 50 μM DMSO (Carl Roth, Germany) as a stimulating and unstimulating control (for a final concentration of 10 μM in a resulting 100 μl sample volume). Subsequently, cells (except for unstimulated controls) were stimulated at 37°C and 5% CO2 for 23 hours using 20 μl / well of PMA (Sigma-Aldrich, USA) at a final concentration of 25 ng / ml in growth medium.

[0193] On day 2, the capture antibody solution was removed, and the MaxiSorp® plate was blocked at room temperature for 1–2 hours with 300 μl / well of TBS and 1% BSA. Meanwhile, the 96-well plate was centrifuged to pellet the cells. In parallel, the blocking buffer was removed from the MaxiSorp® plate, and the plate was washed four times with 350 μl per well of TBS-T (Carl Roth, Germany) using a 96-head plate washer (Tecan Group, Switzerland). To avoid drying, 30 μl of TBS was immediately added to each well of the MaxiSorp® plate, followed by the transfer of 70 μl of cell-free supernatant per sample. Additionally, 100 μl of recombinant human HB-EGF protein (provided as part of the DuoSet ELISA kit), diluted to the defined concentration in TBS, was added to the plate as a standard reference. The plate was incubated at room temperature for 2 hours. 96 head plate washer (Tecan Group, Switzerland) with 350 μl of TBS-T (Carl) per well The plates were washed four times with Roth (Germany), and after the fourth cycle, all traces of buffer were carefully removed. Then, 100 μl of biotinylated goat anti-human HB-EGF detection antibody (provided as part of the DuoSet ELISA kit) was added per well at 50 ng / ml TBS, and the plates were incubated at room temperature for 2 hours, protected from direct light.

[0194] The plates were washed four times with 350 μl of TBS-T (Carl Roth, Germany) per well using a 96-head plate washer (Tecan Group, Switzerland). After the fourth cycle, all traces of buffer were carefully removed, and then 100 μl of streptavidin-AP (R&D Systems, USA), diluted 1:10,000 in TBS, was added to each well. The plates were then incubated at room temperature for 30 minutes, again protected from direct light. Another round of four washes were performed with 350 μl of TBS-T (Carl Roth, Germany) per well using a 96-head plate washer (Tecan Group, Switzerland). After the fourth cycle, all traces of buffer were carefully removed, and then 100 μl of AttoPhos substrate solution (Promega, USA) was added per well for 1 hour of incubation at room temperature in the dark. Fluorescence from each well was collected using an infinite M1000 (Tecan Group, Switzerland) microplate reader at an excitation wavelength of 435 nm and an emission wavelength of 555 nm.

[0195] Figures 9a and 10a show representative results from this experiment, demonstrating the effect of the test products on PMA-induced release of HB-EGF from THP-1 cells in absolute numbers (Figure 9a) and inhibition percentages (Figure 10a). Batymast (BB94), a small molecule inhibitor of metalloproteinase, acts as a positive control, resulting in 99.2% inhibition of PMA-induced release of HB-EGF, while either compound 1 or compound 2 at equal concentrations inhibits PMA-induced release of HB-EGF from THP-1 cells by 95.4% and 77.5%, respectively.

[0196] Figures 9b and 10b show representative results from this experiment, demonstrating the effect of the test products on PMA-induced release of HB-EGF from THP-1 cells in absolute numbers (Figure 9b) and inhibition percentage (Figure 10b). Batymast (BB94), a small molecule inhibitor of metalloproteinase, acts as a positive control, resulting in 99.2% inhibition of PMA-induced release of HB-EGF, while any of compounds 3, 4, 5, and 7 at equal concentrations inhibits PMA-induced release of HB-EGF from THP-1 cells. These inhibit 29.6%, 62.5%, 55.1%, and 95.1% of the target cells, respectively.

[0197] The delta between the stimulated buffer and the unstimulated buffer was defined as 100% inhibition.

[0198] Example 16: Analysis of the inhibitory effect of the compound of the present invention on PMA-induced HB-EGF shedding in primary human material from healthy donors in vitro. In the following study, an ELISA-based HB-EGF release assay was performed to analyze the inhibitory effects of compounds 1, 2, 3, 4, 5, and 7 on the PMA-induced release of endogenous HB-EGF from primary human material obtained from healthy donors using peripheral blood mononuclear cells (PBMCs). The ELISA-based HB-EGF release assay used in this example is described below.

[0199] In short, on day 1, Nunc black MaxiSorp® 96-well plates (Thermo Fisher Scientific, USA) were coated overnight at 4°C with 100 μl / well of mouse anti-human HB-EGF capture antibody (provided as part of the DuoSet ELISA kit) in 2 μg / ml TBS.

[0200] 80,000 PBMCs (SciRhom GmbH, Germany) from healthy donors in 80 μl of standard growth medium were seeded into each well of a Greiner CELLSTAR V-bottom 96-well plate (Greiner Bio-One, Germany). The plates were then pre-incubated for 30 minutes at 37°C, 5% CO2 with 20 μl / well of standard growth medium supplemented with 50 μM batimassat (BB94, Abcam, UK) as a positive control (for a final concentration of 10 μM in a resulting 100 μl sample volume), 50 μM of the compound of the present invention (for a final concentration of 10 μM in a resulting 100 μl sample volume), and 50 μM DMSO (Carl Roth, Germany) for stimulating and non-stimulating controls (for a final concentration of 10 μM in a resulting 100 μl sample volume). Subsequently, cells (except for unstimulated controls) were stimulated at 37°C and 5% CO2 for 22 hours using 20 μl / well of PMA (Sigma-Aldrich, USA) at a final concentration of 25 ng / ml in growth medium.

[0201] On day 2, the capture antibody solution was removed, and the MaxiSorp® plate was blocked at room temperature for 1–2 hours with 300 μl / well of TBS and 1% BSA. Meanwhile, the 96-well plate was centrifuged to pellet the cells. In parallel, the blocking buffer was removed from the MaxiSorp® plate, and the plate was washed four times with 350 μl per well of TBS-T (Carl Roth, Germany) using a 96-head plate washer (Tecan Group, Switzerland). To avoid drying, 30 μl of TBS was immediately added to each well of the MaxiSorp® plate, followed by the transfer of 70 μl of cell-free supernatant per sample. Additionally, 100 μl of recombinant human HB-EGF protein (provided as part of the DuoSet ELISA kit), diluted to the defined concentration in TBS, was added to the plate as a standard reference. The plate was incubated at room temperature for 2 hours. 96 head plate washer (Tecan Group, Switzerland) with 350 μl of TBS-T (Carl) per well The plates were washed four times with Roth (Germany), and after the fourth cycle, all traces of buffer were carefully removed. Then, 100 μl of biotinylated goat anti-human HB-EGF detection antibody (provided as part of the DuoSet ELISA kit) was added per well at 50 ng / ml TBS, and the plates were incubated at room temperature for 2 hours, protected from direct light.

[0202] 96 Head Plate Washer (Tecan Group, Switzerland) Wash four times with 350 μl of TBS-T (Carl Roth, Germany) per well, and after the fourth cycle, carefully remove all traces of buffer, then add 100 μl of streptavidin-AP (R&D) diluted 1:10,000 in TBS. Add 350 μl of TBS-T (Carl Systems, USA) to each well, protect the plate from direct light again, and incubate at room temperature for 30 minutes. Wash 350 μl of TBS-T (Carl Systems, USA) per well in a 96-head plate washer (Tecan Group, Switzerland). Four washes were performed in a separate round using Roth (Germany), and after carefully removing all traces of buffer following the fourth cycle, 100 μl of AttoPhos substrate solution (Promega, USA) was added per well for incubation at room temperature in the dark for 1 hour. Fluorescence from each well was collected using an infinite M1000 (Tecan Group, Switzerland) microplate reader at an excitation wavelength of 435 nm and an emission wavelength of 555 nm.

[0203] Figures 11a and 12a show representative results from this experiment, demonstrating the effectiveness of the test products on PMA-induced release of HB-EGF from PBMCs from healthy donors in absolute numbers (Figure 11a) and inhibition percentages (Figure 12a). Batymast (BB94), a small molecule inhibitor of metalloproteinase, acts as a positive control, resulting in 98.5% inhibition of PMA-induced release of HB-EGF, while either compound 1 or compound 2 at equal concentrations inhibits PMA-induced release of HB-EGF from PBMCs from healthy donors by 100.8% and 100.2%, respectively.

[0204] Figures 11b and 12b show representative results from this experiment, demonstrating the effect of the test products on PMA-induced release of HB-EGF from PBMCs from healthy donors in absolute numbers (Figure 11b) and inhibition percentages (Figure 12b). Batymast (BB94), a small molecule inhibitor of metalloproteinase, acts as a positive control, resulting in a 107.6% inhibition of PMA-induced release of HB-EGF, while any of compounds 3, 4, 5, and 7 at equal concentrations inhibit PMA-induced release of HB-EGF from PBMCs from healthy donors by 22.4%, 38.7%, 34.0%, and 107.1%, respectively.

[0205] The delta between the stimulated buffer and the unstimulated buffer was defined as 100% inhibition.

[0206] Example 17: Analysis of the inhibitory effect of the compound of the present invention on PMA-induced transforming growth factor alpha (TGFα) shedding in human PC3 prostate cancer cells in vitro. In the following study, ELISA-based TGFα release assays were performed to analyze the inhibitory effects of compounds 1, 2, 3, 4, 5, and 7 on PMA-induced release of endogenous TGFα from human PC3 prostate cancer cells. The ELISA-based TGFα release assay used in this example is described below.

[0207] In short, on day 1, Nunc black MaxiSorp® 96-well plates (Thermo Fisher Scientific, USA) were coated overnight at 4°C with 100 μl / well of goat anti-human TGFα capture antibody (provided as part of the DuoSet ELISA kit) in 0.4 μg / ml TBS.

[0208] 75,000 PC3 (European Collection of Authenticated Cell Cultures, UK) cells in 100 μl of standard growth medium were seeded into each well of a 96-well F-bottom cell culture plate (Corning, USA) and incubated overnight at 37°C and 5% CO2. On day 2, the cells were treated with a capture antibody solution. After removing the excess, MaxiSorp® plates were blocked with 300 μl / well TBS, 1% BSA at room temperature for 5 hours. Meanwhile, the cells were washed twice with PBS and pre-incubated for 30 minutes at 37°C, 5% CO2 in 80 μl OptiMEM medium containing 20 μl / well OptiMEM medium supplemented with 50 μM batimassat (BB94, Abcam, UK) as a positive control (for a final concentration of 10 μM in a resulting 100 μl sample volume), 50 μM of the compound of the present invention (for a final concentration of 10 μM in a resulting 100 μl sample volume), and 50 μM DMSO (Carl Roth, Germany) for stimulated and unstimulated controls (for a final concentration of 10 μM in a resulting 100 μl sample volume). Subsequently, cells (except for unstimulated controls) were stimulated at 37°C and 5% CO2 for 2 hours using 20 μl / well of PMA (Sigma-Aldrich, USA) at a final concentration of 25 ng / ml in OptiMEM at 150 ng / ml. In parallel, the barrier buffer was removed from the MaxiSorp® plate, and the plate was washed four times with 350 μl of TBS-T (Carl Roth, Germany) per well using a 96-head plate washer (Tecan Group, Switzerland). To avoid drying, 20 μl of TBS was immediately added to each well of the MaxiSorp® plate, followed by the transfer of 80 μl of cell-free supernatant per sample. Additionally, 100 μl of recombinant human TGFα protein (provided as part of the DuoSet ELISA kit), diluted in TBS to the defined concentration, was added to the plate as a standard reference. Subsequently, 100 μl of biotinylated goat anti-human TGFα detection antibody (provided as part of the DuoSet ELISA kit) at 37.5 ng / ml per well was added to TBS, and the plates were incubated at room temperature for 2 hours, protected from direct light.The plates were washed four times with 350 μl of TBS-T (Carl Roth, Germany) per well using a 96-head plate washer (Tecan Group, Switzerland). After the fourth cycle, all traces of buffer were carefully removed, and then 100 μl of streptavidin-AP (R&D Systems, USA), diluted 1:10,000 in TBS, was added to each well. The plates were then incubated at room temperature for 30 minutes, again protected from direct light. Another round of four washes were performed with 350 μl of TBS-T (Carl Roth, Germany) per well using a 96-head plate washer (Tecan Group, Switzerland). After the fourth cycle, all traces of buffer were carefully removed, and then 100 μl of AttoPhos substrate solution (Promega, USA) was added per well for 1 hour of incubation at room temperature in the dark. Fluorescence from each well was collected using an infinite M1000 (Tecan Group, Switzerland) microplate reader at an excitation wavelength of 435 nm and an emission wavelength of 555 nm.

[0209] Figures 13a and 14a show representative results from this experiment, demonstrating the effect of the test products on PMA-induced release of TGFα from PC3 cells in absolute numbers (Figure 13a) and inhibition percentages (Figure 14a). Batymast (BB94), a small molecule inhibitor of metalloproteinases, acted as a positive control, resulting in a 104.3% inhibition of PMA-induced release of TGFα. However, only very mild effects on TGFα shedding were detected in the presence of equal concentrations of either compound 1 or compound 2, which inhibited PMA-induced release of TGFα from PC3 cells by 25.5% and 9.1%, respectively.

[0210] Figures 13b and 14b show representative results from this experiment, demonstrating the effect of the test product on PMA-induced release of TGFα from PC3 cells in absolute numbers (Figure 13b) and inhibition percentage (Figure 14b). Batymast (BB94), as a small molecule inhibitor of metalloproteinases, acted as a positive control, resulting in a 102.5% inhibition of PMA-induced release of TGFα; however, only a very mild effect on TGFα shedding was detected in the presence of any of compounds 3, 4, 5, and 7 at equal concentrations. These inhibited PMA-induced release of TGFα from PC3 cells by 12.5%, 14.1%, 11.3%, and 27.3%, respectively.

[0211] The delta between the stimulated buffer and the unstimulated buffer was defined as 100% inhibition.

[0212] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references, including but not limited to all patents, patent applications, and publications, referenced herein are incorporated herein by reference in their entirety.

Claims

1. A method for inhibiting iRhom2 / ADAM17 activity, wherein formula (I): 【Chemistry 1】 A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, R １ C ６－１０ Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C ３－１０ It is cycloalkyl; R １ａ C ６－１０ Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C ３－１０ It is cycloalkyl; Each R １ or R １ａ is halo, C １－６ alkyl, C １－６ haloalkyl, C ０－４ alkyl(C ３－６ cycloalkyl), C １－６ alkoxy, C ０－６ alkyl(CN), C ０－６ alkyl(OH), C ０－６ alkyl(NO ２ ), C ０－６ alkyl(NH ２ ), -C ０－４ alkyl(NH(C １－４ alkyl)), -C ０－４ alkyl(N(C １－４ alkyl) ２ ), methylenedioxy, -C ０－４ alkyl(S(C １－４ alkyl)), -C ０－４ alkyl(C(O)(C １－４ alkyl)), -C ０－４ alkyl(C(O)NH ２ ), -C ０－４ alkyl(C(O)NH(C １－４ alkyl)), -C ０－４ alkyl(C(O)N(C １－４ alkyl) ２ ), -C ０－４ alkyl(C(O)O(C １－４ alkyl)), -C ０－４ alkyl(OC(O)(C １－４ alkyl)), -C ０－４ alkyl(OC(O)NH ２ ), -C ０－４ alkyl(OC(O)NH(C １－４ alkyl)), -C ０－４ alkyl(OC(O)N(C １－４ alkyl) ２ ), -C ０－４ alkyl(NHC(O)(C １－４ alkyl)), -C ０－４ alkyl(NHC(O)O(C １－４ alkyl)), -C ０－４ alkyl(NHC(O)NH ２ ), -C ０－４ alkyl(NH C(O)NH(C １－４ alkyl)), -C ０－４ alkyl(NH C(O)N(C １－４ alkyl) ２ ), -C ０－４ alkyl(NH S(O)(C １－４ alkyl)), -C ０－４ alkyl(NH S(O) ２ (C １－４ alkyl)), -C ０－４ alkyl(NH S(O) ２ NH ２ ), -C ０－４ alkyl(NH S(O) ２ NH(C １－４ alkyl)), -C ０－４ alkyl(NH S(O) ２ N(C １－４ alkyl) ２ ), -C ０－４ alkyl(S(O)(C １－４ alkyl)), -C ０－４ alkyl(S(O)NH ２ ), -C ０－４ alkyl(S(O)NH(C １－４ alkyl)), -C ０－４ alkyl(S(O)N(C １－４ alkyl) ２ ), -C ０－４ alkyl(S(O) ２ (C １－４ alkyl)), -C ０－４ alkyl(S(O) ２ NH ２ ), -C ０－４ alkyl(S(O) ２ NH(C １－４ alkyl)), -C ０－４ alkyl(S(O) ２ N(C １－４ alkyl) ２ ), -C ０－４ alkyl(NH C(O)C ６－１０ aryl), -C ０－４ alkyl(NH C(O)-(5-10 membered heteroaryl)), -C ０－４ alkyl(NH C(O)C ３－１０ cycloalkyl), and C ０－４ (May be substituted with one, two, or three substituents selected from the group consisting of alkyl (NHC(O)-(4-10 member heterocycloalkyl))) A method including administering to a patient.

2. R １ However, Halo and C １－６ C may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups. ６－１０ The method according to claim 1, wherein the aryl is used.

3. R １ but 【Chemistry 2】 The method according to claim 1 or 2.

4. R １ａ But, hello, C １－６ Alkyl, C １－４ Alkyl (NHC(O)C １－４ Alkyl), C １－４ Alkyl (C(O)C １－４ Alkyl), C １－４ Alkyl (C(O)NHC １－４ Alkyl), C １－４ Alkyl (OC(O)C １－４ Alkyl) and C １－４ Alkyl((O)COC) １－４ The method according to any one of claims 1 to 3, wherein the heteroaryl molecule is a 5 to 10-membered group which may be substituted with one, two, or three substituents selected from the group consisting of alkyl molecules.

5. R １ａ But, hello, C １－６ Alkyl, C １－４ Alkyl (NHC(O)C １－４ Alkyl), C １－４ Alkyl (C(O)C １－４ Alkyl), C １－４ Alkyl (C(O)NHC １－４ Alkyl), C １－４ Alkyl (OC(O)C １－４ Alkyl) and C １－４ Alkyl((O)COC) １－４ The method according to any one of claims 1 to 4, wherein the indole is an indole which may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups.

6. R １ａ but 【Transformation 3】 The method according to any one of claims 1 to 5.

7. The compound of formula (I) is 【Chemistry 4】 The method according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. A method for inhibiting iRhom2 / ADAM17 activity, wherein formula (II): 【Transformation 5】 A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, X is NH, N(C １－４ Alkyl), O, S, S(O), S(O) ２ , C(O), CH ２ CH (Haro), C (Haro) ２ CH(C) １－４ Alkyl), or C (C １－４ Alkyl) ２ And; R ２ C ６－１０ Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C ３－１０ It is a cycloalkyl; Each R ２ Hello, C １－６ Alkyl, C １－６ Haloalkyl, C ０－４ Alkyl (C ３－６ Cycloalkyl), C １－６ Alkoxy, C ０－６ Alkyl (Cn), C ０－６ Alkyl (OH), C ０－６ Alkyl (NO ２ ), C ０－６ Alkyl (NH ２ ), -C ０－４ Alkyl(NH(C) １－４ Alkyl)), -C ０－４ Alkyl(N(C) １－４ Alkyl) ２ ), methylenedioxy, -C ０－４ Alkyl (S(C) １－４ Alkyl)), -C ０－４ Alkyl (C(O)(C １－４ Alkyl)), -C ０－４ Alkyl (C(O)NH ２ ), -C ０－４ Alkyl(C(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(C(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (C(O)O(C) １－４ Alkyl)), -C ０－４ Alkyl (OC(O)(C １－４ Alkyl)), -C ０－４ Alkyl(OC(O)NH ２ ), -C ０－４ Alkyl(OC(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(OC(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl(NHC(O)(C) １－４ Alkyl)), -C ０－４ Alkyl(NHC(O)O(C) １－４ Alkyl)), -C ０－４ Alkyl (NHC(O)NH ２ ), -C ０－４ Alkyl(NHC(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(NHC(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (NHS(O)(C) １－４ Alkyl)), -C ０－４ Alkyl (NHS(O) ２ (C １－４ Alkyl)), -C ０－４ Alkyl (NHS(O) ２ NH ２ ), -C ０－４ Alkyl (NHS(O) ２ NH(C) １－４ Alkyl)), -C ０－４ Alkyl (NHS(O) ２ N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (S(O)(C) １－４ Alkyl)), -C ０－４ Alkyl (S(O)NH ２ ), -C ０－４ Alkyl(S(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(S(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (S(O) ２ (C １－４ Alkyl)), -C ０－４ Alkyl (S(O) ２ NH ２ ), -C ０－４ Alkyl (S(O) ２ NH(C) １－４ Alkyl)), -C ０－４ Alkyl (S(O) ２ N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (NHC(O)C ６－１０ Aryl), -C ０－４ Alkyl(NHC(O)-(5-10 member heteroaryl)),-C ０－４ Alkyl (NHC(O)C ３－１０ Cycloalkyl), and C ０－４ (May be substituted with one, two, or three substituents selected from the group consisting of alkyl (NHC(O)-(4-10 member heterocycloalkyl))) A method including administering to a patient.

9. The method according to claim 8, wherein X is NH.

10. R ２ But, hello, C １－６ Alkyl, -C(O)(C １－４ Alkyl), -C(O)NH ２ , -C(O)NH(C １－４ Alkyl), -C(O)N(C １－４ Alkyl) ２ , -C(O)O(C １－４ Alkyl), S(O)(C １－４ Alkyl), -S(O)NH ２ , -S(O)NH(C １－４ Alkyl), -S(O)N(C) １－４ Alkyl) ２ , -S(O) ２ (C １－４ Alkyl), -S(O) ２ NH ２ , -S(O) ２ NH(C) １－４ Alkyl), and S(O) ２ N(C) １－４ Alkyl) ２ C may be substituted with one, two, or three substituents selected from the group consisting of the following: ６－１０ The method according to claim 8 or 9, wherein the material is aryl.

11. R ２ but, 【Transformation 6】 The method according to any one of claims 8 to 10.

12. The compound of formula (II) is 【Transformation 7】 The method according to any one of claims 8 to 11, or a pharmaceutically acceptable salt thereof.

13. A method for inhibiting iRhom2 / ADAM17 activity, wherein formula (III): 【Transformation 8】 A method comprising administering a compound of the same, or a pharmaceutically acceptable salt thereof, to a patient.

14. A method for inhibiting iRhom2 / ADAM17 activity, comprising formula (IV): 【Chemistry 9】 A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, R ４ H, C １－４ Haloalkyl, or C １－４ It is alkyl; R ４ａ is, -C ０－６ Alkyl (C ６－１０ Aryl), -C ０－６ Alkyl (5-10 member heteroaryl), -C ０－６ Alkyl (C ３－１０ Cycloalkyl), or C ０－６ It is an alkyl group (a heterocycloalkyl group with 4 to 10 members); R ４ｂ is -C(O)-C ０－４ Alkyl (C ６－１０ Aryl), -C(O)-C ０－４ Alkyl (5-10 member heteroaryl), -C(O)-C ０－４ Alkyl (C ３－１０ Cycloalkyl), -C(O)-C ０－４ Alkyl (4-10 member heterocycloalkyl), -NHC(O)-C ０－４ Alkyl (C ６－１０ Aryl), -NHC(O)-C ０－４ Alkyl (5-10 member heteroaryl), -NHC(O)-C ０－４ Alkyl (C ３－１０ Cycloalkyl), -NHC(O)-C ０－４ Alkyl (4-10 member heterocycloalkyl), -C(O)OC ０－４ Alkyl (C ６－１０ Aryl), -C(O)OC ０－４ Alkyl (5-10 member heteroaryl), -C(O)OC ０－４ Alkyl (C ３－１０ Cycloalkyl), -C(O)OC ０－４ Alkyl (4-10 member heterocycloalkyl), -C(O)NH-C ０－４ Alkyl (C ６－１０ Aryl), -C(O)NH-C ０－４ Alkyl (5-10 member heteroaryl), -C(O)NH-C ０－４ Alkyl (C ３－１０ Cycloalkyl), -C(O)NH-C ０－４ Alkyl (4-10 member heterocycloalkyl), -C(O)N(C １－６ (Alkyl) (C ０－４ Alkyl-C ６－１０ Aryl), -C(O)N(C １－６ (Alkyl) (C ０－４ Alkyl-(5-10 member heteroaryl),-C(O)N(C １－６ (Alkyl) (C ０－４ Alkyl-C ３－１０ Cycloalkyl), or C(O)N(C １－６ (Alkyl) (C ０－４ Alkyl-(4-10 member heterocycloalkyl)); Each R ４ａ or R ４ｂ Hello, C １－６ Alkyl, C １－６ Haloalkyl, C ０－４ Alkyl (C ３－６ Cycloalkyl), C １－６ Alkoxy, C ０－６ Alkyl (Cn), C ０－６ Alkyl (OH), C ０－６ Alkyl (NO ２ ), C ０－６ Alkyl (NH ２ ), -C ０－４ Alkyl(NH(C) １－４ Alkyl)), -C ０－４ Alkyl(N(C) １－４ Alkyl) ２ ), methylenedioxy, -C ０－４ Alkyl (S(C) １－４ Alkyl)), -C ０－４ Alkyl (C(O)(C １－４ Alkyl)), -C ０－４ Alkyl (C(O)NH ２ ), -C ０－４ Alkyl(C(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(C(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (C(O)O(C) １－４ Alkyl)), -C ０－４ Alkyl (OC(O)(C １－４ Alkyl)), -C ０－４ Alkyl(OC(O)NH ２ ), -C ０－４ Alkyl(OC(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(OC(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl(NHC(O)(C) １－４ Alkyl)), -C ０－４ Alkyl(NHC(O)O(C) １－４ Alkyl)), -C ０－４ Alkyl (NHC(O)NH ２ ), -C ０－４ Alkyl(NHC(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(NHC(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (NHS(O)(C) １－４ Alkyl)), -C ０－４ Alkyl (NHS(O) ２ (C １－４ Alkyl)), -C ０－４ Alkyl (NHS(O) ２ NH ２ ), -C ０－４ Alkyl (NHS(O) ２ NH(C) １－４ Alkyl)), -C ０－４ Alkyl (NHS(O) ２ N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (S(O)(C) １－４ Alkyl)), -C ０－４ Alkyl (S(O)NH ２ ), -C ０－４ Alkyl(S(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(S(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (S(O) ２ (C １－４ Alkyl )), -C ０－４ Alkyl (S(O) ２ NH ２ ), -C ０－４ Alkyl (S(O) ２ NH(C) １－４ Alkyl)), -C ０－４ Alkyl (S(O) ２ N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (NHC(O)C ６－１０ Aryl), -C ０－４ Alkyl(NHC(O)-(5-10 member heteroaryl)),-C ０－４ Alkyl (NHC(O)C ３－１０ Cycloalkyl), and C ０－４ (May be substituted with one, two, or three substituents selected from the group consisting of alkyl (NHC(O)-(4-10 member heterocycloalkyl))) A method including administering to a patient.

15. R ４ The method according to claim 14, wherein the substance is methyl.

16. R ４ａ However, halo and OC(O)(C １－４ -C may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups. １－６ Alkyl (C ６－１０ The method according to claim 14 or 15, wherein the aryl is...

17. R ４ａ but, 【Chemistry 10】 The method according to any one of claims 14 to 16, selected from the group consisting of the following.

18. R ４ｂ is -C(O)NH-C １－４ Alkyl (C ６－１０ Aryl), -C(O)NH-C １－４ Alkyl (5-10 member heteroaryl), -C(O)NH-C １－４ Alkyl (C ３－１０ Cycloalkyl), -C(O)NH-C １－４ Alkyl (4-10 member heterocycloalkyl), -C(O)N(C １－６ (Alkyl) (C １－４ Alkyl-C ６－１０ Aryl), -C(O)N(C １－６ (Alkyl) (C １－４ Alkyl-(5-10 member heteroaryl),-C(O)N(C １－６ (Alkyl) (C １－４ Alkyl-C ３－１０ Cycloalkyl), or C(O)N(C １－６ (Alkyl) (C １－４ The method according to any one of claims 14 to 17, wherein the alkyl (4 to 10 membered heterocycloalkyl) is used.

19. R ４ｂ is -C(O)NH-C １－４ The method according to any one of claims 14 to 18, wherein the alkyl (a 5- to 10-membered heteroaryl) is used.

20. R ４ｂ but, 【Chemistry 11】 The method according to any one of claims 14 to 19, selected from the group consisting of the following.

21. The compound of formula (IV) is 【Chemistry 12】 The method according to any one of claims 14 to 20, or a pharmaceutically acceptable salt thereof.

22. The compound of formula (IV) is 【Chemistry 13】 The method according to any one of claims 14 to 20, or a pharmaceutically acceptable salt thereof.

23. The compound of formula (IV) is 【Chemistry 14】 The method according to any one of claims 14 to 20, or a pharmaceutically acceptable salt thereof.

24. The compound of formula (IV) is 【Chemistry 15】 The method according to any one of claims 14 to 20, or a pharmaceutically acceptable salt thereof.

25. A method for treating diseases or disorders associated with inhibition of iRhom2 / ADAM17 activity, wherein the therapeutically effective dose is given by formula (I): 【Chemistry 16】 A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, R １ C ６－１０ Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C ３－１０ It is a cycloalkyl; R １ａ C ６－１０ Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C ３－１０ It is a cycloalkyl; Each R １ or R １ａ Hello, C １－６ Alkyl, C １－６ Haloalkyl, C ０－４ Alkyl (C ３－６ Cycloalkyl), C １－６ Alkoxy, C ０－６ Alkyl (Cn), C ０－６ Alkyl (OH), C ０－６ Alkyl (NO ２ ), C ０－６ Alkyl (NH ２ ), -C ０－４ Alkyl(NH(C) １－４ Alkyl)), -C ０－４ Alkyl(N(C) １－４ Alkyl) ２ ), methylenedioxy, -C ０－４ Alkyl (S(C) １－４ Alkyl)), -C ０－４ Alkyl (C(O)(C １－４ Alkyl)), -C ０－４ Alkyl (C(O)NH ２ ), -C ０－４ Alkyl(C(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(C(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (C(O)O(C) １－４ Alkyl)), -C ０－４ Alkyl (OC(O)(C １－４ Alkyl)), -C ０－４ Alkyl(OC(O)NH ２ ), -C ０－４ Alkyl(OC(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(OC(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl(NHC(O)(C) １－４ Alkyl)), -C ０－４ Alkyl(NHC(O)O(C) １－４ Alkyl)), -C ０－４ Alkyl (NHC(O)NH ２ ), -C ０－４ Alkyl(NHC(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(NHC(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (NHS(O)(C) １－４ Alkyl)), -C ０－４ Alkyl (NHS(O) ２ (C １－４ Alkyl)), -C ０－４ Alkyl (NHS(O) ２ NH ２ ), -C ０－４ Alkyl (NHS(O) ２ NH(C) １－４ Alkyl )), -C ０－４ Alkyl (NHS(O) ２ N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (S(O)(C) １－４ Alkyl)), -C ０－４ Alkyl (S(O)NH ２ ), -C ０－４ Alkyl(S(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(S(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (S(O) ２ (C １－４ Alkyl)), -C ０－４ Alkyl (S(O) ２ NH ２ ), -C ０－４ Alkyl (S(O) ２ NH(C) １－４ Alkyl)), -C ０－４ Alkyl (S(O) ２ N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (NHC(O)C ６－１０ Aryl), -C ０－４ Alkyl(NHC(O)-(5-10 member heteroaryl)),-C ０－４ Alkyl (NHC(O)C ３－１０ Cycloalkyl), and C ０－４ (May be substituted with one, two, or three substituents selected from the group consisting of alkyl (NHC(O)-(4-10 member heterocycloalkyl))) A method comprising administering to a patient who requires treatment for the aforementioned disease or disorder.

26. R １ However, Halo and C １－６ C may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups. ６－１０ The method according to claim 25, wherein the aryl is...

27. R １ but 【Chemistry 17】 The method according to claim 25 or 26.

28. R １ａ But, hello, C １－６ Alkyl, C １－４ Alkyl (NHC(O)C １－４ Alkyl), C １－４ Alkyl (C(O)C １－４ Alkyl), C １－４ Alkyl (C(O)NHC １－４ Alkyl), C １－４ Alkyl (OC(O)C １－４ Alkyl) and C １－４ Alkyl((O)COC) １－４ The method according to any one of claims 25 to 27, wherein the heteroaryl molecule is a 5 to 10 member which may be substituted with one, two, or three substituents selected from the group consisting of alkyl molecules.

29. R １ａ But, hello, C １－６ Alkyl, C １－４ Alkyl (NHC(O)C １－４ Alkyl), C １－４ Alkyl (C(O)C １－４ Alkyl), C １－４ Alkyl (C(O)NHC １－４ Alkyl), C １－４ Alkyl (OC(O)C １－４ Alkyl) and C １－４ Alkyl((O)COC) １－４ The method according to any one of claims 25 to 28, wherein the indole is an indole which may be substituted with one, two, or three substituents selected from the group consisting of alkyl.

30. R １ａ but [Chemistry 18] The method according to any one of claims 25 to 29.

31. The compound of formula (I) is 【Chemistry 19】 The method according to any one of claims 25 to 30, or a pharmaceutically acceptable salt thereof.

32. A method for treating diseases or disorders associated with inhibition of iRhom2 / ADAM17 activity, wherein the therapeutically effective dose is given by formula (II): 【Chemistry 20】 A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, X is NH, N(C １－４ Alkyl), O, S, S(O), S(O) ２ , C(O), CH ２ CH (Haro), C (Haro) ２ CH(C) １－４ Alkyl), or C (C １－４ Alkyl) ２ And; R ２ C ６－１０ Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C ３－１０ It is a cycloalkyl; Each R ２ Hello, C １－６ Alkyl, C １－６ Haloalkyl, C ０－４ Alkyl (C ３－６ Cycloalkyl), C １－６ Alkoxy, C ０－６ Alkyl (Cn), C ０－６ Alkyl (OH), C ０－６ Alkyl (NO ２ ), C ０－６ Alkyl (NH ２ ), -C ０－４ Alkyl(NH(C) １－４ Alkyl)), -C ０－４ Alkyl(N(C) １－４ Alkyl) ２ ), methylenedioxy, -C ０－４ Alkyl (S(C) １－４ Alkyl)), -C ０－４ Alkyl (C(O)(C １－４ Alkyl)), -C ０－４ Alkyl (C(O)NH ２ ), -C ０－４ Alkyl(C(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(C(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (C(O)O(C) １－４ Alkyl)), -C ０－４ Alkyl (OC(O)(C １－４ Alkyl)), -C ０－４ Alkyl(OC(O)NH ２ ), -C ０－４ Alkyl(OC(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(OC(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl(NHC(O)(C) １－４ Alkyl)), -C ０－４ Alkyl(NHC(O)O(C) １－４ Alkyl)), -C ０－４ Alkyl (NHC(O)NH ２ ), -C ０－４ Alkyl(NHC(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(NHC(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (NHS(O)(C) １－４ Alkyl)), -C ０－４ Alkyl (NHS(O) ２ (C １－４ Alkyl)), -C ０－４ Alkyl (NHS(O) ２ NH ２ ), -C ０－４ Alkyl (NHS(O) ２ NH(C) １－４ Alkyl)), -C ０－４ Alkyl (NHS(O) ２ N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (S (O)(C) １－４ Alkyl)), -C ０－４ Alkyl (S(O)NH ２ ), -C ０－４ Alkyl(S(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(S(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (S(O) ２ (C １－４ Alkyl)), -C ０－４ Alkyl (S(O) ２ NH ２ ), -C ０－４ Alkyl (S(O) ２ NH(C) １－４ Alkyl)), -C ０－４ Alkyl (S(O) ２ N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (NHC(O)C ６－１０ Aryl), -C ０－４ Alkyl(NHC(O)-(5-10 member heteroaryl)),-C ０－４ Alkyl (NHC(O)C ３－１０ Cycloalkyl), and C ０－４ (May be substituted with one, two, or three substituents selected from the group consisting of alkyl (NHC(O)-(4-10 member heterocycloalkyl))) A method comprising administering to a patient who requires treatment for the aforementioned disease or disorder.

33. The method according to claim 32, wherein X is NH.

34. R ２ But, hello, C １－６ Alkyl, -C(O)(C １－４ Alkyl), -C(O)NH ２ , -C(O)NH(C １－４ Alkyl), -C(O)N(C １－４ Alkyl) ２ , -C(O)O(C １－４ Alkyl), S(O)(C １－４ Alkyl), -S(O)NH ２ , -S(O)NH(C １－４ Alkyl), -S(O)N(C) １－４ Alkyl) ２ , -S(O) ２ (C １－４ Alkyl), -S(O) ２ NH ２ , -S(O) ２ NH(C) １－４ Alkyl), and S(O) ２ N(C) １－４ Alkyl) ２ C may be substituted with one, two, or three substituents selected from the group consisting of the following: ６－１０ The method according to claim 32 or 33, wherein the aryl is used.

35. R ２ but, 【Chemistry 21】 The method according to any one of claims 32 to 34.

36. The compound of formula (II) is 【Chemistry 22】 The method according to any one of claims 32 to 35, or a pharmaceutically acceptable salt thereof.

37. A method for treating diseases or disorders associated with inhibition of iRhom2 / ADAM17 activity, wherein the therapeutically effective dose is given by formula (III): 【Chemistry 23】 A method comprising administering a compound of the said, or a pharmaceutically acceptable salt thereof, to a patient in need of treatment for the said disease or disorder.

38. A method for treating diseases or disorders associated with inhibition of iRhom2 / ADAM17 activity, wherein the formula for the therapeutically effective dose is (IV): 【Chemistry 24】 A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, R ４ H, C １－４ Haloalkyl, or C １－４ It is alkyl; R ４ａ is, -C ０－６ Alkyl (C ６－１０ Aryl), -C ０－６ Alkyl (5-10 member heteroaryl), -C ０－６ Alkyl (C ３－１０ Cycloalkyl), or C ０－６ It is an alkyl group (a heterocycloalkyl group with 4 to 10 members); R ４ｂ is -C(O)-C ０－４ Alkyl (C ６－１０ Aryl), -C(O)-C ０－４ Alkyl (5-10 member heteroaryl), -C(O)-C ０－４ Alkyl (C ３－１０ Cycloalkyl), -C(O)-C ０－４ Alkyl (4-10 member heterocycloalkyl), -NHC(O)-C ０－４ Alkyl (C ６－１０ Aryl), -NHC(O)-C ０－４ Alkyl (5-10 member heteroaryl), -NHC(O)-C ０－４ Alkyl (C ３－１０ Cycloalkyl), -NHC(O)-C ０－４ Alkyl (4-10 member heterocycloalkyl), -C(O)OC ０－４ Alkyl (C ６－１０ Aryl), -C(O)OC ０－４ Alkyl (5-10 member heteroaryl), -C(O)OC ０－４ Alkyl (C ３－１０ Cycloalkyl), -C(O)OC ０－４ Alkyl (4-10 member heterocycloalkyl), -C(O)NH-C ０－４ Alkyl (C ６－１０ Aryl), -C(O)NH-C ０－４ Alkyl (5-10 member heteroaryl), -C(O)NH-C ０－４ Alkyl (C ３－１０ Cycloalkyl), -C(O)NH-C ０－４ Alkyl (4-10 member heterocycloalkyl), -C(O)N(C １－６ (Alkyl) (C ０－４ Alkyl-C ６－１０ Aryl), -C(O)N(C １－６ (Alkyl) (C ０－４ Alkyl-(5-10 member heteroaryl),-C(O)N(C １－６ (Alkyl) (C ０－４ Alkyl-C ３－１０ Cycloalkyl), or C(O)N(C １－６ (Alkyl) (C ０－４ Alkyl-(4-10 member heterocycloalkyl)); Each R ４ａ or R ４ｂ Hello, C １－６ Alkyl, C １－６ Haloalkyl, C ０－４ Alkyl (C ３－６ Cycloalkyl), C １－６ Alkoxy, C ０－６ Alkyl (CN ), C ０－６ Alkyl (OH), C ０－６ Alkyl (NO ２ ), C ０－６ Alkyl (NH ２ ), -C ０－４ Alkyl(NH(C) １－４ Alkyl)), -C ０－４ Alkyl(N(C) １－４ Alkyl) ２ ), methylenedioxy, -C ０－４ Alkyl (S(C) １－４ Alkyl)), -C ０－４ Alkyl (C(O)(C １－４ Alkyl)), -C ０－４ Alkyl (C(O)NH ２ ), -C ０－４ Alkyl(C(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(C(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (C(O)O(C) １－４ Alkyl)), -C ０－４ Alkyl (OC(O)(C １－４ Alkyl)), -C ０－４ Alkyl(OC(O)NH ２ ), -C ０－４ Alkyl(OC(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(OC(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl(NHC(O)(C) １－４ Alkyl)), -C ０－４ Alkyl(NHC(O)O(C) １－４ Alkyl)), -C ０－４ Alkyl (NHC(O)NH ２ ), -C ０－４ Alkyl(NHC(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(NHC(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (NHS(O)(C) １－４ Alkyl)), -C ０－４ Alkyl (NHS(O) ２ (C １－４ Alkyl)), -C ０－４ Alkyl (NHS(O) ２ NH ２ ), -C ０－４ Alkyl (NHS(O) ２ NH(C) １－４ Alkyl)), -C ０－４ Alkyl (NHS(O) ２ N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (S(O)(C) １－４ Alkyl)), -C ０－４ Alkyl (S(O)NH ２ ), -C ０－４ Alkyl(S(O)NH(C) １－４ Alkyl)), -C ０－４ Alkyl(S(O)N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (S(O) ２ (C １－４ Alkyl)), -C ０－４ Alkyl (S(O) ２ NH ２ ), -C ０－４ Alkyl (S(O) ２ NH(C) １－４ Alkyl)), -C ０－４ Alkyl (S(O) ２ N(C) １－４ Alkyl) ２ ), -C ０－４ Alkyl (NHC(O)C ６－１０ Aryl), -C ０－４ Alkyl(NHC(O)-(5-10 member heteroaryl)),-C ０－４ Alkyl (NHC(O)C ３－１０ Cycloalkyl), and C ０－４ (May be substituted with one, two, or three substituents selected from the group consisting of alkyl (NHC(O)-(4-10 member heterocycloalkyl))) A method comprising administering to a patient who requires treatment for the aforementioned disease or disorder.

39. R ４ The method according to claim 38, wherein the substance is methyl.

40. R ４ａ However, halo and OC(O)(C １－４ -C may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups. １－６ Alkyl (C ６－１０ The method according to claim 38 or 39, wherein the aryl is...

41. R ４ａ but, 【Chemistry 25】 The method according to any one of claims 38 to 40, selected from the group consisting of the following.

42. R ４ｂ is -C(O)NH-C １－４ Alkyl (C ６－１０ Aryl), -C(O)NH-C １－４ Alkyl (5-10 member heteroaryl), -C(O)NH-C １－４ Alkyl (C ３－１０ Cycloalkyl), -C(O)NH-C １－４ Alkyl (4-10 member heterocycloalkyl), -C(O)N(C １－６ (Alkyl) (C １－４ Alkyl-C ６ －１０ Aryl), -C(O)N(C １－６ (Alkyl) (C １－４ Alkyl-(5-10 member heteroaryl),-C(O)N(C １－６ (Alkyl) (C １－４ Alkyl-C ３－１０ Cycloalkyl), or C(O)N(C １－６ (Alkyl) (C １－４ The method according to any one of claims 38 to 41, wherein the alkyl (4 to 10 membered heterocycloalkyl) is used.

43. R ４ｂ is -C(O)NH-C １－４ The method according to any one of claims 38 to 42, wherein the alkyl (a 5- to 10-membered heteroaryl) is used.

44. R ４ｂ but, 【Chemistry 26】 The method according to any one of claims 38 to 43, selected from the group consisting of the following.

45. The compound of formula (IV) is 【Chemistry 27】 The method according to any one of claims 38 to 44, or a pharmaceutically acceptable salt thereof.

46. The compound of formula (IV) is 【Chemistry 28】 The method according to any one of claims 38 to 44, or a pharmaceutically acceptable salt thereof.

47. The compound of formula (IV) is 【Chemistry 29】 The method according to any one of claims 38 to 44, or a pharmaceutically acceptable salt thereof.

48. The compound of formula (IV) is 【Transformation 30】 The method according to any one of claims 38 to 44, or a pharmaceutically acceptable salt thereof.

49. The method according to any one of claims 25 to 48, wherein the disease or disorder is traumatic brain injury.

50. The method according to any one of claims 25 to 48, wherein the disease or disorder is Alzheimer's disease.

51. The method according to any one of claims 25 to 48, wherein the disease or disorder is hemorrhagic stroke.

52. The method according to any one of claims 25 to 48, wherein the disease or disorder is hemophilic arthropathy.

53. The method according to any one of claims 25 to 48, wherein the disease or disorder is cytokine storm / macrophage activation syndrome.

54. The method according to any one of claims 25 to 48, wherein the disease or disorder is rheumatoid arthritis.

55. The method according to any one of claims 25 to 48, wherein the disease or disorder is systemic lupus erythematosus-glomerulonephritis.

56. The method according to any one of claims 25 to 55, wherein the compound is administered to the patient in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient.

57. The method according to claim 56, wherein the pharmaceutical composition is in a pharmaceutical drug administration form.

58. The method according to claim 56 or 57, wherein the administration is parenteral.

59. The method according to claim 56 or 57, wherein the administration is orally.

60. The method according to claim 57 or 59, wherein the pharmaceutically acceptable form of medication is a tablet or a capsule.

61. The method according to any one of claims 25 to 60, wherein the compound is administered to the patient in a daily dose within the range of about 50 mg / day to about 400 mg / day.

62. The method according to any one of claims 25 to 60, wherein the compound is administered to the patient in a daily dose within the range of approximately 50 mg / day to approximately 300 mg / day, approximately 50 mg / day to approximately 300 mg / day, approximately 50 mg / day to approximately 200 mg / day, approximately 50 mg / day to approximately 100 mg / day, approximately 50 mg / day to approximately 75 mg / day, approximately 50 mg / day to approximately 60 mg / day, approximately 300 mg / day to approximately 400 mg / day, approximately 200 mg / day to approximately 400 mg / day, or approximately 100 mg / day to approximately 300 mg / day.

63. The method according to any one of claims 25 to 60, wherein the compound is administered to the patient at a daily dose of about 50 mg / day.

64. The method according to any one of claims 25 to 60, wherein the compound is administered to the patient at a daily dose of about 100 mg / day.

65. The method according to any one of claims 25 to 60, wherein the compound is administered to the patient at a daily dose of about 200 mg / day.

66. The method according to any one of claims 25 to 60, wherein the compound is administered to the patient at a daily dose of approximately 300 mg / day.

67. The method according to any one of claims 25 to 60, wherein the compound is administered to the patient at a daily dose of approximately 400 mg / day.

68. The method according to any one of claims 25 to 67, wherein the compound is administered to the patient once a day.

69. The method according to any one of claims 25 to 67, wherein the daily dose of the compound is administered in multiple divided doses.

70. The method according to any one of claims 25 to 69, wherein the compound is administered to the patient in combination with one or more additional therapeutic agents.

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