IRHOM2 inhibitors and their uses

Abstract

The present application is directed to inhibitors of iRhom2 / ADAM17 activity that are useful in the treatment of a variety of diseases.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 250,398, filed September 30, 2021, which is incorporated by reference in its entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically as an XML file named 27601-0066WO2_SL_ST26.xml. The size of the XML file, created on September 27, 2022, is 10,091 bytes. The contents within the XML file are incorporated herein by reference in their entirety.

[0003] The present application is directed to inhibitors of iRhom2 / ADAM17 activity that are useful in the treatment of a variety of diseases. [Background technology]

[0004] EGFR (epidermal growth factor receptor) is present on the cell surface and is activated by the binding of specific ligands, such as epidermal growth factor and transforming growth factor α (TGFα). Upon activation by growth factor ligands, EGFR transitions from an inactive monomer 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 bind phosphotyrosine through their unique phosphotyrosine-binding SH2 domains. These downstream signaling proteins initiate several signaling cascades, mainly 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 regulate phenotypes such as cell migration, adhesion, and proliferation.

[0005] Mutations that cause overexpression (known as upregulation) or overactivity of EGFR are associated with a number of cancers, including lung cancer, anal cancer, and ovarian 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 EGFR mutation, 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. Can cer 8 (2): 83-96). Mutations, amplification, or misregulation of EGFR or family members are involved in approximately 30% of all epithelial cancers. Mutations related to EGFR can lead to continuous activation of EGFR, resulting in uncontrolled cell division. As a result, EGFR mutations have been identified in several types of cancer and are targets for an expanding class of anticancer 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 anticancer therapeutics directed against EGFR, such as Gefitinib and Erlotinib for lung cancer and Cetuximab for colon cancer. Cetuximab and Panitumumab are examples of monoclonal antibody inhibitors. Other monoclonal drugs in clinical development include Zalutumumab, Nimotuzumab, and Matuzumab. An alternative approach is to use small molecules to inhibit the EGFR tyrosine kinase, which is located on the cytoplasmic side of the receptor. Without kinase activity, EGFR itself cannot be activated, which is a prerequisite for the binding of downstream adaptor proteins. Ostensibly, by shutting down the signaling cascade in cells that depend on this pathway for growth, tumor growth and migration are reduced. Gefitinib, Erlotinib, and Lapatinib (a mixture of EGFR and ERBB2 inhibitors) are examples of small molecule kinase inhibitors.

[0007] The membrane-anchored metalloproteinase TNFα-converting enzyme, TACE (also called "ADAM17"), controls the release of TNFα and EGFR ligands from cells. Thus, inhibition of TACE activity represents another pathway by which EGFR activation may be blocked, providing a means to treat EGFR-dependent pathologies.

[0008] iRhom1 and the related iRhom2 have been found to work together to support the maturation of TACE (also called 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 a key role in regulating several translation-related signaling pathways, such as 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 have the advantage of simultaneously targeting these three disease-causing pathways. Furthermore, iRhom2 / ADAM17 inhibitors may selectively target the more pathogenic aspects of these pathways. Specifically, 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 (RA). The recent discovery that HB-EGF macrophages play a key role in RA further highlights the potential of iRhom2 / ADAM17 inhibitors that may block pathogenic HB-EGF without interfering with the EGFR ligand TGFα and its role in protecting the skin and intestinal barrier (Kuo D, et al., "HBEGF+ macrophages in rheumatoid arthritis"). toid 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 date, to our knowledge, no small molecule inhibitors of iRhom2 / ADAM17 activity have been disclosed. Thus, there is a clinical need to discover inhibitors of iRhom2 / ADAM17 activity with novel activity profiles. This application addresses this and other needs. Summary of the Invention

[0011] Provided herein are compounds that are inhibitors of iRhom2 / ADAM17 activity, useful for the treatment of a variety of diseases associated with inhibition of iRhom2 / ADAM17 function or activity.

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

[0013] [ka]

[0014] or a pharma- ceutically acceptable salt thereof, X is N or CH; R 1a is -C(O)C 6~10 Aryl, -C(O)-(5-10 membered heteroaryl), -C(O)C 3~10 Cycloalkyl, -C(O)-(4-10 membered heterocycloalkyl), -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 Cycloalkyl, -NHC(O)-(4-10 membered heterocycloalkyl), -C(O)OC 6~10 Aryl, -C(O)O-(5-10 membered heteroaryl), -C(O)OC 3~10 Cycloalkyl, -C(O)O-(4-10 membered heterocycloalkyl), -C(O)NHC 6~10 Aryl, -C(O)NH-(5-10 membered heteroaryl), -C(O)NHC 3~10Cycloalkyl, -C(O)NH-(4-10 membered heterocycloalkyl), -C(O)N(C 1~6 Alkyl)C 6~10 Aryl, -C(O)N(C 1~6 alkyl)-(5-10 membered heteroaryl), -C(O)N(C 1~6 Alkyl)C 3~10 Cycloalkyl, or -C(O)N(C 1~6 alkyl)-(4-10 membered heterocycloalkyl); R 1b is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, and R 1a or R 1b are halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 Al Kill), -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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 -NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0015] Some embodiments provide a method of inhibiting iRhom2 / ADAM17 activity, comprising administering to a patient a compound of formula (II):

[0016] [ka]

[0017] or a pharma- ceutically acceptable salt thereof, R 2a is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 2b is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 2c is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, and R 2a , R 2b , or R 2c are halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 -NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1 to 5 substituents selected from the group consisting of -cycloalkyl, -NHC(O)-(4- to 10-membered heterocycloalkyl), and -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0018] Some embodiments provide a method of inhibiting iRhom2 / ADAM17 activity, comprising administering to a patient a compound of formula (III):

[0019] [ka]

[0020] or a pharma- ceutically acceptable salt thereof, R 3a is -(C 1~6 Alkyl)C 6~10 Aryl, -(C1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 3b is C 1~6 Alkyl, C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 3c is H or C 1~4 is alkyl, and R 3a and R 3b are halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 Cycloalkyl, and -NHC(O )-(4- to 10-membered heterocycloalkyl), optionally substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0021] Some embodiments provide a method of inhibiting iRhom2 / ADAM17 activity, comprising administering to a patient a compound of formula (IV):

[0022] [ka]

[0023] or a pharma- ceutically acceptable salt thereof, R 4a is -C(O)C 6~10 Aryl, -C(O)-(5-10 membered heteroaryl), -C(O)C 3~10 Cycloalkyl, -C(O)-(4-10 membered heterocycloalkyl), -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 Cycloalkyl, -NHC(O)-(4-10 membered heterocycloalkyl), -C(O)OC 6~10 Aryl, -C(O)O-(5-10 membered heteroaryl), -C(O)OC 3~10Cycloalkyl, -C(O)O-(4-10 membered heterocycloalkyl), -C(O)NHC 6~10 Aryl, -C(O)NH-(5-10 membered heteroaryl), -C(O)NHC 3~10 Cycloalkyl, -C(O)NH-(4-10 membered heterocycloalkyl), -C(O)N(C 1~6 Alkyl)C 6~10 Aryl, -C(O)N(C 1~6 alkyl)-(5-10 membered heteroaryl), -C(O)N(C 1~6 Alkyl)C 3~10 Cycloalkyl, or -C(O)N(C 1~6 alkyl)-(4-10 membered heterocycloalkyl); R 4b is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 4c is H or C 1~4 is alkyl, and R 4a or R 4b are halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 Cycloalkyl, and -NHC(O )-(4- to 10-membered heterocycloalkyl), optionally substituted with 1, 2, or 3 substituents selected from the group consisting of:

[0024] Some embodiments provide a method of inhibiting iRhom2 / ADAM17 activity, comprising administering to a patient a compound of formula (V):

[0025] [ka]

[0026] or a pharma- ceutically acceptable salt thereof, R 5a is -(C 1~6 Alkyl)C6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 5b is C 1~6 Alkyl, C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 5c is H or C 1~4 is alkyl, R 5d is H or C 1~4 is alkyl, R 5a and R 5b are halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 -NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0027] Some embodiments provide a method of inhibiting iRhom2 / ADAM17 activity, comprising administering to a patient a compound of formula (VI):

[0028] [ka]

[0029] or a pharma- ceutically acceptable salt thereof, R 6a is C 1~6 Alkyl, C 1~6 Alkenyl, C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 6b is C 1~6 Alkyl, C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10is cycloalkyl, R 6c is H or C 1~4 is alkyl, R 6d is H or C 1~4 is alkyl, and R 6b Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 -NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0030] Some embodiments provide a method of inhibiting iRhom2 / ADAM17 activity, comprising:

[0031] [ka]

[0032] [ka]

[0033] [ka]

[0034] [ka]

[0035] [ka]

[0036] [ka]

[0037] [ka]

[0038] [ka]

[0039] [ka]

[0040] [ka]

[0041] [ka]

[0042] [ka]

[0043] [ka]

[0044] [ka]

[0045] [ka]

[0046] [ka]

[0047] [ka]

[0048] [ka] and

[0049] [ka]

[0050] or a pharma- ceutically acceptable salt thereof.

[0051] Some embodiments provide 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 formula (I):

[0052] [ka]

[0053] or a pharma- ceutically acceptable salt thereof to a patient in need thereof, X is N or CH; R 1a is -C(O)C 6~10 Aryl, -C(O)-(5-10 membered heteroaryl), -C(O)C 3~10 Cycloalkyl, -C(O)-(4-10 membered heterocycloalkyl), -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 Cycloalkyl, -NHC(O)-(4-10 membered heterocycloalkyl), -C(O)OC 6~10 Aryl, -C(O)O-(5-10 membered heteroaryl), -C(O)OC 3~10 Cycloalkyl, -C(O)O-(4-10 membered heterocycloalkyl), -C(O)NHC 6~10 Aryl, -C(O)NH-(5-10 membered heteroaryl), -C(O)NHC 3~10 Cycloalkyl, -C(O)NH-(4-10 membered heterocycloalkyl), -C(O)N(C 1~6 Alkyl)C 6~10 Aryl, -C(O)N(C 1~6 alkyl)-(5-10 membered heteroaryl), -C(O)N(C 1~6 Alkyl)C 3~10 Cycloalkyl, or -C(O)N(C 1~6alkyl)-(4-10 membered heterocycloalkyl); R 1b is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 1a or R 1b are halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -S(O)(C1~4 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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 -NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0054] Some embodiments provide 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 formula (II):

[0055] [ka]

[0056] or a pharma- ceutical acceptable salt thereof to a patient in need thereof. A method (wherein R 2a is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 2b is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 2c is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, and R 2a , R 2b , or R 2c are halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 -NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1 to 5 substituents selected from the group consisting of -cycloalkyl, -NHC(O)-(4- to 10-membered heterocycloalkyl), and -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0057] Some embodiments provide 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 formula (III):

[0058] [ka]

[0059] or a pharma- ceutically acceptable salt thereof to a patient in need thereof, R 3a is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 Alkyl)-( 5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 3b is C 1~6 Alkyl, C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 3c is H or C 1~4 is alkyl, and R 3a and R 3b are halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -S(O)(C 1~4 alkyl), -S(O)NH2, -S(O)NH(C 1~4alkyl), -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 -NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0060] Some embodiments provide 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 formula (IV):

[0061] [ka]

[0062] or a pharma- ceutically acceptable salt thereof to a patient in need thereof, R 4a is -C(O)C 6~10 Aryl, -C(O)-(5-10 membered heteroaryl), -C(O)C 3~10 Cycloalkyl, -C(O)-(4-10 membered heterocycloalkyl), -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 Cycloalkyl, -NHC(O)-(4-10 membered heterocycloalkyl), -C(O)OC 6~10 Aryl, -C(O)O-(5-10 membered heteroaryl), -C(O)OC 3~10 Cycloalkyl, -C(O)O-(4-10 membered heterocycloalkyl), -C(O)NHC 6~10 Aryl, -C(O)NH-(5-10 membered heteroaryl), -C(O)NHC 3~10 Cycloalkyl, -C(O)NH-(4-10 membered heterocycloalkyl), -C(O)N(C1~6 Alkyl)C 6~10 Aryl, -C(O)N(C 1~6 alkyl)-(5-10 membered heteroaryl), -C(O )N(C 1~6 Alkyl)C 3~10 Cycloalkyl, or -C(O)N(C 1~6 alkyl)-(4-10 membered heterocycloalkyl); R 4b is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 4c is H or C 1~4 is alkyl, and R 4a or R 4b are halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 -NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0063] Some embodiments provide 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 formula (V):

[0064] [ka]

[0065] or a pharma- ceutically acceptable salt thereof to a patient in need thereof, R 5a is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 5b is C 1~6 Alkyl, C 6~10 Aryl, 5-10 membered heteroaryl, 4- 10-membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 5c is H or C 1~4 is alkyl, R 5d is H or C 1~4 is alkyl, and R 5a and R 5b are halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 -NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0066] Some embodiments provide 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 formula (VI):

[0067] [ka]

[0068] or a pharma- ceutically acceptable salt thereof to a patient in need thereof, R 6a is C 1~6 Alkyl, C 1~6 Alkenyl, C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 6b is C 1~6 Alkyl, C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 6c is H or C 1~4 is alkyl, R6d is H or C 1~4 is alkyl, and R 6b Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10-NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0069] Some embodiments provide a method of treating a disease or disorder associated with inhibition of iRhom2 / ADAM17 activity, comprising:

[0070] [ka]

[0071] [ka]

[0072] [ka]

[0073] [ka]

[0074] [ka]

[0075] [ka]

[0076] [ka]

[0077] [ka]

[0078] [ka]

[0079] [ka]

[0080] [ka]

[0081] [ka]

[0082] [ka]

[0083] [ka]

[0084] [ka]

[0085] [ka]

[0086] [ka]

[0087] [ka] and

[0088] [ka]

[0089] or a pharma- ceutically acceptable salt thereof to a patient in need thereof.

[0090] In some embodiments, the compound is administered to the patient as a pharmaceutical composition comprising the compound and a pharma- ceutically acceptable carrier or excipient.

[0091] In some embodiments, the compound is administered to the patient in combination with one or more additional therapeutic agents. [Brief description of the drawings]

[0092] [Figure 1] FIG. 1 shows the sequence of KL2-AP described in Example 2 (SEQ ID NO: 1) and the translation result (SEQ ID NO: 2). [Diagram 2] FIG. 2 shows the sequence of TGFα-AP described in Example 2 (SEQ ID NO: 3) and the translation result (SEQ ID NO: 4). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0093] In some embodiments, the disclosure provides, inter alia, a method for inhibiting iRhom2 / ADAM17 activity comprising administering to a patient a compound of the disclosure or a pharma- ceutically acceptable salt thereof.

[0094] In some embodiments, the present disclosure provides, inter alia, 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 present disclosure or a pharma- ceutically acceptable salt thereof to a patient in need thereof.

[0095] I. Compounds of the Disclosure Presented herein is a compound of formula (I):

[0096] [ka]

[0097] or a pharma- ceutically acceptable salt thereof, X is N or CH; R 1a is -C(O)C 6~10 Aryl, -C(O)-(5-10 membered heteroaryl), -C(O)C 3~10 Cycloalkyl, -C(O)-(4-10 membered heterocycloalkyl), -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 Cycloalkyl, -NHC(O)-(4-10 membered heterocycloalkyl), -C(O)OC 6~10 Aryl, -C(O)O-(5-10 membered heteroaryl), -C(O)OC 3~10 Cycloalkyl, -C(O)O-(4-10 membered heterocycloalkyl), -C(O)NHC 6~10 Aryl, -C(O)NH-(5-10 membered heteroaryl), -C(O)NHC 3~10 Cycloalkyl, -C(O)NH-(4-10 membered heterocycloalkyl), -C(O)N(C 1~6 Alkyl)C 6~10 Aryl, -C(O)N(C 1~6 alkyl)-(5-10 membered heteroaryl), -C(O)N(C 1~6 Alkyl)C 3~10 Cycloalkyl, or -C(O)N(C 1~6 alkyl)-(4-10 membered heterocycloalkyl); R 1b is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, and R 1a or R1b are halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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 Al Kil), -S(O)2NH2, -S(O)2NH(C 1~4 alkyl), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10-NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -cycloalkyl, -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0098] In some embodiments, X is CH.

[0099] In some embodiments, X is N.

[0100] In some embodiments, R 1a is -C(O)C 6~10 Aryl, -C(O)-(5-10 membered heteroaryl), or -NHC(O)C 3~10 cycloalkyl, and the -C(O)C 6~10 Aryl, -CH2-(5-10 membered heteroaryl), or -NHC(O)C 3~10 Cycloalkyl is halo, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxy, methylenedioxy, and -NHC(O)-(5-10 membered heteroaryl).

[0101] In some embodiments, R 1a teeth,

[0102] [ka] or [ka] It is.

[0103] In some embodiments, R 1b is -CH2C 6~10 Aryl, -CH2- (5-10 membered heteroaryl), or C 6~10 aryl, and the -CH 6~10Aryl, -CH2- (5-10 membered heteroaryl), or C 6~10 Aryl is halo, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxy, methylenedioxy, and -NHC(O)-(5-10 membered heteroaryl).

[0104] In some embodiments, R 1b is -CH2Ph,

[0105] [ka] or

[0106] [ka] It is.

[0107] In some embodiments, the compound of formula (I) is

[0108] [ka]

[0109] [ka]

[0110] [ka]

[0111] [ka]

[0112] [ka]

[0113] [ka]

[0114] [ka]

[0115] [ka]

[0116] [ka]

[0117] [ka]

[0118] [ka]

[0119] [ka]

[0120] [ka]

[0121] [ka] and

[0122] [ka] or selected from the group consisting of

[0123] or a pharma- ceutically acceptable salt thereof.

[0124] In some embodiments, the compound of formula (I) is

[0125] [ka]

[0126] or a pharma- ceutically acceptable salt thereof.

[0127] In some embodiments, the compound of formula (I) is

[0128] [ka]

[0129] or a pharma- ceutically acceptable salt thereof.

[0130] In some embodiments, the compound of formula (I) is

[0131] [ka]

[0132] or a pharma- ceutically acceptable salt thereof.

[0133] Presented herein is a compound of formula (II):

[0134] [ka]

[0135] or a pharma- ceutically acceptable salt thereof, R 2a is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 2b is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 2c is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, and R 2a , R 2b , or R 2c are halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C1~4 alkyl), -C(O)N(C 1~4 alkyl)2, -C(O)O(C 1~4 alkyl), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 -NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1 to 5 substituents selected from the group consisting of -cycloalkyl, -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0136] In some embodiments, R 2a is C 6~10 aryl or 5-10 membered heteroaryl, and 6~10 Aryl or 5-10 membered heteroaryl is halo, C 1~4 Alkyl, C 3~6 Cycloalkyl and C 1~4 Optionally substituted with 1, 2, or 3 substituents selected from alkoxy.

[0137] In some embodiments, R 2a is phenyl.

[0138] In some embodiments, R 2b is C 6~10 aryl or 5-10 membered heteroaryl, and 6~10 Aryl or 5-10 membered heteroaryl is halo, C 1~4 Alkyl, C 3~6 Cycloalkyl and C 1~4 Optionally substituted with 1, 2, or 3 substituents selected from alkoxy.

[0139] In some embodiments, R 2b is pyridyl.

[0140] In some embodiments, R 2c -C 1~4 Alkyl-C 6~10 Aryl, -C 1~4 Alkyl-(5-10 membered heteroaryl), or -C 1~4 alkyl-(4-10 membered heterocycloalkyl), and the -C 1~4 Alkyl-C 6~10 Aryl, -C 1~4 Alkyl-(5-10 membered heteroaryl), or -C 1~4 Alkyl-(4-10 membered heterocycloalkyl) is a 4- to 10-membered heterocycloalkyl group. 1~4 Alkyl, C 3~6 Cycloalkyl and C 1~4 Optionally substituted with 1, 2, or 3 substituents selected from alkoxy.

[0141] In some embodiments, R 2c teeth,

[0142] [ka]

[0143] [ka]

[0144] [ka]

[0145] [ka]

[0146] [ka]

[0147] [ka]

[0148] [ka] or

[0149] [ka] It is.

[0150] In some embodiments, the compound of formula (II) is

[0151] [ka]

[0152] [ka]

[0153] [ka]

[0154] [ka]

[0155] [ka]

[0156] [ka]

[0157] [ka]

[0158] [ka]

[0159] [ka] and

[0160] [ka] or selected from the group consisting of or a pharma- ceutically acceptable salt thereof.

[0161] In some embodiments, the compound of formula (II) is

[0162] [ka]

[0163] or a pharma- ceutically acceptable salt thereof.

[0164] Presented herein is a compound of formula (III): [ka]

[0165] or a pharma- ceutically acceptable salt thereof, R 3a is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 3b is C 1~6 Alkyl, C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 3c is H or C 1~4 is alkyl, and R 3a and R 3b are halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4(alkyl), -OC(O)N(C 1~4 (alkyl)2, -NHC(O)(C 1~4 (alkyl), -NHC(O)O(C 1~4 (alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 (alkyl), -NHC(O)N(C 1~4 (alkyl)2, -NHS(O)(C 1~4 (alkyl), -NHS(O)2(C 1~4 (alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 (alkyl), -NHS(O)2N(C 1~4 (alkyl)2, -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), -S(O)2N(C 1~4 (alkyl)2, -NHC(O)C 6~10 aryl, -NHC(O)-(5- to 10-membered heteroaryl), -NHC(O)C 3~10 cycloalkyl, and -NHC(O)-(4- to 10-membered heterocycloalkyl), which is optionally substituted with 1, 2, or 3 substituents as desired).

[0166] In some embodiments, R 3a is C 6~10 aryl or 5- to 10-membered heteroaryl, and each of C 6~10 aryl or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 substituents selected from halo, NH2, OH, C 1~6 alkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl.

[0167] In some embodiments, R 3a is m-HO phenyl.

[0168] In some embodiments, R 3b is C 1~6 alkyl, and 1~6 Alkyl is a group that can be used with halo, NH2, OH, C 1~6 Alkyl, C 6~10 It is optionally substituted with 1, 2, or 3 substituents selected from aryl, or 5-10 membered heteroaryl.

[0169] In some embodiments, R 3b is methyl.

[0170] In some embodiments, R 3c is H.

[0171] In some embodiments, the compound of formula (III) is

[0172] [ka] and

[0173] [ka] or selected from the group consisting of

[0174] or a pharma- ceutically acceptable salt thereof.

[0175] In some embodiments, the compound of formula (III) is

[0176] [ka]

[0177] or a pharma- ceutically acceptable salt thereof.

[0178] Presented herein is a compound of formula (IV):

[0179] [ka]

[0180] or a pharma- ceutically acceptable salt thereof, R 4a is -C(O)C 6~10 Aryl, -C(O)-(5-10 membered heteroaryl), -C(O)C 3~10 Cycloalkyl, -C(O)-(4-10 membered heterocycloalkyl), -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 Cycloalkyl, -NHC(O)-(4-10 membered heterocycloalkyl), -C(O)OC 6~10 Aryl, -C(O)O-(5-10 membered heteroaryl), -C(O)OC 3~10 Cycloalkyl, -C(O)O-(4-10 membered heterocycloalkyl), -C(O)NHC 6~10 Aryl, -C(O)NH-(5-10 membered heteroaryl), -C(O)NHC 3~10 Cycloalkyl, -C(O)NH-(4-10 membered heterocycloalkyl), -C(O)N(C 1~6 Alkyl)C 6~10 Aryl, -C(O)N(C 1~6 alkyl)-(5-10 membered heteroaryl), -C(O)N(C 1~6 Alkyl)C 3~10 Cycloalkyl, or -C(O)N(C 1~6 alkyl)-(4-10 membered heterocycloalkyl); R 4b is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, and R4c is H or C 1~4 is alkyl, and R 4a or R 4b are halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2 NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C3~10 -NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -cycloalkyl, -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0181] In some embodiments, R 4a is -C(O)C 6~10 aryl or -C(O)(5-10 membered heteroaryl), and -C(O)C 6~10 Aryl or -C(O) (5-10 membered heteroaryl) are each selected from halo, NH, OH, and C 1~6 Optionally substituted with 1, 2, or 3 substituents selected from alkyl.

[0182] In some embodiments, R 4a teeth,

[0183] [ka] or

[0184] [ka]

[0185] It is.

[0186] In some embodiments, R 4b is -(C 1~6 Alkyl)C 6~10 It is aryl.

[0187] In some embodiments, R 4b is CH2phenyl.

[0188] In some embodiments, R 4c is ethyl.

[0189] In some embodiments, the compound of formula (IV) is

[0190] [ka] and

[0191] [ka] or selected from the group consisting of

[0192] or a pharma- ceutically acceptable salt thereof.

[0193] Presented herein is a compound of formula (V):

[0194] [ka]

[0195] or a pharma- ceutically acceptable salt thereof, R 5a is -(C 1~6 Alkyl)C 6~10 Aryl, -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 Alkyl)C 3~10 Cycloalkyl, -(C 1~6 alkyl)-(4-10 membered heterocycloalkyl), C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 5b is C 1~6 Alkyl, C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 5c is H or C 1~4 is alkyl, R 5d is H or C 1~4 is alkyl, and R 5a and R 5bare halo and C, respectively. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4 Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 -NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -cycloalkyl, -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0196] In some embodiments, R 5a is C 6~10 aryl or 5-10 membered heteroaryl, and 6~10 Aryl or 5-10 membered heteroaryl is selected from halo, NH2, OH, C 1~4 Alkoxy, C 1~4 Alkyl, C(O)C 1~4 Alkyl, 4-10 membered heterocycloalkyl, C 6~10 It is optionally substituted with 1, 2, or 3 substituents selected from aryl, or 5-10 membered heteroaryl.

[0197] In some embodiments, R 5a is p-CH3Ophenyl or m-CH3C(O)phenyl.

[0198] In some embodiments, R 5b is C 1~6 alkyl, and 1~6 Alkyl is a group that can be used with halo, NH2, OH, C 1~4 Alkoxy, C 1~4 Alkyl, C(O)C 1~4 Alkyl, 4-10 membered heterocycloalkyl, C 6~10 It is optionally substituted with 1, 2, or 3 substituents selected from aryl, or 5-10 membered heteroaryl.

[0199] In some embodiments, R 5b is CH2-tetrahydrofuran or hydroxypropyl.

[0200] In some embodiments, R 5c is H.

[0201] In some embodiments, R 5d is H.

[0202] In some embodiments, the compound of formula (V) is

[0203] [ka] and

[0204] [ka] or selected from the group consisting of

[0205] or a pharma- ceutically acceptable salt thereof.

[0206] Presented herein is a compound of formula (VI):

[0207] [ka]

[0208] or a pharma- ceutically acceptable salt thereof, R 6a is C 1~6 Alkyl, C 1~6 Alkenyl, C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 6b is C 1~6 Alkyl, C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3~10 is cycloalkyl, R 6c is H or C 1~4 is alkyl, R 6d is H or C 1~4 is alkyl, and R 6b Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, CN, OH, NO2, NH2, -NH(C 1~4 alkyl), -N(C 1~4Alkyl)2, methylenedioxy, -S(C 1~4 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), -OC(O)(C 1~4 alkyl), -OC(O)NH2, -OC(O)NH(C 1~4 alkyl), -OC(O)N(C 1~4 alkyl)2, -NHC(O)(C 1~4 alkyl), -NHC(O)O(C 1~4 alkyl), -NHC(O)NH2, -NHC(O)NH(C 1~4 alkyl), -NHC(O)N(C 1~4 alkyl)2, -NHS(O)(C 1~4 alkyl), -NHS(O)2(C 1~4 alkyl), -NHS(O)2NH2, -NHS(O)2NH(C 1~4 alkyl), -NHS(O)2N(C 1~4 alkyl)2, -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), -S(O)2N(C 1~4 alkyl)2, -NHC(O)C 6~10 Aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C 3~10 -NHC(O)-(4- to 10-membered heterocycloalkyl), optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -cycloalkyl, -NHC(O)-(4- to 10-membered heterocycloalkyl).

[0209] In some embodiments, R 6a is C 1~6 Alkyl or C 1~6 It is alkenyl.

[0210] In some embodiments, R 6b is C 6~10 aryl, and 6~10 Aryl is halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Optionally substituted with 1, 2, or 3 substituents selected from alkoxy, CN, NO2, or NH2.

[0211] In some embodiments, R 6b is p-CH3Ophenyl.

[0212] In some embodiments, R 6c is H.

[0213] In some embodiments, R 6d is H.

[0214] In some embodiments, the compound of formula (VI) is

[0215] [ka] and

[0216] [ka] or selected from the group consisting of

[0217] or a pharma- ceutically acceptable salt thereof.

[0218] Presented herein is

[0219] [ka]

[0220] [ka]

[0221]

change

[0222]

change

[0223]

change

[0224]

change

[0225]

change

[0226]

change

[0227]

change

[0228]

change

[0229]

change

[0230]

change

[0231] [ka]

[0232] [ka]

[0233] [ka]

[0234] [ka]

[0235] [ka]

[0236] [ka] and

[0237] [ka]

[0238] or a pharma- ceutically acceptable salt thereof.

[0239] In some embodiments, the compound is

[0240] [ka]

[0241] or a pharma- ceutically acceptable salt thereof.

[0242] In some embodiments, the compound is

[0243] [ka]

[0244] or a pharma- ceutically acceptable salt thereof.

[0245] Specific compounds used in the methods of the present disclosure are listed below in Table 1. The compounds in Table 1 were obtained from the following commercial sources: Evotec (Hamburg, Germany), Alinda Chemical Ltd. (Moscow, Russia); Ambinter (Orleans, France); BioFocus (Little Chesterford, UK); ChemBridge (San Diego, CA, USA); Enamine Ltd. (Kiev, Ukraine); IF LAB (Kiev, Ukraine); Innovapharm Ltd. (Kiev, Ukraine); Interbioscreen Ltd. (Moscow, Russia); Key Organics (Camelford, Cornwall, UK); Labotest (Germany); Life Chemicals Inc. (Nairia, Canada). Gala on the Lake;Pharmeks (Moscow, Russia);Princeton Biomolecular Research, Inc. (Princeton, NJ, USA);Specs (Zetermeer, Netherlands);TimTec LLC (Tampa, FL, USA);AKos Consulting & Solutions GmbH (Lörrach, Germany); Aurora Fine Chemicals (San Diego, California, USA); and MolPort (Beacon, New York, USA).

[0246] Representative commercial sources with Evotec ID numbers and / or commercial ID numbers for each compound are provided in Table 1.

[0247] [Table 1-1]

[0248] [Table 1-2]

[0249] [Table 1-3]

[0250] [Table 1-4]

[0251] [Table 1-5]

[0252] [Table 1-6]

[0253] Preferred compounds for use in the methods of the present disclosure are listed in Table 2 below.

[0254] [Table 2]

[0255] Furthermore, it should be understood that certain features of the present disclosure that are described for clarity in the context of separate embodiments can also be provided in combination in a single embodiment (with the intention that each embodiment can be combined as if described in a multiple dependent form). Conversely, various features of the present disclosure that are described for brevity in the context of a single embodiment can also be provided individually or in any suitable subcombination. Thus, it is contemplated that features described as embodiments of the compounds of the present disclosure can be combined in any suitable combination.

[0256] At various places in the present specification, certain features of compounds are disclosed in groups or ranges. Such disclosure is specifically intended to include every individual subcombination of each member of such groups and ranges. For example, "C 1~6 The term "alkyl" is specifically intended to individually disclose (without being limited to) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0257] The term "n-membered", where n is an integer, typically refers to the number of ring-forming atoms in a moiety where n is the number of 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.

[0258] At various places in the specification, variables defining divalent linking groups may be described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, -NR(CR'R") n -NR(CR'R") n -and-(CR'R") n Both NR- and NR- are included and each form is intended to be disclosed individually. If a structure requires a linking group, the Markush variable recited for that group is understood to be the linking group. For example, if a structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl", it is understood that "alkyl" or "aryl" represent a linking alkylene group or arylene group, respectively.

[0259] The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted" refers to any level of substitution, such as mono-, di-, tri-, tetra-, or penta-substitution, where permitted, unless otherwise specified. Substituents are independently selected and can be substituted at any chemically accessible position. It is understood that substitution at a given atom is limited by atomic valence. It is understood that the substitution of a particular atom results in a chemically stable molecule. The phrase "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. Two hydrogen atoms can be replaced with one divalent substituent, such as oxo.

[0260] "C n~m " indicates a range including the endpoints, and n and m are integers indicating the number of carbon atoms. 1~4 , C 1~6 etc.

[0261] The term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group which may be straight-chained or branched. n~m The term "alkyl" refers to an alkyl group having n to m carbon atoms. An alkyl group formally corresponds to an alkane with one C-H bond replaced at the point of attachment of the alkyl group to the remainder of the compound. In some embodiments, an alkyl group contains 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 homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, and 1,2,2-trimethylpropyl.

[0262] The term "alkenyl," used alone or in combination with other terms, refers to a straight or branched chain hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. An alkenyl group formally corresponds to an alkene with one C-H bond replaced at the point of attachment of the alkenyl group to the remainder of the compound. n~m The term "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. Examples of alkenyl groups include, but are not limited to, ethynyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0263] The term "alkynyl", used alone or in combination with other terms, means an alkynyl group having one or more carbon atoms. "Alkynyl" refers to a straight or branched chain hydrocarbon group corresponding to an alkyl group having a carbon-carbon triple double bond. An alkynyl group formally corresponds to an alkyne with one C-H bond replaced at the point of attachment of the alkyl group to the remainder of the compound. n~m The term "alkynyl" refers to an alkynyl group having n to m carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0264] 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 with two C-H bonds replaced at the points of attachment of the alkylene group to the remainder of the compound. n~m The term "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, 2-methyl-propane-1,3-diyl, and the like.

[0265] The term "alkoxy", used alone or in combination with other terms, refers to a radical of the formula -O-alkyl, wherein the alkyl radical is as defined above. n~m The term "alkoxy" refers to an alkoxy group, where the alkyl group has n to m carbons. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group contains 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0266] The term "amino" refers to a group of the formula -NH2.

[0267] The term "carbamyl" refers to a group of formula -C(O)NH2.

[0268] The term "carbonyl", used alone or in combination with other terms, refers to a -C(=O)- group, which may also be written as C(O).

[0269] The term "cyano" or "nitrile" refers to a group of formula -C≡N, also sometimes written as -CN.

[0270] The term "halo" or "halogen," used alone or in combination with other terms, refers to fluoro, chloro, bromo, and iodo. In some embodiments, "halo" refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halo group is F.

[0271] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced with a halogen atom. n~m The term "haloalkyl" refers to a C alkyl group having n to m carbon atoms and at least 1 to {2(n to m)+1} halogen atoms. n~mIn some embodiments, the halogen atom is a fluorine atom. In some embodiments, the haloalkyl group has 1-6 or 1-4 carbon atoms. Examples of haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0272] The term "haloalkoxy", used alone or in combination with other terms, refers to a radical of the formula -O-haloalkyl, where the haloalkyl group is as defined above. n~m The term "haloalkoxy" refers to a haloalkoxy group in which the haloalkyl group has n to m carbon atoms. Examples of haloalkoxy groups include trifluoromethoxy, and the like. In some embodiments, the haloalkoxy contains 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0273] The term "oxo" refers to an oxygen atom as a divalent substituent, either attached to a carbon to form a carbonyl group, or attached to a heteroatom to form a sulfoxide, sulfone, or N-oxide group. In some embodiments, heterocyclic groups are optionally substituted with one or two oxo (=O) substituents.

[0274] The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings having aromatic character (i.e., having (4n+2) delocalized (π) electrons, where n is an integer).

[0275] The term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group that may be monocyclic or polycyclic (e.g., having two fused rings). n~mThe term "aryl" refers to an aryl group having n to m ring carbon atoms. Examples of aryl groups include phenyl, naphthyl, indanyl, indenyl, and the like. In some embodiments, an aryl group has from 6 to about 10 carbon atoms. In some embodiments, an aryl group has 6 carbon atoms. In some embodiments, an aryl group has 10 carbon atoms. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is naphthyl.

[0276] As used herein, the term "heteroatom" is meant to include boron, phosphorus, sulfur, oxygen, and nitrogen.

[0277] The term "heteroaryl" or "heteroaromatic", used alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle 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 N forming a ring of the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5-14 or 5-10 ring atoms including carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. In other embodiments, the heteroaryl is an 8-, 9-, or 10-membered fused bicyclic heteroaryl ring. Examples of heteroaryl groups include, but are not limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, and 2,6-naphthyridine), indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, and the like.

[0278] A 5-membered heteroaryl ring is a heteroaryl group having 5 ring atoms, in which one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 5-membered heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thienyl, aryl ... Examples include azolyl, 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.

[0279] A 6-membered heteroaryl ring is a heteroaryl group having 6 ring atoms, where one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0280] The term "cycloalkyl," used alone or in combination with other terms, refers to non-aromatic hydrocarbon ring systems (monocyclic, bicyclic, or polycyclic) including cyclized alkyl and alkenyl groups. n~m The term "cycloalkyl" refers to a cycloalkyl having n to m ring carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbons (C 3~14 In some embodiments, the cycloalkyl group has 3 to 14 ring members, 3 to 10 ring 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 can have any of the following ring groups: 3~6It is a monocyclic cycloalkyl group. The ring-forming carbon atoms of the cycloalkyl group can be optionally oxidized to form an oxo group or a sulfide group. Cycloalkyl groups also include cycloalkylidene. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The definition of cycloalkyl also includes moieties having one or more aromatic rings fused (i.e., having a common bond) to the cycloalkyl ring, such as benzo or thienyl derivatives of cyclopentane, cyclohexane, etc. Cycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0281] 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 the ring structure, has at least one heteroatom ring member independently selected from boron, nitrogen, sulfur, oxygen, and phosphorus, and has 4 to 14 ring members, 4 to 10 ring members, 4 to 7 ring members, or 4 to 6 ring members. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include monocyclic, bicyclic, or polycyclic (e.g., having 2 or 3 fused or bridged rings) ring systems or spirocycles. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group may be optionally oxidized to oxo or sulfide groups or other oxidized bonds (e.g., C(O), S(O), C(S), or S(O), N-oxide, etc.) or to quaternize a nitrogen atom. A heterocycloalkyl group may be bonded through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, a heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, a heterocycloalkyl group contains 0 to 2 double bonds. The heterocycloalkyl group includes a double bond. Also included within the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a common bond) to the heterocycloalkyl ring, for example, benzo or thienyl derivatives such as piperidine, morpholine, azepine, etc. Heterocycloalkyl groups that contain fused aromatic rings may be bonded through any ring-forming atom, including a ring-forming atom 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-tetrahydroquinolinyl, tropanyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, and thiomorpholino.

[0282] In certain places, the definitions or embodiments refer to certain rings (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise specified, these rings may be attached to any ring member, as long as the valence of the atom is not exceeded. For example, an azetidine ring may be attached at any position on the ring, while an azetidin-3-yl ring is attached at the 3-position.

[0283] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. 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 inactive starting materials are known in the art, such as resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomers.

[0284] Resolution of racemic mixtures of compounds can be accomplished by any of a number of methods known in the art. One method involves fractional recrystallization using chiral resolving acids, which are optically active, salt-forming organic acids. Suitable resolving agents for fractional recrystallization are, for example, optically active acids such as D- and L-tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other suitable resolving agents for fractional crystallization include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0285] Resolution of racemic mixtures can also be accomplished by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Appropriate elution solvent compositions can be determined by one skilled in the art.

[0286] In some embodiments, the compounds of the invention have the (R)-configuration. In other embodiments, the compounds have the (S)-configuration. In compounds with multiple chiral centers, unless otherwise specified, each chiral center in the compound may independently be (R) or (S).

[0287] The compounds of the present invention also include tautomers. Tautomers result from the exchange of a single bond with an adjacent double bond with the concomitant transfer of a proton. Tautomers include prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and tautomers in which a proton is transferred to a heterocycle. Cyclic forms that can occupy more than one position in the system include, for example, 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0288] The compounds of the present invention may also include all isotopes of atoms present in intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. 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 an isotope of a naturally or non-naturally abundant atom. In some embodiments, the compounds include at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced or substituted with deuterium. In some embodiments, the compounds include two or more deuterium atoms. In some embodiments, the compounds include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for including isotopes in organic compounds are known in the art.

[0289] The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structures. The term is also meant to refer to compounds of the present invention regardless of how they are produced, for example, by synthesis, by a biological process (e.g., metabolic or enzymatic transformation), or a combination thereof.

[0290] All compounds and their pharma- ceutically acceptable salts may be present together with other substances such as water and solvents (e.g., hydrates and solvates) or may be isolated. When in the solid state, the compounds and their salts described herein may exist in various forms, for example, in the form of solvates, including hydrates. The compounds may be in any solid state form, such as polymorphs or solvates, and therefore, unless otherwise specified, references herein to compounds and their salts should be understood to include any solid state form of the compounds.

[0291] The phrase "pharmacologically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and which possess a reasonable benefit / risk ratio.

[0292] As used herein, the expressions "ambient temperature" and "room temperature" are understood in the art and generally refer to a reaction temperature that is close to the temperature of the room in which the reaction is carried out (e.g., a temperature of about 20° C. to about 30° C.).

[0293] The present invention also includes pharma- ceutically acceptable salts of the compounds described herein. The term "pharma- ceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharma- ceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids. The pharma- ceutically acceptable salts of the present invention include non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharma- ceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from the parent compound which contains a basic or acidic moiety. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Typically, the salts are prepared by reaction with ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, bromine, ethyl acetate ... Non-aqueous media such as methanol (ethanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include N-oxide forms.

[0294] II. Assay We developed two separate screens to identify novel small molecule inhibitors of iRhom2 / ADAM17 activity. As demonstrated in mouse genetic studies, inactivation of iRhom2 in mice blocks TNFα release from bone marrow-derived 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 screen for small molecule inhibitors of iRhom2 / ADAM17 was to screen for inhibitors that block TNFα release from LPS-stimulated THP-1 human myeloid cells, a process that is dependent on iRhom2 and ADAM17. Because TNFα release from THP-1 cells could be blocked at many steps in the LPS / TLR4 / iRhom2 / ADAM17 pathway, we investigated the secretion of another iRhom2 / ADAM17 selective substrate, Kit-ligand2 (KL-2), in a different human cell type, human embryonic kidney cells (HEK293) (Maretzky T et al. (July 2013), “iRhom2 controls the substrate selectivity of We performed a secondary screen for the markers “stimulated ADAM17-dependent ectodomain shedding”, PNAS 110(28): 11433-11438.

[0295] A tertiary counterscreen was also performed to monitor the release of TGFα, a substrate of iRhom1 / ADAM17 and iRhom2 / ADAM17, so that its release was not 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. al. (May 2015), “iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling”, PNAS 112(19): 6080-6085).

[0296] Assay conditions and results using compounds of the present disclosure are provided in the Examples.

[0297] III. Uses of the Compound The compounds of the present disclosure can inhibit the function of iRhom2 / ADAM17 or inhibit iRhom2 / ADAM17 activity, and are therefore useful for treating diseases and disorders associated with related signaling pathways such as TNFα, IL-6, and EGFR. In some embodiments, the present disclosure provides a method for inhibiting the function of iRhom2 / ADAM17 or inhibiting iRhom2 / ADAM17 activity. The method can be performed by administering to the subject a compound of the present disclosure. The present invention includes administering to an individual or patient a compound of any of the formulas described herein, or a compound recited in any of the claims and described herein, or a pharma- ceutically acceptable salt or stereoisomer thereof. The compounds of the present disclosure may be used alone, in combination with other drugs or therapies, or as adjuvants or neoadjuvants, for the treatment of diseases or disorders, including cancer or infectious diseases. Any of the compounds of the present disclosure, including any of its embodiments, may be used for the uses described herein.

[0298] In some embodiments, the present disclosure provides a method for treating a disease or disorder associated with inhibition of iRhom2 / ADAM17 function or inhibition of iRhom2 / ADAM17 activity, comprising administering a therapeutically effective amount of a compound of any of the formulas described herein, or any of the compounds listed in any of the claims and described herein, or a salt or stereoisomer thereof, to an individual or patient in need thereof.

[0299] In some embodiments, the disease or disorder associated with inhibition of iRhom2 / ADAM17 function or inhibition of iRhom2 / ADAM17 activity is traumatic brain injury. Traumatic brain injury (TBI) is a major cause of temporary or permanent cognitive impairment and disability. TBI can be caused by any type of severe head trauma or impact, such as after a fall while biking, skiing, running, or riding a motorcycle, or after other injuries such as during a car accident or combat. TBI causes activation of immune cells in the brain called microglia. In response to such injury, these cells, which are silent and quiescent in a normal, healthy brain, become activated and release proinflammatory cytokines such as TNFα. Dysregulated release of TNFα is known to cause cognitive impairment in mice and will likely have a similar effect in human patients. 1 iRhom2 is required for TNFα release from microglia 2 Inhibiting the function of iRhom2 / ADAM17 or inhibiting iRhom2 / ADAM17 activity will improve or prevent some or all of the consequences of TBI, such as headache, cognitive impairment, depression, and dementia. In some embodiments, a method for treating traumatic brain injury is provided herein. The method includes administering to a patient in need thereof a therapeutically effective amount of a compound of the formula described herein, a compound listed in any of the claims and described herein, or a salt thereof. The expected effect is reduction or prevention of symptoms of TBI.

[0300] In some embodiments, the disease or disorder associated with inhibition of iRhom2 / ADAM17 function or inhibition of iRhom2 / ADAM17 activity is Alzheimer's disease. Alzheimer's disease (AD) and the resulting dementia are devastating conditions that affect the lives of those affected and their relatives and caregivers. ADAM17-dependent TNFα release in immune cells is regulated by iRhom2. 2 Interestingly, a recent study reported a highly significant association between altered methylation of iRhom2 (also known as RHBDF2) and AD in humans. 3 Since iRhom2 / ADAM17-dependent TNFα release from microglia and brain leukocytes contributes to the neuroinflammatory stage of AD, inhibition of iRhom2 / ADAM17 function or inhibition of iRhom2 / ADAM17 activity may be an interesting new target for AD treatment. In some embodiments, a method for treating Alzheimer's disease is provided herein. The method includes administering a therapeutically effective amount of a compound of the formula described herein, a compound listed in any of the claims and described herein, or a salt thereof to a patient in need thereof. The expected effect is reduction or prevention of AD symptoms, reduction of neuroinflammation and brain damage, leading to improved quality of life and cognitive ability compared to untreated patients.

[0301] 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 severe consequences of bleeding disorders, such as hemophilia A or hemophilia 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 effect on the patient's life. 4~7 Blood entry into the joints activates the iRhom2 / ADAM17 / TNFα signaling pathway, which may lead to joint erosion and damage, as well as osteoporosis, which is known to affect patients with HA. 8Therefore, inhibitors of iRhom2 / ADAM17 function or iRhom2 / ADAM17 activity may serve as a novel treatment for HA-associated joint damage and bone erosion. In some embodiments, a method for treating hemophilic arthropathy is provided herein. The method comprises administering a therapeutically effective amount of a compound of the formula described herein, a compound listed in any of the claims and described herein, or a salt thereof, to a patient in need thereof. The expected effect is to reduce or prevent joint erosion and damage, osteoporosis and osteopenia in patients suffering from HS, leading to improved quality of life and mobility of the affected patients. The compounds of the present invention can be combined with other treatments for HA patients, such as factor VIII replacement, to enhance the therapeutic effect and further improve the quality of life of the affected patients.

[0302] 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 brain tissue damage due to displacement caused by unexited bleeding in the closed skull cavity. However, neuroinflammation, which occurs as a secondary consequence, is thought to be a consequence of activation of microglia by blood and blood breakdown products in a similar manner to how macrophages (which are very similar to microglia) are activated in patients with hemophilic arthropathy ( 8 (See Example 3 and Example 4). Microglial activation leads to the release of TNFα, which causes negative sequelae such as cognitive impairment and dementia, as described above for AD and TBI. Because TNFα production induced by the blood of HA patients is dependent on iRhom2, 8It is predicted that inhibiting the function of iRhom2 / ADAM17 or inhibiting iRhom2 / ADAM17 activity will help prevent some or all of the devastating consequences of HS. In some embodiments, a method of treating hemorrhagic stroke is provided herein. The method includes administering a therapeutically effective amount of a compound of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof, to a patient in need thereof. The expected effect is to reduce or prevent the symptoms of HS, reduce neuroinflammation and brain damage, leading to improved quality of life and cognitive ability compared to untreated patients.

[0303] In some embodiments, the disease or disorder associated with inhibition of iRhom2 / ADAM17 function or inhibition of iRhom2 / ADAM17 activity is cytokine storm and macrophage activation syndrome. Cytokine storm (CS) and macrophage activation syndrome (MAS) are believed to be important contributors to the pathogenesis of COVID-19 and other acute respiratory syndromes caused by novel coronavirus disease (CoV), influenza virus, and other acute damage to the lungs. Viral infection or other causes of cytokine storm activate the release of TNFα and interleukin 6 receptor (IL-6R) from macrophages, which can result in disease progression and severe and even fatal outcomes for affected patients. As iRhom2 is required for the release of TNFα and IL-6R from macrophages, 9~11 (No data on IL-6R is shown), iRhom2 is the target of choice for the treatment of CS / MAS. In some embodiments, provided herein is a method for treating cytokine storm and macrophage activation syndrome. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof. The expected effect is a reduction in CS / MAS, which is predicted to significantly improve the outcome of acute respiratory syndrome and other effects of CS / MAS, including damage to internal organs such as the liver, kidneys, heart, and intestines. .

[0304] In some embodiments, the disease or disorder associated with inhibition of iRhom2 / ADAM17 function 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 excellent targets for the treatment of RA. However, despite the success of these individual pro-inflammatory pathway inhibitors, a significant number of patients treated with anti-TNF biologics (e.g., Humira, Etanercept) do not respond and are switched to IL-6 pathway inhibitors (e.g., Tocilizumab), and vice versa. Inhibitors of iRhom2 / ADAM17 function or activity can be used to treat TNFα 9~11 and IL-6R (data on IL-6R not shown) and the newly implicated HB-EGF / EGFR pathway. 12 Since both are blocked simultaneously, excellent protection from RA can be expected. In some embodiments, a method for treating rheumatoid arthritis is provided herein. The method includes administering a therapeutically effective amount of a compound of the formula described herein, a compound listed in any of the claims and described herein, or a salt thereof to a patient in need thereof. The expected effect is relief from RA and excellent protection by blocking all three disease-causing pathways simultaneously.

[0305] In some embodiments, the disease or disorder associated with inhibition of iRhom2 / ADAM17 function or inhibition of iRhom2 / ADAM17 activity is systemic lupus erythematosus-glomerulonephritis. Systemic lupus erythematosus (SLE) is a condition caused by the deposition of immune complexes that mediate the activation of Fcγ receptors (FcγRs) 13It is a classic autoimmune disease in which neutrophils and monocytes are recruited and activated via the FcγR and C5a receptors (C5aR). FcγR and complement play an important role in immune complex-induced inflammation and subsequent organ damage. Engagement of FcγR and complement receptors on neutrophils (first responders) and monocytes leads to the production of reactive oxidants, release of proteolytic enzymes, phagocytosis, and upregulation of growth factors including chemokines, cytokines, most notably TNFα, and HB-EGF. 14 Studies in mice have shown that inactivating iRhom2, which is required for cellular release of TNFα and HB-EGF, prevents lethal and severe glomerulonephritis (GN) induced in a mouse model of SLE. 15 Furthermore, patients with SLE-GN have a predisposing condition caused by activation of iRhom2 / ADAM17. 16 , as they also have dysregulated HB-EGF signaling 14 In this way, inhibitors of iRhom2 / ADAM17 function or activity will be used to treat patients with SLE-GN. In some embodiments, a method of treating systemic lupus erythematosus-glomerulonephritis is provided herein. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the formulas described herein, a compound listed in any of the claims and described herein, or a salt thereof. The expected effect is a reduction in SLE-GN and superior protection by simultaneously blocking two disease-causing pathways (TNFα, HB-EGF).

[0306] It is believed that the compounds of the present disclosure, or any of its embodiments, may have a satisfactory pharmacological profile and promising biopharmaceutical properties, such as toxicological profile, metabolism and pharmacokinetic properties, solubility, and permeability. It will be understood that determining appropriate biopharmaceutical properties, such as determining cytotoxicity in cells or inhibition of specific targets or channels to determine potential toxicity, is within the knowledge of one of ordinary skill in the art.

[0307] The terms "individual" or "patient" are used interchangeably and refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0308] The phrase "therapeutically effective amount" refers to the amount of In some cases, the term "quantity of active compound or drug" refers to the amount of active compound or drug that elicits a biological or medicinal response in a tissue, system, animal, individual, or human.

[0309] The term "treating" or "treatment" as used herein refers to one or more of: (1) suppressing a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting a pathology or symptom of the disease, condition, or disorder (i.e., preventing further progression of the pathology and / or symptoms); and (2) ameliorating a disease, e.g., reducing the severity of the disease, improving a disease, condition, or disorder in an individual experiencing or exhibiting a pathology or symptom of the disease, condition, or disorder (i.e., ameliorating the pathology and / or symptoms).

[0310] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases mentioned herein, e.g., preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but has not yet experienced or exhibited the pathology or symptoms of the disease.

[0311] Combination therapy The compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, can 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, systemic lupus erythematosus-glomerulonephritis, and the like.

[0312] When two or more agents are administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (eg, for two or more agents).

[0313] In some embodiments, the one or more additional therapeutic agents for the treatment of hemophilic arthropathy comprise clotting factor replacement, for example, FVIII replacement therapy.

[0314] In some embodiments, one of the additional therapeutic agents for the treatment of rheumatoid arthritis comprises one or more agents selected from methotrexate, an anti-TNF biologic, and an anti-IL-6 biologic.

[0315] IV. Formulations, Dosage Forms, and Methods of Administration When used as a pharmaceutical, the compounds of the present disclosure may be administered in the form of a pharmaceutical composition. Thus, the present disclosure provides compositions comprising a compound described herein or a pharma- ceutically acceptable salt thereof, or any of its embodiments, and at least one pharma- ceutically acceptable carrier or excipient. These compositions may be prepared by methods well known in the pharmaceutical art and may be administered by various routes, depending on whether local or systemic treatment is required and the area to be treated. Administration may be topical (including transdermal, epidermal, ocular, and mucosal delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., intratracheal or intranasal, by inhalation or insufflation of powder or aerosol with a nebulizer), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial (e.g., intrathecal or intraventricular) administration. Parenteral administration may be in the form of a single bolus dose, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0316] The present disclosure also relates to a method for the preparation of a pharmaceutical composition comprising, as an active ingredient, a compound of the present disclosure or a pharma- ceutical agent having a medicament for use in a pharmaceutical composition ... or more pharma- ceutical compositions containing the active ingredient in combination with a pharma- ceutical acceptable carrier or excipient. In some embodiments, the composition is suitable for topical administration. In preparing the compositions of the present disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier, for example in the form of a capsule, sachet, paper, or other container. When an excipient functions as a diluent, it is a solid, semi-solid, or liquid substance that functions as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection liquids, and sterile packaged powders.

[0317] When preparing a formulation, active compound can be milled to a suitable particle size before being combined with other components.If active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh.If active compound is substantially water-soluble, its particle size can be adjusted by milling to provide substantially uniform distribution in the formulation (for example, about 40 mesh).

[0318] The compounds of the present disclosure can be milled using known milling procedures, such as wet milling, to obtain a particle size suitable for tablet formation and other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the present disclosure can be prepared by processes known in the art (see, for example, WO 2002 / 000196).

[0319] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methylhydroxybenzoates and propylhydroxybenzoates, sweeteners, and flavoring agents.The composition of the present disclosure may be formulated to provide rapid, sustained, or delayed release of active ingredient after administration to a patient by using procedures known in the art.

[0320] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide (w / w).

[0321] In some embodiments, the composition is a sustained release composition comprising at least one compound described herein or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one compound described herein or a pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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 Fas t Flo™ 316. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., METHOCEL™ K4M Premium) and / or hydroxypropyl methylcellulose 2208 K100LV (e.g., METHOCEL™ K00LV). In some embodiments, the polyethylene oxide is polyethylene oxide WSR1105 (e.g., POLYOX™ WSR1105).

[0322] In some embodiments, a wet granulation process is used to manufacture the composition. In some embodiments, a dry granulation process is used to manufacture the composition.

[0323] The compositions may be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 50 mg to about 400 mg, of the active ingredient. In some embodiments, each dosage contains about 50 mg of active ingredient. In some embodiments, each dosage contains about 100 mg of active ingredient. In some embodiments, each dosage contains about 200 mg of active ingredient. In some embodiments, each dosage contains about 300 mg of active ingredient. In some embodiments, each dosage contains about 400 mg of active ingredient.

[0324] In some embodiments, the compound is administered to the patient at a daily dose ranging from about 50 mg / day to about 400 mg / day. In some embodiments, the compound is administered to the patient at a daily dose ranging from about 50 mg / day to about 300 mg / day, from about 50 mg / day to about 300 mg / day, from about 50 mg / day to about 200 mg / day, from about 50 mg / day to about 100 mg / day, from about 50 mg / day to about 75 mg / day, from about 50 mg / day to about 60 mg / day, from about 300 mg / day to about 400 mg / day, from about 200 mg / day to about 400 mg / day, or from about 100 mg / day to about 300 mg / day.

[0325] In some embodiments, the compound is administered to the patient at a daily dose of about 50 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of about 100 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of about 200 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of about 300 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of about 400 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of about 500 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of about 750 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of about 1000 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of about 10 mg / day. In some embodiments, the compound is administered to the patient at a daily dose of about 1 mg / day.

[0326] In some embodiments, the daily dose is within the range of about 1 mg / day to about 1000 mg / day, about 10 mg / day to about 750 mg / day, about 10 mg / day to about 500 mg / day, about 10 mg / day to about 400 mg / day, about 10 mg / day to about 300 mg / day, about 10 mg / day to about 200 mg / day, about 10 mg / day to about 100 mg / day, about 10 mg / day to about 50 mg / day, about 50 mg / day to about 500 mg / day, about 50 mg / day to about 400 mg / day, about 50 mg / day to about 300 mg / day, about 50 mg / day to about 200 mg / day, or about 50 mg / day to about 100 mg / day. In some embodiments, the method comprises administering a single dose of the composition to the patient. In some embodiments, the method comprises administering multiple doses of the composition to the patient, hi some embodiments, the method comprises administering 1-4 doses of the composition to the patient per day.

[0327] The term "unit dosage form" refers to a physical form suitable as a unitary dose for human subjects and other animals. It generally refers to discrete units each containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in combination with a suitable pharmaceutical excipient.

[0328] Ingredients used in formulating pharmaceutical compositions are of high purity and substantially free of potentially harmful contaminants (e.g., at least National Food grade, usually at least analytical grade, and more typically at least pharmaceutical grade). Particularly for human consumption, the compositions are preferably manufactured or formulated in accordance with Good Manufacturing Practices as defined in applicable regulations of the U.S. Food and Drug Administration. For example, suitable formulations may be sterile and / or substantially isotonic and / or in full compliance with all U.S. Food and Drug Administration Good Manufacturing Practice regulations.

[0329] The active compound may be effective over a wide dosage range and is usually administered in a therapeutically effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician depending on the relevant circumstances, including the condition to be treated, the selected route of administration, the compound actually administered, the age, weight, response, severity of the patient's symptoms, etc.

[0330] The therapeutic dose of the compounds of the present disclosure may vary according to, for example, the particular application for which the treatment is made, the method of administration of the compound, the health condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present disclosure in a pharmaceutical composition may vary depending on a number of factors, including the dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present disclosure 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 dosage ranges are from about 1 μg / kg body weight to about 1 g / kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. In some embodiments, the dosage range is about 0.02 mg / kg body weight to about 20 mg / kg body weight, about 0.05 mg / kg body weight to about 10 mg / kg body weight, 0.1 mg / kg body weight to about 10 mg / kg body weight, 0.2 mg / kg body weight to about 8 mg / kg body weight, 0.5 mg / kg body weight to about 5 mg / kg body weight, 1 mg / kg body weight to about 5 mg / kg body weight, or 2 mg / kg body weight to about 3 mg / kg body weight per day. In some embodiments, the dosage is about 0.5 mg / kg body weight, about 1 mg / kg body weight, about 2 mg / kg body weight, about 3 mg / kg body weight, about 4 mg / kg body weight, about 5 mg / kg body weight, about 6 mg / kg body weight, about 7 mg / kg body weight, about 8 mg / kg body weight, about 9 mg / kg body weight, or about 10 mg / kg body weight per day.

[0331] The dosage administered will likely depend on such variables as the type and extent of the disease or disorder, the overall health of the particular patient, the relative biological availability of the selected compound, the excipient formulation, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0332] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogenous mixture of the compounds of the present disclosure. When these preformulation compositions are referred to as homogenous, the active ingredient is usually dispersed evenly throughout the composition so that the composition can be readily subdivided into similarly effective unit dosage forms such as tablets, pills, capsules, and the like. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, about 0.1 to about 1000 mg of the active ingredient of the present disclosure.

[0333] The tablets or pills of the present disclosure can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage component and an outer dosage component, the latter in the form of an envelope over the former. The two components are resistant to disintegration in the stomach, allowing the inner component to pass intact into the duodenum or be released. Such enteric layers or coatings can be a variety of materials, including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0334] Liquid forms into which the compounds and compositions of the present disclosure can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions including edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0335] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. The liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. The compositions may be nebulized using an inert gas. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0336] Topical formulations may include 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, white petrolatum, and the like. Cream carrier compositions may be based on water in combination with glycerol and one or more other ingredients, for example, glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. Gels may be formulated using isopropyl alcohol and water in suitable combination with other ingredients, for example, glycerol, hydroxyethylcellulose, and the like. In some embodiments, topical formulations contain at least about 0.1% by weight, at least about 0.25% by weight, at least about 0.5% by weight, at least about 1% by weight, at least about 2% by weight, or at least about 5% by weight of the compound of the present disclosure. Topical formulations may be suitably packaged, for example, in 100 g tubes, optionally associated with instructions for the treatment of a selected indication, for example, psoriasis or other skin conditions.

[0337] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration, such as prophylaxis or treatment, the condition of the patient, the method of administration, etc. In therapeutic applications, the compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will be determined by the judgment of the attending physician depending on factors such as the condition of the disease being treated, as well as the severity of the disease, the age, weight, and general condition of the patient.

[0338] The compositions administered to a patient may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for use as is or may be lyophilized and combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations is typically 3-11, more preferably 5-9, most preferably 7-8. It will be appreciated that the use of certain of the excipients, carriers, or stabilizers described above results in the formation of pharmaceutical salts.

[0339] The therapeutic dosage of the compounds of the present disclosure may vary according to, for example, the particular application for which the treatment is made, the manner in which the compound is administered, the health of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition may vary depending on a number of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present disclosure may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Typical dose ranges are from about 1 μg / kg body weight to about 1 g / kg body weight per day. In some embodiments, the dose range is from about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. The dosage will likely depend on variables such as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological availability of the selected compound, the excipient formulation, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0340] V. Labeled Compounds and Analytical Methods The compounds of the present disclosure may further be useful for studying biological processes in normal and abnormal tissues.Accordingly, another aspect of the present disclosure relates to the labeled compounds (radiolabeled, fluorescently labeled, etc.) of the present disclosure that may be useful for imaging techniques as well as for both in vitro and in vivo assays for localizing and quantifying iRhom2 in tissue samples, including humans, and for identifying iRhom2 ligands by inhibiting the binding of the labeled compounds.Accordingly, the present disclosure includes iRhom2 binding assays that include such labeled compounds.

[0341] The present disclosure further includes isotopically labeled compounds of the present disclosure. An "isotopically" or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present disclosure include: 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 These include, but are not limited to, I. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced or substituted with deuterium atoms.

[0342] One or more constituent atoms of the compounds provided herein can be replaced or substituted with an isotope of a naturally or non-naturally abundant atom. In some embodiments, the compounds contain at least one deuterium atom. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compounds contain 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compounds can be replaced or substituted with deuterium atoms.

[0343] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labeling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, including NMR spectroscopy, metabolic experiments, and assays.

[0344] Substitution with heavier isotopes, such as deuterium, may be preferable in some circumstances because it may confer certain therapeutic advantages, such as increased metabolic stability, e.g., increased half-life in vivo, or reduced dosage requirements (e.g., A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. al. J. Label Compd. Radiopharm. 2015, 5 8, 308-312). In particular, substitution at one or more metabolic sites may confer one or more therapeutic advantages.

[0345] The radionuclide that is incorporated in the radiolabeled compounds of the invention will depend on the particular application of that radiolabeled compound. For example, in in vitro PD-L1 protein labeling and competition assays: 3 H, 14 C. 82 Br, 125 I, 131 I, or 35 Compounds incorporating S are generally most useful. For radioimaging applications, 11 C. 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br, or 77 Br helps.

[0346] By "radiolabeled" or "labeled compound" is understood a compound into which at least one radionuclide has been incorporated. In some embodiments, the radionuclide is 3 H, 14 C. 125 I, 35 S, and 82 Br.

[0347] The present disclosure may further include synthetic methods for incorporating radioisotopes into the disclosed compounds. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and one of ordinary skill in the art will readily recognize methods that are applicable to the disclosed compounds.

[0348] The labeled compounds of the present disclosure can be used in screening assays to identify and / or evaluate compounds. For example, a labeled newly synthesized or identified compound (i.e., a test compound) can be evaluated for its ability to bind to iRhom2 by monitoring its concentration change when it contacts iRhom2 through tracking of the label. For example, a test compound (labeled) can 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 iRhom2 protein directly correlates with its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is not labeled. Thus, the concentration of the labeled standard compound is monitored to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is ascertained.

[0349] VI. Kits The present disclosure also includes pharmaceutical kits useful, for example, for treating or preventing diseases or disorders associated with the activity of iRhom2 / ADAM17, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein. Such kits may further include one or more of a variety of conventional pharmaceutical kit components, such as, for example, a container with one or more pharma- ceutically acceptable carriers, additional containers, etc., as will be readily apparent to one of skill in the art. Instructions indicating the amounts of components to be administered, administration guidelines, and / or mixing guidelines of the components may be included in the kit as an insert or label.

[0350] 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 reach 50% of activity inhibition); kg (kilograms); KL-2 or KitL2 (Kit-ligand-2); LPS (lipopolysaccharide); M (molar (concentration)); mg (milligrams); min (minutes); mL (milliliters); mM (millimoles); NaOH (sodium hydroxide); nL (nanoliters); nM (nanomoles); μg (micrograms); μL (microliters); μM (micromole); PMA (phorbol 12-myristate 13-acetate); pNP (para-nitrophenyl phenol); pNPP (para-nitrophenyl phosphate); RA (rheumatoid arthritis); RT (room temperature); SLE-GN (systemic lupus erythematosus-glomerulonephritis); TBI (traumatic brain injury); TNF (tumor necrosis factor alpha); XC 50 (concentration required to reach 50% of activity inhibition).

[0351] The present invention will be described in more detail below with specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any manner. Those skilled in the art will easily recognize various non-critical parameters that can be changed or modified to essentially achieve the same results. Compounds of the present disclosure have been found to inhibit iRhom2 / ADAM17 activity according to at least one assay described herein. [Prior art documents] [Non-patent literature]

[0352] 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 U S 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. Orthopaedic 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.

[0353] 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 signaling 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 炎症性关节炎的介质。《临床研究杂志》。2013年;123(2):928 - 932。 12. 郭D、丁J、科恩IS等。类风湿性关节炎中的HBEGF(+)巨噬细胞 诱导成纤维细胞侵袭性。《科学转化医学》。2019年;11(491)。 13. 尼默亚恩F、拉韦奇JV。Fcγ受体作为免疫反应的调节因子。《自然评论:免疫学》。2008年;8(1):34 - 47。 14. 博勒G、弗拉芒M、肖尔丹S等 表皮生长因子受体在快速进展性新月体性肾小球肾炎中促进肾小球损伤和肾衰竭。《自然医学》。2011年;17(10):1242 - 1250。 15. 青X、奇内科诺夫Y、雷德查P等。iRhom2通过TNF - α和EGFR信号通路促进狼疮性肾炎。《临床研究杂志》。2018年;128(4):1397 - 1412。 16. 马雷茨基T、麦基尔韦恩DR、伊苏雷PD等。iRhom2控制受刺激的ADAM17依赖性胞外域脱落的底物选择性。《美国国家科学院院刊》。2013年;110(28):11433 - 11438。

Examples

[0354] Example 1a. Primary Screening: LPS / PMA-Stimulated TNFα Release from THP-1 Cells THP-1 cells were seeded in 384-well or 1,536-well plates and transferred to the ultra-high throughput screening (uHTS) platform MarkIII, where TNFα shedding was initiated by LPS stimulation of THP-1 cells. The extent of released TNFα was detected with corresponding HTRF antibodies labeled with europium cryptate (donor) and d2 (acceptor). HTRF signal was generated by the proximity of europium cryptate and d2. All detection reagents were purchased from CIsbio. TNFα detection was performed according to the manufacturer's protocol (Cisbio's product inserts for TNFα(h) kit, product numbers 62HTNFAPEG and 62HTNFAPEH; https: / / www.cisbio.com / media / asset / c / i / cisbio_dd_pi_62htnfapeg-62htnfapeh.pdf, accessed September 28, 2020).

[0355] 7.5 nL of compounds and controls in DMSO [10 μM in assays, 0.25% DMSO in 3 μL assays] were dissolved in 2 μL of cell suspension [2.4E6 / mL, 4800 cells / well, cultured without Pen-Strep] and pre-incubated with 1 μL of LPS [100 ng / mL in 3 μL assays] for 15 min at 37 °C and 5% CO2. The cells were incubated with 2 μL of HTRF-mix [final concentration 1:300] ([1:300 fc]) at 37 °C and 5% CO2 for 3 h. After more than 2 h of incubation at room temperature, HTRF readout was performed. Data evaluation for normalization against 50 μM Batimastat control (=100% activation) was then applied. As an additional control, 300 nM Batimastat was used to monitor the performance of the cells and assay the sensitivity over time.

[0356] Example 1b. Primary Screening: LPS / PMA-Stimulated TNFα Release from THP-1 Cells THP-1 cells were seeded in low volume 384-well plates (10,000 cells per well in 12.6 μL RPMI medium) with inhibitors or 10 μM BB94 and incubated overnight. The next day, TNFα release was initiated by stimulating THP-1 cells with 100 ng / mL LPS (1.8 μL of 800 ng / mL LPS stock) for 3 h at 37°C. The extent of released TNFα was detected with corresponding HTRF antibodies labeled with europium cryptate (donor) and d2 (acceptor). HTRF signal was generated by the proximity of europium cryptate and d2. All detection reagents were purchased from CIsbio. Detection of TNFα was performed according to the manufacturer's protocol (Cisbio TNFα(h) Kit product inserts part numbers 62HTNFAPEG and 62HTNFAPEH; https: / / www.cisbio.com / media / asset / c / i / cisbio_dd_pi_62htnfapeg-62htnfapeh.pdf, accessed September 28, 2020).

[0357] Low volume 384-well plates were precoated with small molecule library compounds at a final concentration of 20 μM in 15 μL reactions or 0.75 μL of a 200 μM stock in 5% DMSO containing BB94 (final concentration 0.25%). 12.6 μL of cell suspension [8 × 10 5 / mL (8E5 / ml), 10,000 cells / well, cultured RPMI medium] overnight at 37 °C, 5% CO2. The next day, 1.8 μL of 800 ng / mL LPS stock was added [final concentration 100 ng / mL in 15 μL assay] and the cells were incubated for 3 h at 37 °C, 5% CO2. Subsequently, 3 μL of HTRF mix [HTRF human TNF from Cisbio was used diluted 1:3] was added and the plate was incubated for another 2 h at 25 °C. After 2 h incubation at room temperature, HTRF readout was performed. Data evaluation for normalization to 10 μM batimastat control (= 100% activation) was then applied.

[0358] Example 2a. Cell Generation of Example 3a and Example 4a (Secondary Screening, Counter Screening) First, expression plasmids for alkaline phosphatase (AP)-fused KL2 and TGFα were designed, generated by gene synthesis, and subcloned into pcDNA3.1(+) / Hygro expression vector. The sequence of KL2-AP (SEQ ID NO:1) and the translated result (SEQ ID NO:2) are shown in Figure 1. The sequence of TGFα-AP (SEQ ID NO:3) and the translated result (SEQ ID NO:4) are shown in Figure 2. Then, DNA amplification was performed to obtain sufficient amounts of expression vectors. The quality of the DNA and gene sequences was confirmed by restriction enzyme digestion and Sanger sequencing. We started culturing THP-1 and HEK-293 cells by running the same protocol. Master and working cell banks were prepared. Both cell lines were scaled up and transfected with the respective constructs by electroporation. During cell culture, cell density and viability were monitored to ensure optimal conditions for transfection. After PMA stimulation, AP-bound KL2 or TGFα was detected by measuring AP activity in the supernatant. Initial experiments on TGFα shedding showed good performance of HEK-293. In contrast, THP-1 cells proved not to be a suitable transfection host and cell viability was lost after transfection. It was decided to proceed with HEK-293 for both selectivity assays and to establish polyclonal cell lines stably expressing AP-bound KL2 or TGFα.

[0359] After electroporation, cells were further cultured in the presence of the selection antibiotic hygromycin B to generate stably transfected polyclonal cell pools. For both assays of KL2 and TGFα shedding, the selected pools were found to be suitable. Final assay conditions were determined for the selected pools. In all experiments, batimastat (30 μM) was used as a positive control to completely inhibit KL2 or TGFα shedding.

[0360] Example 2b. Cell Generation of Example 3b and Example 4b (Secondary Screening, Counterscreening) Expression plasmids for alkaline phosphatase (AP)-fused human KL2 and TGFα were designed in advance, generated by gene synthesis, and subcloned into the pcDNA3.1(+) / Hygro expression vector. The sequence of KL2-AP (SEQ ID NO:1) and the translated result (SEQ ID NO:2) are shown in Figure 1. The sequence of TGFα-AP (SEQ ID NO:3) and the translated result (SEQ ID NO:4) are shown in Figure 2. DNA amplification was then performed to obtain sufficient amounts of expression vectors. The quality of the DNA and gene sequences was confirmed by restriction enzyme digestion and Sanger sequencing. In parallel, HEK-293 cell cultures were started. Master and working cell banks were prepared, scaled up, and transfected with the respective constructs by electroporation. During cell culture, cell density and viability were monitored to ensure optimal conditions for transfection. After PMA stimulation, AP-bound KL2 or TGFα was detected by measuring AP activity in the supernatant.

[0361] After electroporation, cells were further cultured in the presence of the selection antibiotic hygromycin B to generate stably transfected polyclonal cell pools. For both assays of KL2 and TGFα shedding, the selected pools were found to be suitable. Final assay conditions were determined for the selected pools. In all experiments, batimastat (BB94, 10 μM) was used as a positive control to completely inhibit KL2 or TGFα shedding.

[0362] Example 3a. Secondary Screening: PMA-Stimulated KL2 Release from HEK-293 Cells 60 μL of cells (40,000 cells / well) were added to a sterile 384-well plate. After overnight incubation at 37°C (5% CO2), 50 μL of medium was removed and 20 μL of pre-diluted compounds were added to the cells. After 15 min of incubation, 20 μL of PMA (final concentration 500 ng / mL) was added. The cells were incubated for 2 h at 37°C (5% CO2). Then, 20 μL of the supernatant was transferred to a new plate and 20 μL of pNPP (final concentration 5 mM) was added. The AP reaction was carried out for 1 h at room temperature. The reaction was stopped by adding 20 μL of sodium hydroxide (NaOH) (final concentration 1 M) and the absorbance of pNP was measured at 405 nm.

[0363] Example 3b. Secondary Screening: PMA-Stimulated KL2 Release from HEK-293 Cells Wells of a sterile 384-well flat-bottom clear plate for KL2-AP assay were coated with 10 μL of 0.1 mg / mL poly-d-lysine for 3-4 hours at 25°C or overnight at 4°C. Washed twice with PBS and patted dry. 60 μL of cells (40,000 cells / well) were added to a sterile 384-well plate and incubated overnight at 37°C (5% CO2) in Opti-MEM® (with 2% FCS and 1% Pen-Strep). After overnight incubation, 55 μL of medium was removed with a BioTek EL406 and 10 μL of pre-diluted compound was added to the cells to a final concentration of 20 μM. After 15 minutes of incubation, 15 μL of PMA (final concentration 100 ng / mL) was added. Cells were incubated for 2 hours at 37°C (5% CO2). The plate was then centrifuged at 1000 rpm for 5 min, 3 μL of the supernatant was transferred to a new 384-well plate, and 9 μL of AP Balance Buffer was added per well. L of pNPP p-nitrophenyl phosphate (1M pNPP final) was added. The AP reaction was carried out for 1 h at 37° C. The reaction was stopped by adding 12 μL of NaOH (1M final concentration), the plate was centrifuged to remove air bubbles, and the absorbance of pNP was measured at 405 nm.

[0364] Example 4a. Counterscreen: PMA-stimulated TGFα release from HEK-293 cells 60 μL of cells (20,000 cells / well) were added to a sterile 384-well plate. After overnight incubation at 37°C (5% CO2), 50 μL of medium was removed and 20 μL of pre-diluted compounds were added to the cells. After 15 min of incubation, 20 μL of PMA (final concentration 100 ng / mL) was added. The cells were incubated for 2 h at 37°C (5% CO2). Then, 20 μL of the supernatant was transferred to a new plate and 20 μL of pNPP (final concentration 5 mM) was added. The AP reaction was carried out for 1 h at room temperature. The reaction was stopped by adding 20 μL of sodium hydroxide (NaOH) (final concentration 1 M) and the absorbance of pNP was measured at 405 nm.

[0365] Example 4b. Counterscreen: PMA-stimulated TGFα release from HEK-293 cells Wells of a sterile 384-well flat-bottom clear plate for TGF-AP assay were coated with 10 μL of 0.1 mg / mL poly-d-lysine for 3-4 hours at 25°C or overnight at 4°C. Washed twice with PBS and patted dry. 60 μL of cells (20,000 cells / well) were added to a sterile 384-well plate and incubated overnight at 37°C (5% CO2) in Opti-MEM® (with 2% FCS and 1% Pen-Strep). After overnight incubation, 55 μL of medium was removed with a BioTek EL406 and 10 μL of pre-diluted compound was added to the cells to a final concentration of 20 μM. After 15 minutes of incubation, 15 μL of PMA (final concentration 100 ng / mL) was added. Cells were incubated for 2 hours at 37°C (5% CO2). The plate was then centrifuged at 1000 rpm for 5 min and 12 μL of the supernatant was transferred to a new 384-well plate. 12 μL of pNPP p-nitrophenyl phosphate (1M pNPP final) was added. The AP reaction was carried out at 37°C for 1 h. The reaction was stopped by adding 12 μL of NaOH (1M final concentration), the plate was centrifuged to remove air bubbles and the absorbance of pNP was measured at 405 nm.

[0366] Example 5. Treatment of traumatic brain injury Patients suffering from traumatic brain injury (TBI) are treated with a compound of the invention in capsule or tablet form, in single or divided doses, at 1-400 mg / day, for example 50-400 mg / day, The expected effect is reduction or prevention of symptoms of TBI.

[0367] Example 6. Treatment of Alzheimer's Disease Patients suffering from Alzheimer's disease (AD) or determined to be at risk for Alzheimer's disease (AD) based on genetic predisposition or predictive cognitive tests or based on biomarkers for the disease are treated with 1-400 mg / day of a compound of the invention, for example 50-400 mg / day of a compound of the invention, in capsule or tablet form, as a single or divided dose. The expected effect is reduction or prevention of AD symptoms, reduction of neuroinflammation and brain damage, leading to improved quality of life and cognitive performance compared to untreated patients.

[0368] Example 7. Treatment of hemophilic arthropathy Patients with hemophilic arthropathy (HA) or acute or chronic intra-articular bleeding episodes are treated with the compounds of the invention in capsule or tablet form, as single or divided doses, at 1-400 mg / day, for example 50-400 mg / day. The expected effect is to reduce or prevent joint erosion and damage, osteoporosis and osteopenia in patients with HA, leading to improved quality of life and mobility of affected patients. Inhibitors of iRhom2 / ADAM17 activity can be combined with other treatments for HA patients, such as factor VIII replacement, to enhance the therapeutic effect and further improve the quality of life of affected patients.

[0369] Example 8. Treatment of hemorrhagic stroke Patients suffering from hemorrhagic stroke are treated with a compound of the invention in capsule or tablet form, in single or divided doses, at 1-400 mg / day, for example 50-400 mg / day. The expected effect is reduction or prevention of HS symptoms, reduction of neuroinflammation and brain damage, leading to improved quality of life and cognitive abilities compared to untreated patients.

[0370] Example 9. Treatment of Cytokine Storm and Macrophage Activation Syndrome Patients suffering from cytokine storm and macrophage activation syndrome (CS / MAS) are treated with 1-400 mg / day, e.g., 50-400 mg / day, of a compound of the invention in capsule or tablet form, as a single or divided dose. The expected effect is a reduction in CS / MAS, which is predicted to significantly improve the outcome of acute respiratory syndrome and other effects of CS / MAS, including damage to internal organs such as the liver, kidneys, heart, and intestines.

[0371] Example 10. Treatment of rheumatoid arthritis Patients suffering from rheumatoid arthritis (RA) are treated with 1-400 mg / day, for example 50-400 mg / day, of the compounds of the invention in capsule or tablet form, in single or divided doses. The expected effect is relief from RA and superior protection by simultaneously blocking all three disease-causing pathways.

[0372] Example 11. Treatment of systemic lupus erythematosus-glomerulonephritis Patients suffering from systemic lupus erythematosus-glomerulonephritis (SLE-GN) are treated with a compound of the invention in capsule or tablet form, in single or divided doses, at 1-400 mg / day, e.g., 50-400 mg / day. The expected effect is a reduction in SLE-GN and superior protection by simultaneously blocking two disease-causing pathways (TNFα, HB-EGF).

[0373] Results of the disclosed compounds Example 1a, Example 3a, and Example 4a Compounds of the present disclosure were evaluated in a primary screen (Example 1a), a secondary screen (Example 3a), and a counterscreen (Example 4a), respectively, and the results are shown in Table 3.

[0374] [Table 3]

[0375] Results of the disclosed compounds Example 1b, Example 3b, and Example 4b Compounds of the present disclosure were evaluated in a primary screen (Example 1b), a secondary screen (Example 3b), and a counterscreen (Example 4b), respectively, and the results are shown in Table 4.

[0376] [Table 4]

[0377] In addition to those described herein, various modifications of the present invention will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to be included within the scope of the appended claims. Each prior art document, including without limitation all patents, patent applications, and publications cited in this application, is hereby incorporated by reference in its entirety.

Claims

1. A pharmaceutical composition for inhibiting iRhom2 / ADAM17 activity, comprising: A pharmaceutical composition comprising one or more compounds selected from the group consisting of the following a) to f): a) Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof: (In the formula, X is N or CH; R １ａ is -C(O)C ６～１０ Aryl, —C(O)—(5- to 10-membered heteroaryl), —C(O)C ３～１０ cycloalkyl, —C(O)—(4- to 10-membered heterocycloalkyl), —NHC(O)C ６～１０ Aryl, —NHC(O)—(5- to 10-membered heteroaryl), —NHC(O)C ３～１０ cycloalkyl, —NHC(O)—(4- to 10-membered heterocycloalkyl), —C(O)OC ６～１０ Aryl, —C(O)O—(5- to 10-membered heteroaryl), —C(O)OC ３～１０ cycloalkyl, —C(O)O—(4- to 10-membered heterocycloalkyl), —C(O)NHC ６～１０ Aryl, —C(O)NH—(5- to 10-membered heteroaryl), —C(O)NHC ３～１０ cycloalkyl, —C(O)NH—(4- to 10-membered heterocycloalkyl), —C(O)N(C １～６ alkyl) C ６～１０ Aryl, —C(O)N(C １～６ alkyl)-(5- to 10-membered heteroaryl), —C(O)N(C １～６ alkyl) C ３～１０ Cycloalkyl, or —C(O)N(C １～６ alkyl)-(4- to 10-membered heterocycloalkyl), R １ｂ is -(C １～６ alkyl) C ６～１０ Aryl, -(C １～６ alkyl)-(5- to 10-membered heteroaryl), -(C １～６ alkyl) C ３～１０ cycloalkyl, -(C １～６ alkyl)-(4- to 10-membered heterocycloalkyl), C ６～１０ aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C ３～１０ is cycloalkyl, and R １ａ or R １ｂ are halo and C, respectively. １～４ Alkyl, C １～４ Haloalkyl, C ３～６ Cycloalkyl, C １～４ Alkoxy, CN, OH, NO ２ , N.H. ２ , —NH(C １～４ alkyl), -N(C １～４ alkyl) ２ , methylenedioxy, -S(C １～４ 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), —OC(O)(C １～４ alkyl), —OC(O)NH ２ , -OC(O)NH(C １～４ alkyl), —OC(O)N(C １～４ alkyl) ２ , -NHC(O)(C １～４ alkyl), -NHC(O)O(C １～４ alkyl), —NHC(O)NH ２ , -NHC(O)NH(C １～４ alkyl), -NHC(O)N(C １～４ alkyl) ２ , -NHS(O)(C １～４ alkyl), -NHS(O) ２ (C １～４ alkyl), -NHS(O) ２ NH ２ , -NHS(O) ２ NH (C １～４ alkyl), -NHS(O) ２ N (C １～４ alkyl) ２ , -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), -S(O) ２ N (C １～４ alkyl) ２ , -NHC(O)C ６～１０ Aryl, —NHC(O)—(5- to 10-membered heteroaryl), —NHC(O)C ３～１０ optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl, and —NHC(O)—(4- to 10-membered heterocycloalkyl); b) Formula (II): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof: (In the formula, R 2a is -(C 1-6 alkyl)C 6-10 aryl, -(C 1-6 alkyl)-(5- to 10-membered heteroaryl), -(C 1-6 alkyl)C 3-10 cycloalkyl, -(C 1-6 alkyl)-(4- to 10-membered heterocycloalkyl), C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 2b is -(C 1-6 alkyl)C 6-10 aryl, -(C 1-6 alkyl)-(5- to 10-membered heteroaryl), -(C 1-6 alkyl)C 3-10 cycloalkyl, -(C 1-6 alkyl)-(4- to 10-membered heterocycloalkyl), C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 2c is -(C 1-6 alkyl)C 6-10 aryl, -(C 1-6 alkyl)-(5-10 membered heteroaryl), -(C 1-6 alkyl)C 3-10 cycloalkyl, -(C 1-6 alkyl)-(4-10 membered heterocycloalkyl), C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3-10 cycloalkyl; and R 2a , R 2b , and R 2c are each halo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, CN, OH, NO 2 , NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , methylenedioxy, —S(C 1-4 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), —OC(O)(C 1-4 alkyl), —OC(O)NH 2 , —OC(O) NH(C 1-4 alkyl), —OC(O)N(C 1-4 alkyl) 2 , —NHC(O)(C 1-4 alkyl), —NHC(O)O(C 1-4 alkyl), —NHC(O)NH 2 , —NHC(O)NH(C 1-4 alkyl), —NHC(O)N(C 1-4 alkyl) 2 , —NHS(O)(C 1-4 alkyl), —NHS(O) 2 (C 1-4 alkyl), —NHS(O) 2 NH 2 , —NHS(O) 2 NH(C 1-4 alkyl), —NHS(O) 2 N(C 1-4 alkyl) 2 , —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), —S(O) 2 N(C 1-4 alkyl) 2 , —NHC(O)C 6-10 aryl, —NHC(O)—(5-10 membered heteroaryl), —NHC(O)C 3-10 cycloalkyl, and —NHC(O)—(4-10 membered heterocycloalkyl); c) Formula (III): 【Chemistry 3】 or a pharmaceutically acceptable salt thereof: (In the formula, R 3a is -(C 1-6 alkyl)C 6-10 aryl, -(C 1-6 alkyl)-(5- to 10-membered heteroaryl), -(C 1-6 alkyl)C 3-10 cycloalkyl, -(C 1-6 alkyl)-(4- to 10-membered heterocycloalkyl), C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 3b is C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 3c is H or C 1-4 alkyl, and R 3a and R 3b are each halo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, CN, OH, NO 2 , NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , methylenedioxy, —S(C 1-4 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), —OC(O)(C 1-4 alkyl), —OC(O)NH 2 , —OC(O)NH(C 1-4 alkyl), —OC(O)N(C 1-4 alkyl) 2 , —NHC(O)(C 1-4 alkyl), —NHC(O)O(C 1-4 alkyl), —NHC(O)NH 2 , —NHC(O)NH(C 1-4 alkyl), —NHC(O)N(C 1-4 alkyl) 2 , —NHS(O)(C 1-4 alkyl), —NHS(O) 2 (C 1-4 alkyl), —NHS(O) 2 NH 2 , —NHS(O) 2 NH(C 1-4 alkyl), —NHS(O) 2 N(C 1-4 alkyl) 2 , —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 , optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -S(O)2(C1-4 alkyl), -S(O)2NH2, -S(O)2NH(C1-4 alkyl), -S(O)2N(C1-4 alkyl)2, -NHC(O)C6-10 aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C3-10 cycloalkyl, and -NHC(O)-(4-10 membered heterocycloalkyl); d) Formula (IV): 【Chemistry 4】 or a pharmaceutically acceptable salt thereof: (In the formula, R 4a is —C(O)C 6-10 aryl, —C(O)—(5- to 10-membered heteroaryl), —C(O)C 3-10 cycloalkyl, —C(O)—(4- to 10-membered heterocycloalkyl), —NHC(O)C 6-10 aryl, —NHC(O)—(5- to 10-membered heteroaryl), —NHC(O)C 3-10 cycloalkyl, —NHC(O)—(4- to 10-membered heterocycloalkyl), —C(O)OC 6-10 aryl, —C(O)O—(5- to 10-membered heteroaryl), —C(O)OC 3-10 cycloalkyl, —C(O)O—(4- to 10-membered heterocycloalkyl), —C(O)NHC 6-10 aryl, —C(O)NH—(5- to 10-membered heteroaryl), —C(O)NHC 3-10 cycloalkyl, —C(O)NH—(4-10 membered heterocycloalkyl), —C(O)N(C 1-6 alkyl)C 6-10 aryl, —C(O)N(C 1-6 alkyl)-(5-10 membered heteroaryl), —C(O)N(C 1-6 alkyl)C 3-10 cycloalkyl, or —C(O)N(C 1-6 alkyl)-(4-10 membered heterocycloalkyl); R 4b is -(C 1-6 alkyl)C 6-10 aryl, -(C 1-6 alkyl)-(5- to 10-membered heteroaryl), -(C 1-6 alkyl)C 3-10 cycloalkyl, -(C 1-6 alkyl)-(4- to 10-membered heterocycloalkyl), C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 4c is H or C 1-4 alkyl, and R 4a or R 4b is independently halo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, CN, OH, NO 2 , NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , methylenedioxy, —S(C 1-4 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), —OC(O)(C 1-4 alkyl), —OC(O)NH 2 , —OC(O)NH(C 1-4 alkyl), —OC(O)N(C 1-4 alkyl) 2 , —NHC(O)(C 1-4 alkyl), —NHC(O)O(C 1-4 alkyl), —NHC(O)NH 2 , —NHC(O)NH(C 1-4 alkyl), —NHC(O)N(C 1-4 alkyl) 2 , —NHS(O)(C 1-4 alkyl), —NHS(O) 2 (C 1-4 alkyl), —NHS(O) 2 NH 2 , —NHS(O) 2 NH(C 1-4 alkyl), —NHS(O) 2 N(C 1-4 alkyl) 2 , —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 , optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -S(O)2(C1-4 alkyl), -S(O)2NH2, -S(O)2NH(C1-4 alkyl), -S(O)2N(C1-4 alkyl)2, -NHC(O)C6-10 aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C3-10 cycloalkyl, and -NHC(O)-(4-10 membered heterocycloalkyl); e) Formula (V): 【Chemistry 5】 or a pharmaceutically acceptable salt thereof: (In the formula, R 5a is -(C 1-6 alkyl)C 6-10 aryl, -(C 1-6 alkyl)-(5- to 10-membered heteroaryl), -(C 1-6 alkyl)C 3-10 cycloalkyl, -(C 1-6 alkyl)-(4- to 10-membered heterocycloalkyl), C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 5b is C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 5c is H or C 1-4 alkyl; R 5d is H or C 1-4 alkyl, and R 5a and R 5b are each halo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, CN, OH, NO 2 , NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , methylenedioxy, —S(C 1-4 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), —OC(O)(C 1-4 alkyl), —OC(O)NH 2 , —OC(O)NH(C 1-4 alkyl), —OC(O)N(C 1-4 alkyl) 2 , —NHC(O)(C 1-4 alkyl), —NHC(O)O(C 1-4 alkyl), —NHC(O)NH 2 , —NHC(O)NH(C 1-4 alkyl), —NHC(O)N(C 1-4 alkyl) 2 , —NHS(O)(C 1-4 alkyl), —NHS(O) 2 (C 1-4 alkyl), —NHS(O) 2 NH 2 , —NHS(O) 2 NH(C 1-4 alkyl), —NHS(O) 2 N(C 1-4 alkyl) 2 , —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 , optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -S(O)2(C1-4 alkyl), -S(O)2NH2, -S(O)2NH(C1-4 alkyl), -S(O)2N(C1-4 alkyl)2, -NHC(O)C6-10 aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C3-10 cycloalkyl, and -NHC(O)-(4-10 membered heterocycloalkyl); f) Formula (VI): 【Chemistry 6】 or a pharmaceutically acceptable salt thereof: (In the formula, R 6a is C 1-6 alkyl, C 1-6 alkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 6b is C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 6c is H or C 1-4 alkyl; R 6d is H or C 1-4 alkyl, and R 6b is halo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, CN, OH, NO 2 , NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , methylenedioxy, —S(C 1-4 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), —OC(O)(C 1-4 alkyl), —OC(O)NH 2 , —OC(O)NH(C 1-4 alkyl), —OC(O)N(C 1-4 alkyl) 2 , —NHC(O)(C 1-4 alkyl), —NHC(O)O(C 1-4 alkyl), —NHC(O)NH 2 , —NHC(O)NH(C 1-4 alkyl), —NHC(O)N(C 1-4 alkyl) 2 , —NHS(O)(C 1-4 alkyl), —NHS(O) 2 (C 1-4 alkyl), —NHS(O) 2 NH 2 , —NHS(O) 2 NH(C 1-4 alkyl), —NHS(O) 2 N(C 1-4 alkyl) 2 , —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), —S(O) 2 N(C 1-4 alkyl) 2 , —NHC(O)C 6-10 aryl, —NHC(O)—(5-10 membered heteroaryl), —NHC(O)C 3-10 cycloalkyl, and —NHC(O)—(4-10 membered heterocycloalkyl).

2. a) The compound of formula (I) 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 and 【Chemical 21】 is a compound selected from the group consisting of: b) The compound of formula (I) 【Chemical 22】 is; c) The compound of formula (I) 【Chemical 23】 is; or d) The compound of formula (I) 【Chemistry 24】 The pharmaceutical composition of claim 1, wherein

3. a) The compound of formula (II) 【Chemistry 25】 【Chemical 26】 【Chemical 27】 【Chemical 28】 【Chemical 29】 【Chemistry 30】 【Chemical 31】 【Chemical 32】 and 【Chemical 33】 or a compound selected from the group consisting of b) The compound of formula (II) 【Chemical 34】 The pharmaceutical composition of claim 1, wherein

4. a) The compound of formula (III) 【Chemical 35】 and 【Chemical 36】 or a compound selected from the group consisting of b) The compound of formula (III) 【Chemical 37】 The pharmaceutical composition of claim 1, wherein

5. The compound of formula (IV) is 【Chemical 38】 and 【Chemical Formula 39】 2. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of:

6. The compound of formula (V) is 【Chemistry 40】 and 【Chemistry 41】 2. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of:

7. The compound of formula (VI) is 【Chemistry 42】 and 【Chemistry 43】 2. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of:

8. A pharmaceutical composition for inhibiting iRhom2 / ADAM17 activity, comprising: A pharmaceutical composition comprising one or more compounds selected from the group consisting of the following a) to c) or pharmaceutically acceptable salts thereof: a) 【Chemical 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 【Chemistry 50】 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemical Formula 54】 【Chemistry 55】 【Chemical 56】 【Chemical 57】 【Chemistry 58】 【Chemical Formula 59】 【Chemistry 60】 【Hua 61】 and 【Hua 62】 or a pharmaceutically acceptable salt thereof; b) 【Chemistry 63】 or a pharmaceutically acceptable salt thereof; and c) 【Hua 64】 or a pharmaceutically acceptable salt thereof.

9. 1. A pharmaceutical composition for the treatment of a disease or disorder associated with inhibition of iRhom2 / ADAM17 activity, comprising: wherein the pharmaceutical composition is administered to a patient in need thereof; The pharmaceutical composition comprises: a) Formula (I): 【Chemistry 65】 or a pharmaceutically acceptable salt thereof: (In the formula, X is N or CH; R １ａ is -C(O)C ６～１０ Aryl, —C(O)—(5- to 10-membered heteroaryl), —C(O)C ３～１０ cycloalkyl, —C(O)—(4- to 10-membered heterocycloalkyl), —NHC(O)C ６～１０ Aryl, —NHC(O)—(5- to 10-membered heteroaryl), —NHC(O)C ３～１０ cycloalkyl, —NHC(O)—(4- to 10-membered heterocycloalkyl), —C(O)OC ６～１０ Aryl, —C(O)O—(5- to 10-membered heteroaryl), —C(O)OC ３～１０ cycloalkyl, —C(O)O—(4- to 10-membered heterocycloalkyl), —C(O)NHC ６～１０ Aryl, —C(O)NH—(5- to 10-membered heteroaryl), —C(O)NHC ３～１０ cycloalkyl, —C(O)NH—(4- to 10-membered heterocycloalkyl), —C(O)N(C １～６ alkyl) C ６～１０ Aryl, —C(O)N(C １～６ alkyl)-(5- to 10-membered heteroaryl), —C(O)N(C １～６ alkyl) C ３～１０ Cycloalkyl, or —C(O)N(C １～６ alkyl)-(4- to 10-membered heterocycloalkyl), R １ｂ is -(C １～６ alkyl) C ６～１０ Aryl, -(C １～６ alkyl)-(5- to 10-membered heteroaryl), -(C １～６ alkyl) C ３～１０ Cycloalkyl, -( C １～６ alkyl)-(4- to 10-membered heterocycloalkyl), C ６～１０ aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C ３～１０ is cycloalkyl, and R １ａ or R １ｂ are halo and C, respectively. １～４ Alkyl, C １～４ Haloalkyl, C ３～６ Cycloalkyl, C １～４ Alkoxy, CN, OH, NO ２ , N.H. ２ , —NH(C １～４ alkyl), -N(C １～４ alkyl) ２ , methylenedioxy, -S(C １～４ 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), —OC(O)(C １～４ alkyl), —OC(O)NH ２ , -OC(O)NH(C １～４ alkyl), —OC(O)N(C １～４ alkyl) ２ , -NHC(O)(C １～４ alkyl), -NHC(O)O(C １～４ alkyl), —NHC(O)NH ２ , -NHC(O)NH(C １～４ alkyl), -NHC(O)N(C １～４ alkyl) ２ , -NHS(O)(C １～４ alkyl), -NHS(O) ２ (C １～４ alkyl), -NHS(O) ２ NH ２ , -NHS(O) ２ NH (C １～４ alkyl), -NHS(O) ２ N (C １～４ alkyl) ２ , -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), -S(O) ２ N (C １～４ alkyl) ２ , -NHC(O)C ６～１０ Aryl, —NHC(O)—(5- to 10-membered heteroaryl), —NHC(O)C ３～１０ optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl, and —NHC(O)—(4- to 10-membered heterocycloalkyl); b) Formula (II): 【Hua 66】 or a pharmaceutically acceptable salt thereof: (In the formula, R 2a is -(C 1-6 alkyl)C 6-10 aryl, -(C 1-6 alkyl)-(5- to 10-membered heteroaryl), -(C 1-6 alkyl)C 3-10 cycloalkyl, -(C 1-6 alkyl)-(4- to 10-membered heterocycloalkyl), C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 2b is -(C 1-6 alkyl)C 6-10 aryl, -(C 1-6 alkyl)-(5- to 10-membered heteroaryl), -(C 1-6 alkyl)C 3-10 cycloalkyl, -(C 1-6 alkyl)-(4- to 10-membered heterocycloalkyl), C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 2c is -(C 1-6 alkyl)C 6-10 aryl, -(C 1-6 alkyl)-(5-10 membered heteroaryl), -(C 1-6 alkyl)C 3-10 cycloalkyl, -(C 1-6 alkyl)-(4-10 membered heterocycloalkyl), C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C 3-10 cycloalkyl; and R 2a , R 2b , and R 2c are each independently halo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, CN, OH, NO 2 , NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , methylenedioxy, —S(C 1-4 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), -OC(O)(C 1-4 alkyl), -OC(O)NH 2 , -OC(O)NH(C 1-4 alkyl), -OC(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -NHC(O)O(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)NH(C 1-4 alkyl), -NHC(O)N(C 1-4 alkyl) 2 , -NHS(O)(C 1-4 alkyl), -NHS(O) 2 (C 1-4 alkyl), -NHS(O) 2 NH 2 , -NHS(O) 2 NH(C 1-4 alkyl), -NHS(O) 2 N(C 1-4 alkyl) 2 , -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), -S(O) 2 N(C 1-4 alkyl) 2 , -NHC(O)C 6-10 optionally substituted with 1 to 5 substituents selected from the group consisting of aryl, —NHC(O)—(5-10 membered heteroaryl), —NHC(O)C 3-10 cycloalkyl, and —NHC(O)—(4-10 membered heterocycloalkyl); c) Formula (III): 【Chemical Formula 67】 or a pharmaceutically acceptable salt thereof: (In the formula, R 3a is -(C 1-6 alkyl)C 6-10 aryl, -(C 1-6 alkyl)-(5- to 10-membered heteroaryl), -(C 1-6 alkyl)C 3-10 cycloalkyl, -(C 1-6 alkyl)-(4- to 10-membered heterocycloalkyl), C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 3b is C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 3c is H or C 1-4 alkyl, and R 3a and R 3b are each halo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, CN, OH, NO 2 , NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , methylenedioxy, —S(C 1-4 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), —OC(O)(C 1-4 alkyl), —OC(O)NH 2 , —OC(O)NH(C 1-4 alkyl), —OC(O)N(C 1-4 alkyl) 2 , —NHC(O)(C 1-4 alkyl), —NHC(O)O(C 1-4 alkyl), —NHC(O)NH 2 , —NHC(O)NH(C 1-4 alkyl), —NHC(O)N(C 1-4 alkyl) 2 , —NHS(O)(C 1-4 alkyl), —NHS(O) 2 (C 1-4 alkyl), —NHS(O) 2 NH 2 , —NHS(O) 2 NH(C 1-4 alkyl), —NHS(O) 2 N(C 1-4 alkyl) 2 , —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), —S(O) 2 N(C 1-4 alkyl) 2 , —NHC(O)C 6-10 aryl, —NHC(O)-(5-10 membered heteroaryl), —NHC(O)C 3-10 cycloalkyl, and —NHC(O )-(4- to 10-membered heterocycloalkyl) optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: d) Formula (IV): 【Chemistry 68】 or a pharmaceutically acceptable salt thereof: (In the formula, R 4a is —C(O)C 6-10 aryl, —C(O)—(5- to 10-membered heteroaryl), —C(O)C 3-10 cycloalkyl, —C(O)—(4- to 10-membered heterocycloalkyl), —NHC(O)C 6-10 aryl, —NHC(O)—(5- to 10-membered heteroaryl), —NHC(O)C 3-10 cycloalkyl, —NHC(O)—(4- to 10-membered heterocycloalkyl), —C(O)OC 6-10 aryl, —C(O)O—(5- to 10-membered heteroaryl), —C(O)OC 3-10 cycloalkyl, —C(O)O—(4- to 10-membered heterocycloalkyl), —C(O)NHC 6-10 aryl, —C(O)NH—(5- to 10-membered heteroaryl), —C(O)NHC 3-10 cycloalkyl, —C(O)NH—(4-10 membered heterocycloalkyl), —C(O)N(C 1-6 alkyl)C 6-10 aryl, —C(O)N(C 1-6 alkyl)-(5-10 membered heteroaryl), —C(O)N(C 1-6 alkyl)C 3-10 cycloalkyl, or —C(O)N(C 1-6 alkyl)-(4-10 membered heterocycloalkyl); R 4b is -(C 1-6 alkyl)C 6-10 aryl, -(C 1-6 alkyl)-(5- to 10-membered heteroaryl), -(C 1-6 alkyl)C 3-10 cycloalkyl, -(C 1-6 alkyl)-(4- to 10-membered heterocycloalkyl), C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 4c is H or C 1-4 alkyl, and R 4a or R 4b is independently halo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, CN, OH, NO 2 , NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , methylenedioxy, —S(C 1-4 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), —OC(O)(C 1-4 alkyl), —OC(O)NH 2 , —OC(O)NH(C 1-4 alkyl), —OC(O)N(C 1-4 alkyl) 2 , —NHC(O)(C 1-4 alkyl), —NHC(O)O(C 1-4 alkyl), —NHC(O)NH 2 , —NHC(O)NH(C 1-4 alkyl), —NHC(O)N(C 1-4 alkyl) 2 , —NHS(O)(C 1-4 alkyl), —NHS(O) 2 (C 1-4 alkyl), —NHS(O) 2 NH 2 , —NHS(O) 2 NH(C 1-4 alkyl), —NHS(O) 2 N(C 1-4 alkyl) 2 , —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 , optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -S(O)2(C1-4 alkyl), -S(O)2NH2, -S(O)2NH(C1-4 alkyl), -S(O)2N(C1-4 alkyl)2, -NHC(O)C6-10 aryl, -NHC(O)-(5-10 membered heteroaryl), -NHC(O)C3-10 cycloalkyl, and -NHC(O)-(4-10 membered heterocycloalkyl); e) Formula (V): 【Chemical Formula 69】 or a pharmaceutically acceptable salt thereof: (In the formula, R 5a is -(C 1-6 alkyl)C 6-10 aryl, -(C 1-6 alkyl)-(5- to 10-membered heteroaryl), -(C 1-6 alkyl)C 3-10 cycloalkyl, -(C 1-6 alkyl)-(4- to 10-membered heterocycloalkyl), C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 5b is C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 5c is H or C 1-4 alkyl; R 5d is H or C 1-4 alkyl; R 5a and R 5b are each halo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, CN, OH, NO 2 , NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , methylenedioxy, —S(C 1-4 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), —OC(O)(C 1-4 alkyl), —OC(O)NH 2 , —OC(O)NH(C 1-4 alkyl), —OC(O)N(C 1-4 alkyl) 2 , —NHC(O)(C 1-4 alkyl), —NHC(O)O(C 1-4 alkyl), —NHC(O)NH 2 , —NHC(O)NH(C 1-4 alkyl), —NHC(O)N(C 1-4 alkyl) 2 , —NHS(O)(C 1-4 alkyl), —NHS(O) 2 (C 1-4 alkyl), —NHS(O) 2 NH 2 , —NHS(O) 2 NH(C 1-4 alkyl), —NHS(O) 2 N(C 1-4 alkyl) 2 , —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 , optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: —S(O) 2 (C 1-4 alkyl), —S(O) 2 NH 2 , —S(O) 2 NH(C 1-4 alkyl), —S(O) 2 N(C 1-4 alkyl) 2 , —NHC(O)C 6-10 aryl, —NHC(O)-(5-10 membered heteroaryl), —NHC(O)C 3-10 cycloalkyl, and —NHC(O)-(4-10 membered heterocycloalkyl); or f) Formula (VI): 【Chemistry 70】 or a pharmaceutically acceptable salt thereof: (In the formula, R 6a is C 1-6 alkyl, C 1-6 alkenyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 6b is C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, or C 3-10 cycloalkyl; R 6c is H or C 1-4 alkyl; R 6d is H or C 1-4 alkyl, and R 6b is halo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, CN, OH, NO 2 , NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , methylenedioxy, —S(C 1-4 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), —OC(O)(C 1-4 alkyl), —OC(O)NH 2 , —OC(O)NH(C 1-4 alkyl), —OC(O)N(C 1-4 alkyl) 2 , —NHC(O)(C 1-4 alkyl), —NHC(O)O(C 1-4 alkyl), —NHC(O)NH 2 , —NHC(O)NH(C 1-4 alkyl), —NHC(O)N(C 1-4 alkyl) 2 , —NHS(O)(C 1-4 alkyl), —NHS(O) 2 (C 1-4 alkyl), —NHS(O) 2 NH 2 , —NHS(O) 2 NH(C 1-4 alkyl), —NHS(O) 2 N(C 1-4 alkyl) 2 , —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), —S(O) 2 N(C 1-4 alkyl) 2 , —NHC(O)C 6-10 aryl, —NHC(O)-(5-10 membered heteroaryl), —NHC(O)C 3-10 cycloalkyl, and —NHC(O)-(4-10 membered heterocycloalkyl); A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I).

10. 1. A pharmaceutical composition for the treatment of a disease or disorder associated with inhibition of iRhom2 / ADAM17 activity, comprising: the pharmaceutical composition is administered to a patient in need thereof; 【Chemical 71】 【Chemical 72】 【Chemical Formula 73】 【Chemical 74】 【Chemistry 75】 【Chemical 76】 【Chemical 77】 【Chemical Formula 78】 【Chemical Formula 79】 【Chemistry 80】 【Chemistry 81】 【Chemistry 82】 【Chemistry 83】 【Chemistry 84】 【Chemistry 85】 【Chemistry 86】 【Hua 87】 【Hua 88】 and 【Chemistry 89】 A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

11. A composition comprising a pharmaceutically acceptable carrier or excipient, 11. The pharmaceutical composition according to claim 9 or 10, in a pharmaceutical dosage form.

12. The pharmaceutical composition of claim 11, which is a tablet or capsule.

13. The disease or disorder is a) traumatic brain injury, b) Alzheimer's disease, c) hemorrhagic stroke; d) hemophilic arthropathy, e) cytokine storm / macrophage activation syndrome; f) rheumatoid arthritis, and g) Systemic lupus erythematosus-glomerulonephritis 11. The pharmaceutical composition according to claim 9 or 10, selected from the group consisting of:

14. The pharmaceutical composition of claim 9 or 10, a) the compound in the pharmaceutical composition is administered at a daily dose in the range of 50 mg / day to 400 mg / day; the pharmaceutical composition is administered to the patient in a dose; b) administering the pharmaceutical composition such that the compound in the pharmaceutical composition is administered to the patient at a daily dose ranging from 50 mg / day to 300 mg / day; c) administering the pharmaceutical composition such that the compound in the pharmaceutical composition is administered to the patient at a daily dose of 50 mg / day; d) administering the pharmaceutical composition such that the compound in the pharmaceutical composition is administered to the patient at a daily dose of 100 mg / day; e) administering the pharmaceutical composition such that the compound in the pharmaceutical composition is administered to the patient at a daily dose of 200 mg / day; f) administering the pharmaceutical composition such that the compound in the pharmaceutical composition is administered to the patient at a daily dose of 300 mg / day; g) the pharmaceutical composition is administered such that the compound in the pharmaceutical composition is administered to the patient at a daily dose of 400 mg / day; or h) A pharmaceutical composition wherein the pharmaceutical composition is administered such that the compound therein is administered to the patient in a single daily dose.

15. 15. The pharmaceutical composition of claim 14, wherein the daily dose of the compound is divided into multiple doses.

16. The pharmaceutical composition of claim 14, administered to the patient in combination with one or more additional therapeutic agents.

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